Pulmonary Manifestations of Pediatric Diseases

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PULMONARY MANIFESTATIONS OF PEDIATRIC DISEASES ISBN: 978-1-4160-3031-7
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Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are
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Library of Congress Cataloging-in-Publication Data

Pulmonary manifestations of pediatric diseases / [edited by] Nelson L.
Turcios, Robert J. Fink.--1st ed.
p. ; cm.
Includes bibliographical references.
ISBN 978-1-4160-3031-7
1. Pulmonary manifestations of general diseases. 2. Pediatric respiratory diseases. I. Turcios, Nelson L.
II. Fink, Robert J., 1948-
[DNLM: 1. Lung Diseases--etiology. 2. Adolescent. 3. Child. 4. Infant. 5. Lung Diseases--diagnosis.
6. Signs and Symptoms, Respiratory. WS 280 P9825 2009]
RJ431.P85 2009
618.920 2–dc22
2008032070
Acquisitions Editor: Dolores Meloni

Developmental Editor: Elena Pushaw
Project Manager: Jagannathan Varadarajan
Design Direction: Steven Stave
Publishing Services Manager: Hemamalini Rajendrababu
Marketing Manager: Courtney Ingram
Printed in the United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1

Dedication
To my loving wife, Minnie, and to our children, Nelson, Jr., and Melissa, for
their love, patience, and encouragement during the preparation of “the book.”
To my parents, Aurora Trinidad and José Mártir, even when you are not here,
I know you are always with me. I miss you. To my sisters, Olga Nelly and
Lillian Marina, for their support. I also recognize that my participation in
editing this book was made possible only because of the lessons learned from
so many wonderful patients, families, and colleagues.
Nelson L. Turcios, M.D.
To my wife, Lois, who has always been at my side to support and encourage me
throughout my career. To my mother, Mary P. Fink, who instilled in me the love
of reading and academics. To my father, Dr. L. Jerome Fink, who introduced me
to the joys and rewards of a career in medicine. To all the parents who have
entrusted me with the care of their most precious children. And to my dream
for a cure for cystic fibrosis and for a world free of lung disease and pollution,
in which all children are born free, to live and breathe free.
Robert J. Fink, M.D.
v
Preface
Pediatric pulmonology can trace its roots to under discussion by the American Board of
the 1940s and 1950s when early pioneers in Pediatrics as to whether it should be recog-
the field recognized pediatric lung disorders nized as its own, distinct subspecialty. How-
as being significantly different from their ever, pediatric pulmonology, still in its
adult pulmonary counterparts. In 1938, nascent stages, was seen as lacking the
Dr. Dorothy Andersen published an autopsy knowledge base to distinguish it as a unique
series; it was the first to describe the combina- subspecialty. With this primary criticism,
tion of diarrhea, pancreatic abnormalities, and the application was denied.
pneumonia seen in young infants. She coined By the 1980s, the field had developed to
the name, “cystic fibrosis of the pancreas.” such an extent that its appeal to be recognized
Scarcely more than a decade later, in New as a boarded subspecialty was met with well-
York City, Dr. Paul A. di Sant’Agnese discov- deserved success. In 1985, pediatric pulmo-
ered the sweat defect of patients with cystic nology became an established subspecialty
fibrosis. This landmark finding would lead of the American Board of Pediatrics. The
to the development of the sweat test for first board examination was given on July 1,
the diagnosis of cystic fibrosis, a test which 1986, and 158 candidates were certified. Over
is still widely used today. the next 22 years, more than 500 pediatri-
In 1967, Dr. Edwin L. Kendig published cians have become board-certified pediatric
the first pediatric pulmonology textbook, pulmonologists.
Disorders of the Respiratory Tract in Children. Pediatric pulmonology now has a consid-
This decade was marked by the development erable presence at all major children’s hospi-
of the first comprehensive treatment pro- tals, not only in the United States, but
gram for cystic fibrosis in Cleveland, Ohio. worldwide. Diseases addressed by pediatric
The National Cystic Fibrosis (CF) Foundation pulmonologists include cystic fibrosis,
was formed and CF Centers began to develop asthma, chronic lung disease of prematurity,
at most children’s hospitals. The “CF Club” ventilator dependency, sleep disorders, pri-
began to hold annual conferences in conjunc- mary ciliary dyskinesias, recurrent pneumo-
tion with the SPR-APS (now Pediatric nia, interstitial lung disease, airway and
Academic Societies (PAS)). The CF Club (now pulmonary anomalies, lung transplantation,
the North American CF Conference) and and many other, less common conditions.
the American Thoracic Society conferences Pulmonary function testing, fiberoptic lar-
brought together physicians and researchers yngoscopy and bronchoscopy, genetic test-
who shared a common interest in CF, asthma, ing and counseling, and polysomnography
and pediatric lung disease. Many pediatric are some of the tools commonly used for
pulmonologists today still benefit from the the diagnosis and monitoring of pediatric
fellowship, intellectual stimulation, and sci- pulmonary disorders.
entific presentations at these conferences. The knowledge base of pediatric pulmo-
The 1970s saw the advent of more forma- nology has grown dramatically since the
lized fellowship programs in cystic fibrosis 1970s. Annually, hundreds of clinical and
and pediatric lung disease. Major advances research articles are published in peer-
were made in the diagnosis and treatment reviewed journals on various respiratory dis-
of pediatric asthma during this decade. For orders that affect the entire pediatric age
the first time, pediatric pulmonary physiol- group. Numerous textbooks are devoted
ogy was described, and pediatric pulmonary exclusively to cystic fibrosis, pediatric
function testing was developed and used asthma, pediatric interstitial lung disease,
to assess the clinical course of lung disorders sudden infant death syndrome, chronic
in children. Because of the tremendous lung disease of prematurity, sleep disorders,
advances in medical knowledge in the pediatric pulmonary function testing, and
1970s, pediatric pulmonology rapidly pediatric lung imaging. The “Bible” for
matured as a subspecialty. By the end of the every pediatric pulmonologist, Disorders of
decade, pediatric pulmonology was already the Respiratory Tract in Children, is now in
vii
viii Preface
its 7th edition. Once criticized as an under- their field of expertise offer the reader the
developed field with an insufficient knowl- benefit of their accumulated insight and expe-
edge base, after a mere 30 years it has rience. The pulmonary manifestations of
become impossible for the modern pediatric pediatric extrapulmonary diseases are com-
pulmonologist to read all of the pertinent mon and often misdiagnosed. The authors of
literature in the subspecialty. the chapters in this book hope that their
As the body of medical information efforts lead to early recognition and prompt
grows and the field of pediatric pulmonol- treatment of this very variable, but important,
ogy matures, it has become increasingly evi- group of respiratory manifestations.
dent that even disorders and conditions not We also hope that this textbook will
primarily associated with the lung often become an invaluable reference for pediatric
have significant ramifications on lung func- pulmonologists, pediatricians, and other
tion and health. It is on these effects and health professionals not only to educate,
interactions that this textbook is focused. but also to improve patient care, for this
The first of its kind, Pulmonary Manifesta- has always been our most important
tions of Pediatric Diseases presents a fresh endeavor.
outlook on how the clinician can think
about diseases addressed in this textbook. Nelson L. Turcios, MD
Chapters contributed by some of the most Robert J. Fink, MD
distinguished and recognizable physicians in
Acknowledgments
I am pleased to take this opportunity to Senior Editor, for her extraordinary efforts
acknowledge my daughter Melissa, for her towards making this project possible, and
invaluable contributions. She spent more to Jagannathan Varadarajan, our Project
hours logged onto the computer and on the Manager, for his diligence and attention to
telephone during the editing and proofread- detail. Lastly, and most importantly, we must
ing of this book that I can’t thank her enough. also thank Ginny Doyle, Health Sciences
I am also grateful to Elizabeth Herron and Professional Representative, for her encour-
Linda Scott for their invaluable help in agement to pursue this enterprise.
finding pertinent literature. We also acknowledge the outstanding
We are particularly indebted to our many group of reviewers for their thoughtful
renowned and dedicated authors whose comments: Drs. Balu Athreya, Victor
scholarly and practical contributions repre- Chernick, Bernard Cohen, Marc Eberhardt,
sent the essence of this endeavor. Addition- Hugh E. Evans, Santiago Martinez, Seza
ally, the highly professional and devoted Ozen, Arnold C. G. Platzker, Jean-Paul
staff at Saunders/Elsevier merits our grati- Praud, José Salcedo, Girish Sharma, and
tude, in particular Elena Pushaw, our Edito- William W. Waring.
rial Assistant for her kind guidance,
technical knowledge, and unrelenting sup-
port. Our thanks also go to Dolores Meloni, Nelson L. Turcios, MD
ix
Contributors
JAMES M. ADAMS, M.D. TED M. KREMER, M.D.

Professor of Pediatrics – Neonatology, Baylor Assistant Professor of Pediatrics, University of
College of Medicine, Attending Neonatolo- Massachusetts Memorial Medical Center,
gist Director, Chronic Pulmonary Care Team, Worcester, Massachusetts
Texas Children’s Hospital, Houston, Texas Pulmonary Manifestations of Systemic Vasculitis
Chronic Lung Disease of Infancy
JOSEPH LEVY, M.D.

SHERMAN J. ALTER, M.D. Professor of Pediatrics, New York University
Associate Professor of Pediatrics, Boonshoft
School of Medicine, Director, Pediatric Gas-
School of Medicine Wright State University,
troenterology and Nutrition, Children’s
Director, Division of Pediatric Infectious Dis-
Medical Center, New York University, New
eases, Children’s Medical Center, Dayton, Ohio
York, New York
Pulmonary Manifestations of Parasitic Diseases
Pulmonary Manifestations of Gastrointestinal
Diseases
JOHN R. BACH, M.D.
Professor of Medicine and Pediatrics, UMDNJ-
New Jersey Medical School, Vice-Chairman, J. MARC MAJURE, M.D.
Department of Physical Medicine and Reha- Associate Clinical Professor of Pediatrics, Duke
bilitation, New Jersey Medical School-Univer- University, Attending Physician, Division of
sity Hospital, Newark, New Jersey Pediatric Pulmonary and Sleep Medicine,
Pulmonary Manifestations of Neuromuscular Duke University Medical Center, Durham,
Diseases North Carolina
Pulmonary Manifestations of Rheumatoid
Diseases
KUSHAL Y. BHAKTA, M.D.
Assistant Professor of Pediatrics – Section of
Neonatal – Perinatal Medicine, Baylor Col- CARLOS MILLA, M.D., M.P.H
lege of Medicine, Attending Neonatologist, Associate Professor of Pediatrics, Stanford Uni-
Texas Children’s Hospital, Houston, Texas versity, Attending Physician, Division of
Chronic Lung Disease of Infancy Pediatric Pulmonology, Children’s Hospital
Medical Center, Palo Alto, California
MICHAEL R. BYE, M.D. Pulmonary Manifestations of Endocrine and
Professor of Clinical Pediatrics, Columbia Uni- Metabolic Diseases
versity, Attending, Pediatric Pulmonary
Medicine, Morgan Stanley Children’s Hospi-
tal, New York- Presbyterian Hospital, New
THOMAS M. MURPHY, M.D.
Professor of Pediatrics, Duke University, Direc-
York, New York
Pulmonary Manifestations of Human Immunode- tor Pediatric Pulmonary and Sleep Medicine,
ficiency Virus (HIV) Infection Duke University Medical Center, Durham,
North Carolina
GUILLERMO CHANTADA, M.D. Diseases
Attending Physician, Division Pediatric Hema-
tology and Oncology, Hospital J P Garrahan,
Buenos Aires, Argentina BRIAN P. O’SULLIVAN, M.D.
Pulmonary Manifestations of Hematologic and Professor of Pediatrics, University of
Oncologic Diseases Massachusetts, Director Cystic Fibrosis Cen-
ter, Associate Director Pediatric Pulmonology,
EDWARD FELS, M.D. University of Massachusetts Memorial Chil-
Fellow in Adult and Pediatric Rheumatology, dren’s Medical Center, Worcester,
Duke University Medical Center, Durham, Massachusetts
North Carolina Pulmonary Manifestations of Systemic
Pulmonary Manifestations of Rheumatoid Diseases Vasculitis
xi
xii Contributors
BETH A. PLETCHER, M.D. ANN R. STARK, M.D.

Associate Professor of Pediatrics, UMDNJ-New Professor of Pediatrics – Neonatology, Baylor
Jersey Medical School, Attending Physician, College of Medicine, Chief, Neonatology
Center for Human Genetics & Molecular Service, Texas Children’s Hospital, Houston,
Biology, New Jersey Medical School – Uni- Texas
versity Hospital, Newark, New Jersey Chronic Lung Disease of Infancy
Pulmonary Manifestations of Genetic Diseases
JAMES M. STARK, M.D., PH.D.

Associate Professor of Pediatrics, Wright State
C.D. EGLA RABINOVICH, M.D., M.P.H University, Attending Pulmonologist, Divi-
Assistant Professor of Pediatrics, Duke Univer-
sion of Pediatric Pulmonology, The Chil-
sity, Attending Physician, Division of Pediat-
dren’s Medical Center, Dayton, Ohio
ric Rheumatology, Duke University Medical Pulmonary Manifestations of Immunosuppressive
Center, Durham, North Carolina Diseases other than Human
Pulmonary Manifestations of Rheumatoid Immunodeficiency Virus (HIV) Infection
Diseases
JACQUELINE R. SZMUSZKOVICZ, M.D.

RAUL C. RIBEIRO, M.D. Assistant Professor of Pediatrics, Keck School of
Director, Leukemia / Lymphoma Division, Medicine, University of Southern California
Director, International Outreach Program, at Los Angeles, Pediatric Cardiologist, Divi-
St Jude’s Children’s Research Hospital, Pro- sion of Pediatric Cardiology, Childrens Hos-
fessor, Pediatrics, College of Medicine, Uni- pital Los Angeles, Los Angeles, California
versity of Tennessee Health Science Center, Pulmonary Manifestations of Cardiac Diseases
Memphis, Tennessee
Pulmonary Manifestations of Hematologic and
Oncologic Diseases NELSON L. TURCIOS, M.D.
Director, Pediatric Pulmonology & Asthma Insti-
tute, Somerville, New Jersey, Attending Physi-
CARLOS RODRÍGUEZ-GALINDO, M.D. cian, Division of Pediatric Pulmonology/
Attending Physician, Division of Pediatric Cystic Fibrosis, UMDNJ- Robert Wood John-
Hematology and Oncology, St Jude’s son University Hospital, New Brunswick,
Children’s Research Hospital, Memphis, New Jersey
Tennessee Pulmonary Manifestations of Dermatologic
Pulmonary Manifestations of Hematologic and Diseases
Oncologic Diseases Pulmonary Manifestations of Parasitic Diseases
Pulmonary Manifestations of Renal Diseases
JOSEPH C. SHANAHAN, M.D. MARLYN S. WOO, M.D.

Assistant Consulting Professor of Medicine,
Assistant Professor of Pediatrics, Keck School
Division of Rheumatology and Immunology,
of Medicine, University of Southern
Duke University Medical Center, Durham,
California at Los Angeles, Attending Pulmo-
North Carolina;
nologist, Division of Pediatric Pulmonology,
Associate, Carolina Arthritis, Wilmington,
Childrens Hospital Los Angeles, Los Angeles,
North Carolina
California
Pulmonary Manifestations of Cardiac Diseases
Diseases
HEATHER J. ZAR, M.D., PH.D.

ROBERT SIDBURY, M.D., M.P.H. Chair of Paediatrics and Child Health, Head of
Assistant Professor of Pediatrics, Harvard Med- Paediatric Pulmonology, School of Child
ical School, Attending Physician, Division of and Adolescent Health, University of Cape
Pediatric Dermatology, Children’s Hospital Town, Red Cross Childrens Hospital, Cape
of Boston, Boston, Massachusetts Town, South Africa
Pulmonary Manifestations of Dermatologic Pulmonary Manifestations of Human Immunode-
Diseases ficiency Virus (HIV) Infection
CHAPTER 1
Chronic Lung Disease of Infancy

KUSHAL Y. BHAKTA, JAMES M. ADAMS, AND ANN R. STARK
Historical Overview 1 Minimal Ventilation 14

Definitions of Bronchopulmonary High-Frequency Oscillatory Ventilation 14
Dysplasia 2 Vitamin A 15
Epidemiology 4 Systemic Corticosteroids 15
Pathogenesis 4 Inhaled Corticosteroids 16
Prenatal Events 5 Inhaled Nitric Oxide 16
Hyperoxia and Oxidant Stress 5 Caffeine 17
Mechanical Ventilation and Volutrauma 6 Superoxide Dismutase 17
Infection 6 Summary 17
Inflammation 7 Outcome 17
Bombesin-like Peptides 7 Mortality 17
Nutrition 7 Respiratory Infections 18
Genetic Factors 7 Pulmonary Function 18
Pathology 8 Neurodevelopment 18
Clinical Features 9 Growth 19
Physical Examination 9 Tracheobronchomalacia 19
Chest Radiograph 9 Glottic and Subglottic Damage 20
Clinical Course 9 Tracheal Stenosis, Bronchial Stenosis, or
Cardiopulmonary Function 10 Granuloma Formation 20
Management 11 Monitoring 21
Respiratory Care 11 Cardiovascular Monitoring and
Nutrition and Fluid Management 12 Oxygenation 21
Diuretics 12 Growth 21
Bronchodilator Therapy 13 Development, Vision, and Hearing 21
Corticosteroids 13 Coordination of Care and Discharge
Prevention 13 Planning 21
Antenatal Corticosteroids 13 References 22
Fluid Restriction 14
Historical Overview RDS and required prolonged mechanical ven-

tilation with high inflation pressures and
Bronchopulmonary dysplasia (BPD) or inspired oxygen concentrations. The pathol-
chronic lung disease of the premature com- ogy was characterized by abnormalities of
prises a heterogeneous group of respiratory the terminal airways, the hallmark of which
diseases of infancy that usually evolve from was an intense interstitial fibrosis and hy-
an acute respiratory disorder experienced by perplasia of the smooth muscle (Fig. 1-1).
a newborn. Chronic lung disease of the pre- Affected infants experienced chronic respira-
mature most commonly occurs in infants tory failure, with hypoxemia and hyper-
with birth weights less than 1500 g, and capnia, and many developed cor pulmonale.
especially in infants with birth weights less More recently, as the use of antenatal ster-
than 1000 g and who are treated for respira- oids and surfactant replacement therapy has
tory distress syndrome (RDS). This entity was resulted in increased survival of smaller pre-
first described by Northway and colleagues1,2 term infants, the features of the so-called
in 1967 in premature infants who had severe new BPD differ from the older descriptions
1
2 Pulmonary Manifestations of Pediatric Diseases
Figure 1-1. A, Classic bron-

chopulmonary dysplasia in a
9-month-old, former premature
(25 weeks gestation) infant. Micro-
scopically, there is marked hyper-
expansion of airspaces
compressing adjacent paren-
chyma. Focal interstitial fibrosis
also is noted. (Hematoxylin and
eosin, 20.) B, Secondary pulmo-
A B
nary hypertension in the same
patient is reflected microscopically
by marked muscularization of the
normally thin-walled intralobular
arterioles. (Hematoxylin and eosin,
100.) C, Classic bronchopulmon-
ary dysplasia in a 2-year-old, former
premature (26 weeks gestation)
infant. The lungs grossly show
hyperinflated pale areas alternating
with areas of collapse and pleural
retraction, producing pseudofis-
sures. (Courtesy of Megan K. Dishop,
MD, Department of Pathology, Texas
Children’s Hospital and Baylor Col-
lege of Medicine, Houston, TX.)
C
and include milder respiratory distress that dysplasia” (BPD) and “chronic lung disease of
often requires minimal ventilatory support infancy” (CLDI) are sometimes used inter-
with low fractions of inspired oxygen changeably to describe chronic respiratory
(FiO2) preceding the chronic condition.3-6 disease after treatment for RDS in preterm
Pathologic examination typically shows an infants. A working definition of BPD is neces-
arrest in pulmonary development and sary because it is from BPD that most cases of
alveolarization, with simplification of the CLDI arise. Three clinical definitions have been
terminal airways (Fig. 1-2). used to define BPD in neonates, as follows:
• Oxygen requirement at 28 days postnatal
age7,8
Definitions of • Oxygen requirement at 36 weeks post-
Bronchopulmonary Dysplasia menstrual age (PMA)9,10
• Diagnostic criteria proposed by a National
The terminology used to describe chronic Institute of Child Health and Human
lung disease arising from neonatal insults is Development (NICHD) workshop based
confusing. The terms “bronchopulmonary on gestational age and disease severity11,12
A B
Figure 1-2. A, Normal lung in a 2-year-old, former term (38 weeks gestation) infant. (Hematoxylin and eosin, 20.)
B, Chronic neonatal lung disease with “new” bronchopulmonary dysplasia pattern in an 8-month-old, former premature
(29 weeks gestation) infant. The lung architecture is altered with diffuse mild enlargement of airspaces with simplification
and deficient septation. (Hematoxylin and eosin, 20.) (Courtesy of Megan K. Dishop, MD, Department of Pathology, Texas
Children’s Hospital and Baylor College of Medicine, Houston, TX.)
Chapter 1 — Chronic Lung Disease of Infancy 3
In the 1990s, several studies showed that • Patients who are less than 32 weeks gesta-
administration of supplemental oxygen at tion are assessed at 36 weeks PMA or
36 weeks PMA rather than 28 days postnatal when discharged home, whichever comes
age more accurately predicted abnormal first.
pulmonary outcome at 2 years of age.9,10 In • Patients who are equal to or greater than
one study, the positive predictive value for 32 weeks gestation are assessed at 29 to
abnormal outcome in very-low-birth-weight 55 days of life or when discharged home,
(VLBW) infants (birth weight <1,500 g) whichever comes first.
(63% versus 38%) was better for supplemen- At the time of assessment, patients are
tal oxygen administration at 36 weeks PMA evaluated for the severity of their disease.
than at 28 postnatal days.10 Outcome was Infants who received treatment with sup-
normal in 90% of infants who did not receive plemental oxygen for at least 28 postnatal
oxygen at 36 weeks PMA. As a result, the def- days are classified as having mild, moderate,
inition of BPD as requiring administration or severe BPD, depending on the extent of
of supplemental oxygen at 36 weeks PMA oxygen supplementation and other respira-
became widely used. tory support.11
A precise definition of BPD is especially In a study from the NICHD Neonatal
important when outcomes are compared Research Network of infants with BPD who
among different centers or when new thera- were born at less than 32 weeks gestational
peutic interventions are tested. The increased age and with birth weight less than 1000 g,
survival of extremely-low-birth-weight (ELBW) these criteria predicted pulmonary and neuro-
infants (birth weight <1,000 g or gestational developmental outcomes at 18 to 22 months
age <30 weeks) suggested that the definition corrected age.11 The severity of BPD (mild,
of BPD could be refined to include infants moderate, severe) was associated with use of
with milder disease and account for develop- pulmonary medications (30%, 41%, 47%)
mental changes that occur with increasing and rehospitalization for pulmonary disease
gestational age. In 2001, the NICHD work- (27%, 34%, 40%). The incidence of any
shop proposed diagnostic criteria for BPD that neurodevelopmental impairment, including
included gestational age and disease severity cerebral palsy, blindness, hearing deficit re-
(Table 1-1).12 This scheme divides patients quiring amplification, and lower mental and
into the following two groups based on gesta- psychomotor development index scores,
tional age, which determines the timing of also increased with the severity of BPD.
clinical assessment for BPD: The patients who had severe BPD often
Diagnostic Criteria for Bronchopulmonary Dysplasia Proposed by National Institute of

Table 1-1 Child Health and Human Development Workshop
GESTATIONAL AGE <32 WEEKS PMA GESTATIONAL AGE 32 WEEKS PMA
Time of 36 wk PMA or discharge to home* >28 days but <56 days postnatal age or
assessment discharge to home*
Mild CLD Treatment with oxygen >21% for at least Breathing room air by 56 days postnatal age or
28 days plus discharge*
Breathing room air at 36 wk PMA or
discharge*
Moderate CLD Need{ for FiO2 <30% at 36 wk PMA or Need{ for FiO2 <30% at 56 days postnatal age or
discharge* discharge*
Severe CLD Need{ for FiO2 30% and/or positive Need{ for FiO2 30% and/or positive pressure
pressure (IPPV or NCPAP) at 36 wk PMA or (IPPV or NCPAP) at 56 days postnatal age or
discharge* discharge*
*Whichever comes first.

{
At the time of the workshop, a physiologic test to confirm oxygen requirement had yet to be defined.
CLD, chronic lung disease of the premature; IPPV, intermittent positive-pressure ventilation; NCPAP, nasal continuous positive
airway pressure; PMA, postmenstrual age.
From Jobe AH, Bancalari E: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 163:1723-1729, 2001.
had substantial associated morbidity during levels for acceptable oxygen saturation.16
their hospitalization at birth, such as severe The overall incidence of BPD was 23% of
intraventricular hemorrhage (25%), peri- the VLBW infants, and increased with
ventricular leukomalacia (10%), necrotizing decreasing birth weight. Compared with
enterocolitis (14%), late-onset infection the entire cohort, there were increased pro-
(54%), and postdischarge deaths (5%), and portions of males with BPD and severe BPD
were often treated with postnatal corticos- (54% for entire cohort, 60% for males with
teroids (78%). In this cohort, many infants BPD, and 67% for males with severe BPD).
who needed oxygen during the first 28 days In an 8-year (1994 to 2002) retrospective
of life no longer required oxygen at 36 weeks cohort study of six NICUs, the overall inci-
PMA and might not have been classified dence of BPD remained constant at 12%
as having BPD. This study did not include for preterm infants born before 33 weeks
an objective physiologic measure of oxygen gestation.17 Although there has been no
requirement, however. These criteria, espe- change in the overall incidence of BPD,
cially with the addition of a physiologic test, there has been a significant decline in the
may improve the ability to compare thera- incidence of severe BPD, from 10% in 1994
peutic interventions in clinical trials and to 4% in 2002, with severe BPD defined as
evaluate long-term outcomes. requiring positive-pressure respiratory sup-
In most neonatal intensive care units port (i.e., mechanical ventilation or contin-
(NICUs), supplemental oxygen is adjusted uous positive airway pressure [CPAP]) at 36
to maintain the infant’s oxygen saturation weeks PMA. The risk for any degree BPD
within a target range. As a result, the use of increases with mechanical ventilation, as
supplemental oxygen depends partly on described in a case-cohort study conducted
the NICU policy for the target range, which at two centers (two Boston hospitals and
varies among centers. To standardize the use Babies’ and Children’s Hospital in New
of supplemental oxygen, the NICHD work- York), in which the higher rate of BPD in
shop also proposed that the need for oxygen Boston (22% versus 4%) reflected the higher
less than or greater than 30% be confirmed rate of mechanical ventilation (75% versus
by a physiologic test. Such a test was devel- 29%) and surfactant administration (45%
oped, based on oxygen administration and versus 10%) as part of the initial respiratory
oxygen saturation, including a timed room management of VLBW infants.16 The risk of
air challenge in selected patients. It was BPD increases with decreasing birth weight.
found to be safe, feasible, and reliable.13 In BPD is rare in infants older than 32 weeks
a prospective multicenter study of VLBW gestation.
infants who remained hospitalized at 36
weeks PMA,14 fewer infants had BPD when
the physiologic definition was used (25% Pathogenesis
versus 35%) compared with the clinical
definition (oxygen supplementation at 36 The etiology of BPD is multifactorial.
weeks PMA), and there was less variation Inflammation caused by mechanical venti-
among centers. lation, oxygen toxicity, or infection plays
an important role. The lung seems to be
most vulnerable before the saccular stage
Epidemiology of development, which occurs at approxi-
mately 31 to 34 weeks gestation, and during
The rate of BPD varies among institutions. which alveolar formation is initiated.18,19
In a report from the NICHD Neonatal The preterm lung is especially at risk of
Research Network (1995 to 1996), the rate injury because of its structural and func-
of BPD ranged from 3% to 43% in the 14 tional immaturity. Lungs in preterm infants
participating centers.15 Variability in inci- have poorly developed airway supporting
dence among centers may reflect neonatal structures, surfactant deficiency, decreased
risk factors or care practices, such as target compliance, underdeveloped antioxidant
mechanisms, and inadequate fluid clearance airway remodeling, hyperreactivity, and

compared with term infants.20 inflammatory alterations similar to that
seen in BPD.28 Higher degrees of hyperoxia
(FiO2 0.95) for shorter durations (72
Prenatal Events hours) result in inhibition of distal airway
branching with simplification of architec-
Many events that occur before birth affect
ture in fetal mouse lung explants.29
the development of the lung. In infants less
The imbalance between pro-oxidant and
than 27 weeks gestation—the period of high-
antioxidant systems in a preterm neonate in
est risk for development of BPD—the human
favor of pro-oxidant processes also may
lung is in the saccular stage of development;
contribute to the development of BPD.30-32
alveolarization begins at approximately 32
Preterm infants have few antioxidant
weeks and proceeds through 40 weeks
defenses and are often exposed to supple-
PMA.21 Any factor that has an adverse effect
mental oxygen to treat pulmonary insuffi-
on this process leads to disruption of lung
ciency. They also are prone to infection, and
architecture and alveolar simplification, a
many of the proinflammatory cytokines
hallmark of the “new BPD.”22
activate the production of reactive oxygen
Inflammation, as discussed later, is consid-
species (ROS), such as superoxide free radi-
ered one of the central aspects in the patho-
cal, hydrogen peroxide, hydroxyl free radical,
genesis of BPD. Several studies suggest that
and singlet oxygen, which are produced
the timing, the type, and the intensity of the
as the result of oxidative stress. In addition,
inflammatory response that determine the
preterm infants have higher plasma and
subsequent effects on the developing preterm
tissue-free iron concentrations compared
lung.23 A series of studies in fetal rabbits and
with term infants, which can promote the
fetal sheep showed that intra-amniotic expo-
propagation of ROS.
sure to interleukin (IL)-1 or endotoxin accel-
The toxicity of these ROS, particularly
erated lung maturation and the synthesis
in response to exposure to hyperoxia, has been
of surfactant proteins.24 In these studies,
shown in experimental animals; when
repeated exposure to proinflammatory agents
exposed to equal to or greater than 0.50 FiO2,
did not cause progressive inflammation, but
they exhibited irreversible changes in lung
rather induced tolerance and suppression of
growth and DNA synthesis.32 At the cellular
fetal monocyte function.25 If IL-1 or endo-
level, ROS cause the uncoupling of respira-
toxin treatment was done with two doses,
tion from adenosine triphosphate (ATP) syn-
given 7 days apart, the fetal monocytes
thesis and disruption of the outer mito-
reacted in a manner similar to that seen in
chondrial membrane. Subsequently, this
adult sheep.25 Concomitant treatment with
disruption allows release of pro-apoptotic fac-
corticosteroids and IL-1 or endotoxin initially
tors, such as cytochrome-c, apoptosis-inducing
suppressed the inflammatory response, but
factor, and pro-caspases, from the mitochon-
caused an exaggerated inflammatory response
dria into the cytosol, leading to cell death.31
at 5 to 15 days post-treatment.26,27 Antenatal
Various antioxidant defenses are available
exposure to endotoxin and corticosteroids
in mature human organisms to combat this
modulates lung injury and maturation in a
oxidative stress. They include superoxide
time-dependent manner.
dismutase, catalase, glutathione-S-transfer-
ase (GST), and glutathione peroxidase, and
Hyperoxia and Oxidant Stress nutrients such as vitamins A and E, iron,
copper, zinc, and selenium, which help pre-
High concentrations of inspired oxygen can vent oxygen toxicity. Preterm infants have
damage the lungs, although the exact level inadequate antioxidant defenses and are at
or duration of exposure that is unsafe is risk of oxygen free radical damage. In some
unknown. In a study conducted in neonatal species, antioxidant enzyme concentrations
rats, exposing neonatal rat pups to moder- are lower in preterm than term animals,33
ate hyperoxia (FiO2 0.50) for 15 days caused and are poorly induced in response to
oxidative stress.34 Similarly, activities of with lower tidal volumes (5 mL/kg and
catalase, glutathione peroxidase, and copper/ 10 mL/kg).44
zinc superoxide dismutase in human cord In two retrospective cohort studies (n ¼ 235
blood are lower in preterm than in term and n ¼ 188), the authors found that increased
newborns.35 In a small study of preterm ventilation resulting from large tidal volumes
infants (gestational age 25 to 30 weeks), cop- resulted in hypocarbia, a risk factor for
per/zinc superoxide dismutase levels were subsequently developing BPD.7,45 In vitro
greater in infants who subsequently devel- cyclic cell stretch has been shown to upregu-
oped BPD; these infants also had a higher late the expression of proinflammatory cyto-
cumulative oxygen exposure.36 These results kines by human alveolar epithelial cells
suggest that in preterm infants with BPD, without any structural cell damage.46,47 Tidal
superoxide dismutase activity is upregulated volumes large enough to cause similar cell
and may be a marker for increased oxygen stretch in vivo, without causing structural
exposure and potentially increased reactive damage, may similarly initiate the cascade
oxygen metabolites. of proinflammatory cytokines, recruiting
inflammatory cells and causing tissue dam-
age. All of the above-described pulmonary
Mechanical Ventilation and insults occur at a time when most preterm
Volutrauma infants have a relative adrenocortical insuffi-
ciency, which may potentiate the inflamma-
Lung injury associated with mechanical ven- tory effects.
tilation contributes to the development of
BPD, and it is known that positive-pressure
ventilation typically induces bronchiolar Infection
lesions.37 Pulmonary interstitial emphysema
is a result of barotrauma and is associated Although the role of infection is incompletely
with a high incidence of CLDI. understood, infants exposed to antenatal and
Disruption of airways may occur early in postnatal infection seem to be at higher risk
the course of treatment and may be mani- for developing BPD.46 Antenatal chorioam-
fested by increased pulmonary resistance.38 nionitis may play a key role in the production
In one study of ventilated preterm infants of a fetal pulmonary inflammatory response
in the first 5 days after birth, mean pulmo- to the release of proinflammatory cyto-
nary resistance was significantly greater in kines.48,49 This response can lead to aberrant
infants who subsequently developed BPD wound healing and fibrosis, causing inhibi-
compared with infants who did not.39 tion of alveolarization and vascular develop-
Animal studies suggest that volutrauma is ment, hallmarks of the new BPD. Similarly,
more important than barotrauma in causing infants who developed late-onset sepsis (>3
airway injury.16,18,40 Distention of the air- days of age) were more likely to need long-
ways to near-maximum lung volume causes term mechanical ventilation, and were more
shear injury, capillary leak, and pulmonary likely to develop BPD.50 In a retrospective
edema.41,42 In studies in preterm lambs and study, early tracheal colonization also pre-
rabbits and in adult rats, animals given large disposed to the subsequent development
tidal volume breaths had significantly worse of BPD.51
pulmonary mechanics and showed histologic Nosocomial infection plays a role in some
evidence of widespread lung injury.37,43,44 In cases of CLDI, especially in association with
newborn lambs, large tidal volumes seem to a symptomatic patent ductus arteriosus PDA,
impair the response to subsequent surfactant particularly in ELBW infants. In a series
administration.44 In one study, preterm of 119 ELBW infants who had mild or no
lambs ventilated with large tidal volumes initial RDS, BPD was significantly more
(20 mL/kg) showed lower compliance, lower likely to occur with patent ductus arteriosus
ventilatory efficiency, higher recovery of (odds ratio [OR] 6.2) and sepsis (OR 4.4).52
protein, and lower recovery of surfactant The risk of BPD increased substantially in
by 6 hours compared with animals ventilated infants with both conditions (OR 48.3).
Neither ductal ligation nor prophylactic use disorder.59,60 In infants 28 weeks gesta-
of low-dose indomethacin initiated in the tional age, elevated urine BLP levels in the
first 24 hours has been shown to reduce sig- first 4 days after birth were associated with
nificantly the incidence of CLDI, however. an increased risk of BPD.61
Specific organisms also may play a role. In
one report, development of BPD was asso-
ciated with isolation of Ureaplasma urealyti- Nutrition
cum in tracheal aspirates performed on the
Premature infants have very poor nutritional
first (before surfactant administration) and
reserves and are at high risk for being mal-
fourth days of mechanical ventilation in
nourished and entering a catabolic state if
infants less than 28 weeks gestational age.53
not provided with adequate nutrition. The
goal of postnatal nutrition is to provide ade-
Inflammation quate substrate to approximate the intrauter-
ine rate of growth. In VLBW infants, this
Macrophages, lymphocytes, and platelets in goal can be extremely difficult to achieve for
the lung release multiple inflammatory me- the following reasons62:
diators, including cytokines, lipid mediators, • Fluid restriction to prevent pulmonary
and platelet factors, which interact with endo- edema
thelial and epithelial cells.54 The airspaces of • Heart failure secondary to a patent ductus
ventilated preterm infants contain many arteriosus
proinflammatory and chemotactic factors that • Use of postnatal corticosteroids
are present in greater concentration in infants • Decreased gastrointestinal absorption sec-
who subsequently develop BPD.12,54-57 The ondary to suspected or proven necrotizing
presence of these mediators is associated with enterocolitis
complement activation, increased vascular • Hypoxia and chronic respiratory acidosis
permeability, protein leakage, and mobiliza- • Anemia of prematurity
tion of neutrophils into the interstitial and • Medications that increase metabolic
alveolar compartments. Release of ROS, rate, such as methylxanthines and b-
elastase, and collagenase by activated neutro- sympathomimetics
phils can damage lung structures. Interaction Malnutrition or undernutrition renders an
between macrophages and other cell types infant more susceptible to injury resulting
may perpetuate the production of proinflam- from hyperoxia, volutrauma/barotrauma,
matory mediators and sustain the cycle of and infections, and impairs the infant’s abil-
lung injury. Persistence of factors such as mac- ity to recover from this injury.63 In addition,
rophage inflammatory protein-1 and IL-8 and infants with BPD are significantly more
decreases of counter-regulatory cytokines likely to have lower early protein and total
such as IL-10 may lead to unregulated and energy intake.64
persistent inflammation.12
Genetic Factors
Bombesin-like Peptides
The pathogenesis of BPD is complex, with an
Injury may be mediated partly by bombe- intricate interaction of preterm birth, the in
sin-like peptides (BLP), which are derived utero environment, inflammation/infection,
from pulmonary neuroendocrine cells and fluid management, vascular maldevelop-
play an important role in normal lung ment, surfactant deficiency, mechanical ven-
growth and maturation. In one study, the tilation, the balance of oxidative stress and
number of BLP-positive cells was greater in antioxidant systems, and nutrition. Not all
infants who died with BPD than in con- factors are required to develop BPD, and
trols.58 In a baboon model, urine BLP levels severe BPD may develop in infants who have
were increased soon after birth in animals a benign perinatal course. It had been postu-
who developed BPD, and administration lated that there might be a genetic predis-
of anti-BLP antibody attenuated the position to develop BPD. Several studies
have looked at the development of BPD in Finally, the role of allelic variants of vari-
singleton and multiple gestation VLBW ous surfactant proteins in the development
infants.65-69 In the earliest study comparing of RDS and BPD has been explored. Specifi-
the rate of BPD among 108 VLBW twins, it cally, the surfactant protein A (SP-A) allele
was reported that BPD in one twin signifi- 6A-6 is more common in infants with
cantly predicted BPD in the other twin BPD.78 Many loss-of-function mutations of
(adjusted OR 12.3, P <.001), even after adjust- the surfactant protein B (SP-B) gene have
ing for birth weight, gestational age, gender, been reported. The clinical phenotype can
RDS, pneumothorax, and patent ductus vary, ranging from chronic respiratory fail-
arteriosus.67 More recently, in a multicenter ure to refractory hypoxic respiratory failure
retrospective study of 450 twin pairs born at in the neonatal period.79-81 One group
32 weeks, the concordance of BPD was higher looked at polymorphisms in intron 4 of
in monozygotic twins than predicted, after the SP-B gene. They found that BPD was
controlling for all covariates. more common in infants who had the poly-
In addition to twin studies, many other morphisms in intron 4.82 The definition of
investigators have attempted to look for can- BPD that they used was that of oxygen
didate genes that may predispose to develop- requirement at 28 postnatal days, however;
ing BPD. Genes involved in the differential if the definition of oxygen requirement at
regulation of lung development and the 36 weeks PMA was used, there were no dif-
response to lung injury have been probed to ferences in the wild-type versus the intron
determine whether they participate in the 4 variants.
pathogenesis of BPD. Two separate studies
looking at polymorphisms of angiotensin-
converting enzyme (ACE) hypothesized that Pathology
increased ACE activity, leading to increased
aldosterone production and increased water In surfactant-treated ELBW infants, the char-
retention, would increase the incidence of acteristic pathologic finding of BPD is disrup-
BPD. Kazzi and Quasney70 found that the tion of lung development.12 Decreased
polymorphism that conferred increased ACE septation and alveolar hypoplasia lead to
activity showed increased incidence of BPD, fewer and larger alveoli. Reduced microvas-
whereas Yanamandra and colleagues71 did cular development also may occur. These
not find an association between ACE activity changes have been observed in infants who
and incidence of BPD. died of BPD,83 biopsy specimens from severely
Other groups have examined the role of affected infants, and a baboon model of the
polymorphisms in the gene encoding for disorder.18 These findings are in contrast to
GST. GST is an innate defense mechanism BPD seen in infants before the availability of
against ROS and is found in various human surfactant replacement therapy. The promi-
tissues. A polymorphism of the GST-P1 gene nent pathologic findings in those cases were
produces two isoforms, one of which is airway injury, inflammation, and parenchy-
significantly more efficient in eliminating mal fibrosis.12,83 Similar changes may be seen
oxidative toxins.72,73 In a small pilot study in surfactant-treated infants who develop
of 35 infants with BPD, it was shown that severe BPD. In severely affected infants, fibro-
infants who developed BPD were more likely sis, bronchial smooth muscle hypertrophy,
to have the less efficient form of the and interstitial edema may be superimposed
enzyme.74 Groups that have attempted to on the characteristic reduced numbers of
determine the role of various polymorphisms alveoli and capillaries. Pulmonary vascular
of the anti-inflammatory cytokines IL-4 changes, such as abnormal arterial musculari-
and IL-10, the anti-inflammatory transform- zation and obliteration of vessels, may occur.
ing growth factor-b (TGF-b), and the Lung injury also is associated with in-
proinflammatory chemokine monocyte che- creased elastic tissue formation and thick-
moattractant protein-1 have found no asso- ening of the interstitium. These tissue
ciation between allelic variants and the deformations may compromise septation
development of BPD.75-77 and capillary development. Disturbed
elastic tissue maturation was shown in a Physical Examination

study of 44 infants, 23 to 30 weeks gesta-
tional age, who died at 5 to 59 days of The physical examination is variable. Infants
age.84 In infants with high respiratory scores usually are tachypneic, and depending on
computed from supplemental oxygen con- the extent of pulmonary edema or atelectasis
centration and mean airway pressure, the or both, they may have mild to severe retrac-
volume, density, and absolute quantity of tions, and crackles may be audible. Intermit-
elastic tissue were significantly greater than tent expiratory wheezing may be present in
those of infants with low scores or control infants with increased airway reactivity.
infants. Alveolar and duct diameters and
septal thickness also were greater. With
increased elastic tissue content and thick-
Chest Radiograph
ened interstitium, the lungs tend to collapse As BPD evolves, the chest radiograph becomes
at end expiration and have a low functional diffusely hazy, reflecting inflammation or pul-
residual capacity (FRC). monary edema or both (Fig. 1-3A), with low
to normal lung volumes. There may be areas
of atelectasis that alternate with areas of gas
Clinical Features trapping, related to airway obstruction from
secretions or other debris. The chest radio-
BPD predominantly affects ELBW infants, graph in infants who develop severe BPD
and most affected infants are ventilator- shows hyperinflation (Fig. 1-3B). Streaky den-
dependent from birth with severe RDS sities or cystic areas may be prominent,
requiring surfactant therapy. The evolution corresponding to fibrotic changes. During
to BPD typically is recognized at approxi- acute exacerbations, pulmonary edema may
mately 2 weeks of age as pulmonary func- be apparent (Fig. 1-3C).
tion deteriorates rather than improves. The
infant remains ventilator-dependent, and
the concentration of supplemental oxygen Clinical Course
must be increased to maintain adequate
oxygen saturation. Wide swings in oxygena- Most infants improve gradually during the
tion may occur, likely caused by intermit- next 3 to 4 months. As pulmonary function
tent atelectasis. improves, infants can be weaned to CPAP,
Figure 1-3. A, Chest radiograph

of a former preterm (25 weeks ges-
tation) infant on day of life (DOL)
10, with evolving lung disease.
The diffuse haziness indicates pul-
monary edema or inflammation or
both. B, Chest radiograph of the
same infant, now on DOL 285,
A B with a tracheostomy tube in place.
Note the extreme degree of hyper-
inflation and air trapping. Also
evident are diffuse interstitial mark-
ings representing areas of fibrosis.
C, Chest radiograph of the same
infant, now on DOL 317. Cystic
areas can be seen with hyperinfla-
tion, prominent lung markings,
and areas of opacification, nearly
obliterating bilateral heart borders.
Significant pulmonary edema also
C is present, as seen by the marked
diffuse bilateral haziness.
then supplemental oxygen alone, until they Cardiopulmonary Function

can maintain adequate oxygenation breath-
ing room air. Some infants develop severe Abnormalities of pulmonary function in
BPD that leads to prolonged ventilator severe BPD include decreased tidal volume,
dependence. The clinical course during the increased airway resistance, and low dynamic
first few weeks after birth includes marked lung compliance, which become frequency
instability with frequent changes in oxyge- dependent. Uneven airway obstruction leads
nation and intermittent episodes of acute to air trapping and hyperinflation with
deterioration requiring increased ventilator abnormal distribution of ventilation.86
support. The marked instability typically Bronchomalacia can result in airway collapse
improves after 4 to 6 weeks. during expiration, and severely affected in-
Severely affected infants may develop pul- fants can have hypoxemia and hypercapnia.
monary hypertension and cor pulmonale.85 Pulmonary vascular resistance is increased
Elevated pulmonary vascular resistance may because of reduced cross-sectional area of
impair pulmonary lymphatic drainage and pulmonary vessels (Fig. 1-4). In addition,
exacerbate interstitial edema. In some cases, alveolar hypoxia in underventilated areas
anastomoses develop between pulmonary of the lung induces local vasoconstriction.
and systemic vessels that may worsen the Intact vessels in well-ventilated areas of the
pulmonary hypertension.85 lung accept a disproportionate amount of
Q = 0.33 V = 0.33
Q = 0.33 H 2O
Right Left
V = 0.33 heart
heart
Q = 0.33 H2O
Lymphatics V = 0.33
H2O
Figure 1-4. A, Schematic H2O H 2O
representation of the inter- H2O
action of the heart and lungs
in a normal infant. The pul- A
monary vascular resistance
is low, and matching of ven-
tilation (V) and perfusion Q=0 V=0
(Q) is uniform. Interstitial Obliterated
fluid is cleared effectively
by pulmonary lymphatics.
B, Derangements of the
heart-lung interaction in
bronchopulmonary dyspla-
sia. There is mismatching of Q = 0.7
ventilation (V) and perfusion Right Left
heart V = 0.9 heart
(Q) with gas trapping. Pul-
monary vascular resistance Q = 0.3 H2O H2O
is elevated because of vascu-
lar obliteration and regional
hypoxic vasoconstriction.
Increased capillary filtration V = 0.1
produces interstitial edema, H2O H2O H2O H2O H2O H2O H2O H2O
and lymphatic drainage of
the lung is impaired by ele-
vated right heart pressures. B
pulmonary blood flow. Because these vessels strategy did not change the relative risk of
are already fully recruited and dilated, the death or BPD at 36 weeks PMA, the primary
additional flow results in elevated pressure outcome.90 Although the very low tidal
and increased right ventricular afterload. The volumes associated with high-frequency oscil-
high microvascular pressure promotes latory ventilation (HFOV) might be expected
increased fluid filtration into the perivascular to reduce the rate of BPD, only one of two
interstitium. Elevated right atrial pressure large trials comparing HFOV and conven-
inhibits pulmonary lymphatic drainage, tional ventilation in patients at the highest
further promoting pulmonary edema. risk showed an effect.91,92 This finding sug-
gests that routine initial use of HFOV gener-
ally is not warranted.
Management The most appropriate range of arterial oxy-
genation in preterm infants with acute or
The management of infants with BPD chronic respiratory failure is unknown. High
begins with prevention, attempting to avoid levels of oxygen saturation seem to offer no
or minimize contributory factors. advantages, however, and pulmonary injury
may result from the increased concentration
of supplemental oxygen required to maintain
Respiratory Care higher saturations, as shown by two studies.
In the STOP-ROP trial, providing supplemen-
Respiratory care of an infant with developing tal oxygen to maintain higher compared with
or established BPD is supportive and should routine oxygen saturation (96% to 99% versus
aim to minimize additional lung injury by 89% to 94%) in infants with prethreshold
judicious use of mechanical ventilation and retinopathy of prematurity did not reduce
supplemental oxygen. Early use of continu- progression to threshold retinopathy of pre-
ous distending pressure in at-risk infants maturity or the need for peripheral retinal
reduces the need for subsequent positive- ablation.93 The incidence of pulmonary
pressure ventilation.87 The COIN trial com- events, including pneumonia/exacerbation
pared CPAP with mechanical ventilation in of BPD, and the need for oxygen, diuretics,
infants born at 25 to 28 weeks gestation. In and hospitalization at 3 months corrected
a preliminary report, the authors found that age was higher, however, in the higher satura-
there were no significant differences in the tion group. Similarly, in the BOOST trial, in
incidence of BPD (oxygen treatment at 36 infants less than 30 weeks gestation who were
weeks PMA), days of respiratory support, oxy- oxygen dependent at 32 weeks PMA, no
gen treatment, hospital stay, incidence of differences were detected in growth and
grade III or IV intraventricular hemorrhage, neurodevelopment at 12 months corrected
cystic periventricular leukomalacia, or home age—the primary outcomes—between the
oxygen use.88 There was an increased rate of groups maintained at high (95% to 98%) or
pneumothorax in the CPAP group. standard (91% to 94%) oxygen saturation
If mechanical ventilation is needed, the ranges.94 Infants in the high saturation group
lowest peak airway pressure necessary to ven- received oxygen for a longer time, however,
tilate adequately should be used, and large and had higher rates of oxygen dependence
tidal volumes should be avoided. Although at 36 weeks PMA and home oxygen therapy.
this strategy is supported by few data in Respiratory management in infants with
human neonates, the use of lower than rou- developing or established BPD should ensure
tine tidal volumes decreased mortality and adequate tissue oxygenation to promote
increased the number of ventilator-free days growth and prevent pulmonary arterial hyper-
in adults with acute respiratory distress syn- tension that can result from chronic hypox-
drome.89 In addition, in a multicenter trial emia, and should minimize lung injury from
conducted by the NICHD Neonatal Research excessive oxygen levels or mechanical ventila-
Network, the need for ventilator support at tion. Although the safest levels are unknown,
36 weeks PMA was significantly lower in the oxygen saturation is generally maintained in
minimal ventilation group, although this the 85% to 95% range, with PaO2 greater than
50 mm Hg, and PaCO2 should be allowed to strong correlation between low vitamin E
increase to 50 to 60 mm Hg or possibly even levels in the cord blood and on the third
higher in infants with the most severe disease day of life and the subsequent development
as long as the pH is normal. When the infant of BPD,102 but further studies are needed
is able to maintain adequate PaCO2 and PaO2 before the routine use of vitamin E supple-
on the lowest ventilator settings, weaning mentation can be recommended. Another
from assisted ventilation should be attempted. key antioxidant that is deficient in preterm
Episodes of hypoxemia should be avoided infants is vitamin C. In a pilot study with pre-
because these are associated with increased mature baboons, high-dose vitamin C treat-
airway resistance.95,96 Supplemental oxygen ment did not prevent pulmonary oxygen
may be needed for several months or longer toxicity.103 Of concern is that vitamin C in
in the most severe cases. high doses can induce oxidative stress and
have adverse effects on the developing
lung.31 At this time, it is recommended that
Nutrition and Fluid Management specific vitamin deficiencies should be
avoided in infants with BPD by providing
Nutrition is a key component of the man- adequate supplementation.
agement of infants with BPD. Nutrition, Inflammatory changes in the lungs of
supplied enterally or parenterally or both, infants with BPD promote water retention.
must be sufficient to promote somatic As a result, these infants tolerate excess fluid
growth and the development of new alveoli; administration poorly,97,104 and fluids should
this should facilitate weaning from mechan- be modestly restricted (140 to 150 mL/kg/day)
ical ventilation and decrease vulnerability to to avoid pulmonary edema. Further restric-
infection that is associated with malnutrition may be needed in severely affected
tion.97,98 Energy also must be sufficient to infants. Additional supplementation of hu-
meet the demands of increased work of man milk or formula with calories or protein
breathing. Plans for dietary support of or both may be required to ensure adequate
infants with BPD who fail to thrive should nutrition in these infants.
consider that an excessive intake of carbo-
hydrate might be associated with increased
CO2 production and impair respiratory Diuretics
function further. Insufficient caloric intake
may potentiate oxygen toxicity and impair Administration of the loop diuretic furose-
cell multiplication and lung growth. Defi- mide, hydrochlorothiazide, or spironolac-
ciencies in sulfur-containing amino acids tone, which acts on the distal tubule, results
may reduce lung glutathione, an important in acute, nonsustained improvements in
antioxidant.30 The adequacy of nutrition pulmonary mechanics.105-107 The improve-
should be monitored closely, and growth ment in pulmonary mechanics seen with
charts for weight, head circumference, and furosemide administration may be indepen-
length should be maintained.97,98 dent of its diuretic effect, as venous capaci-
Vitamin deficiency may occur and inter- tance increases, and pulmonary blood flow
fere with lung healing. Vitamin A is an essen- decreases in response to furosemide adminis-
tial micronutrient for the normal growth and tration.108 In a Cochrane systematic review
differentiation of epithelial cells. Vitamin A and meta-analysis, however, diuretic admin-
levels are lower in infants with severe BPD istration did not reduce the need for ventila-
than in infants without BPD.99,100 In animal tor support, reduce the duration of hospital
models, low vitamin A levels contribute to stay, or improve long-term outcomes.
airway abnormalities, such as loss of ciliated Long-term administration of a diuretic is
epithelium or squamous metaplasia, similar often complicated by metabolic abnormal-
to histologic changes seen in BPD, and these ities, such as a hypokalemic, hypochloremic
changes are reversed by normalization of metabolic alkalosis, hypercalciuria leading
vitamin A levels.101 Vitamin E is another to nephrocalcinosis, osteopenia, impaired
important micronutrient and is a ubiquitous growth, and hearing loss (with furosemide
antioxidant. A small study has shown a administration).
Although no evidence exists for long-term reduces inflammation and improves lung
benefit, diuretics frequently are used in the mechanics, facilitating extubation.112,113 Sys-
management of infants with BPD to improve temic corticosteroid use is associated with
pulmonary function acutely. This use of di- short-term adverse effects, however, such as
uretics may be beneficial in infants with a pul- hyperglycemia, glucosuria, and hypertension,
monary exacerbation thought to be caused by and mortality is not reduced. In addition, out-
pulmonary edema or to reduce the effects of come studies have suggested that cortico-
circulatory overload after a packed red blood steroid treatment, especially dexamethasone,
cell transfusion. Whether diuretic therapy may contribute to poor neurodevelopmental
facilitates optimal nutrition by reducing the outcome and cerebral palsy.114 These con-
need for fluid restriction requires further cerns led the American Academy of Pediatrics
study. If diuretics are used, close monitoring Committee on Fetus and Newborn to recom-
of serum electrolytes is needed, and supple- mend that the routine use of dexamethasone
mentation may be required to compensate should be avoided and its use limited to
for urinary losses. extreme circumstances.115 That the likelihood
of dexamethasone treatment leading to
adverse outcomes is influenced by the base-
Bronchodilator Therapy line risk of developing BPD was suggested
by a meta-regression analysis.116 Whether
Infants with severe BPD have increased base-
infants at extremely high baseline risk for
line airway resistance that increases further
developing BPD would benefit from dexa-
with periods of hypoxemia, leading to respira-
methasone remains to be established in
tory decompensation owing to bronchocon-
clinical trials.
striction. This condition is sometimes treated
Data on the use of inhaled steroids are insuf-
with inhaled bronchodilators, a practice that
ficient to recommend their routine use.117
has been extrapolated from the treatment
Corticosteroids given via a metered dose
of asthma. Infants with BPD treated with
inhaler and holding chamber or nebulized
b-agonists respond with a short-term increase
budesonide have been used successfully, how-
in compliance and tidal volume and decrease
ever, even in patients younger than 1 year.118
in airway resistance.109,110 This treatment
The inhaled route is the preferred route for
has not been shown to affect long-term out-
preventing side effects of systemic cortico-
come, however. In one trial in which 173 ven-
steroids. Infants with CLDI treated with
tilator-dependent infants less than 31 weeks
inhaled corticosteroids should be monitored
gestation were randomly assigned to inhaled
for potential side effects, including delayed
salbutamol (albuterol), beclomethasone,
growth, increased blood pressure, osteoporo-
combination salbutamol and beclometha-
sis, adrenal suppression, and cataracts.
sone, or placebo, treatment resulted in no
difference in duration of mechanical ventila-
tion or oxygen supplementation, diagnosis
or severity of BPD at 28 days, or survival.111 Prevention
The efficacy of anticholinergic agents in
the treatment of BPD has not been studied Antenatal Corticosteroids
in randomized trials. Individual infants can
Antenatal corticosteroids given to women at
be treated with bronchodilators to achieve
risk for preterm delivery decreases the risk of
short-term improvement in pulmonary
RDS, intraventricular hemorrhage, and mor-
mechanics. Continued use should depend
tality. They should be given to any pregnant
on clinical response assessed by improvement
woman 24 to 34 weeks gestation with intact
in gas exchange and respiratory effort.
membranes at high risk for preterm delivery
within 7 days of administration. Treatment
Corticosteroids does not decrease the incidence of BPD,
however, partly because increased survival
Administration of systemic corticosteroids has resulted in more infants at risk for the
to infants with evolving or established BPD condition.
Fluid Restriction because of excess adverse events in infants

treated with dexamethasone. There was no
Higher fluid intake associated with a lack difference between ventilator groups in the
of postnatal weight loss during the immedi- combined primary outcome of death or
ate postnatal period has been proposed as BPD. At 36 weeks PMA, the proportion of
a predisposing risk factor for BPD. This infants requiring mechanical ventilation
hypothesis is supported by a retrospective was significantly less in the minimal group
report of premature infants (birth weight (16% versus 1%).
401 to 1,000 g) from the Neonatal Research The lack of difference in lung injury
Center study that found infants who either between the minimal and routine ventilation
died or developed BPD had a higher fluid groups may be due partly to an insufficient
intake and a lower weight loss during the first sample size. Another reason may be that target
10 days of life compared with infants who levels of PCO2 rather than tidal volume distin-
survived without BPD.119 Small trials of fluid guished the groups because the former usually
restriction have not shown a consistent is not measured continuously, and the
effect on the development of BPD, although difference in PCO2 between groups was small.
this strategy may minimize pulmonary Because ventilated infants continued to
edema.120,121 In one study, 168 ventilated breathe spontaneously, the measured PCO2
infants, gestational age 23 to 33 weeks, were reflected the selected airway pressure (which
randomly assigned to receive routine fluid determines the tidal volume) and rate and
volumes (60 mL/kg on the first day, progress- the infant’s own ventilation. Spontaneous
ing to 150 mL/kg on the seventh day) or 80% breathing may have resulted in the modest
of routine volume.120 Similar proportions in increase in PCO2 in the minimal ventilation
each group had BPD (26% versus 25%) and group and minimized the difference between
survived without oxygen dependency at 36 groups.
weeks PMA (58% versus 52%). Significantly
fewer restricted infants received postnatal
corticosteroid treatment (19% versus 43%), High-Frequency Oscillatory
however, suggesting that their clinicians Ventilation
may have considered them less ill than were
controls. In addition, the duration of oxygen HFOV, a technique of rapid ventilation with
requirement was significantly associated very small tidal volumes, reduces lung
with colloid infusion. injury in animal models compared with
conventional ventilation. Nearly all trials
Minimal Ventilation comparing HFOV with conventional venti-
lation performed in preterm infants at risk
Ventilation with high tidal volumes results in for the disorder since surfactant replace-
mechanical injury to the lung. Mechanical ment therapy has been available show no
ventilation with small tidal volumes and effect on the rate of BPD.92,123-126
target goals of modest permissive hypercap- In one trial in 500 preterm infants, 601
nia (PCO2 50 to 55 mm Hg) may protect the to 1,200 g birth weight, the proportion of
lung from mechanical injury. The benefit infants who survived without BPD was
of permissive hypercapnia has not been slightly greater with HFOV (56% versus
shown definitively in newborns at high risk 47%).91 This study was performed in centers
for BPD, although additional studies are experienced in the use of HFOV and fol-
needed.90,122,123 In one trial, infants with lowed strict protocols for management. Sim-
birth weight 501 to 1,000 g requiring ilar results may not be achieved at centers
mechanical ventilation before 12 hours of with less experience or without strict proto-
age were randomly assigned to minimal ven- cols.92,127 It is recommended that conven-
tilation (target PCO2 >52 mm Hg) or routine tional ventilation with low tidal volumes
ventilation (PCO2 <48 mm Hg) and a course and modest hypercapnia, rather than HFOV,
of dexamethasone or placebo.90 The trial was be employed as the initial mode of mechan-
stopped after enrollment of 220 infants ical ventilation for most preterm infants.127
Vitamin A development of BPD at 36 weeks PMA and

the need for oxygen supplementation at 28
Extremely preterm infants may have vita- postnatal days, and promoted earlier extuba-
min A deficiency, which may promote the tion, compared with control.113,131 Survival
development of BPD. Possible mechanisms did not improve with treatment, however.
include impaired lung healing, increased In addition, systemic corticosteroid use was
squamous cell metaplasia, reduced alveolar associated with short-term adverse effects,
number, increased susceptibility to infec- including hypertension, hyperglycemia, poor
tion, and increased loss of cilia.128 Supple- growth, and gastrointestinal bleeding and
mentation with vitamin A reduces the risk perforation.113,131
of BPD in susceptible infants. Systematic reviews of long-term outcome
In the largest trial, 807 infants with birth (4 years of age) suggest that postnatal dexa-
weight 401 to 1,000 g who received mechan- methasone use increases neurodevelop-
ical ventilation or supplemental oxygen at mental delay and cerebral palsy.115,116,132,133
24 hours of age were randomly assigned to A review that included nine randomized con-
receive 5000 IU vitamin A intramuscularly trolled trials of postnatal corticosteroids ad-
three times per week for 4 weeks or a ministered within the first week of life found
sham injection.128 The combined outcome that the risk of cerebral palsy was greater
of death or BPD (oxygen requirement at 36 among surviving infants who were treated
weeks PMA) occurred significantly less often compared with controls (24% versus 14%, rel-
in the vitamin A group compared with con- ative risk 1.75, 95% confidence interval 1.25
trol group (55% versus 62%). No clinical or to 2.44).116 A potential problem in the inter-
biochemical evidence of vitamin A toxicity pretation of these results is that many infants
was detected. In a subsequent study of the enrolled in trials of corticosteroids were trea-
original cohort, vitamin A supplementation ted with dexamethasone by their clinicians
did not differ from placebo in reduc- in addition to the study drug (open-label treat-
ing hospitalizations or pulmonary prob- ment).132 Children who participated in one of
lems after discharge from the nursery.129 In the trials134 included in the above-mentioned
addition, at a corrected age of 18 to 22 systematic reviews115,116,132,133 were evalu-
months, there were no differences in mor- ated at school age.135 Among the original
tality or neurodevelopmental impairment cohort of 262 infants, 159 survived to school
between the treated and nontreated infants. age, and 146 were included in follow-up
Some clinicians provide supplemental vita- (evenly distributed between treatment and
min A (5000 IU intramuscularly three times control groups). Clinically significant dis-
per week for 4 weeks) to infants 1,000 g abilities (motor skills, coordination, visual
birth weight who require ventilatory support motor integration, and IQ) were more com-
within 24 hours after birth. The decision to mon among children from the treatment
treat may depend on a balance of factors, group (39% versus 16%). Differing rates of dis-
such as the local incidence, the value of a ability persisted when the children who
modest decrease in BPD, and the need for received open-label dexamethasone treat-
repeated intramuscular injections.130 ment were excluded from the analysis (41%
versus 21%).
Systemic Corticosteroids Even when administered in low doses or
when other agents aside from dexametha-
Administration of systemic corticosteroids sone are used, systemic corticosteroids are
reduces the risk of BPD. Routine use of cortico- associated with serious adverse effects. In a
steroid therapy is not recommended, how- multicenter trial, mechanically ventilated
ever, because there are concerns about ELBW infants were randomly assigned to
significant short-term and long-term adverse hydrocortisone therapy or placebo to deter-
effects. In systematic reviews by the Cochrane mine whether prophylaxis of early adrenal
database, treatment with corticosteroids insufficiency affected clinical stability and
(usually dexamethasone) before 96 hours of incidence of BPD.136 Infants receiving hy-
age or at 7 to 14 days of age reduced the drocortisone were treated with 1 mg/kg/day
for 12 days and then 0.5 mg/kg/day for birth weight 1,250 g who were mechani-
3 days. Enrollment was discontinued early cally ventilated at 3 to 14 days of age were
because of an increase of spontaneous gas- randomly assigned to a 4-week course of
trointestinal perforation in the hydrocor- beclomethasone (tapering dose of 40 mg/kg/
tisone group (9% versus 2%). Overall day to 5 mg/kg/day) or placebo.137 The need
survival without BPD did not differ between for supplemental oxygen at 28 days (43% ver-
groups. sus 45%) and 36 weeks PMA (18% versus 20%)
Although most of the data show the neg- was similar in the beclomethasone and pla-
ative impact of corticosteroids, with risk of cebo groups. Beclomethasone significantly
short-term and long-term adverse effects reduced the rate of systemic corticosteroid
including impaired neurodevelopmental use (relative risk 0.8) and mechanical ventila-
outcomes, it remains unclear whether there tion (relative risk 0.8) at 28 days of age. No
is a potential role for corticosteroids in adverse effects were observed. In a separate
selected populations. In the meta-analysis report from the same trial, beclomethasone
described earlier,116 there was a significant therapy was associated with slightly lower
negative correlation between the corticoster- median basal cortisol levels (5 mg/dL versus
oid effect on combined outcome of death 6 mg/dL) compared with placebo, but similar
and cerebral palsy and the rate for BPD in response to cosyntropin stimulation.138
the control groups. The rate of BPD was
used as a marker for the risk for BPD and
was not a variable available at trial entry. Inhaled Nitric Oxide
This relationship suggests that in a popula-
tion of preterm infants at high risk for Inhaled nitric oxide (iNO) is used in the
BPD, corticosteroid therapy may decrease management of term neonates with hy-
the risk of death or cerebral palsy. At pres- poxic respiratory failure, but little is known
ent, the American Academy of Pediatrics about the effects of iNO in the preterm pop-
and the Canadian Pediatric Society recom- ulation. Multiple physiologic effects of
mend that dexamethasone should not be nitric oxide are known. Exposure to chronic
used routinely in VLBW infants to treat or hypoxemia leads to remodeling that
prevent chronic lung disease because of its includes increased proliferation of pulmo-
limited short-term benefits, no apparent nary vascular smooth muscle, leading to
long-term benefits, and substantial risk of increased pulmonary vascular pressures,
short-term and long-term complications.115 and eventual right ventricular hypertrophy
They further recommend that dexametha- and cor pulmonale. Several animal studies
sone use should be limited to controlled have shown that iNO prevents or amelio-
trials. Outside of a trial, corticosteroids rates this remodeling of the pulmonary vas-
should be used only in exceptional clinical cular bed.139-142 Of particular concern is the
circumstances, such as an infant who effect of iNO on coagulation; iNO is known
requires maximal ventilatory and oxygen to increase bleeding time in adult patients,
support. In this case, the parents should be presumably via a cyclic guanosine mono-
made aware of potential risks and agree to phosphate–dependent mechanism causing
treatment. platelet dysfunction.143,144 In a preterm
infant already at risk for intraventricular
hemorrhage, this complication would add
Inhaled Corticosteroids significant long-term morbidity.
Several studies of the use of iNO in pre-
In a systematic review and meta-analysis by term neonates have been conducted, and
the Cochrane database, early postnatal several included BPD as an outcome.145-149
administration of inhaled corticosteroids A Cochrane systematic review and meta-
did not prevent BPD, but was associated analysis has shown that the use of iNO in
with lower rates of systemic corticosteroid infants less than 35 weeks of age does not
treatment.117 In the largest trial, 253 infants show any benefit in terms of survival with-
with gestational age less than 33 weeks and out BPD; there also is a trend toward an
increase in the combined outcome of severe found in the rate of oxygen dependence at
intraventricular hemorrhage or periventri- 28 postnatal days or 36 weeks PMA.154 At 1
cular leukomalacia.150 year of age, infants who received rhSOD had
less respiratory illness, however. Growth
and neurodevelopmental status were similar.
Caffeine
Caffeine has been shown to reduce the fre- Summary

quency of apnea of prematurity and the need
for mechanical ventilation.151 A study of Multiple strategies are needed to prevent
1917 infants with birth weight 500 to 1,250 g BPD in high-risk patients.
showed that the rate of BPD (a secondary out- • Although antenatal corticosteroids do not
come) in infants treated with caffeine was sig- affect the incidence of BPD, they reduce
nificantly lower than in the placebo group the risk of RDS and intraventricular hem-
(36% versus 47%).151 The rates of adverse orrhage, and improve survival in preterm
outcomes—specifically death, brain abnor- infants. Antenatal corticosteroids should
malities by head ultrasonography, and necro- be given to pregnant women at high risk
tizing enterocolitis—were not different for preterm delivery.
between the two groups. This cohort has been • Excessive fluid administration should be
followed to assess the primary outcome mea- avoided in ELBW infants, and fluids
sure, which is the combined rate of mortality should be restricted to minimize the
and neurodevelopmental disability in survi- development of pulmonary edema. Use
vors at a corrected age of 18 to 21 months, of colloid infusions should be avoided.
and the authors more recently reported • Conventional ventilation with low tidal
improved survival without neurodevelopmen- volumes and reasonable ventilation goals
tal disability in the caffeine-treated group.152 (initially, PaCO2 50 to 55 mm Hg) should
Neurodevelopmental outcomes in this cohort be used in preterm infants with respira-
also will be followed up at 5 years of age. tory failure in most cases. In centers expe-
rienced with the technique, HFOV may be
an appropriate alternative.
Superoxide Dismutase • Optimal nutrition should be provided to
Preterm infants may have inadequate anti- promote somatic and lung growth.
oxidant defense because of nutrient defi- Administration of supplemental vitamin
ciencies or immature enzyme development. A (5000 IU intramuscularly three times
Postnatal administration of antioxidants per week for 4 weeks) to ELBW infants
such as superoxide dismutase may protect who require early respiratory support
against oxidant injury, although additional should be considered.
evidence is needed. In one study performed • Routine use of postnatal dexamethasone
after replacement surfactant became avail- should be avoided.
able, 33 infants with birth weight 700 to • Use of iNO to prevent BPD should await
1,300 g who were mechanically ventilated publication of follow-up studies.
for RDS were randomly assigned to intra- • Caffeine decreases the rate of BPD in infants
tracheal administration of recombinant 500 to 1,250 g, without neurodevelopmen-
human copper/zinc superoxide dismutase tal sequelae at 18 to 21 months of age.
(rhSOD) (2.5 mg/kg or 5 mg/kg) or saline
every 48 hours while they remained intu-
bated, for up to seven doses.153 Clinical Outcome
outcomes did not differ between groups.
Tracheal aspirate inflammatory markers Mortality
(neutrophil chemotactic activity, albumin
concentration) were lower, however, in the Infants with severe BPD have a higher risk
rhSOD groups than in the control group. In of mortality than unaffected infants or
a larger multicenter trial, no difference was infants with mild disease. Death usually is
caused by respiratory failure, unremitting history of BPD had findings consistent with
pulmonary hypertension with cor pulmo- airflow obstruction and air trapping. In
nale, or sepsis. The risk of mortality another study, 39 preterm infants (mean
increases with the duration of mechanical gestational age 29.8 weeks) with BPD had
ventilation. In one report, among 47 infants serial measurements of pulmonary function
mechanically ventilated for more than 27 from 1 to 36 months of age.163 Compared
days, 20 died.155 In another study of 144 with normal controls, infants with BPD
newborns who required prolonged mechan- had evidence of decreased pulmonary func-
ical ventilation after birth, death occurred in tion that remained fairly constant up to 6
35% and 90% of infants ventilated for months of age, and steadily improved by
2 months and more than 4 months.156 At the 36-month follow-up. All of these infants
30 days of age, the mean airway pressure still had mildly reduced pulmonary func-
and a diagnosis of bacterial sepsis during tion parameters (approximately 85% of nor-
the previous month were significant predic- mal) at the 36-month follow-up. These
tors of mortality. In patients who still findings are consistent with formation of
required ventilation at 60 days of age, mean new alveoli in early infancy, leading to
airway pressure and oxygen concentration improved compliance. Airway growth is
were the best predictors. slow during the first 6 months after birth,
but subsequent faster growth results in
improved conductance.
Respiratory Infections
Late Childhood
Infants with BPD are at increased risk In some patients, abnormal pulmonary func-
for respiratory infections, including respiration persists through later childhood. In one
tory syncytial virus (RSV), which may be study, children 11 years old who had BPD
life-threatening.157 Episodes of wheezing had diminished airflow and higher residual
that suggest bronchiolitis or asthma also volume compared with controls, but few
are common before 2 years of age.158 Respi- had abnormalities that were clinically signif-
ratory illnesses contribute to high rates of icant.164 Similar findings were noted in a
rehospitalization, especially in the first year small but more contemporary series of
of life.159-161 In one report, infants with patients with moderate to severe BPD, of
BPD were rehospitalized more often during whom most had pulmonary function testing
the first year (58% versus 35%) and more at 24 months of age and at a mean of 8.8
likely to be readmitted for respiratory illness years.165,166 Among 18 children, 15 had mild
(39% versus 20%) than controls.159 to severe airflow limitation, with mean
forced expiratory volume in 1 second
Pulmonary Function (FEV1) and forced mid-expiratory flow (FEF
25%-75%) less than 60% of predicted in 4
Early Childhood and 9 children. Abnormalities in childhood
Infants with severe BPD may have abnormal correlated with reduced maximal airflow
pulmonary function tests for many years, values at functional residual capacity (FRC)
even though some are asymptomatic.158 measured in infancy. Most children had no
Pulmonary function normalizes in early signs of airway obstruction, although three
childhood in most cases, however, espe- had reduced exercise tolerance, and one used
cially in infants with milder disease. In one medication for asthma-like symptoms.
study, 28 children (<3 years old) with a his-
tory of prematurity (mean gestational age Neurodevelopment
26.4 weeks, mean birth weight 898 g) and
BPD underwent routinely scheduled infant Infants with severe BPD are at increased risk
lung testing at a mean age of 68 weeks.162 for neurodevelopmental sequelae. In a large
Compared with a previously studied group cohort of ELBW infants cared for in the
of healthy term infants, infants with a centers of the NICHD Neonatal Research
Network and evaluated at 18 to 22 months Growth

corrected age, BPD was a significant risk fac-
tor for abnormal neurologic examination and The effect of BPD on long-term growth is
scores less than 70 (>2 standard deviations uncertain. Poor growth of infants with BPD
below the mean) on the mental development was seen in some follow-up studies, although
index and psychomotor development index others have shown no difference from unaf-
scales of the Bayley Scales of Infant Develop- fected infants. One study followed 20 pre-
ment.167 In a separate study, follow-up at 3 term infants with BPD for 2 years after term
years of age showed that significantly more PMA.173 The infants were severely growth
VLBW infants with BPD had scores less than restricted at term, with the average weight
70 for the mental development index (21% and height less than or equal to the 3rd per-
versus 11% and 4%) and psychomotor devel- centile. Growth accelerated as respiratory
opment index (20% versus 9% and 1%) com- symptoms improved. At 2 years, weight for
pared with control groups of unaffected boys and girls was 3rd to 10th percentile,
VLBW infants and term infants.168 In another and height was 10th to 25th percentiles for
report from the same center, children with boys and girls respectively. In another series
BPD had poorer receptive and expressive lan- of 16 affected children evaluated at 2 years,
guage skills at 3 years old compared with height and weight were less than 10th per-
controls.169 centile in 37% and 25%, respectively.174
The effect of BPD on outcome persists In other reports, BPD does not seem to
through school age. In one study, VLBW affect growth at 8 to 10 years of age, which
infants with BPD tested at 8 to 10 years old might be influenced more by factors other
scored poorest on all eight measures of cog- than respiratory disease, such as low birth
nitive performance compared with control weight.172,175 In one report, infants with
groups of term and unaffected VLBW in- BPD were significantly smaller than unaf-
fants.170 In another report, neuromotor out- fected infants.175 After adjustment for con-
come was evaluated at approximately 10 founding variables, however, no significant
years of age in children who had severe BPD differences were detected.
and required home oxygen therapy and was
compared with neuromotor outcome of un-
affected preterm controls.171 Neurologic Tracheobronchomalacia
abnormalities, including subtle neurologic
signs, cerebral palsy, microcephaly, and behav- Abnormalities of the trachea and bronchi
ioral problems, were significantly more preva- always must be considered in infants with
lent in the BPD group (71% versus 19%). BPD who remain persistently ventilator-
More than half of the BPD group had abnor- dependent.176 Depending on the series,
malities of gross or fine motor skills or both. 16% to 50% of infants with BPD show
When interpreting follow-up studies such evidence of tracheobronchomalacia at bron-
as the above-cited studies, many factors choscopy.177-180 Owing to acute collapse of
influence outcome, including incidence of the airways, leading to a marked increase
neurologic risk factors (e.g., cranial ultra- in total airway resistance and decreased air-
sound abnormalities), neurosensory prob- flow, infants can experience life-threatening
lems (e.g., retinopathy of prematurity, episodes that are characterized by extreme
hearing impairment), hospital course, and difficulty in ventilation.176 The use of bron-
poor social environment. In one study, chodilators generally worsens or prolongs
infants with BPD evaluated at 8 years had these episodes.
significantly poorer psychoeducational and Acquired tracheobronchomalacia is dif-
school performance test scores than con- ferentiated clinically from congenital tra-
trols.172 Most variance in academic achieve- cheobronchomalacia by a history of airway
ment was attributed to the lowest recorded intubation and mechanical ventilation. Other
pH or PaO2 and the father’s socioeconomic lesions that cause airway compression, such
status. as vascular rings, hypertensive enlarged
pulmonary arteries, and hyperinflated lobes, only inspiratory stridor. Postextubation stri-
must be ruled out. Acquired tracheobron- dor is a significant marker for the presence
chomalacia in CLDI has been attributed to of moderate to severe subglottic stenosis or
barotrauma, chronic or recurrent infection, laryngeal injury.
and local effects of artificial airways. The Risk factors for laryngeal injury include
immature trachea is a highly compliant struc- intubation for 7 days or more and three or
ture that undergoes progressive stiffening more intubations.186 These same factors also
with age.181 These changes seem to parallel are associated with acquired subglottic ste-
changes in cartilage mechanics, rather than nosis. Use of inappropriately large endotra-
passive properties of tracheal smooth muscle. cheal tubes also is an important risk factor
Infants with abnormal central airway col- for the development of subglottic stenosis.
lapse may be asymptomatic at rest or have A tube size-to-gestational age (in weeks)
wheezing, often unresponsive to broncho- ratio greater than 0.1 has been correlated
dilator therapy. Wheezing becomes promi- with acquired airway obstruction.187
nent with increased expiratory effort, and
cyanotic spells may result. Tracheal Stenosis, Bronchial
One treatment modality available after this Stenosis, or Granuloma Formation
diagnosis is made is CPAP via nasopharyn-
geal, endotracheal, or tracheostomy tube.182 Acquired tracheal and bronchial stenosis or
Zinman has shown that by providing suffi- granuloma formation has been reported in
cient CPAP to prevent collapse of the affected infants with CLDI 3 weeks to 17 months
segment, dynamic lung compliance is in- old.180 Endoscopic findings consist of airway
creased, and airway resistance is decreased.183 narrowing or obstruction by thickened respi-
ratory mucosa or circumferential nodular or
Glottic and Subglottic Damage polypoid granulations in the distal trachea,
often extending into main bronchi.188
Endotracheal intubation has been associated Stenosis and granulation formation may
with injury to supraglottic, glottic, subglottic, not be complications of CLDI per se, but
and tracheal tissues in newborns.184-185 Some instead may be the result of extended endo-
degree of epithelial damage after endotracheal tracheal intubation and vigorous suctioning
intubation is common, ranging from focal techniques. Because these lesions tend to
epithelial necrosis over the arytenoid or cri- occur in the distal trachea and right-sided
coid cartilages or vocal cords to extensive bronchi, repeated mucosal injury from suc-
mucosal necrosis of the trachea. Because tion catheters has been implicated as the
superficial lesions seen at the time of extuba- likely mechanism.
tion often resolve without sequelae, early Acute mucosal injury to the carina and
endoscopy after tracheal extubation overesti- main bronchi occurs from unrestricted or
mates the possibility of long-term damage. “deep” suctioning.189 The size of the catheter
The relationship between acute laryngeal or should be small enough (usually 5F to 6F in
subglottic damage and development of newborns) so as not to occlude the artificial
acquired subglottic stenosis is unclear. airway completely, avoiding excessive nega-
Acquired subglottic stenosis has been tive pressure.190 Catheters with multiple side
reported to occur in about 10% of previ- holes on several planes are less likely to cause
ously intubated neonates. Clinical manifes- invagination of airway mucosa into the cath-
tations include postextubation stridor, eter than catheters with single side or end
hoarseness, apnea, and bradycardia; failure holes. Use of negative pressures greater than
to tolerate extubation; and cyanosis or pal- 50 to 80 cm H2O increases the likelihood of
lor. Similar manifestations can result from mucosal damage and does not increase the
vocal cord injuries, glottic or subglottic cysts efficiency of secretions removal.191 The most
or webs, laryngomalacia, or extrathoracic important preventive measure is to limit pas-
tracheomalacia. Fixed lesions of the glottis sage of the suction catheter to the distal tip
and subglottis often produce biphasic stri- of the artificial airway, so that the airway
dor, whereas variable lesions usually cause mucosa is protected from injury.192
Monitoring occlusion, to assess the severity of pulmo-

nary hypertension, to test the reactivity to
Infants with BPD need close monitoring to oxygen or vasodilators, and to assess for
minimize further lung injury, reduce the development of large systemic-pulmonary
risks of pulmonary and systemic hyperten- collaterals.196 Systemic blood pressure
sion, and promote adequate growth and should be monitored routinely because of
development. This monitoring should begin the risk of systemic hypertension.191,192
during hospitalization and continue after Systemic hypertension should be treated if
discharge. it is detected.
Cardiovascular Monitoring Growth

and Oxygenation
As previously noted, nutrition is an impor-
The pulmonary circulation in infants with tant component of the care of infants with
BPD has structural, functional, and anatomic CLD. Hospitalized infants should be
abnormalities.189,190 Structural alterations weighed two to three times per week, and
include smooth muscle hyperplasia, increased length and head circumference should be
fibroblast incorporation, and adventitial measured weekly. Biochemical monitoring,
thickening. Functional abnormalities include including measurement of blood urea nitro-
impaired vasodilation and increased hypoxic gen, albumin, calcium, phosphorus, and
vasoconstriction. Anatomic changes include alkaline phosphatase, may assist with nutri-
decreased total blood vessel mass and de- tional assessment. Serum electrolytes should
creased total surface area. These changes be followed in infants on diuretic therapy,
can result in pulmonary arterial and systemic and supplements should be provided as
arterial hypertension, eventually leading to needed. Infants who exhibit oromotor dys-
right and left ventricular hypertrophy.193 function or other feeding disorders inhibit-
The major approach to avoid or treat pulmo- ing growth should be evaluated and receive
nary hypertension is maintaining adequate specific intervention.
oxygenation, although pharmacologic treat-
ment may be required in severe cases.189,190
Generally, in infants with severe BPD who do Development, Vision, and Hearing
not have pulmonary hypertension, oxygen
saturations are maintained greater than 92%; As discussed previously, infants with BPD
in infants with pulmonary hypertension, generally have poorer neurodevelopmental
saturations are maintained higher (94% to outcomes than unaffected infants.168 Devel-
96%).194 opmental assessment should begin while
Serial echocardiographic screening for pul- the infant is still hospitalized and continue
monary arterial hypertension is recom- on a regular basis after discharge. Infants
mended in premature infants with BPD who should have serial eye examinations to
have gestational age at birth of less than or detect retinopathy of prematurity or other
equal to 25 weeks or birth weight less than eye disorders, and receive appropriate inter-
or equal to 600 g, small for gestational age, vention. Routine hearing screening should
requirement for prolonged mechanical be done to detect impairment, with early
ventilation, oxygen requirement out of pro- intervention by an audiologist if needed.
portion to the severity of lung disease, or
persistent poor growth despite adequate
caloric intake.195 A pediatric cardiologist Coordination of Care and
should follow patients with pulmonary Discharge Planning
arterial hypertension. Cardiac catheteriza-
tion may be recommended for patients Infants with severe BPD usually have a pro-
with severe pulmonary hypertension to longed hospitalization and require substan-
rule out anatomic cardiac disease, pulmo- tial planning for discharge to home and
nary vein stenosis, or pulmonary vein postdischarge care. Discharge should be
planned by a multidisciplinary care team 11. Ehrenkranz RA, et al: Validation of the National
Institutes of Health consensus definition of bron-
that ideally includes individuals with skills chopulmonary dysplasia. Pediatrics 116:1353-
in neonatology, pulmonology, nursing, 1360, 2005.
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sia. Am J Respir Crit Care Med 163:1723-1729,
nutrition, physical and occupational ther- 2001.
apy, and, if needed, audiology. This team 13. Walsh MC, et al: Safety, reliability, and validity of
can ease the transition from the hospital to a physiologic definition of bronchopulmonary
dysplasia. J Perinatol 23:451-456, 2003.
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the rest of the family. Depending on the tion on bronchopulmonary dysplasia rates. Pedi-
severity of CLDI, some infants may be dis- atrics 114:1305-1311, 2004.
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charged home on supplemental oxygen or, of the National Institute of Child Health and
rarely, on mechanical ventilation. Parents Human Development Neonatal Research Net-
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NICHD Neonatal Research Network. Pediatrics
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ary dysplasia rates between 1994 and 2002.
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ary dysplasia on growth at school age. Pediatrics acquired subglottic stenosis in infants. J Pediatr
95:855-859, 1995. 109:322-327, 1986.
176. Doull IJM, Mok Q, Tasker RC: Tracheobronchoma- 188. Grylack LJ, Anderson KD: Diagnosis and treat-
lacia in preterm infants with chronic lung disease. ment of traumatic granuloma in tracheobronchial
Arch Dis Child Fetal Neonatal Ed 76:F203-F205, tree of newborn with history of chronic intuba-
1997. tion. J Pediatr Surg 19:200-201, 1984.
177. Downing GJ, Kilbride HW: Evaluation of airway 189. Brodsky L, Reidy M, Stanievich JF: The effects of
complications in high-risk preterm infants: appli- suctioning techniques on the distal tracheal
cation of flexible fiberoptic airway endoscopy. mucosa in intubated low birth weight infants.
Pediatrics 95(4):567-572, 1995. Int Ped Otorrrhinolaryngol, 14:1-14, 1987.
178. Greenholz SK, et al: Surgical implications of 190. Hodge D: Endotracheal suctioning and the infant:
bronchopulmonary dysplasia. J Pediatr Surg a nursing care protocol to decrease complications.
22(12):1132-1136, 1987. Neonatal Netw, 77:202-207, 1991.
179. Lindahl H, et al: Bronchoscopy during the first 191. Kuzenski BM: Effect of negative pressure on tra-
month of life. J Pediatr Surg 27(5):548-550, 1992. cheobronchial trauma. Nurs Res, 27:260-263,
180. Miller RW, et al: Tracheobronchial abnormalities 1978.
in infants with bronchopulmonary dysplasia. 192. Runton N: Suctioning artificial airways in chil-
J Pediatr 111(5):779-782, 1987. dren: appropriate technique. Pediatr Nurs 18:
181. Shaffer TH, Bhutani VK, Wolfson MR, et al: In vivo 115-118, 1992.
mechanical properties of the developing airway. 193. Malnick G, et al: Normal pulmonary vascular
Pediatr Res 25:143-146, 1989. resistance and left ventricular hypertrophy in
182. Panitch HB, Allen JL, et al: Effects of CPAP on lung young infants with bronchopulmonary dysplasia:
mechanics in infants with acquired tracheo- an echocardiographic and pathologic study. Pedi-
bronchomalacia. Am J Resp Crit Care Med 150: atrics 66(4):589-596, 1980.
1341-1346, 1994. 194. Kotecha S, Allen J: Oxygen therapy for infants
183. Zinman R: Tracheal stenting improves airway with chronic lung disease. Arch Dis Child Fetal
mechanics in infants with tracheobronchomala- Neonatal Ed 87(1):F11-4, 2002.
cia. Pediatr Pulmonol 19(5):275-281, 1995. 195. Abman SH: Monitoring cardiovascular function in
184. Strong RM, Passy V: Endotracheal intubation: infants with chronic lung disease of prematurity.
complications in neonates. Arch Otolaryngol Arch Dis Child Fetal Neonatal Ed 87(1):F15-8,
103:329-335, 1977. 2002.
185. Fan LL, Flynn JW, et al: Predictive value of stridor 196. Apkon MNR, Lister G: Cardiovascular abnormal-
in detecting laryngeal injury in extubated neo- ities in BPD, in Chronic Lung Disease of Infancy.
nates. Crit Care Med 10:453-455, 1982. Bland RD, Coalson JJ, Eds. Marcel Dekker: New
186. Fan LL, Flynn JW, et al: Risk factors predicting York p. 321-356, 2000.
laryngeal injury in intubated neonates. Crit Care
Med 11:431-433, 1983.
CHAPTER 2
Pulmonary Manifestations of
Human Immunodeficiency Virus
(HIV) Infection
HEATHER J. ZAR AND MICHAEL R. BYE
Epidemiology 28 Chronic Pulmonary Infections 42

Pathogenesis 29 Immune Reconstitution Inflammatory
Acute Respiratory Infections 29 Syndrome 42
Bacterial Pneumonia 30 Bronchiectasis 43
Mycobacterial Infection 32 Malignancy 43
Viral Infection 35 Diagnostic Evaluation of an HIV-1-
Pneumocystis Infection 37 Infected Child with Pulmonary
Fungal Infection 40 Manifestations 43
Chronic Lung Disease 41 Summary 44
Lymphocytic Interstitial Pneumonia 41 References 44
Interstitial Pneumonitis 42
Respiratory complications in children in- pneumonia-specific mortality rates are three

fected with human immunodeficiency virus to six times higher than the rates of HIV-1-
(HIV) are common and responsible for sub- negative patients.4
stantial morbidity and mortality.1 With The burden of HIV-associated respiratory
advances in diagnostic, therapeutic, and disease in developing countries often occurs
preventive strategies for HIV, the spectrum in the context of existing high rates of
of childhood respiratory disease has childhood pneumonia, poverty, coexisting
changed. In developed countries, programs malnutrition, suboptimal immunization
to prevent perinatal HIV-1 transmission, coverage, and under-resourced or inacces-
early diagnosis of HIV-1 infection in infants, sible health care facilities. HIV-infected chil-
and use of Pneumocystis prophylaxis and dren have a higher risk of respiratory
highly active antiretroviral therapy (HAART) infections and diseases and of more severe
have led to a substantial decline in pediatric illness compared with immunocompetent
HIV incidence and associated respiratory children. Increasing evidence also suggests,
infections.2 In contrast, the major burden however, that HIV-exposed but uninfected
of pediatric HIV now exists in developing children also are at greater risk of respiratory
countries.3 In these areas, acute and chronic infections and illnesses compared with chil-
HIV-associated respiratory disease remain a dren born to uninfected mothers.
major cause of childhood morbidity and
mortality.1,4 This situation is compounded
by limited access to appropriate health care Epidemiology
and antiretroviral therapy. In the absence of
HAART, 90% of HIV-1-infected children may Globally, there are approximately 33.2 mil-
develop a severe respiratory illness sometime lion HIV-1-infected individuals, of whom 2.5
in the course of their HIV disease.1,4 Pneumo- million are children younger than 15 years
nia is the most common cause of hospita- old.3 Most of these HIV-1-infected children—
lization in African HIV-1-infected children; almost 2.2 million—reside in sub-Saharan
28
Chapter 2 — Human Immunodeficiency Virus (HIV) Infection 29
Africa.3 In 2006, there were an estimated The primary target cell of HIV-1 is the
420,000 new HIV-1 infections in children human CD4þ lymphocyte. The HIV-1
(370,000 in sub-Saharan Africa) and approx- gp120 envelope protein binds to the CD4þ
imately 330,000 childhood deaths from molecule on the host cell membrane with
HIV-1 (290,000 in sub-Saharan Africa).3 Con- high affinity. This binding allows the virus
versely, in the last decade in developed to enter the T cell and to integrate its genome
countries, the number of HIV-infected into the host DNA. HIV-1 also infects mono-
children has greatly declined because of a cytes and macrophages but with less marked
dramatic reduction in perinatal HIV trans- cytopathic effects. Infected monocytes serve
mission.2 New cases of HIV-1 infection in as a reservoir for HIV-1, allowing further
children in developed countries occur pre- spread of the virus throughout the body.5
dominantly in adolescents secondary to Infection with HIV-1 results in progressive
sexual transmission; most adolescents depletion of the CD4þ helper lymphocytes.
remain asymptomatic until adulthood.2 This depletion serves as a marker of the sever-
HIV-1 infection and AIDS have dispropor- ity of HIV-1 infection because the incidence
tionately affected minority populations in of opportunistic infections and other compli-
the United States. cations correlates with the number and per-
Most new HIV-1 infections in children centage of CD4þ lymphocytes, particularly
occur through perinatal transmission in utero, in children older than 1 year.6
intrapartum, or through breastfeeding. Breast- The ability to produce cytokines, such as
feeding may account for 40% of infants interleukin-2 and interferon-, is progres-
becoming infected after delivery, especially sively lost in HIV-1-infected children. Natu-
in developing countries, where mothers con- ral killer cell–mediated cytotoxicity also is
tinue to breastfeed for prolonged periods or reduced in HIV-1-infected children. In addi-
mixed feeding is introduced early. tion, B cell dysfunction with defective
The impact of HIV-1 on children is com- humoral immunity further predisposes to
pounded by maternal HIV-1 infection. Infec- severe infection.7
tion rates in African women are two to five
fold higher than in men, with women of
childbearing age most affected.3 In many Acute Respiratory Infections
countries in sub-Saharan Africa, more than
20% of pregnant women are HIV-1-infected. Respiratory infection was the most common
As a result, many HIV-1-exposed children cause of death in children younger than 6
may be cared for by ill mothers, and other years of age in a U.S. cohort of HIV-1-
caregivers, or be orphaned. Maternal illness infected children in the pre-HAART era; the
and inability to work exacerbates the cycle of frequency of pulmonary disease as a cause
poverty and child illness. Children living in of death was greatest in infants, with 56%
sub-Saharan Africa are particularly vulnerable of respiratory-related deaths occurring
to HIV-1-associated illness because access to within the first year of life.8 The rate of
antiretroviral therapy and appropriate medi- acute respiratory infections and opportunis-
cal care may be very limited or unaffordable. tic infections has decreased dramatically
with the use of HAART (Table 2-1).5-9 Before
HAART, bacterial pneumonia, Pneumocystis
pneumonia (PCP), disseminated Mycobacte-
Pathogenesis rium avium-intracellulare complex (MAC),
and tracheobronchial candidiasis were the
HIV-1 is a retrovirus, belonging to a group of most frequent respiratory infections, occur-
heterogeneous, lipid-enveloped RNA viruses. ring at an event rate of more than 1 per
Another retrovirus, HIV-2, is relatively rare 100 child-years; these all have declined
and causes a less severe AIDS-like syndrome. substantially with HAART (see Table 2-1).5,9
HIV-1 has two major viral envelope pro- Although the frequency of bacterial infec-
teins—the external glycoprotein gp120 and tions has declined substantially, pneumonia
the transmembrane glycoprotein gp41. or secondary respiratory failure remains the
Table 2-1 Impact of HAART on Opportunistic Respiratory Infections
INFECTION PRE-HAART RATE9 POST-HAART RATE5

Incidence Rate per 95% CI Incidence Rate per 95% CI
100 Child-Years 100 Child-Years
PCP 1.3 1.1-1.6 0.1 0.04-0.2
Bacterial pneumonia 11.1 10.3-12.0 2.2 1.8-2.6
Bacteremia 3.3 2.9-3.8 0.4 0.2-0.5
Disseminated MAC 1.8 1.5-2.1 0.1 0.1-0.3
Tracheobronchial or esophageal 1.2 1.0-1.5 0.1 0.03-0.2
candidiasis
CI, confidence interval; HAART, highly active antiretroviral therapy; MAC, Mycobacterium avium-intracellulare complex; PCP,
Pneumocystis pneumonia.
predominant cause of death in children HIV-1 infection has been associated with
receiving HAART, accounting for 27% of an increase in the antimicrobial resistance
deaths.5 In children not receiving HAART patterns of bacterial pneumonia, with impli-
or children resistant to antiretroviral ther- cations for empiric antibiotic therapy.11
apy, acute respiratory infections are com- Methicillin-resistant S. aureus (MRSA) has
mon, often severe, and the most frequent increasingly emerged as a pathogen in HIV-
cause of hospitalization or death. Bacteria, 1-infected children.16 Data on the preva-
mycobacteria, viruses, Pneumocystis, or fungi lence of penicillin-resistant pneumococcal
may cause respiratory infections; mixed infection are variable, but no clear differ-
infections also commonly occur (Table 2-2). ences in clinical outcome for susceptible
and resistant strains have been shown except
Bacterial Pneumonia for isolates with high-level resistance.21
Etiologic diagnosis of bacterial pneumonia
Before HAART, bacterial pneumonia was the is difficult because signs are nonspecific, coin-
most common serious infection in HIV-1- fection with more than one organism occurs
infected children with an event rate of 11 frequently, and culture of upper respiratory
per 100 child-years9; this rate has declined tract secretions or sputum may reflect coloni-
to 2.2 in the HAART era (see Table 2-1).5 zation rather than pathogenic organisms.
Pneumonia, particularly caused by Streptococ- Blood culture, may be useful because of
cus pneumoniae, Haemophilus influenzae type higher rates of bacteremia, occurring in ap-
b, and Staphylococcus aureus, is a major cause proximately 15% of HIV-1-infected children
of hospitalization and death in children hospitalized for pneumonia.11,16 Empiric
in developing countries.10-12 S. pneumoniae therapy for pneumonia should include
is the most important bacterial pathogen in broad-spectrum antibiotics, based on the local
HIV-1-infected and uninfected children.11-16 prevalence of antimicrobial resistance and
HIV-1-infected children also are at increased recent use of prophylactic or therapeutic
risk for recurrent infections. antibiotics (see Table 2-2).1,6 A combination
S. aureus is an increasingly important cause of a b-lactam with an aminoglycoside or a
of pneumonia in HIV-1-infected children and second-generation or third-generation cepha-
is the most common pathogen in catheter- losporin alone is appropriate empiric therapy.
associated bacteremia.16,18 Staphylococcal The choice of antimicrobial agent should be
pneumonia may be complicated by empyema, modified according to culture results and
pneumatoceles, or lung abscess (Fig. 2-1). susceptibility testing.
A wider range of bacteria, including gram neg- The outcome of HIV-1-infected children
ative pathogens such as Klebsiella pneumoniae, with bacterial pneumonia is worse than the
Pseudomonas aeruginosa, H. influenzae, non- outcome for immunocompetent children
typhoid salmonella, and Escherichia coli, cause with more severe disease and higher case-
pneumonia with or without bacteremia in fatality rates.1,4 In addition, HIV-1-exposed
HIV-1-infected children.11,12,16,19,20 but uninfected children have higher rates of
Table 2-2 Etiology and Therapy of Lower Respiratory Infections in HIV-Infected Children
INFECTION PATHOGENS FIRST-LINE THERAPY

Bacterial pneumonia Streptococcus pneumoniae Broad-spectrum antibiotic—b-lactam with an
aminoglycoside or a second- or third-generation
cephalosporin
Haemophilus influenzae Add antistaphylococcal antibiotics if S. aureus
Staphylococcus aureus suspected or vancomycin if methicillin-resistant
S. aureus suspected
Nontyphoid salmonella
Klebsiella pneumoniae
Streptococcus milleri
Escherichia coli
Moraxella catarrhalis
PCP Pneumocystis jiroveci Trimethoprim-sulfamethoxazole
Corticosteroids if hypoxic
Mycobacterial Mycobacterium tuberculosis Isoniazid, rifampin, pyrazinamide as induction for
2 mo (add fourth drug if suspected drug resistance
or smear-positive pulmonary TB or smear-negative
pulmonary TB with extensive parenchymal
involvement or severe extrapulmonary TB or severe
concomitant HIV disease); then maintenance with
isoniazid, rifampin for 4-7 mo for pulmonary TB
Mycobacterium bovis Corticosteroids if endobronchial disease, pericardial
effusion, meningitis
Mycobacterium avium- Surgical excision of localized disease; 4-drug therapy
intracellulare complex for disseminated disease (isoniazid, rifampin,
ethambutol, ofloxacin or ciprofloxacin)
Clarithromycin plus ethambutol
Viral pneumonia Respiratory syncytial virus
CMV Ganciclovir for CMV
Human metapneumovirus
Parainfluenza viruses 1 and 3
Adenovirus
Influenza viruses A and B Neuraminidase inhibitor for influenza A or B
Measles virus High-dose vitamin A for measles
HSV Acyclovir for HSV
Varicella-zoster virus Acyclovir for varicella-zoster virus
HPV types 6 and 11 Laser or surgery, topical therapy for HPV
Fungal Candida species Topical nystatin or oral itraconazole, fluconazole
Aspergillus species Amphotericin B
Histoplasma capsulatum Amphotericin B, itraconazole, fluconazole for mild
illness
Cryptococcus neoformans Amphotericin B, itraconazole, fluconazole
Coccidioides immitis Amphotericin B, itraconazole, fluconazole for mild
illness
CMV, cytomegalovirus; HPV, human papillomavirus; HSV, herpes simplex virus; PCP, Pneumocystis pneumonia; TB, tuberculosis.
treatment failure and mortality compared inactivated vaccines (diphtheria, pertussis,

with children born to uninfected mothers.16 tetanus toxoid; inactivated poliovirus;
Prevention of bacterial pneumonia H. influenzae type b; hepatitis B; and pneu-
through immunization is an important strat- mococcal conjugate vaccine) should be given
egy, although the efficacy may be reduced in to HIV-1-infected children at the usual
HIV-1-infected children. Immunization with recommended age.22 Use of the H. influenzae
Mycobacterial Infection
Respiratory disease also may result from infec-

tion with numerous mycobacteria. Mycobac-
terium tuberculosis is the most common cause
of respiratory infection, but localized or
disseminated disease from Mycobacterium bovis
or the nontuberculous mycobacteria (NTM),
particularly MAC may occur (see Table 2-2).
In high tuberculosis (TB) prevalence areas,
M. tuberculosis is an important cause of acute
pneumonia and of chronic respiratory infec-
tion in HIV-1-infected children. Culture-
confirmed pulmonary TB has been reported
in approximately 8% to 15% of children
hospitalized with acute pneumonia in
Figure 2-1. Chest x-ray of a young child with S. aureus
infection showing a large pneumatocele. these areas.11,12,16,29 The incidence of TB
usually primary infection, than in non-HIV
type b conjugate vaccine potentially may infected children is higher in HIV-1-infected
reduce Hib invasive disease by 46% to children.29-32 Coinfection with M. tuberculo-
93% in immunocompetent vaccine recipi- sis and HIV-1 results in more rapid dete-
ents.23,24 The efficacy of this vaccine against rioration of immune dysfunction, viral
invasive disease is reduced, however, in HIV- replication, and HIV-1 progression, and other
1-infected children not receiving antiretrovi- more frequent and severe infections.33-36
ral therapy (44% in HIV-infected compared HIV-1-infected children with TB may pre-
with 96% in uninfected children).19 The sent with nonspecific signs, such as weight
pneumococcal conjugate vaccine has lower loss, failure to thrive, or fever; with signs
efficacy in HIV-1-infected children25-27; nev- and symptoms of acute pneumonia or air-
ertheless, it reduces the incidence of invasive way obstruction (Fig. 2-2); or with chro-
disease caused by vaccine strains by 65% and nic, persistent respiratory symptoms.29,33-36
prevents 13% of radiologically confirmed Cavitary lung disease, or extrapulmonary
pneumonia in HIV-1-infected children not spread. (Fig. 2-3) occurs more commonly in
receiving HAART.25 Immunization also HIV-1-infected children. Multidrug-resistant
reduces the incidence of infection with drug- TB is increasingly prevalent in TB-endemic
resistant pneumococcal strains.25 Reimmu- areas and has a poor prognosis.37 In the
nization after 3 to 5 years is recommended. United States, multidrug-resistant TB is
Adolescents should receive the 23-valent
polysaccharide vaccine.9
Intravenous immunoglobulin (IVIG) is cur-
rently recommended in HIV-1-infected chil-
dren with hypogammaglobulinemia (IgG <4
g/L); two or more severe bacterial infections
in a 1-year period; failure to form antibodies
to common antigens; or chronic parvovirus
B19 infections.14,22,28 IVIG may not offer
additional protection, however, if children
are taking trimethoprim-sulfamethoxazole
(TMP-SMX) prophylaxis.14 Moreover there is
no evidence to suggest that IVIG therapy
offers additional protection for children
receiving HAART. Children with bron-
Figure 2-2. Chest x-ray of a child with culture-con-
chiectasis may benefit from monthly immu- firmed tuberculosis showing compression of the trachea
noglobulin infusions.22 by lymph nodes.
A B
Figure 2-3. A, Chest x-ray of a child with miliary tuberculosis with diffuse nodules, producing a “snowstorm” appear-
ance. B, Chest CT scan of a child with miliary tuberculosis showing multiple diffuse small nodules.
uncommon, reported in 2.8% of foreign- young children.6,43 Primary and secondary

born and 1.4% of U.S.-born cases.32 prophylaxis is recommended for severely
Localized or disseminated M. bovis infec- immunosuppressed children based on CD4þ
tion, including pneumonia, has been reported counts.43,44
in HIV-1-infected children occurring weeks to Establishing the diagnosis of pulmonary
years after receiving bacille Calmette-Guérin TB is difficult in HIV-1-infected children,
(BCG) immunization.38-40 The most common for whom clinical scoring systems have not
manifestation of M. bovis disease is ulceration been developed, and in whom anergy may
at the site of vaccination or localized lymph- reduce the reliability of the tuberculin skin
adenopathy; systemic dissemination occurs test. A tuberculin skin test of 5mm or more
more rarely. The risk of disseminated BCG of induration is regarded as positive.7 Tests
disease is greatly increased in HIV-1-infected of T lymphocyte interferon-¡ production
infants.38 The clinical presentation of are promising. A study of children with sus-
disseminated M. bovis may be indistinguish- pected TB reported that the T cell–based
able from M. tuberculosis infection.40 enzyme-linked immunospot assay (ELI-
Disseminated M. bovis infection has a poor SPOT) had a higher sensitivity than the
prognosis with a case-fatality rate of approxi- tuberculin skin test. In HIV-1-infected chil-
mately 50%. dren, the ELISPOT sensitivity was 73% com-
NTM, particularly MAC, may cause pared with 36% for the skin test.45
disseminated disease, including pulmonary Definitive diagnosis and drug resistance
infection, in severely immunosuppressed testing require culture confirmation of M.
HIV-1-infected children; isolated pulmonary tuberculosis.46 Sputum induction was
disease is rare.41 The incidence of NTM dis- reported more recently to be effective and
ease has declined significantly from a rate of safe for culture confirmation in infants and
1.8 per 100 child-years before HAART to 0.1 children, with the yield from a single
after HAART (see Table 2-1).5,9 Children with induced sputum equivalent to that obtained
pulmonary disease are at high risk for dissem- from three gastric lavages.47 Induced spu-
ination; 72% may develop systemic disease tum should be the primary diagnostic
within 8 months.6 Disseminated MAC seems procedure in a child with suspected pulmo-
to be more common in children who have nary TB. In contrast, the culture yield from
transfusion-acquired HIV-1 rather than peri- a single bronchoalveolar lavage (BAL) is
natal acquisition.42 Disease occurs in adults lower than that from three properly per-
with CD4þ counts less than 50 cells/mL; how- formed consecutive gastric lavages.48 The
ever, the threshold is less well established in efficacy of polymerase chain reaction has
been disappointing, with sensitivity on gas- months even years, and a normal radiograph
tric aspirates ranging from 45% to 83% in is not a criterion for discontinuing therapy.6
HIV-1-negative children.46 For children receiving HAART, the antiret-
Definitive diagnosis of M. bovis or MAC roviral regimen should provide optimal TB
relies on isolation of the organism from the and HIV-1 therapy and minimize potential
blood or biopsy specimens.6 If lymphade- toxicity and drug interactions.35,49 Rifampin
nopathy is present, an aspirate and culture induces hepatic cytochrome P-450 enzymes
can be diagnostic. Multiple mycobacterial and may reduce levels of antiretroviral
blood cultures may be necessary to improve agents, particularly protease inhibitors (Pls)
the yield. Culture is essential to differentiate and non-nucleoside reverse transcriptase
NTM from M. tuberculosis and to determine inhibitors (NNRTIs). Rifampin should not
drug susceptibilities. be used in conjunction with single protease
The response to standard TB therapy in inhibitors except for ritonavir.6 Alternatively,
HIV-1-infected children is poorer than in rifampin may be used in conjunction with
HIV-1-negative children, with lower cure rates ritonavir-boosted saquinavir, provided that
and higher mortality.36,37 Optimal therapy high-dose ritonavir boosting (400mg) is
for HIV-1-infected children has not been used.6 Concurrent rifampin with the non-
tested in well-designed clinical studies. nucleoside reverse transcriptase inhibitor
Empiric therapy for pulmonary TB in HIV-1- delavirdine is not recommended; however,
infected children should include three drugs use with efavirenz is possible. Use with nevi-
(isoniazid, rifampin, pyrazinamide) daily for rapine is recommended only when there are
a 2-month induction period; a fourth drug no other options because of the potential
(ethambutol, ethionamide, or streptomycin) decrease in nevirapine levels. Rifabutin is a
should be added if drug resistance is suspected less potent inducer of the P-450 enzymes,
or if there is smear-positive pulmonary TB, and is a suitable alternative to rifampin, but
smear-negative pulmonary TB with extensive there is limited experience with its use in
parenchymal involvement, severe extrapul- children. Adjustments in dosage of rifabutin
monary TB, or severe concomitant HIV-1 and coadministered antiretroviral drugs
disease.6,35,37,49 may be necessary because some drugs
After the induction phase, therapy with decrease rifabutin levels, whereas others
two drugs (isoniazid, rifampin) should be increase levels. For antiretroviral-naı̈ve chil-
continued either daily or three times a dren, the timing of HAART after initiation of
week.22,49 Directly observed therapy (DOT) TB therapy depends on the clinical and
is advised to promote adherence and reduce immunologic severity of disease. In children
the rate of treatment relapse or failure. with severe clinical illness or advanced HIV-
Because high rates of treatment failure occur 1 infection, HAART should be started 2 to
in children treated for 6 months, some 8 weeks after TB therapy to minimize the risk
guidelines recommend 9 months.6,49,50 For of immune reconstitution inflammatory
extrapulmonary TB, the duration of therapy syndrome (IRIS), to optimize adherence,
may be increased to 12 months.6,49 Therapy and to differentiate potential side effects sec-
for drug-resistant TB should be individua- ondary to TB or antiretroviral drugs.49,51-54
lized, using a minimum of three drugs, at Management of BCG disease is difficult.
least two of which are bactericidal. Adjunc- The inherent resistance of M. bovis to pyrazi-
tive corticosteroids may be beneficial in namide, inherent intermediate resistance of
children with complicated TB, including some strains to isoniazid, and the emer-
pericardial disease, meningitis, or an endo- gence of resistance owing to inappropriate
bronchial lesion with airway obstruction; a therapy complicate treatment.55 Although
suggested regimen is 1 to 2mg/kg/day of localized BCG disease is usually self-limited
prednisone tapered over 6 to 8 weeks. A in immunocompetent children, in HIV-1-
chest radiograph should be obtained at infected children, treatment is warranted
baseline and repeated 2 to 3 months into because of the risk of dissemination and
therapy to evaluate response; however, the poor outcome.40 Surgical excision of loca-
chest radiograph may remain abnormal for lized lymphadenopathy is one option.
Alternatively, therapy with four drugs (isoni-

Indications for Pneumocystis
azid, rifampin, ethambutol, ofloxacin, or Table 2-3 Pneumonia Prophylaxis in HIV-
ciprofloxacin) in high doses is recom- Infected Children
mended. The optimal duration of therapy is
unknown, but at least 9 months of treatment AGE CD4þT LYMPHOCYTE COUNT*
is recommended, based on experience with 4-6 wk to 12 All patients regardless of
adults.56 mo{ CD4þcount
Treatment of MAC should consist of com- 1-5 yr <500/mm3or <15%
bination therapy with a minimum of two >5 yr <200/mm3or <15%
drugs because monotherapy with a macro- *If CD4þ counts are unavailable, prophylaxis should be given
lide leads rapidly to resistance.6 Initial {
to all symptomatic children indefinitely.100
HIV-exposed children should receive prophylaxis from
recommended therapy is clarithromycin or 4-6 weeks to 4 months; thereafter, prophylaxis may be
azithromycin with ethambutol. Rifabutin discontinued if HIV infection has been excluded, and the
mother is not breastfeeding.
may be added as a third drug in patients Data from references 22 and 100.
with severe disseminated infection; addition
to ciprofloxacin, amikacin, or streptomycin
may be considered depending on the sever- prevent recurrence. Lifelong prophylaxis
ity of illness. is indicated; the safety of discontinuing
For prevention of mycobacterial disease, secondary prophylaxis in the context of sus-
the BCG vaccine may be beneficial for HIV- tained immune restoration after HAART has
1-exposed but uninfected children in areas not been well studied in children.
of high TB prevalence. Chemoprophylaxis
with isoniazid is recommended for a child
who has been exposed to a household con- Viral Infection
tact with TB after active TB disease has been
excluded or for a child with evidence of TB Although respiratory viruses are identified
infection (tuberculin skin test >5mm indu- less frequently in HIV-1-infected children
ration but asymptomatic with a normal hospitalized for pneumonia (approximately
chest radiograph).6,22,49 A study in a high 15%) compared with HIV-1-negative chil-
TB prevalence area found that isoniazid pro- dren (45%), the absolute burden of hospital-
phylaxis given to HIV-1-infected children ization for viral-associated pneumonia is
regardless of tuberculin skin reactivity or a twofold to eightfold greater in HIV-1-
household TB contact substantially reduced infected children.58 HIV-1-infected children
TB incidence by almost 70% and mortality in whom respiratory viruses are identified
by more than 50%. The effect of isoniazid are more likely to develop pneumonia, to
occurred in all categories of clinical HIV-1 have a more prolonged hospital stay, and
illness and in children of all ages. Isoniazid to have a higher case-fatality rate than
prophylaxis should be considered for HIV- HIV-1-uninfected children. Respiratory syn-
1-infected children living in TB endemic cytial virus (RSV) is the most common cause
areas, especially children who are not taking of viral pneumonia, although human
HAART.57 metapneumovirus is emerging as an impor-
Primary prophylaxis for NTM with azithro- tant respiratory pathogen with a spectrum
mycin or clarithromycin should be con- of disease similar to RSV.59 Other respiratory
sidered for severely immunosuppressed viruses causing lower respiratory tract in-
children (Table 2-3) as follows: children young- fection include cytomegalovirus (CMV), ade-
er than 1 year, CD4þ less than 750/mL; chil- novirus, influenza, parainfluenza, and
dren 1 to 2 years old, CD4þ less than 500/mL; measles (see Table 2-2).58 Treatment may be
children 2 to 6 years old, CD4þ less than beneficial for specific viral pathogens. For
75/mL; children 6 years or older, CD4þ less influenza A or B, a neuraminidase inhibitor,
than 50/mL.22 Rifabutin may be an alternative such as oseltamivir or zanamivir, can reduce
agent in children older than 6 years. Second- the severity of illness and complications.22
ary prophylaxis should be given to children Concurrent bacterial infection has been
with a history of disseminated MAC to reported in 30% to 50% of children
hospitalized with viral pneumonia.16 Pneu- considered in children with mild immuno-
mococcal conjugate vaccine reduces the inci- suppression.22 Varicella vaccine should be
dence of hospitalization for viral-associated considered at 12 to 15 months for asymptom-
pneumonia, suggesting that more severe atic or mildly symptomatic HIV-1-infected
pneumonia requiring hospitalization may children without immunosuppression (Cen-
be the result of viral and S. pneumoniae ters for Disease Control and Prevention cate-
coinfection.60 Influenza vaccine should be gories N1 and A1); vaccine should not be
given annually to all HIV-1-infected children administered to symptomatic immunosup-
at the start of the influenza season.22 The pressed children because of the potential
efficacy of the humanized monoclonal spe- for disseminated disease. Administration of
cific antibody against RSV (palivizumab) or varicella-zoster globulin should be considered
RSV IVIG has not been well evaluated in for HIV-1-infected children exposed to vari-
HIV-1-infected children. Nevertheless, chil- cella or zoster who have no prior history of
dren at risk for severe RSV infection, such as varicella infection or immunization and who
HIV-1-infected infants born prematurely, have not received immunoglobulin within
children younger than 2 years with chronic 2 weeks of exposure.
lung disease, or severely immunosuppressed Measles may result in severe pneumonia
children, may benefit from palivizumab proin HIV-1-infected children; measles may
phylaxis. A dose should be given monthly for present without the typical skin rash,
the duration of the RSV season. making the diagnosis particularly difficult.66
CMV is a herpesvirus that can cause pri- Children with suspected measles should be
mary pneumonitis or severe, disseminated given a single high dose of vitamin A
disease in HIV-1-infected children.6 CMV because studies in HIV-1-negative children
infection is more likely to occur in children have shown that vitamin A reduces morbid-
with low CD4þ counts. Coinfection with ity and mortality from measles-associated
CMV and HIV-1 results in more rapid pro- pneumonia.67 Measles, mumps, rubella vac-
gression of HIV-1 disease.6,61 The incidence cine (MMR), a live attenuated vaccine,
of CMV infection has decreased with the should be given to HIV-1-infected children
use of HAART.5,9 CMV may occur in associa- at 12 months of age, unless they are severely
tion with other pathogens, especially Pneu- immunocompromised.22 HIV-1-infected chil-
mocystis.62 Treatment of CMV disease dren exposed to measles should receive a
focuses on preventing disease progression dose of intramuscular immunoglobulin
and not on cure. Ganciclovir is most widely regardless of immunization status.
used, with drug dosing separated into induc- Human papillomavirus (HPV) type 6 or
tion and maintenance dosage.6,22 Prophy- type 11 may produce lesions in the oral cav-
laxis against CMV with oral ganciclovir or ity, pharynx, and larynx and rarely in the
valganciclovir should be given to severely lower airways or lungs; the disease has a ten-
immunosuppressed children or children dency to recur.68 Clinically, the disease may
with a history of disseminated CMV disease manifest as progressive hoarseness, stridor,
to prevent recurrence.63 There are few data wheezing, and respiratory distress.69 Rarely,
on the safety of discontinuing prophylaxis lung nodules, cysts, recurrent pneumonia,
after sustained immune reconstitution on emphysema, or atelectasis occurs in immu-
HAART has occurred. nocompetent children.68,69 Little is known
Other herpesvirus infections may also about the epidemiologic risk of disease in
involve the respiratory tract in HIV-1-infected HIV-1-infected children. An increased preva-
children. Oral herpes simplex virus lesions lence of HPV in HIV-1-infected compared
may spread to involve the upper airways and with HIV-1-uninfected women has been
the larynx, resulting in croup64; disseminated reported; however, the rate of HPV transmis-
disease including pneumonia also may occur. sion to children has not been associated
Pneumonia may occur as a complication of with the HIV-1 status of the mother or
varicella-zoster virus infection.65 Intravenous child.70,71 Laryngeal HPV lesions are diffi-
acyclovir is recommended for therapy; high- cult to treat. Therapy is directed at main-
dose oral acyclovir or valacyclovir may be taining airway patency, so obstructing
papillomas should be removed. Adjuvant chest retractions.77 Infants younger than 6

therapy using intralesional cidofovir has months are especially at risk for PCP and
been reported to result in regression and have an acute, severe illness characterized
reduced need for surgery in HIV-1-uninfected by rapidly prominent and progressive hy-
children.72 poxia and increasing respiratory distress.77
In HIV-1-infected children not taking
HAART, four clinical variables have been
Pneumocystis Infection reported to be associated with PCP: age
younger than 6 months, respiratory rate
Children with HIV-1 who are not taking greater than 59 breaths/min, arterial hemo-
HAART or TMP-SMX prophylaxis are at high globin saturation less than 92%, and
risk of developing PCP. Pneumocystis jiroveci absence of a history of vomiting.78 Clinical
(formerly Pneumocystis carinii) originally was signs may be compounded by coinfection
classified as a protozoan. Studies of RNA with bacterial or viral pathogens.16,62,79
sequences show a similarity between fungi Most children have significant hypoxemia
and P. jiroveci, and the organism is now classi- with an alveolar-arterial oxygen gradient
fied as a fungus. Two morphologic forms of greater than 30mmHg.
the organism are found in infected lungs: Laboratory findings include a normal
thin-walled, single-nucleated trophozoites white blood cell count, elevated serum lac-
adherent to type I pneumocytes, and thick- tate dehydrogenase (LDH), and normal IgG
walled cysts containing four to eight single- level. LDH values greater than 1000 IU/L are
nucleated sporozoites. The organism attaches associated with PCP, but they are nonspecific
to the alveolar epithelium, resulting in des- and may reflect the extent of lung involve-
quamation of alveolar cells. As the infection ment.80,81 The chest radiograph usually
progresses, a diffuse desquamative alveolitis shows a diffuse pattern, which progresses to
ensues, and alveoli become filled with a foamy alveolar opacification (Fig. 2-4); however,
exudate consisting of alveolar macrophages hyperinflation, focal infiltrates, cavities, a
and cysts. Interstitial inflammation develops. miliary pattern, pneumothoraces, pleural
PCP was the most common opportunistic effusion, or even a normal appearance also
infection in HIV-1-infected infants before may occur.82,83 Less commonly, PCP may
widespread prenatal HIV-1 screening, TMP- manifest with a pneumothorax, cyst, pneu-
SMX prophylaxis, and HAART.9 In the United matoceles, or a bronchiolitis-like picture.83,84
States, the incidence of PCP has declined sub-
stantially from 1.3 per 100 child-years before
HAART to 0.1 after HAART.5,9 In developed
countries, PCP occurs most commonly in
infants born to women with unrecognized
HIV-1 infection.73 In developing countries,
PCP remains a frequent presentation of HIV-
1 infection in infants and a major cause of
severe pneumonia and death.10,16,74-76 The
incidence of PCP ranges from 8% to 49%
among HIV-1-infected African children hospi-
talized for pneumonia.16,74-76 Increasingly,
PCP also has been reported in older HIV-1-
infected children; 25% of cases in a Zambian
postmortem study occurred in children older
than 6 months.10 Moreover, HIV-1-exposed
but uninfected children have been described
to have a higher risk of PCP compared with
children born to HIV-1-uninfected mothers.16
Children with PCP most commonly have Figure 2-4. Chest x-ray of an infant with Pneumocystis
acute onset of cough, fever, tachypnea, and pneumonia showing diffuse interstitial infiltrates.
PCP is associated with high mortality rang- Transbronchial biopsy may be positive 10
ing from 35% to 87% with higher rates days after starting therapy; the sensitivity
in children with respiratory failure requir- of biopsy is 87% to 95%.6,8
ing mechanical ventilation.74-76,85,86 Timely Because P. jiroveci cannot be cultured,
anti-Pneumocystis therapy may improve the identification requires special stains.77 Silver
outcome, as suggested by historical compari- methenamine, toluidine blue O, and calco-
sons and adult studies in which early use of fluor white are useful for staining cyst forms,
corticosteroids has been associated with whereas Giemsa, modified Wright-Giemsa,
improved survival.87-89 Mutations in P. jiro- and modified Papanicolaou stains iden-
veci dihydropteroate synthetase genes—a tify trophozoites.77,87 Fluorescein-conjugated
key enzyme target of TMP-SMX—have been monoclonal antibodies provide greater sensi-
described in HIV-1-infected patients with tivity, detecting the cyst and trophozoite
PCP, especially with widespread use of TMP- forms.87 Polymerase chain reaction tech-
SMX prophylaxis.87 The clinical importance niques with a high sensitivity and specificity
of mutant strains is unclear, however, and and potential to improve diagnostic accuracy
the response to TMP-SMX treatment varies. are promising, but currently are used mainly
HIV-1-exposed but uninfected children as a research tool.
may also be at increased risk of PCP.16 Empiric therapy for Pneumocystis should be
Transmission of P. jiroveci from an HIV-1- given to any HIV-1-infected child with sus-
infected mother to her HIV-1-uninfected pected PCP because untreated infection is
infant has been reported in a few cases.90-92 usually fatal.77 The most effective therapy is
HIV-1-exposed children may be at risk for TMP-SMX (15 to 20mg/kg/day of TMP) intra-
PCP as a result of close and early exposure venously three to four times a day for 21
to the organism from the mother, reduced days (see Table 2-4).6,22,77,87 Oral treatment
passage of functional maternal antibody, can be used if intravenous therapy is not fea-
impaired cell-mediated immunity, or con- sible, if disease is mild, or after clinical
comitant malnutrition. improvement occurs. The response to ther-
Definitive diagnosis requires identifica- apy may be slow with clinical improvement
tion of P. jiroveci from sputum, bronchial observed by 5 to 7 days.77 Adverse reactions
washings, or lung tissue. Induced sputum to TMP-SMX occur in approximately 15%
using nebulized hypertonic saline has been of cases, but treatment should be discontin-
used to diagnose PCP in children; a positive ued only if reactions are severe, such as neu-
yield has been reported in infants 1 month tropenia or a severe skin rash.22,77,93
of age.75 In this procedure, the child inhales Intravenous pentamidine (4mg/kg/once
a mist of 3% to 5% saline generated by a jet daily) may be an alternative treatment for
nebulizer for 10 to 15 minutes. The diag- children who cannot tolerate TMP-SMX, or
nostic yield using this technique depends who have not responded after 5 to 7 days of
on collection of an adequate specimen. TMP-SMX (see Table 2-4).6,22 Pentamidine is
Nasopharyngeal aspirates have been used associated with a high incidence of adverse
to identify P. jiroveci, but the yield is lower reactions, including pancreatitis, hyperglyce-
than with induced sputum.74-76 Induced mia and hypoglycemia, renal dysfunction,
sputum combined with nasopharyngeal cardiac dysrhythmias, fever, neutropenia,
aspirates may provide a higher yield than and hypotension.94 Patients who show clini-
either technique alone; the sensitivity and cal improvement after 7 to 10 days of intrave-
specificity for induced sputum and naso- nous pentamidine may be switched to an oral
pharyngeal aspirates for diagnosis of PCP drug to complete 21 days of therapy. Other al-
compared with the yield on autopsy have ternative anti-Pneumocystis agents include
been reported to be 75% and 80%.76 BAL atovaquone, dapsone with trimethoprim,
with fiberoptic bronchoscopy is the diag- trimetrexate glucuronate with leucovorin,
nostic procedure of choice in young chil- and clindamycin with primaquine, but
dren, with reported sensitivity of 55% to there is little information on the efficacy or
97%.6 Transbronchial biopsy is not recom- tolerability of these regimens in children
mended unless BAL is nondiagnostic.6 (see Table 2-4).6,22
Table 2-4 Treatment of Pneumocystis Pneumonia in Children*
DRUG DOSE ROUTE COMMENTS

TMP-SMX 15-20mg/kg TMP/75-100mg/kg SMX Intravenous or oral First choice. Oral therapy
per day q6h only if mild disease or
after clinical
improvement occurs
Pentamidine 4 mg/kg once daily Intravenous Use in children who
cannot tolerate TMP-
SMX or when no
response after 5-7 days.
High incidence of side
effects. Should not be
administered with
didanosine owing to
risk of pancreatitis
Atovaquone 30-45 mg/kg/day Oral Limited experience
in children
Trimetrexate No studies in children of established Intravenous Limited experience
glucuronate doses. Adult dose 45mg/m2/day in children
with leucovorin trimetrexate glucuronate with
20mg/m2 leucovorin q6h
Dapsone and No studies in children of established Oral Limited experience
trimethoprim doses. Adult dose 100mg dapsone in children
daily (pediatric equivalent 2mg/kg)
and 15mg/kg trimethoprim
Primaquine and No studies in children of established Oral/intravenous Limited experience in
clindamycin doses. Primaquine adult dose 30mg children. Most effective
daily orally (pediatric equivalent alternative therapy for
0.3mg/kg daily orally). Clindamycin adults with PCP
adult dose 600mg intravenously unresponsive to
q6h for 10 days, then 300-450mg primary therapy
orally q6h for 11 days (pediatric
equivalent 10mg/kg q6h orally or
intravenously)
*Corticosteroids should be added for children with hypoxia.

PCP, Pneumocystis pneumonia; TMP-SMX, trimethoprim-sulfamethoxazole
Corticosteroids are recommended in hy- A few case reports have described the use of
poxemic children. Although no controlled surfactant to improve pulmonary function in
trials on the use of corticosteroids in children children with severe PCP.96,97 Children with
have been performed, corticosteroid use has PCP may be co-infected with bacterial or viral
been reported to reduce the need for mechan- pathogens16,62,79; additional antimicrobial
ical ventilation and to improve survival com- therapy for these should be used when appro-
pared with historical controls.88,89,95 Studies priate. Specifically, CMV co-infection has
of hypoxemic HIV-1-infected adults with been associated with more severe disease
PCP found that corticosteroids improve oxy- requiring mechanical ventilation and a poor
genation and reduce the incidence of respira- outcome. The effect of corticosteroid therapy
tory failure when used within 72 hours of for PCP on CMV pneumonitis is unclear.
starting anti-Pneumocystis therapy.87,89 Corti- Because of the high mortality and morbid-
costeroids are recommended for patients ity associated with PCP, prevention should be
with a PaO2 less than 70mmHg or an alveo- the primary objective. Prevention of PCP is
lar-arterial oxygen gradient greater than an important and effective intervention, if
35mmHg.6 The optimal dose and duration initiated in HIV-1-exposed infants within the
have not been determined, but a recom- first weeks of life.98 Oral TMP-SMX is the most
mended regimen is prednisone, 2mg/kg/day effective prophylactic agent.17,22 In the only
for 7 to 10 days with tapering doses over the randomized controlled study of TMP-SMX
next 10 to 14 days.88 prophylaxis in HIV-1-infected children,
mortality was reduced by 43% and morbidity, pentamidine preclude its use in younger
including hospitalization, was reduced by children.
23% in Zambia.99 The impact on mortality
occurred in children of all ages, suggesting
that prophylaxis may also provide protection Fungal Infection
against bacterial infections.99 TMP-SMX pro-
phylaxis (150mg/m2/day of TMP) may be Chronic Candida infection is common in
given three times a week (single dose on 3 con- HIV-1-infected children and may produce
secutive days, or two divided doses on consec- oropharyngeal, laryngeal, or esophageal can-
utive or alternate days). didiasis and promote the development of
Current recommendations for PCP prophy- gastroesophageal reflux disease.5,6,9,106 The
laxis include the following (see Table 2-3)22,100; incidence of tracheobronchial or esopha-
• All infants born to HIV-1-infected mothers geal candidiasis has declined substantially
from 6 weeks of age until HIV-1 infection with HAART (see Table 2-1).5,9 Infection of
has been excluded in the child and the the upper airways may result in Candida
mother is no longer breastfeeding. supraglottitis, epiglottitis, and a croup-like
• All HIV-1-infected children from 6 weeks of picture.107,108 Laryngeal candidiasis may
age until 1 year. HIV-1-infected children manifest as severe acute airway obstruc-
older than 1 year should receive prophy- tion.107 Pulmonary disease may also occur
laxis if their CD4þ counts are less than in the context of severe disseminated disease.
15% of lymphocytes or if they have symp- Uncomplicated oropharyngeal candidiasis
tomatic HIV-1 disease. A higher CD4þ can be treated with topical therapy (see
threshold for providing prophylaxis may Table 2-2).109 Oral fluconazole, itraconazole,
be applicable in developing countries, how- or ketoconazole are effective alternative
ever, as evidenced by a trial in Zambia agents.6,22,110 For esophageal disease, flucon-
where prophylaxis reduced mortality in chil- azole or itraconazole is recommended.6,22
dren, even in children with higher CD4þ Other fungal infections, including aspergil-
counts.99 Prophylaxis should be continued losis, histoplasmosis, cryptococcosis, and
indefinitely regardless of age or CD4þ counts coccidioidomycosis, may produce respira-
when HAART is unavailable.100 tory illness usually in the context of severe
• Prophylaxis should be continued in chil- immunosuppression and disseminated dis-
dren taking HAART for at least 6 months. ease (see Table 2-2). Pulmonary cryptococcosis
There is little information on the safety of without dissemination may manifest with
discontinuing prophylaxis after immune fever, intrathoracic adenopathy, and pulmo-
reconstitution has occurred. Discontinua- nary infiltrates.6 Occasionally, pulmonary
tion of prophylaxis may be considered in cryptococcosis may be asymptomatic and
children with confirmed immune restora- manifest on routine chest x-rays as pulmo-
tion for 6 months or more as indicated by nary nodules. Pulmonary coccidioidomycosis
two measurements of CD4þ greater than may produce nodules, cavities, or diffuse
25% at least 3 to 6 months apart in chil- reticulonodular infiltrates associated with
dren 2 to 6 years old.101 fungemia and systemic disease. Children
Lifelong prophylaxis should be given to all with severe pulmonary cryptococcosis should
children who have had an episode of PCP; be treated with amphotericin B; maintenance
the safety of discontinuing secondary prophy- therapy with fluconazole or itraconazole
laxis in the context of immune reconstitution can be substituted after improvement has
has not been established. If TMP-SMX is not occurred.6,8,22 Mild or moderate pulmonary
tolerated or cannot be used, alternatives cryptococcosis can be treated with oral flu-
include dapsone (2mg/kg once daily), paren- conazole or itraconazole.6,22 Lifelong suppres-
teral pentamidine (4mg/kg every 2 to 4 sive therapy with fluconazole or itraconazole
weeks), or aerosolized pentamidine (300mg is necessary to prevent relapse.6 There are
via Respigard II inhaler every 4 weeks) if the few data on treatment of pulmonary coc-
child is older than 5 years.6,22,102-105 Safety cidioidomycosis in children, and recomm-
and efficacy concerns regarding aerosolized endations are based on adult data, with
amphotericin B recommended for the acute Persistent or recurrent pneumonia is an

illness followed by long-term suppressive important cause of chronic lung disease. In
therapy with fluconazole or itraconazole.6,111 African children, TB commonly produces
Alternatively, in mild disease therapy may be chronic lung disease.30,32-35
initiated with fluconazole or itraconazole.6
Lymphocytic Interstitial Pneumonia

Chronic Lung Disease
LIP, resulting from diffuse interstitial lympho-
cytic infiltration of the lungs, is common in
Chronic lung disease was reported as com-
HIV-1-infected children. The etiology is
mon in HIV-1-infected children before
unknown, but evidence suggests that infec-
HAART.112,113 A longitudinal birth-cohort
study before widespread HAART usage tion with Epstein-Barr virus may initiate a
reported a cumulative incidence of chronic lymphoproliferative response in the presence
radiographic lung changes in HIV-1-infected of HIV-1 infection.114 Clinically, children
children of 33% by 4 years of age.112 The most develop chronic respiratory symptoms, prin-
cipally cough and mild tachypnea.115 Lym-
common chronic radiologic changes were
phoproliferation occurring in other organs
increased bronchovascular markings, reticular
may produce generalized lymphadenopathy,
densities, or bronchiectasis (Fig. 2-5).112,113
These radiographic findings were associated bilateral nontender parotid enlargement, and
with an increased frequency of tachypnea, hepatosplenomegaly.115-117 Digital clubbing
frequently occurs. Hypoxia, if present, is usu-
crackles and clubbing, and a decreased oxygen
ally mild. Children may survive for years with
saturation. Resolution of these chronic
changes was associated with reduced CD4þ a course characterized by recurrent episodes of
cell counts and higher viral loads, and thus acute lower respiratory tract infections.118 Cor
pulmonale or bronchiectasis may develop.119
may be an indication of progression of HIV-1
Children with LIP have moderately ele-
infection.112
vated serum IgG and LDH levels and titers to
The spectrum of chronic lung disease in
viral capsid antigen of Epstein-Barr virus.114
HIV-1-infected children includes lympho-
Chest radiographs often show a diffuse reticu-
cytic interstitial pneumonia (LIP), interstitial
lonodular pattern, more pronounced cen-
pneumonitis, immune reconstitution inflam-
matory syndrome (IRIS), bronchiectasis, trally (Fig. 2-6A), which may be difficult to
distinguish from pulmonary or miliary TB
malignancies, and bronchiolitis obliterans.
(see Fig. 2-3A).117 Clinically, mild respiratory
illness, the presence of parotid enlargement,
and a reticulonodular pattern on chest x-
ray or computed tomography (CT) scan may
help to distinguish children with LIP from
children with miliary TB.117 Peribronchiolar
thickening alone or normal chest radiographs
also may occur.116,117 Radiographic lesions
may resolve in association with worsening
immune status.120,121 Respiratory status may
improve with the use of HAART122; among
HIV-1-infected adults with LIP, HAART has
been reported to result in resolution of radio-
graphic abnormalities.122
High-resolution CT may improve diagnos-
tic certainty; typical features include microno-
dules of 1 to 3mm in diameter, with a
perilymphatic distribution, and subpleural
Figure 2-5. Early radiologic evidence of chronic HIV-
associated lung disease showing increased broncho- nodules (see Fig. 2-6B).123 The role of nuclear
vascular markings. scanning in confirming the diagnosis has not
increases. Corticosteroids are tapered to 0.5

to 0.75mg/kg on alternate days, provided
that the arterial oxygen saturation remains
adequate.127 Further tapering may be possi-
ble as long as adequate oxygenation is
maintained. No data exist on the use of
inhaled corticosteroids.
LIP is categorized as a World Health Orga-
nization stage 3 AIDS-defining illness and is
an indication for initiating HAART in chil-
dren who are not yet receiving antiretroviral
therapy.128
A
Interstitial Pneumonitis
Non-specific interstitial pneumonitis may

occur in children with AIDS. The clinical
manifestations are cough, progressive dys-
pnea, and hypoxemia; chest radiographs
show interstitial pneumonitis. Interstitial
pneumonitis may be difficult to distinguish
from LIP or TB without open lung biopsy,117
which is required for definitive diagnosis.
Chronic Pulmonary Infections
Chronic infection, resulting from recurrent

or persistent pneumonia, may produce
B
chronic lung disease. Infection with
Figure 2-6. A, Chest x-ray of a child with lymphocytic M. tuberculosis is a particularly important
interstitial pneumonia showing multiple nodular densities
throughout the lung fields. B, High-resolution chest CT
and prevalent cause of chronic lung disease
scan of a child with lymphocytic interstitial pneumonia in developing countries.29,30,33-35,117 Distin-
showing a diffuse micronodular pattern. guishing pulmonary or miliary M. tuberculo-
sis from LIP may be difficult; generally,
children with LIP are older and less severely
been well studied, but diffuse pulmonary ill, enlarged parotid glands may occur, and
gallium uptake has been reported in an HIV- chest radiograph shows a reticulonodular
1-infected child with LIP.124 Definitive diagno- pattern.117 A few case reports have described
sis requires lung biopsy.116 Lung biopsies chronic P. jiroveci infection occurring in
reveal collections of lymphoid aggregates, HIV-1-infected children, usually manifest-
often with germinal centers, surrounding the ing with cystic disease or with pneumato-
airways and a significant interstitial infiltrate cele formation.84,129
composed primarily of lymphocytes.
Treatment is symptomatic, including anti-
biotics for acute infections and inhaled Immune Reconstitution
bronchodilators. Oxygen is administered Inflammatory Syndrome
for hypoxia as needed. Although there are
no trials of efficacy, case reports indicate a With increasing use of HAART, IRIS asso-
response to systemic corticosteroids.125-127 ciated with mycobacterial infection and
Oral corticosteroids are recommended for with other opportunistic infections such as
children with hypoxia.127 A suggested regi- CMV has been reported.130 IRIS may occur
men is prednisone, 2mg/kg/day for 2 to weeks to months after initiation of HAART
4 weeks, until the arterial oxygen saturation and may result either from unrecognized
mycobacterial infection or from a florid and aggressive treatment of intercurrent infec-

immune response directed against a myco- tions. Use of IVIG therapy at 600mg/kg per
bacterial antigen in patients already receiv- dose at monthly intervals may be beneficial.
ing therapy for mycobacterial infection.130
IRIS has been described with different myco-
bacterial species, including M. tuberculosis,
Malignancy
M. bovis, or MAC infection.51,131,132 Most
HIV-1-infected children have an increased risk
cases of IRIS have been described in HIV-1- of malignancy; malignant tumors occur in
infected adults,52,53 but IRIS is increasingly
2.5% of children with AIDS in the United
being recognized in HIV-1-infected children
States.134 Non-Hodgkin lymphoma is most
from high TB prevalence areas.51,54
common, followed by Kaposi sarcoma, leio-
Clinically, IRIS is characterized by a seem-
myosarcoma, and Hodgkin lymphoma.135,138
ingly paradoxical worsening in signs with
Infection with Epstein-Barr virus has been
increasing lymphadenopathy, new clinical
associated with the development of non-
and radiologic respiratory signs, and
Hodgkin lymphoma in HIV-1-infected
fever.51,53,54,132 The tuberculin skin test may children, including children with mild immu-
become positive, and chest radiographs may
nosuppression.135 Primary non-Hodgkin
show development of lymphadenopathy or
lymphoma may arise in a lymph node or be
new infiltrates.53,54 IRIS must be distinguished
extranodal.134,135 AIDS-related non-Hodgkin
from other infections, multidrug-resistant
lymphoma may occur in almost any
TB, or secondary to nonadherence to TB
extranodal site, including the lungs; in addi-
therapy.53 To minimize the risk of IRIS,
tion, pulmonary disease may result from
HIV-1-infected children with confirmed or
dissemination from a primary focus.
probable TB should be treated with antitu- In African HIV-1-infected children, Kaposi
berculous drugs for 2 to 8 weeks before
sarcoma is the most common AIDS-defining
starting HAART.49,53 When IRIS develops in
malignancy, probably because of the preva-
a child who was unknown to have TB,
lence of human herpes virus-8 infec-
therapy for TB should be initiated. If lymph-
tion.136-138 Human herpesvirus-8 may be
adenopathy or respiratory manifestations are
transmitted to a child from an infected
particularly severe, oral corticosteroids may
mother.138 The most common clinical presen-
be beneficial, although there are no con- tation is of violaceous plaques on the skin.139
trolled trials in children.53 Kaposi sarcoma lesions may produce upper
airway obstruction. Pulmonary dissemination
may result in persistent cough, chronic pro-
Bronchiectasis gressive dyspnea, and fever; hemoptysis may
occur with endobronchial lesions.137-139
Bronchiectasis may occur secondary to acute
Abnormalities on chest radiograph include
or chronic infection, including M. tuberculosis;
bilateral adenopathy; perihilar infiltrates;
after recurrent bacterial infections; after a
pleural effusion; or combinations of intersti-
severe viral lower respiratory tract infection; tial, alveolar, or nodular patterns. The finding
or as a consequence of LIP.119,133 Develop-
of poorly marginated discrete lesions on CT
ment of bronchiectasis may be associated
scan might be specific for Kaposi sarcoma.140
with the severity of immunosuppression; of
Definitive diagnosis is made by lung biopsy.
23 HIV-infected children (median age 7.5
years) with bronchiectasis, all had CD4þ cell
counts less than 100cells/mm3.133 Clinical
manifestations include increased sputum pro- Diagnostic Evaluation of an
duction, halitosis, abnormalities on chest aus- HIV-1-Infected Child with
cultation, and digital clubbing. Bronchiectasis Pulmonary Manifestations
should be suspected radiologically when there
are persistent infiltrates or atelectasis in the An HIV-1-infected child often presents with
same anatomic area for longer than 6 months. fever and tachypnea. The differential diagnosis
High-resolution CT is useful to confirm the is extensive, and a systematic approach based
diagnosis. Therapy includes physiotherapy on the clinical course of HIV-1 infection and
epidemiologic context is useful. Most severe for Pneumocystis. For children with milder
complications are infectious, and the likeli- illness, oral antibiotics may be indicated, or
hood increases with decreasing CD4þ cell specific treatment may be given according
counts. Many lower respiratory tract infections to the etiology (see Table 2-2).
are due to coinfections, such as bacterial-viral,
bacterial-bacterial, viral-Pneumocystis, or bac-
terial-Pneumocystis.16 Progressive ventricular Summary
dysfunction and cardiomyopathy also occur
in HIV-1-infected children, associated with Acute and chronic respiratory diseases are
immunocompromise.141,142 It is important an important cause of morbidity and mor-
to exclude cardiac involvement with conges- tality in HIV-1-infected children. The bur-
tive heart failure as a cause of respiratory den of childhood HIV and associated
manifestations. respiratory illness occurs predominantly in
If a child has acute severe respiratory developing countries. Antiretroviral therapy
symptoms, chest x-ray, oxygen saturation, has changed the spectrum of pulmonary
complete blood count, and blood cultures diseases in HIV-1-infected children, result-
should be obtained. Hypoxia with a diffuse ing in a marked reduction in opportunistic
interstitial infiltrate may suggest PCP. A dif- respiratory infections.
fuse miliary pattern may suggest TB, but this
also can be confused with LIP. For etiologic References
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CHAPTER 3
Pulmonary Manifestations
of Immunosuppressive Diseases
Other than Human
Immunodeficiency Virus Infection
JAMES M. STARK
Primary Immunodeficiencies 50 Diagnosis and Treatment of

Deficiencies in Immunoglobulin Respiratory Abnormalities in a Child
Production 50 with Secondary Immunocompromise
Deficiencies in Cellular Immunity 53 Owing to Cancer or
Deficiencies in Phagocyte Numbers, Function, Transplantation 74
and Opsonization 59 Radiography 74
Secondary Immunodeficiencies 62 Sputum and Nasopharyngeal Washes, and
Overview 62 Other Indirect Methods for Pathogen
Factors Contributing to the Secondary Detection 74
Immunodeficient State 63 Flexible Bronchoscopy 75
Pulmonary Complications of Cancer Transthoracic Needle Aspiration Biopsy 75
Therapy 64 Open Lung Biopsy 75
Transplant-Related Pulmonary Summary 76
Complications 67 References 76
Infection in an immunocompromised child defenses for even an immunocompetent host.

presents many diagnostic challenges. In The anatomy of the lung, lung products, cell
patients with primary immunodeficiencies, receptors, and host cellular responses all con-
the clinician is often faced with the difficulty tribute to the normal lung defense and disease
of not only diagnosing the infectious agent prevention. A defect in any of these defenses
in the lung but also determining whether this can result in an increased susceptibility to
child with “too many” respiratory infections infection.
actually has an underlying immune problem This chapter first focuses on the primary
predisposing to repeat or atypical infections. immunodeficiencies and the associated cel-
Many of the basic defects in patients with lular defects that predispose to pulmonary
the primary immunodeficiencies come into infections. In this section the discussion of
play in those who are immunosuppressed by roles of specific cell types in lung defenses
cancer chemotherapy or by specific antirejec- provides background for the discussion of
tion therapies after organ transplantation: immune defects arising from cancer chemo-
decreased number or function of B lympho- therapy or use of immunosuppressive drugs
cytes, T lymphocytes, and phagocytic cells as after organ transplantation. Although this
well. The conducting airways branch 20 to portion of the chapter cannot provide an
25 times between the trachea and the alveoli. exhaustive review of all pulmonary abnorm-
The large surface area of the conducting air- alities in primary immunodeficiency states,
ways and alveolar surfaces (>70m2 in an we will also focus on the major immunode-
adult) poses a great challenge for the lung ficiencies as examples of alterations in the
49
cellular immune system and their pulmo- immunoglobulin and T cell defects. The
nary manifestations. Readers are referred to knowledge of the genetic defects underlying
several more recent reviews for more details these immunodeficiency states continues to
on primary immunodeficiency states.1-6 grow; there are now more than 10 known
The focus of the chapter changes to the gene alterations associated with the pheno-
general principles underlying the immune type of SCID.4 As the molecular genetics
and nonimmune pulmonary complications of these diseases becomes better understood,
of cancer chemotherapy and immunosup- the ability to treat the severe forms of pri-
pressive therapy after organ transplanta- mary immunodeficiency disease with stem
tion. Many of the cellular defects described in cell transplant (SCT) or gene therapy has
the section on primary immunodeficiencies improved in recent years.
come into play in those patients with second-
ary immunocompromise. The chapter con-
cludes with a discussion of diagnostic tools Deficiencies in Immunoglobulin
available for defining the underlying causes Production
of pulmonary abnormalities in patients with
immunodeficiency or immunosuppression. Overview
IgG and IgA are found in the epithelial
airway–lining fluid and play important roles
Primary Immunodeficiencies in lung defense against bacteria. Deficien-
cies in these antibodies occur in many
This section focuses on the pulmonary mani- primary immunodeficiencies and usually
festations of primary immunodeficiency result in chronic sinopulmonary infections.
diseases. More than 100 primary immunode- Secretory IgA is the predominant immuno-
ficiency diseases are well-characterized clini- globulin isotype present in airway secretions.2
cally or at the molecular level, or both.1,4 Secretory IgA serves several functions, includ-
Antibody deficiencies are the most common ing neutralization of viruses and exotoxin,
primary immunodeficiency diseases, account- enhancement of lactoferrin and lactoperoxi-
ing for about 70% of cases.7 Patients with dase activities, and inhibition of microbial
deficiencies in antibody production typically growth. Because dimeric IgA is able to bind
acquire infections from encapsulated (Strepto- two antigens simultaneously, it is capable of
coccus pneumoniae, Haemophilus influenzae, forming large antigen-antibody complexes.
and Staphylococcus species) and gram-negative In this manner, IgA neutralizes microbes,
(Pseudomonas species) organisms. Chronic facilitates their removal by mucociliary clear-
fungal and opportunistic infections are rare. ance, inhibits microbial binding to epithelial
Viral infections are handled normally, with cells, and inhibits uptake of potential aller-
the exception of enteroviruses, which can gens. Although concentrations of IgG in
cause persistent meningoencephalitis.3,7 the upper airway are less than the concentra-
In contrast, defects in T cell function lead tions of IgA, all IgG subclasses are detectable
to infections by viruses and opportunistic in respiratory secretions, and it is the primary
organisms. Affected infants can present antibody found in lower respiratory secre-
early in life with chronic diarrhea and failure tions. As opposed to IgA, which is actively
to thrive. Persistent infections with opportu- transported into the airway, IgG reaches
nistic organisms (Candida albicans, Pneumo- the airway largely by transudation through
cystis jiroveci [formerly P. carinii]) and viral the mucosa. IgG functions by opsonizing
infections often can be fatal.3,7 Patients with microbes for phagocytosis and killing, activat-
T cell defects cannot reject allografts, placing ing the complement cascade, and neutralizing
them at risk for fatal graft-versus-host disease many bacterial endotoxins and viruses.
(GVHD) if they receive nonirradiated blood Deficiencies in IgA and IgG result in loss of
or blood product transfusions. Infants with mucosal protection against numerous patho-
severe combined immunodeficiency (SCID) gens. Selective IgA deficiency (defined by
have absent T cell and B cell function, placing a serum IgA concentration <0.05mg/mL)
them at risk for infections manifested by may be asymptomatic; it is often detected
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases 51
in healthy individuals during routine blood Patients with X-linked agammaglobulin-

donor screening. Symptomatic individuals emia have a block in differentiation at all
present with various manifestations, includ- stages of B cell development, whereas T cell
ing recurrent sinusitis, otitis media, pharyngi- numbers and function are preserved. Ini-
tis, bronchitis, pneumonia, chronic diarrhea, tially, infants with X-linked agammaglobu-
and autoimmune syndromes. Individuals linemia are protected by circulating
with associated IgE deficiency tend to have maternal antibodies, but later develop recur-
less serious pulmonary disease, in contrast to rent sinopulmonary infections and may
individuals with normal or high IgE, who in progress to bronchiectasis.9,11,12
addition to the aforementioned disorders Similar to X-linked agammaglobulinemia,
may have allergic respiratory problems and common variable immunodeficiency is
pulmonary hemosiderosis. IgA deficiency is characterized by impaired antibody pro-
associated with increased frequency of neo- duction of all major classes. In contrast to
plastic and autoimmune disorders.2 IgG defi- X-linked agammaglobulinemia, patients
ciency is associated with recurrent otitis with common variable immunodeficiency
media, sinusitis, bronchitis, and pneumonia. have normal numbers of circulating B cells;
In addition, recurrence of airway infections however, these B cells do not differentiate
may result in chronic airway injury with into antibody-secreting plasma cells. Com-
bronchiectasis more frequently in patients mon variable immunodeficiency affects
with IgG deficiency than in patients with males and females, and in some cases seems
isolated IgA deficiency. The combination of to be inherited in an autosomal domi-
altered opsonic activity and bronchiectasis nant pattern with incomplete penetrance.
can result in chronic colonization with Patients can present in infancy but may pre-
respiratory pathogens, such as Pseudomonas sent in late childhood to adulthood. Common
aeruginosa. variable immunodeficiency likely represents
Compared with IgG and IgA, IgM seems several different genetic disorders.13-16
to play little role in lung defense. Most Isolated IgA deficiency is the most com-
IgM remains in the vascular space owing to mon primary immunodeficiency disease,
its high molecular weight. IgM does gain with an incidence of 1 in 333 to 1 in 700 in
access to the airway, however, by exudation whites. The clinical manifestations of isolated
or by active secretion via secretory compo- IgA deficiency vary. Some affected patients
nents. IgM is capable of agglutinating bacte- are asymptomatic, whereas others can have
ria and activating the complement cascade. recurrent respiratory and gastrointestinal
IgE seems to participate in immunity to infections, allergy, and increased incidence
parasites. It binds to the parasites, and eosino- of autoimmune disease and malignancies.2,3
phils bind to the opsonized organisms via Because these patients can make IgG, how-
the IgE Fc receptors. Eosinophils are stimu- ever, bronchiectasis is uncommon compared
lated to release granular contents, resulting with X-linked agammaglobulinemia or com-
in lysis of the parasite. The major manifes- mon variable immunodeficiency.
tation of the presence of IgE in the respira- Isolated IgM deficiency is not associated
tory tract is related to its role in allergic with recurrent respiratory infections. Indi-
disease. viduals with IgM deficiency seem to have a
specific defect in B lymphocyte maturation,
Specific Diseases but the B lymphocytes are capable of secret-
Antibody production is altered in many pri- ing other antibody isotypes. The autosomal
mary immunodeficiency states (Table 3-1). recessive form of hyper-IgM syndrome
Severe recurrent infections associated with is caused by deficiency in nucleotide-
bronchiectasis occur with combined defi- modifying enzymes, UNG (uracil nucleoside
ciencies in IgA and IgG production. X-linked glycosylase) and AID (activation-induced
agammaglobulinemia, the first primary im- cytidine deaminase), expressed only in B
munodeficiency disease to be recognized, by cells that operate on sequential steps in anti-
Bruton in 1952,8 has been found to result body class switching.17 This form of hyper-
from mutations in Bruton tyrosine kinase.9,10 IgM syndrome is accompanied by decreased
52
Table 3-1 Primary Immunodeficiencies with Antibody Underproduction
Pulmonary Manifestations of Pediatric Diseases

GENE
DEFICIENCY INHERITANCE LOCUS GENETIC DEFECT CELLULAR DEFECTS CLINICAL FINDINGS
X-linked agammaglobulinemia X-linked Xq21.3- Deficiency in Bruton <1% circulating B cells Recurrent sinopulmonary
(Bruton agammaglobulinemia) Xq22 tyrosine kinase infections
Block in B cell differentiation Most manifest in infancy, 20%
manifest in 3-5 yr old
Deficiency in Bronchiectasis in right middle
immunoglobulins of all lobe and bases
types and isotypes
IgA deficiency Variable (1/333- 17p11 TACI Deficient isotype switch to IgA Bacterial pneumonias, sinus
1/700 births) disease
Possibly Others Associated gastrointestinal
6p21.3 infections
Increased atopy and neoplastic
and autoimmune disorders
Common variable AD with 17p11.2 TACI Impaired production of all Onset from early childhood to
immunodeficiency (likely incomplete major antibody classes adulthood
several diseases) penetrance 2q33 ICOS Absent immunoglobulins Increased susceptibility to
recurrent sinopulmonary
infections
16p11.2 Others Normal number of B cells Leads to bronchiectasis
22q13.1- Failure to differentiate into Associated with autoimmunity
22q12.21 antibody-secreting cells in 20%
Abnormal T cells in 60%
Autosomal recessive AR Mutations in m, a, l5, All isotypes, decreased B cells Severe bacterial infections
agammaglobulinemia BLNK, or LRRCE genes
Immunoglobulin heavy chain AR D14q32 D immunoglobulin Decreased IgG1, IgG2, IgG4, Recurrent bacterial infections
deletions heavy chains IgE, IgA1, IgA2
ICOS deficiency AR 2q33 Mutation in ICOS gene Decreased all isotypes Recurrent bacterial infections
Hyper-IgM syndrome AR 12p13 Mutation in AID and Decreased IgG and IgA Recurrent bacterial infections
UNG
12q23- Deficient B cell switching
2q24.1 Normal T cells
AD, autosomal dominant; AID, activation-induced cytidine deaminase; AR, autosomal recessive; ICOS, inducible T cell costimulator; TACI, transmembrane activator and calcium modulator
and cyclophilin ligand interactor; UNG, uracil nucleoside glycosylase.
levels of IgG and IgA, resulting in an defense. Bronchial-associated lymphoid tis-

increased propensity to bacterial infection sue comprises intraepithelial lymphocytes,
(see Table 3-1).17 macrophages, dendritic cells, and natural
Isolated IgE deficiency has not been killer (NK) and NK-T cells that recognize for-
reported. IgE deficiency in combination with eign substances, invading organisms or their
IgG4 deficiency has been described in a exoproducts, and products of cell injury
patient who had recurrent otitis media and using innate receptor systems. The dendritic
sinusitis. Hyper-IgE syndrome is discussed in cells or macrophages interact with them
the section focusing on phagocytic disorders. and interact with lymphocytes to create the
cellular immune responses, or to signal anti-
Diagnosis body production. These cells migrate to local
In patients with suspected immunoglobulin lymph nodes, tonsils, or adenoids; process
deficiency, quantitation of total serum IgA antigens; generate cytokines; and generate
and IgG, and IgG subclasses should be per- the adaptive immune responses. Extensive
formed along with measurement of the anti- reviews of humoral (B cell mediated) and
body response to protein (diphtheria and cellular (T cell mediated) immunity, antigen
tetanus toxoids) and polysaccharide (S. presentation, and cellular activation are well
pneumoniae, H. influenzae, Neisseria meningi- beyond the scope of this chapter; however,
tidis) vaccines. In addition, flow cytometry we briefly discuss the roles of T lympho-
to quantify B and T cell numbers and B cytes and cellular immunity with respect to
and T cell stimulation studies should be lung defense.
done if immunoglobulin levels are low. Spe- Several types of T lymphocytes contribute
cific genetic studies can be done to identify to lung immunity and tissue pathology.18-23
patients with several of the immunoglobu- Two major types of antigen receptors are
lin primary immunodeficiency diseases used by T lymphocytes—the gd T cell recep-
(see Table 3-1). tor (discussed later) and the ab receptor
(used by the CD4þ and CD8þ T cell popula-
Treatment tions). The ab T cell mounts cytolytic
IgG-deficient patients with recurrent respira-
responses to infected cells, makes cytokines,
tory tract infections often benefit from pro-
and stimulates B cell responses (see later). ab
phylactic antibiotics, intravenous gamma
T cells expressing the receptor protein, CD4,
globulin therapy, and the use of airway
are termed T helper cells. CD4þ T cells recog-
clearance techniques. Patients with selective nize antigens presented via the MHC class II
IgA deficiency are treated symptomatically antigen and provide effector function pri-
for respiratory, gastrointestinal, and aller- marily by the release of cytokines. T helper
gic problems. Because most preparations cells can be differentiated further phenotyp-
of gamma globulin contain IgA, the use of ically into Th1 and Th2 populations based
gamma globulin increases the risk of ana- on their profiles of cytokine production.
phylaxis if the recipient has anti-IgA anti- Th1 cells differentiate in the presence of
bodies. Transfusion of blood products interleukin (IL)-12 and IL-18, and produce
presents a similar problem for these indivi- interferon-g, IL-2, and tumor necrosis fac-
duals. In patients with a combined IgA and tor-a in response to antigen. These cells
IgG deficiency who need immunoglobulin have been regarded as responsible for the
therapy or the transfusion of blood pro- delayed hypersensitivity response to viral
ducts, it is crucial to ensure that the recipi- or bacterial infection, stimulating local mac-
ent does not have IgA antibodies or use a rophage activation and neutrophil recruit-
preparation that does not contain IgA. ment, and altering specific T cell responses.
Th2 cells are driven to differentiate by the
Deficiencies in Cellular Immunity presence of IL-4, and in the presence of
antigen they respond by making IL-4, IL-5,
Overview IL-10, and IL-13. These cytokines are respon-
Bronchial-associated lymphoid tissue func- sible for driving B lymphocytes to make
tions in the development of adaptive lung antibodies and lead to the recruitment and
activation of basophils and eosinophils. The births.7 Children with defects in T cell func-
Th2 phenotype has been associated with an tion can present with abnormal ability to limit
allergic/asthmatic phenotype in mouse “usual” childhood respiratory viral infections,
models and human studies.24 which can be persistent or life-threatening
ab T cells expressing CD8 are cytotoxic (e.g., respiratory syncytial virus [RSV], parain-
cells. In response to peptides presented by fluenza virus, influenza virus, and adenovi-
the MHC class I molecules, CD8þ T cells rus). Common childhood viral infections,
function in target cell toxicity. CD8þ T cell such as varicella-zoster virus and measles, can
toxicity is mediated by the release of cellular cause serious lung infections in immunode-
granules containing perforin (perturbs the ficient or immunosuppressed children. Chil-
cell membrane) and granzymes (disrupt dren with T cell immunodeficiencies are
target cells by altering intracellular targets). more susceptible to opportunistic patho-
In addition, CD8þ T cells can initiate apop- gens—agents that typically do not cause
tosis in target cells by Fas-FasL interactions. infections except in the context of immunode-
CD8þ cells reinforce viral defenses by ren- ficiency or immunosuppression, such as cyto-
dering adjacent cells resistant to infection, megalovirus (CMV) and P. jiroveci (Fig. 3-1).
presumably by release of interferons. Children with T cell deficiencies can present
Three additional subsets of T cells con- in the first months of life with diarrhea and
tribute to innate lung responses, including failure to thrive, or with persistent infections
recognition and elimination of tumor cells with Candida albicans, P. jiroveci, varicella-zos-
and certain pathogens using limited sets of ter virus, adenovirus, RSV, or CMV.7,34 Patients
conserved recognition receptors. NK cells with T cell primary immunodeficiency disease
are bone marrow–derived lymphocytes that may show abnormalities in antibody produc-
are distinct from either B or T cells. NK-T tion because B cell function in antibody pro-
cells are T cells that express the NK cell duction is T cell–dependent. T cell primary
marker, NK1, a highly restricted/limited rep- immunodeficiency disease can manifest with
ertoire of the CD3/T cell receptor complex bacterial infections as in patients with primary
with specificity for antigens presented in antibody deficiencies as described earlier.3
association with CD1. These cells most Severe combined immunodeficiency
closely resemble CD4þ T cells in terms of (SCID) is an immunodeficiency character-
cytokine production. Finally, gd T cells have ized by a severe reduction in the number
a limited diversity of T cell receptors that or function of T cells, which results in the
recognize self and bacterial/protozoan anti- absence of adaptive responses (Table 3-2).
gens. These innate lymphocytes are consid-
ered to be a first line of defense against
tumors and infection, and in modulating
inflammation in the lung.25,26
T cell responses are tightly regulated. T cell
responses are necessary to eliminate patho-
gens and for immune memory; lack of T cell
function can lead to serious life-threatening
infections.1,3,4,6,7,27 Uncontrolled responses
can cause autoimmune inflammatory dis-
eases, however.28-33 In this section, we dis-
cuss primary immunodeficiency disease
associated with T lymphocyte dysfunctions.
Specific Diseases
Mutations in the function of B cells or T cells Figure 3-1. Chest radiograph shows bilateral interstitial
result in immunodeficiencies of antibody pro- and alveolar infiltrates in a child with acute lymphocytic
duction, cellular immunity, or both. The inci- leukemia and Pneumocystis jiroveci (formerly P. carinii)
pneumonia. (From Long S, et al: Principles and Practice of
dence of these deficiencies is unknown, but Pediatric Infectious Disease, 2nd ed. Philadelphia, Churchill
has been estimated to be 1 in 10,000 live Livingstone, 2003. page 578)
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases
Table 3-2 Primary Immunodeficiencies with T Cell Defects (Examples)
GENE
TBþNK SCID
gc deficiency XL Xq13.1 Mutations in common g chain of IL-2, Markedly decreased Severe infections with opportunistic organisms
IL-4, IL-7, IL-9, IL-15, and IL-21 natural killer cells soon after neonatal period
Markedly decreased Manifest with failure to thrive, chronic diarrhea,
T cells persistent thrush, pneumonia, sepsis
Decreased serum
immunoglobulin
CD45 deficiency AR 1q31- Mutation in CD45 gene As per gc SCID As above
1q32
Jak3 deficiency AR 19p13.1 Janus kinase-3 deficiency (Jak3) As per gc SCID As above
TBþNKþ SCID
IL7Ra deficiency AR 5p13 Mutation in IL7RA gene Marked decrease in As above
T cells
Decreased serum
immunoglobulin
CD3d deficiency AR 11q23 Mutation in CD3D gene As per IL7Ra As above
CD3e deficiency AR 11q23 Mutation in CD3E gene As per IL7Ra As above
TBNK SCID
ADA deficiency AR 20q13.11 Mutation in ADA gene As per gc SCID As above
Axial skeletal abnormalities
(Continued)
55
56
Table 3-2 Primary Immunodeficiencies with T Cell Defects (Examples)—Cont’d
GENE
TBNKþ SCID
RAG1/2 AR 11p13 Mutation in RAG-1 or RAG-2 Markedly decreased T As above
deficiency and B cell numbers
Decreased serum
immunoglobulin
Defective VDJ
recombination
Artemis AR 10p13 Mutation in artemis gene As above for RAG1/2 As above
deficiency
Other T Cell Defects
X-linked hyper- XL Xq26- Mutations in CD40 ligand (CD154) Normal T cells Neutropenia, thrombocytopenia, opportunistic
IgM syndrome Xq27 Only IgM and IgD infections
bearing B cells
Neutropenia
CD8 deficiency AR 2q12 Mutation in CD8A gene Absent CD8, normal As for Artemis
CD4 numbers
TAP-1 and TAP-2 AR 6p21.3 Mutation in TAP-1 or TAP-2 As for CD8 deficiency As for CD8, vasculitis occurs
deficiency
DiGeorge AD 22q11.2 TBX1 Decreased or absent Cardiac and thymic defects, variable TCID
syndrome CD3þ cells
AD, autosomal dominant; AR, autosomal recessive; SCID, severe combined immunodeficiency; TCID, T cell immunodeficiency; XL, X-linked.
This disease phenotype is the consequence deficiency. DiGeorge syndrome is usually

of mutations in at least 10 different genes due to gene defects on chromosome 22,
located on six different chromosomes (see leading to abnormal development of the
Table 3-2).4,5 Four lymphocyte phenotypes third and fourth pharyngeal pouches dur-
have been identified associated with SCID, ing embryogenesis. This leads to aberrant
based on the effects of the mutation on development of several organs, including
T cell, B cell, and NK cell maturation the thymus, parathyroid glands, and heart.
(TBþNKþ, TBþNK, TBNKþ, TBNK) The degree of thymic hypoplasia varies,
(see Table 3-2). SCID causes severe infec- resulting in a variable severity in the T cell
tions with opportunistic infections in the deficiency.3,36 In 80% of patients, the
neonatal period. immunodeficiency is mild. Severe T cell
Because of lack of graft rejection capabil- deficiency and secondary deficient anti-
ity, these infants are at risk for GVHD if body responses can result from the thymic
transfused with nonirradiated blood prod- hypoplasia, however, leading to a severe
ucts. They are also at risk for severe systemic disease phenotype (approaching SCID in
infection when immunized with live viruses severity). It is important to evaluate the
(e.g., polio, measles, or varicella) or with presence of a thymus in patients with con-
bacille Calmette-Guérin. Diagnosis is possi- otruncal cardiac defects and hypocalcemia
ble at birth, with most affected infants hav- because the T cell deficiency in DiGeorge
ing lymphopenia (<2000 lymphocytes/mL syndrome places these patients at risk of
blood) and decreased in vitro proliferation GVHD after transfusion with nonirradiated
studies.5 Even in the absence of a normal blood products.3,36
thymus, T cell development can be Not all T cell immunodeficiencies mani-
achieved after SCT, and this is the standard fest with a severe propensity for infections.
of care for these infants. Survival is Isolated CD8þ T cell developmental and sig-
improved if SCT occurs within the first 4 naling defects can have a milder form of
weeks of life.5 The improved survival of immunodeficiency. Mutations in the CD8a
early transplants is attributed to the acqui- molecule prevent the final assembly of the
sition of opportunistic infections and their CD8þ T cell receptor signaling complex.
complications. Mutations in the MHC-1 molecule (binds
The X-linked form of hyper-IgM syndrome to the T cell receptor) caused by TAP1/TAP2
is caused by a defect in the CD40 ligand mutations or a mutation in the TAP-binding
(CD40L) expressed by activated CD4þ T cells protein prevent normal antigen presenta-
(see Table 3-2). The CD40-CD40L interaction tion to the T cell receptor. These mutations
is crucial in B cell–T cell signaling. A defect cause a deficiency in CD8þ T cell function
in this interaction results in normal to ele- but no deficiency in the CD4þ T cells,
vated IgM; reduced serum IgG, IgA, and and lead to a milder disease phenotype
IgE; and reduced memory B cells.17,35 In (see Table 3-2).1,5-7
addition to the immunoglobulin defects, The dysregulation of cellular immunity can
patients with X-linked hyper-IgM syn- lead to immunodeficiency, autoimmunity,
drome have opportunistic infections, neu- and malignancy, as described previously for
tropenia, thrombocytopenia, seronegative X-linked hyper-IgM syndrome (Table 3-3).
arthritis, inflammatory bowel disease, and Wiskott-Aldrich syndrome is an X-linked dis-
greater likelihood of malignancies. The order characterized by eczema, thrombocyto-
increased risk of opportunistic infections, penia with small defective platelets, and
autoimmune diseases, and malignancies is recurrent infections. Patients with Wiskott-
attributed to defective T cell–antigen-pre- Aldrich syndrome have impaired response to
senting cell interactions owing to the polysaccharides and protein antigens and
CD40L defect. P. jiroveci pneumonia has aberrant T cell function.37 Systemic and
been reported in 40% of patients with chronic sinopulmonary infections develop
mutations in CD40L. in the first year of life. Pulmonary infections
The cellular immunodeficiency in DiGeorge can be caused by encapsulated bacteria
syndrome results from primary T cell (S. pneumoniae), viruses (herpes simplex virus),
58
Table 3-3 Other Defined Immunodeficiency Syndromes with Autoimmunity or Malignancies
GENETIC
DEFICIENCY INHERITANCE GENE LOCUS DEFECT CELLULAR DEFECTS CLINICAL FINDINGS
Wiskott-Aldrich XL Xp11.22-11.23 Mutation in Cytoskeletal defect Thrombocytopenia
syndrome WASP gene affecting Immunodeficiency
hematopoietic stem
cell derivatives Autoimmune disease
Malignancy
Progressive decrease in T cells
Ataxia-telangiectasia AR 11q22-q23 ATM Disorder of cell cycle Thymic hypoplasia
checkpoint leading to Increased a-fetoprotein
chromosomal
instability Telangiectasia
Sensitivity to Ionizing Radiation
Increased risk of malignancies, particularly lymphoid
X-linked XL Xq25 SH2D1A Altered adapter protein Uncontrolled T cell proliferation in Epstein-Barr virus
lymphoproliferative regulating intracellular infection, fatal mononucleosis, ineffective viral
disease signaling elimination, lymphoma, hypogammaglobulinemia
ALPS1a AR 10q24.1 CD95 Excessive CD4CD8 ab Autoimmunity
TCRþ T cells Hypergammaglobulinemia
Defective lymphocyte Lymphoproliferation
apoptosis
Increased risk of lymphoma
ALPS1b AR 1q23 CD95L As above As above, plus lupus syndrome
ALPS2b AR 2q33-2q34 CASP8 Defective lymphocyte Recurrent bacterial and viral infections
apoptosis and Autoimmunity, hypergammaglobulinemia,
activation lymphoproliferation
ALPS, autoimmune lymphoproliferative syndrome; AR, autosomal recessive; CASP, caspase; SH2D1A, gene encoding SAP (signaling lymphocytic activation molecule [SLAM]-associated protein);
XL, X-linked.
or opportunistic organisms (P. jiroveci).3,37 Treatment

Patients rarely survive beyond teenage years Treatment depends on the specific immuno-
without SCT. Death usually results from infec- deficiency. Prophylactic antibiotics, antiviral
tion, vasculitis, autoimmune cell cytopenias, agents, or intravenous immunoglobulin can
or lymphoreticular malignancy.37 be used to prevent or ameliorate serious infec-
Ataxia telangiectasia is another complex tions.40 For severe T cell deficiency, SCT early
disease resulting from a disorder of cell cycle in life can be lifesaving. Thymic transplants
regulation that leads to chromosomal have been performed to reconstitute the T cell
instability. Ataxia telangiectasia represents a defects in DiGeorge syndrome.36 Gene therapy
combined immunodeficiency associated has been investigated for specific primary
with neurologic, cutaneous, and immune immunodeficiency disease, but success has
abnormalities.7 These patients have recur- been tempered by the occurrence of leukemia
rent sinopulmonary infection. Their cells in subjects resulting from the insertion of the
have defective DNA repair and are sensitive retrovirus vectors near oncogenes.41 Newer vec-
to ionizing radiation. A concern is that tors may improve the safety of this mode of
repeated exposure to x-rays used in usual therapy.
diagnostic studies places them at risk for lym-
phoreticular cancers and adenocarcinoma.38
Several cellular defects can result in Deficiencies in Phagocyte Numbers,
unchecked cell proliferation and susceptibil- Function, and Opsonization
ity to infections and to tumors. X-linked lym-
phoproliferative disease is another example of Overview
immunodeficiency from aberrant cellular Neutrophils constitute about half the circulat-
control (see Table 3-3). In X-linked lympho- ing white blood cell population, and their pri-
proliferative disease, there is failure to control mary function is phagocytosis and killing of
proliferation of cytotoxic T cells after infection invading pathogens. For the neutrophil to
with Epstein-Barr virus (EBV).39 The most accomplish this, it must respond to signals in
common presentation is severe infectious the area of injury; adhere and transmigrate
mononucleosis, which is fatal in 80% of through the vascular endothelium; migrate to
patients. The defect is in the gene encoding the area of infection; and recognize the patho-
an adapter protein, SH2D1A, a protein that gen, phagocytose, and kill it. Interruption of
helps regulate the proliferation of T cells any of these steps would leave the host suscep-
and NK cells. Autoimmune lymphoproli- tible to infections. When the neutrophil has
ferative syndrome results from defects in migrated into the tissue, its primary purpose
cellular apoptosis (regulated cell death) is to recognize, ingest, and destroy pathogens.
mediated by CD95 (FAS). These patients have Phagocytosis comprises two steps: recognition
autoimmunity, hypergammaglobulinemia, and internalization of the foreign material into
lymphoproliferation, and excessive numbers the phagosome. Killing or neutralization
of CD3þ, CD4, and CD8 T lymphocytes involves a secretory response. Materials may
(see Table 3-3).5 bind directly to the neutrophil, resulting in
ingestion, or opsonization by serum proteins
occurs. Neutrophils exhibit specific Fc-
Diagnosis mediated binding and nonspecific binding
In an infant with possible T cell deficiency, using complement receptors CR1 and CR3.
total blood lymphocyte counts are a reason- Intracellular killing generally is associated with
able place to begin for diagnosis. Functional the initiation of the respiratory burst. The
studies (immunoglobulin responses to pro- importance of this process is shown by
tein and polysaccharide antigen immuniza- patients with chronic granulomatous disease
tions), activation studies, and B, T, and NK (discussed later), whose neutrophils cannot
cell markers can define the nature of the undergo the oxidative burst.42 Deficiencies in
deficiency further. Finally, specific genetic neutrophil numbers, ability to migrate, opso-
studies can be conducted to identify several nization, phagocytosis, or function can render
of the defined mutant genes. the host susceptible to infection (Table 3-4).
60
Table 3-4 Examples of Immunodeficiency Syndromes with Abnormal Neutrophils, Chemotaxis, or Opsonization

GENETIC
DEFICIENCY INHERITANCE GENE LOCUS DEFECT CELLULAR DEFECTS CLINICAL FINDINGS
Neutrophil Numbers
Kostmann syndrome AD 19p13.3 or 1p22 Defects in ELA2 Mistrafficking or repression Neutropenia
or Gfi1 of neutrophil elastase Susceptibility to bacterial and
fungal infections
Congenital neutropenia AD 19p13.3 ELA2 defect As per Kostmann syndrome As above
Cyclic neutropenia AD 19p13.3 ELA2 defect As per Kostmann syndrome Susceptibility to infection at
nadir of neutrophil counts
X-linked neutropenia XL Xp11.22-11.23 WASP Defective regulator of actin Neutropenia, infections as per
cytoskeleton Kostmann syndrome
Chemotaxis
LAD1 AR 21q22.3 INTG2 (CD18) Defective neutrophil and Delayed umbilical stump
lymphocyte migration separation, recurrent gingivitis
from blood
Lack CD18 Absent tissue neutrophils, blood
neutrophilia
Function
Hyper-IgE syndrome ADv 4q21 Unknown Unknown High IgE and eosinophilia
Skin abscesses, pneumonia with
pneumatocele formation
CGD AD Xp23 CYBB;gp91phox Absent cytochrome b 70% Granulomatous lesions of lung,
of cases skin, lymph nodes, and liver:
XL 16q24 CYBA;p22phox Absent cytochrome b <5% Staphylococcus aureus,
of cases Burkholderia cepacia,
Serratia marcescens, Nocardia
AR 7q11.23 NCF1;p67phox Cytochrome positive and Aspergillus species
1q225 NCF2;p67phox
IFNgR1 deficiency AR, AD 6q23 IfngR1 Loss of IFN-g binding Severe infections: Salmonella,
HSV, CMV, parainfluenza, RSV,
mycobacteria
IFNgR2 deficiency AR, AD 21q22 IfngR2 Loss of IFN-g binding As above
Opsonization
Complement C2 AR 6p21.3 C2 defect Absent complement activity Pyogenic infection, vasculitis,
SLE-like
Complement C3 AR 19p13.3-p13.2 C3 defect As above Recurrent pyogenic infections
MBL deficiency AR 10q11.2-q21 MBL2 Deficiency in MBL2 Increased pyogenic infections
and sepsis
AR, autosomal recessive; AD, autosomal dominant; ADv, autosomal dominant with variable penetrance; CGD, chronic granulomatous disease; CMV, cytomegalovirus; HSV, herpes simplex
virus; IFN-g, interferon-g; LAD, leukocyte adhesion defect; MBL, mannose binding lectin; RSV, respiratory syncytial virus; SLE, systemic lupus erythematosus; XL, X-linked.
Specific Diseases the reduced nicotinamide adenine dinucleo-

Defects in neutrophil numbers, such as tide phosphate (NADPH) oxidase complex
Kostmann syndrome and cyclic neutropenia, responsible for production of superoxide.3,46
can result from a deficiency in elastase 2 Onset of the disease occurs early in life, with
(see Table 3-4). In cyclic neutropenia, periph- pulmonary infection the most frequent
eral blood counts oscillate in about a 21-day presentation, with fungal organisms pre-
cycle with a nadir approaching an absolute dominating.3,46 Five organisms cause most
neutrophil count (ANC) of 0 and a peak near infections in chronic granulomatous disease:
normal. Life-threatening infections occur S. aureus, Burkholderia cepacia, Serratia marces-
during days around the nadir of neutrophil cens, Nocardia species, and Aspergillus species.
counts. In Kostmann syndrome, the neutro- Bacteremia is rare. Patients with mutations
penia is static. One variant of Kostmann syn- leading to the complete loss of the inter-
drome is caused by a deficiency in ELA2 feron-g receptors (IFNgR1 and IFNgR2) are less
(coding for neutrophil elastase 2). Mutations capable of killing mycobacteria and intracellu-
causing a deficiency of Gfi1 (a zinc finger lar organisms. These patients have been iden-
transcriptional repressor oncoprotein) result tified because of extreme susceptibility to
in ELA2 deficiency and neutropenia.43,44 nontuberculous mycobacteria.46 Viral agents,
Deficiencies in neutrophil migration from including herpes simplex virus, CMV, and
the circulation can result in recurrent infec- RSV, also present severe problems. Mortality
tions. Patients with leukocyte adhesion defi- is high because of recurrent severe infection.
ciency are unable to recruit neutrophils into Opsonization is necessary for neutrophil
sites of inflammation, and, as a result, they killing of several organisms. Serum proteins
sustain recurrent, life-threatening infec- reach the lung through transudation in
tions.45 Patients with leukocyte adhesion response to inflammation, including the
deficiency lack the normal b2 integrins to complement family and mannose-binding
allow neutrophil recruitment from the cir- lectin (MBL) (see Table 3-4). The comple-
culation. These patients have peripheral ment protein cascade is activated by three
neutrophilia, but do not form pus and have independent pathways: (1) the classic path-
difficulty localizing infections because of way, which is activated by antigen-antibody
their defect in neutrophil migration. Recur- complexes (involving IgG or IgM); (2) the
rent infections of the skin, upper and lower alternative pathway, which is activated by
airways, bowel, and perirectal area are com- foreign carbohydrates, such as bacterial
mon and are usually caused by Staphyloccocus and fungal components; and (3) the lectin
aureus or gram-negative bacilli.46 pathway (involving MBL44). The comple-
When neutrophils arrive at the site of ment system functions to coat foreign parti-
infection, defective function can limit their cles in opsonin via the alternative pathway,
ability to clear infection. Job syndrome making the particles more likely to be pha-
(hyper-IgE syndrome) is caused by an gocytosed, to activate phagocytic cells by
unclear defect in phagocyte function and is the local release of chemotactic agents such
characterized by recurrent skin and lower as C5a, and to lyse cells through the activa-
respiratory tract infections, eczema, elevated tion of the late complement components
IgE levels, and eosinophilia. Symptoms C5, C6, C7, C8, and C9 (the membrane
occur within the first month of life with attack complex). Other important aspects
severe eczema, mucocutaneous infections, of the complement pathway are the genera-
sinusitis, and lower respiratory tract infection of anaphylatoxins, such as C3a and
tions with S. aureus or H. influenzae. Devel- C5a, which cause the release of vasoactive
opment of empyema, lung abscesses, and mediators from mast cells, and the genera-
persistent pneumatoceles is common. tion of C3b and C4 on the cell surface,
Chronic granulomatous disease is the most where they interact with specific receptors
common phagocyte disorder, with the on phagocytic cells.47
X-linked form accounting for two thirds of Complement deficiency is associated with
the reported cases (see Table 3-4). Chronic recurrent infections, glomerulonephritis, or
granulomatous disease is caused by defects in collagen vascular diseases such as systemic
lupus erythematosus. Early complement defi- IFNgR1, and IFNgR2) can be measured using
ciencies are associated with systemic lupus flow cytometry. Oxidative burst can be meas-
erythematosus, glomerulonephritis, or other ured using assays for superoxide production
rheumatologic diseases. Pneumonia has been or by measuring NADPH oxidoreductase func-
described in association with C1 deficiency, tion in specialized laboratories. Measuring
although bacterial meningitis is a more com- the CH50 or AH50 can perform functional
mon manifestation. Pneumonia complicated screening for complement deficiency. Specific
by empyema, pneumatoceles, and liver complement components and MBL can be
abscesses has been described as a consequence measured using immunoassays.
of C1r deficiency. Autoimmune disorders
are associated with C2 and C4 deficiency, Treatment
although bacterial infections also occur in Cyclic neutropenia and congenital neutrope-
children with C2 deficiency (the most com- nias can be treated with granulocyte colony-
mon complement deficiency). C3 deficiency stimulating factor.43 Prophylactic antibiotics
(clinically the most severe and least common and antifungal agents, and aggressive therapy
of the complement deficiencies) is associated during acute infections are keys for long-term
with autoimmune disorders and recurrent survival. Patients with chronic granuloma-
infections. C3 acts as an opsonizing agent tous disease also are treated with prophylactic
and plays roles in the classic and alternative trimethoprim-sulfamethoxazole, antifungal
pathways. C3 deficiency results in otitis therapy, and recombinant human inter-
media, pneumonia, sepsis, meningitis, and feron-g. In addition, SCT has been performed
osteomyelitis, most commonly caused by with success in patients with chronic granulo-
S. pneumoniae, N. meningitidis, Klebsiella spe- matous disease.43,46 Treatment of opsonic
cies, Escherichia coli, and Streptococcus pyogenes. defects (complement and MBL) also involves
C5 deficiency produces a complex defect prophylactic antibiotics and immunization
owing to the loss of chemotactic and anaphyla- against encapsulated organisms. Replacement
toxin activities; it leads to decreased lung therapy is usually ineffective.
clearance of S. pneumoniae, but not S. aureus,
in C5-deficient mice. The late complement
deficiencies (C5 through C9) impair serum bac- Secondary
tericidal and cytolytic activities. Susceptibility Immunodeficiencies
to systemic infection with encapsulated organ-
isms, such as N. meningitidis and S. pneumoniae, Overview
is increased; however, pulmonary infections
are uncommon. C3 deficiency manifests with Predisposition to infection occurs when there
the most severe disease phenotype.44 is an imbalance between the invading organ-
MBL also participates in opsonization ism and the host’s ability to prevent the infec-
through activation of the complement path- tion. This imbalance can occur because of the
way.44 MBL deficiency is common, occurring organism itself (portal of entry, type of organ-
in 10% of the general population.48 Although ism, antibiotic resistance, virulence factors) or
infections are uncommon in healthy individ- host factors that prevent the ability of the host
uals, MBL deficiency in patients receiving che- to prevent or limit invasion. Host defenses
motherapy or SCT or with specific leukemias consist of innate and adaptive processes.
can result in suppression of phagocytic activ- Innate immunity provides the initial defense
ity. MBL deficiency is associated with autoim- against infection, whereas adaptive immunity
mune and inflammatory diseases.48 develops slowly and provides specific defense
against specific invading organisms and mem-
Diagnosis ory to protect from reinfection.
Assessment of neutrophil deficiency begins Earlier in this chapter, we discussed pri-
with performing cell counts and assessing mary defects in the immune system and
the ANC. Specialized laboratories can perform how they predispose to infections. In this
specific measures of neutrophil chemotaxis section, the focus is on secondary immuno-
and oxidative burst. Receptor levels (CD18, deficiencies that arise after childhood
cancers and chemotherapy, and related to respiratory epithelium also serves functions
transplantation (heart, liver, kidney, and in the regulation of water and ion movement
lung transplantation, and SCT). Many of into the airway mucus,51 and serves as its
the concepts presented earlier apply to the own reservoir for injury repair.50
secondary immunodeficient states. Defi- The respiratory epithelium also performs
cient numbers of lymphocytes or phago- more specific interactions with the innate
cytic cells or defective functions that can and adaptive immune systems. Alveolar type
occur in the primary immunodeficiency dis- II cells manufacture surfactant proteins A and
ease also can occur secondary to the under- D (described later).52,53 The respiratory epi-
lying malignancy, chemotherapeutic agents thelium can be induced to produce numer-
used for the cancer, or immunosuppression ous bioactive cytokines,54 and express
after transplantation. The common themes numerous adhesion molecules that support
and several disease-related processes that interactions between the epithelial cell and
occur and predispose the host to lung com- inflammatory cells recruited to the lung.
plications are reviewed. We first consider The other epithelial layers throughout the
the broad issues that apply in the secondary body serve similar functions. Disruption of
immunodeficiency states in general, then the epithelial layer by injury caused by che-
focus on problems specific to cancer chemo- motherapeutic agents, irradiation, or GVHD
therapy, solid organ transplantation, SCT, can allow invasion by potentially pathogenic
and lung transplantation. organisms, such as S. aureus, gram-negative
bacilli, and Candida species, which normally
colonize the various epithelial surfaces.
Factors Contributing to the Bypassing the epithelial barrier by transcuta-
Secondary Immunodeficient State neous catheters provides potential routes of
entry for infection. Treatment with broad-
The airway epithelium is more than a pas- spectrum antibiotics reduces the normal flora
sive barrier to airway water loss or a passive at the epithelial surfaces, allowing over-
fortification against bacterial and viral infec- growth of potentially more invasive organ-
tion. Published data support the active par- isms and potentially selecting for antibiotic-
ticipation of the airway epithelium in the resistant organisms (Table 3-5).
regulation of airway smooth muscle tone, The underlying disease state or chemother-
the physical removal of inhaled substances apy (cytotoxic or immunosuppressive) can
through ciliary clearance, and secreting or alter the numbers or function of lymphocytes
transporting broad-spectrum antimicrobial and phagocytic cells, resulting in immunode-
substances. Finally, the respiratory epithelium ficient states similar to those discussed earlier
is a functional interface between the patho- in the sections on primary immunodeficiency
gen and innate or adaptive immune response. disease. Organ failure resulting from the under-
The airway epithelium is a pivotal structure lying disease state or secondary to chemother-
in respiratory physiology and pathology. apy can reduce further the host defenses to
The respiratory epithelium participates in infection (e.g., renal failure with uremia, liver
passive lung immunity in many different failure with loss of complement or MBL
ways. The epithelium presents a physical bar- production, splenectomy secondary to malig-
rier to viral and bacterial invasion, lining the nancy). Thrombocytopenia may reduce heal-
respiratory tract from the nose to the alveoli ing, extending the duration of breakdown of
with a wide range of cell phenotypes.49,50 Cil- the epithelial barriers. The underlying disease
iated epithelial cells are important in moving or its treatment can alter the nutritional state
mucus up the airway, removing particulate of the patient, further limiting healing and
material, and injury to these cells by agents epithelial barrier functions (see Table 3-5).
such as oxidants can alter ability to remove Moreover, the patient’s previous “immune
mucus from the airway. Tracheobronchial experience” can alter his or her ability to fight
glands and goblet cells are important sources infection. Preexisting antibody or immune
of airway mucus, which nonspecifically traps memory can help protect the patient when sub-
particulates and potential pathogens. The sequently exposed to the potentially infectious
Factors Predisposing to Infection and Pulmonary Complications after Cancer Therapy

Table 3-5 or Organ Transplantation
Underlying Disease
Alteration in neutrophil, lymphocyte, or platelet function secondary to underlying disease, malignancy,
or autoimmune state
Organ dysfunction secondary to underlying malignancy or autoimmune state
Change in Physical Barriers
Breakdown in physical barriers owing to mucositis, defective healing, chemotherapy, graft-versus-host disease
Changes in colonizing bacteria and fungi
New routes of entry (intravenous catheters, shunts)
Use of Broad-Spectrum Antibiotic Therapy for Acute Infections or Prophylaxis (“Rule Out” Infection)
Eliminate normal flora and allow secondary bacterial or fungal overgrowth
Select resistant organisms
Quantitative Defects in Normal Circulating Blood Cells
Neutropenia
Lymphopenia
Thrombocytopenia
Qualitative Differences in Function of Lymphocytes and Phagocytic Cells
Lymphocytes: antibody production and cytotoxic cells
Neutrophil and macrophage functional defects
Defective wound healing
Organ Dysfunction
Liver, heart, or renal failure; asplenia or splenic hypofunction
Epithelial defects allowing bacterial invasion
Diabetes mellitus
Nutritional Defects
Iron deficiency
Vitamin deficiency
Catabolic state
Previous Infections
Colonization (respiratory, gut, renal system)
Previous viral infections with persistent virus (EBV, CMV, HSV, herpesvirus 6)
Preexisting immunity owing to immunization or infection
Concurrent Infection
Infections acquired from donor organs or blood products
Naturally occurring infection that causes further immunosuppression
CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus.
agent. CMV is a good example of an opportu- or as complications to the cancer therapy

nistic infection that can be ameliorated if the (Table 3-6). Superior vena cava syndrome and
patient had previous immune experience or tracheal compression can complicate the ini-
exposure. Alternatively, CMV infection can be tial presentation of tumors or tumor ther-
life-threatening in a patient on chemotherapy apy (see Chapter 7). Space-occupying tumors
or immunosuppressants after organ transplan- (non-Hodgkin lymphoma, Hodgkin disease,
tation with no previous immune experience. acute lymphoblastic leukemia, neuroblastoma,
Ewing sarcoma, thyroid tumors, thymoma,
Pulmonary Complications of Cancer rhabdomyosarcoma) can cause obstruction or
Therapy compression of the superior vena cava and tra-
chea, resulting in respiratory distress. Superior
Pulmonary complications of cancer therapy vena cava syndrome also can be a complica-
can arise from the primary malignancy, from tion of thrombosis secondary to central lines
infections resulting from immunosuppression, in cancer patients. Patients may complain of
Table 3-6 Pulmonary Complications of Malignancies, Transplantation, and Related Medications
COMPLICATIONS OF UNDERLYING INFECTIOUS NONINFECTIOUS

MALIGNANCY COMPLICATIONS COMPLICATIONS
Immunosuppression (related to primary Bacterial infection Alveolar hemorrhage
neoplasm or secondary to chemotherapy
or radiation therapy)
Pulmonary invasion Viruses (HSV, EBV, VZV, Superior vena cava
RSV, adenovirus) syndrome or superior
mediastinal syndrome
Airway obstruction with secondary infection Mycobacteria (M. Drug reactions
tuberculosis and atypical
mycobacteria)
Leukemia and lymphomatous involvement Fungi (Aspergillus, Secondary neoplasms
with Nocardia, Pneumocystis) Pulmonary embolism
Leukostasis Pulmonary edema
Leukemic cell lysis Airway obstruction owing
Hyperleukocytic reaction to mucositis
ARDS, acute lung injury
Interstitial pneumonitis
(drug or radiation induced)
ARDS, acute respiratory distress syndrome; EBV, Epstein-Barr virus; HSV, herpes simplex virus; RSV, respiratory syncytial virus;
VZV, varicella-zoster virus.
dyspnea, orthopnea, hoarseness, chest pain, tumors within the thoracic or abdominal cav-
cough, or syncope. On examination, patients ities can impair normal excursion of the dia-
may present with signs of superior vena cava phragm, impair normal chest wall motion,
obstruction (cyanosis, swelling of face, neck, or decrease available volume for lung expan-
or upper arms), stridor or wheezing, and signs sion. Benign tumors (ganglioneuroma, tera-
of pleural or pericardial effusions.55 In these toma) can grow slowly and allow the child
patients, presentation with signs and symp- to adapt to the pulmonary function abnor-
toms of airway obstruction can be a medical/ mality with minimal symptoms until critical
surgical emergency. Surgical airway manage- restrictive deficits are present. Likewise,
ment can be lifesaving. Occasionally, airway slow-growing tumors in the neck or mediasti-
decompression must be accomplished with num can cause upper airway or tracheal com-
radiation therapy, steroids, or other chemo- pression. Primary lung tumors are rare in
therapeutic agents.55 children56; however, secondary invasion can
The hyperleukocytosis syndrome (cells occur. Lung tumors may manifest as hemop-
>100,000/mL) can occur in 50% of children tysis or postobstructive pneumonias, and usu-
with acute lymphoblastic leukemia and acute ally manifest in an advanced state. In
myeloblastic leukemia in the chronic phase addition, extrinsic compression of an airway
(see Chapter 7). Pulmonary injury is the result can occur as a result of tumor or adenopathy,
of hyperviscosity leading to sluggish blood leading to stridor, wheezing, or postobstruc-
flow and aggregation of leukeuric cells; this tive pneumonia. Secondary invasive solid
can lead to oxygenation defects and pulmo- tumors (Ewing sarcoma, neuroblastoma) on
nary endothelial injury, leading to pulmo- either side of the diaphragm can lead to pul-
nary hemorrhage. Chest radiographs show monary impairment—intrathoracic tumors
diffuse interstitial haziness. Therapy is aimed by decreasing available space for lung expan-
at decreasing the circulating cell numbers, sion; extrathoracic tumors by impeding dia-
and includes leukapheresis and exchange phragmatic excursion—leading to restrictive
transfusion.55 lung disease. Finally, intracranial tumors can
Tumors can lead to pulmonary dysfunction lead to central apnea or central hypoventila-
by occupying space (see Chapter 7). Large tion syndromes.55
Treatment of tumors with chemothera- (see Table 3-7). Chronic side effects include
peutic agents or radiation therapy can lead diffuse alveolar damage, interstitial fibrosis,
to secondary pulmonary complications interstitial pneumonitis, and bronchiolitis
(Table 3-7). Improved cancer survival has obliterans syndrome. In addition, radiation
led to increasing awareness of short-term therapy to the lungs, mediastinal structures,
and long-term pulmonary complications of and vertebrae can cause abnormal growth
cancer therapies (chemotherapy and radia- and lead to restrictive lung disease as the child
tion therapy).55,57-60 In addition to causing continues to grow.
direct injury to the lung itself, disruption Pulmonary infections are common com-
of the epithelial barriers or host primary plications of cancer therapies.55,61 Neutro-
defenses by cancer therapy (radiation ther- penia and subsequent infection are major
apy, cancer chemotherapy, immunosuppres- dose-limiting complications of these thera-
sive agents) or secondary organ dysfunction pies. Neutropenia is defined as an ANC of
(kidney, liver, heart) can lead to pulmonary less than 1500/mL, and the risk of infection
dysfunction or pneumonia (see Tables 3-5 increases with ANC values of less than 1000/
and 3-6). mL. The magnitude and duration of the neu-
Acute and chronic side effects of chemo- tropenia determine the risk of infection by
therapy have been recognized (see Table 3-7). many agents (see Table 3-6).55,61 Chemother-
Acute side effects include hypersensiti- apy can result in altered neutrophil function,
vity reactions, bronchospasm, and urticaria breakdown of mucosal barriers, and other
Table 3-7 Complications of Chemotherapeutic Agents
IMMEDIATE/SHORT-TERM COMPLICATIONS
Agent Complication
Carboplatin Hypersensitivity
Etoposide Hypersensitivity
Asparaginase Hypersensitivity
Vindesine Bronchospasm
Vinblastine Bronchospasm
Cyclophosphamide Urticaria, angioedema
LONG-TERM COMPLICATIONS
Agent Complication
Radiation therapy Pneumonitis, fibrosis
Bleomycin Diffuse alveolar damage, interstitial fibrosis/pneumonia, bronchiolitis
obliterans syndrome
Alkylating Agents
Busulfan Diffuse alveolar damage, interstitial fibrosis
Cyclophosphamide Diffuse alveolar damage, interstitial pneumonia, interstitial fibrosis,
diffuse pulmonary hemorrhage
Melphalan Diffuse alveolar damage, interstitial fibrosis
Nitrosoureas
Carmustine Diffuse alveolar damage, interstitial pneumonitis
Lomustine Diffuse alveolar damage, interstitial pneumonitis
Semustine Diffuse alveolar damage, interstitial pneumonitis
VM-26 Noncardiogenic pulmonary edema
Cyclophosphamide Noncardiogenic pulmonary edema
Cytarabine Noncardiogenic pulmonary edema, pulmonary hemorrhage
Methotrexate Noncardiogenic pulmonary edema, hypersensitivity pneumonitis
dysfunctions (organ dysfunction, nutrition; the surface of donor cells, or recipient anti-
summarized in Table 3-5) that allow microbial gen-presenting cell presentation of donor-
invasion, or prevent the child from fighting derived peptides for solid organ transplants
infection or healing mucosal surfaces appro- (Fig. 3-2). SCT is different because the donor
priately.55,61,62 Alkylating agents, purine ana- T cells engraft, then respond to the recipient
logues, and newer monoclonal antibody (GVHD). The ablative therapy before SCT
regimens can cause prolonged, severe, multili- removes host T cells. The immunosuppres-
neage cytopenias.62 These infections include sive agents involve many classes of drugs
common bacterial pathogens at the skin often used in combination, which differ in
(S. aureus, other staphylococci, gram-negative their specificity for cell types or subtypes,
bacilli) or mucosal surfaces (Streptococcus viri- or signaling pathway used by the effector
dans, other streptococci, Enterococcus, gram- cells (Table 3-8).63,64
negative bacilli). Opportunistic infections In addition to their immunosuppressive
can occur owing to impaired neutrophil effects, the use of these agents (see Table 3-8)
and humoral immunity (members of the can be accompanied by significant side
herpesvirus family, fungal infections includ- effects with pulmonary implications. Cyclo-
ing P. jiroveci, and Toxoplasma). In the immu- sporine and tacrolimus have significant
nocompromised state, common childhood renal side effects: nephrotoxicity occurring
infections may be life-threatening (e.g., in 5% to 50%, and blood pressure abnor-
RSV, varicella).34,55,61,62 The febrile, neutro- malities in 25% to 70% of treated patients.63
penic child is at great risk for sepsis or pneu- Mycophenolate mofetil may have fewer
monia. Diagnostic evaluation and treatment renal complications, but causes bone mar-
of this group of patients are discussed row suppression and increases rates of sepsis.
subsequently. The use of monoclonal antibodies, such as
basiliximab or daclizumab, may decrease
renal toxicity by allowing lower doses of
Transplant-Related Pulmonary cyclosporine or tacrolimus. Post-transplant
Complications lymphoproliferative disorder (PTLD) and
Transplantation has become the curative

treatment for many immunodeficiency dis-
Regulatory Apoptosis
eases and for organ failure. Solid organ
transplantation (liver, kidney, heart) is now
so successful that more than 80% of chil- Paralyzed
dren survive to become adolescents and Resting memory T (anergic)
adults,63 largely owing to improvements in
immunosuppression and antimicrobial pro-
phylaxis regimens. Immunosuppression Effector
requires a balance: On the one hand, there
is the need to prevent allograft rejection
and to preserve organ function; on the Cytotoxic Helper
other hand, this suppression leaves the host
susceptible to infections, including pulmo-
nary infection. The side effects of these Th1 Th17 Th2
agents can result in secondary organ failure
Figure 3-2. T cell responses can take many directions:
and further pulmonary complications.63,64 Following an encounter with an antigen-presenting cell,
Transplant rejection is mediated primarily naive T cells can respond in various ways, including
by T cells, although B cell–mediated anti- apoptosis (programmed cell death), the induction of
effector T cells, the induction of regulatory T cells, and a
body production plays a role in hyperacute form of immunologic paralysis known as anergy. After
rejection (caused by preformed antibody to initial T cell expansion, a few cells survive as long-lasting
donor antigens, including HLA antigens). memory cells, ready to respond rapidly in the event of
later exposure to the same antigen. (From Taussig L,
Acute and chronic cellular rejection Landau L: Pediatric Respiratory Medicine, 2nd ed. St Louis,
involves T cell recognition of antigen on Mosby, 2008, p 43.)
Table 3-8 Immunosuppressive Agents Used in Transplantation
68
AGENT ACTIVITY

Corticosteroids Potent, but least specific of immunosuppressive agents
Negative regulation effect in lymphocytes by directly inhibiting transcription factors AP-1 and NF-kB
Anti-AP-1 effect: blocks IL-2 production
Anti-NF-kB effect: prevents upregulation of IL-1, IL-2, IL-3, IL-6, IFN-g, CD40 ligand, TNF-a, GMCSF, MHC molecules
Interfere with breakdown of cytokine mRNA and interfere with tyrosine phosphorylation
Inhibit functions of many nonlymphoid cells, including APC, inhibiting MHC class II expression
Calcineurin inhibitors Inhibit T cell activation by binding to intracellular immunophyllins
Calcineurin, a calmodulin-activated serine-threonine phosphatase, dephosphorylates inactive NFAT, leading to nuclear translocation
and subsequent activation of T cells
Cyclosporine Binds to cyclophilin A, inhibiting action
Inhibits production of IL-1b, IL-2, IL-6, IL-8, IFN-g, and TNF-a
Inhibits Jun N terminal kinase and p38 pathways
Suppresses antigen presentation by APC
Tacrolimus Binds to FK-binding protein 12, inhibiting action
Activity as for cyclosporine
Preferentially inhibits Th1 cells over Th2 cells
Less anti-HLA antibody formation
Inhibits glucocorticoid-induced apoptosis of antigen-stimulated T cells
Antimetabolites
Azathioprine Antimetabolite agent: inhibits DNA and RNA production
Lymphocytes use de novo pathway for purine synthesis. Blocks de novo synthesis, preventing clonal expression of T cells and B cells
Inhibits DNA synthesis, purine metabolism, nucleotide synthesis, and CD28 costimulation pathway
Inhibits production of AMP and GMP
Results in suppression of all hematopoietic cell lines
Mycophenolate mofetil More potent and selective inhibitor of de novo purine pathway
No significant effect on hematopoietic or neutrophil populations
Inhibits proliferation of T cells and B cells, blocks antibody formation, and decreases generation of NK cells
Target of rapamycin inhibitors Bind to kinase named target of rapamycin, preventing translation of mRNA responsible for cell cycle regulation
Sirolimus (rapamycin) Inhibits FK binding proteins
Prevents T cell proliferation by blocking progress from G1 to S phase
Inhibits growth factor–driven proliferation of smooth muscle, fibroblasts, and endothelial cells—leads to high incidence of
anastomotic dehiscence when used in lung transplantation
Everolimus Same activity as sirolimus
Polyclonal antilymphocyte Polyclonal antibody made in animals specific for target cell lines (lymphocytes, thymocytes, T cell lines)
antibodies Lymphocyte depletion owing to complement-mediated opsonization or Fas-mediated apoptosis
Cause profound, long-lasting lymphopenia
Very nonspecific—contain antibodies to wide variety of lymphocytes and costimulatory molecules
Monoclonal antibodies More specific, directed against specific T cell antigens or cytokine receptors
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases

OKT3 (Muromonab-CD3) Murine IgG2a monoclonal antibody directed against the epsilon subunit of CD3
CD3 facilitates translation expression of TcR-a and TcR-b chains on cell surface for intracellular killing—needed for CD4þ cell activation
Initially activates T cells, causing cytokine release, but within hours causes internalization of TcR-a and TcR-b chains, rendering T cell
unresponsive to antigen
Causes nonspecific T cell depletion
M-CD3 also causes T cell opsonization and removal from circulation by liver and spleen
Causes apoptosis of activated T cells and NK-T cells
Daclizumab Humanized mouse monoclonal
Basiliximab Human/mouse chimeric monoclonal antibody
Directed against a-chains of CD25 molecule (IL-2 receptor)
Inhibits IL-2 induced T cell proliferation
Eliminates activated T cells through Fas-Fas ligand interactions (apoptosis)
No depletion of other T cell populations
Efalizumab Humanized mouse IgG1 against CD11a chain
Non–lymphocyte depleting
Blocks LFA-1:ICAM-1 interactions preventing T cell adhesion, activation, and trafficking
LEA29Y Antibody against CD80 and CD86 (B7 molecules), a costimulatory signal necessary for T cell activation
Rituximab Human-mouse chimeric anti-CD20 (B cell antibody): depletes B cells, eliminating hyperacute antibody-mediated rejection in cardiac,
renal, and liver transplantation
Alemtuzumab Anti-CD52/campath-1H
Humanized IgG1 antibody: depletes T cells by complement-mediated cell lysis (T, B, NK, and dendritic cells, not hematopoietic
stem cells)
FTY720 Sphingosine-1 phosphate receptor agonist
Reduces recirculation of lymphocytes from lymph nodes back into the circulation, causes peripheral lymphopenia
AP-1, activating protein 1; NF-kB, nuclear factor kappa B; Anti-AP-1: anti-activating protein 1; IFN-g, interferon gamma; TNF-a, tumor necrosis factor alpha; GMCSF, granulocyte-macrophage-
colony stimulating factor; MHC, major histocompatibity complex; APC, adenomatous polyposiscoli; LFA-1, lymphocyte function associated antigen; ICAM-1, intercellular adhesion
molecule; NK-T, natural killer T lymphocytes.
69
secondary malignancies can result from long- Renal Transplantation

term immunosuppression in a small but Renal transplants were among the first suc-
significant number of patients. It is important cessful transplants done in children. With
to differentiate these noninfectious complica- current immunosuppressive protocols, the
tions from infection in this group of patients. 1-year graft survival is expected to be greater
The overall risk of infection or rejection in than 90% with an acute rejection rate of
a transplant patient results from the balance 22%.74 Ten-year graft survival approaches
of net state of immunosuppression, the type 70%. Complications of immunosuppressive
of transplant, and the degree of exposure to therapy include hypertension (70%), PTLD
the particular pathogen (see Table 3-5).63,64 (7%), malignancy (17%), and overall retrans-
Comorbid conditions (preexisting or second- plantation rates of 25% (improved with
ary to the transplantation or immunosup- newer immunosuppressive protocols). The
pressive agents) can increase susceptibility incidence of immunosuppressive nephrotox-
to infectious or noninfectious complications icity is uncertain because of difficulties in dis-
further (see Table 3-6). Infectious complica- tinguishing drug toxicity from chronic
tions of solid organ transplantation occur in rejection.63 Use of mycophenolate mofetil
a predictable pattern.65 Based on the type of or sirolimus for maintenance prevents signif-
organism and the timing of occurrence, icant renal dysfunction and can be steroid-
prophylactic regimens have developed over sparing. CMV and EBV infections are
the years to prevent these infections,63-68 common in immunosuppressed renal trans-
including the use of prophylaxis for P. jiroveci, plant patients because of the lack of effective
Candida, and CMV. Latent infections (either immunization before transplant and the
latent in the host or the donor organ) occur high incidence of infection by these viruses
early after transplantation (CMV, herpes sim- in adult donors. In one study, 12% of kidney
plex virus, EBV), as can azole-resistant fungal recipients developed CMV disease—the inci-
infections. Duncan and Wilkes64 review the dence of developing CMV disease increased
common “time lines” for appearance of vari- significantly if the donor was seropositive.75
ous infectious agents and the effects of pro-
phylaxis on the appearance of these agents. Liver Transplantation
Significant progress has been made in pediat-
Heart Transplantation ric liver transplantation, largely owing to
The 10-year survival of cardiac transplant in improvements in immunosuppressive thera-
children is 60% to 80%.63 With this good pies. The current 10-year survival rate is 80%
prognosis, prevention of acute rejection while to 85% after liver transplantation.63,64,76
minimizing the side effects of immunosup- Side effects of immunosuppression in this
pressive agents is important.63,69 Freedom group include nephrotoxicity (5%), hyper-
from acute rejection after 5 years was found tension (28%), PTLD (5% to 7%), secondary
to be 40% with cyclosporine, 56% with tacro- malignancy (12%), and organ failure requir-
limus, and 62% with mycophenolate mofetil ing retransplantation (5% to 10%). EBV and
treatment for immunosuppression.63,69 This CMV infections pose major problems in the
suppression comes with a price of nephrotox- liver transplant patient.63,76 Many protocols
icity (4%), hypertension (35%), PTLD (17%), include prophylaxis for CMV with intrave-
and secondary malignancies (1% to 4%). In nous or oral ganciclovir for 3 months post-
addition, chronic rejection can lead to organ transplantation.
failure requiring retransplantation (5%).70-72 Hepatopulmonary syndrome and porto-
Infectious and noninfectious events can pulmonary hypertension can present major
cause pulmonary complications as listed in problems in the patient before transplanta-
Table 3-6. Pneumonias in heart transplant tion.77,78 Hepatopulmonary syndrome is
patients are frequently multimicrobial in characterized by pulmonary vascular dilation
origin; CMV was the most common single and abnormal gas exchange (see Chapter 5).
pathogen and copathogen in this patient Structurally, the parenchyma of the lung is
group.70-73 Many of these infections likely normal, but there is generalized vasodilation
resulted from reactivation of latent infection. at the capillary level resulting in arteriovenous
communication (shunt) and severe hypox- provides a point of possible narrowing of

emia. Hepatopulmonary syndrome is recog- the airway. Infectious agents can be trans-
nized as an independent risk factor for death ferred passively from the donor to the recip-
in patients with advanced liver disease. Porto- ient during transplantation. The additional
pulmonary hypertension is a process defined complications related to lung transplanta-
by pulmonary hypertension associated with tion likely account for the lower survival
portal hypertension. Histologically, it appears statistics compared with other solid organ
identical to primary pulmonary hypertension transplants (1-year survival 77%, 3-year sur-
with smooth muscle hypertrophy, intimal vival 63%, and 5-year survival 54%).80 Graft
fibrosis, and plexiform lesions in small lung failure accounts for most deaths in the first
injury. It is initially asymptomatic, but evolves 60 days post-transplant (56%), whereas
to rapidly progressive impairment of right infection is an uncommon cause of early
heart function. The prognosis is poor, with death. Late deaths primarily result from
mean survival of 15 months after diagnosis. obliterative bronchiolitis (62%), infection
Hepatopulmonary syndrome frequently re- (22%), and malignancies (14%).80,81
verses after liver transplantation, whereas por- Immunosuppression after lung transplan-
topulmonary hypertension seems to resolve tation often consists of cyclosporine or tacro-
less frequently. Both of these entities must be limus, corticosteroids, and mycophenolate
considered in a patient with dyspnea before mofetil. The steroid dose is commonly
or just after liver transplantation.77,78 tapered 2 to 3 months post-transplant.80,81
Infection, allograft rejection, PTLD, and
Lung Transplantation obliterative bronchiolitis are major pulmo-
Lung transplantation presents a unique set of nary complications in the post-transplant
problems for the balance of immunosuppres- period. The antibiotic regimen is tailored to
sion in the transplanted organ (prevention of the most likely pathogens. In a patient with-
rejection versus risk of infection) in part out cystic fibrosis, a first-generation cephalo-
because the transplanted lung is an interface sporin is likely the first-line treatment, unless
between the outside environment and the a center has a high incidence of methicillin-
host defenses. The large epithelial surface area resistant S. aureus. In cystic fibrosis patients,
in the conducting airways and at the alveolar antibiotics are directed to the pathogens
surfaces (>70m2 in the adult) poses a great present in the most recent respiratory cul-
challenge for the lung defenses, particularly ture; antifungal agents are initiated based
in the context of immunosuppression. The on previous or current positive cultures.
anatomy of the lung, lung products, cell Viruses can pose serious problems in a post–
receptors and subsequent signaling mecha- lung transplant patient; as in other solid organ
nisms activated, and host cellular responses transplants, CMV and EBV are important
all contribute to the normal lung defense pathogens.81 Most centers use ganciclovir or
and disease prevention. A defect in any of valganciclovir as prophylaxis for the first 5 to
these defenses can result in an increased sus- 6 months post-transplant. In the context of
ceptibility to infection or increased propen- immunosuppression, however, infection by
sity to inflammation, which can lead to common respiratory viruses (particularly
rejection or development of obliterative bron- RSV, parainfluenza virus, adenovirus, or vac-
chiolitis (see later) that can be life-threatening cinia) can be life-threatening. Prophylaxis
in the lung transplant patient.76,79-81 with palivizumab (anti-RSV monoclonal anti-
Immunosuppressive agents used to pre- body) can provide passive immunity for
vent transplant rejection alter the lung young infants at risk for RSV infection. It also
defenses. Local alteration of lung defenses is advantageous to keep these children out of
contribute further to propensity to infec- the daycare setting. Aside from acute pneu-
tion: denervation of the transplanted organ monias, viral infections may be associated
results in decreased cough reflex; ischemic with early graft loss and rapid development
injury to the mucosa causes impairment in of obliterative bronchiolitis.
mucociliary clearance; the anastomosis PTLD occurs more commonly in pediatric
between host and transplanted organ lung transplant patients than in adults.
Because the first response to development of SCT recipients provides strong evidence that
PTLD is reduction in immunosuppression, immunopathologic response contributes to
survival from PTLD often is complicated by the development of obliterative bronchiolitis
episodes of rejection or obliterative bronchi- in the transplant setting. After lung trans-
olitis. Use of rituximab (anti-CD-20 anti- plantation, recurrent episodes of acute rejec-
body) has resulted in a significant reduction tion are a risk factor for developing
in morbidity and mortality from PTLD. obliterative bronchiolitis. Early and accurate
Allograft rejection is less common in chil- diagnosis of acute rejection and aggressive
dren than in adults; however, surveillance treatment are thought to be important in
and timely and accurate diagnosis of rejec- preventing the long-term development of
tion may be more important and more diffi- obliterative bronchiolitis. Because of sam-
cult in children because of the frequency of pling limitations in transbronchial biopsies
respiratory viral infections. Spirometry is and risk associated with performing the
employed after lung transplantation to biopsy itself, investigators have sought sensi-
assess allograft function, and evidence for tive and noninvasive methods to detect early
restrictive lung disease is concerning for acute rejection and obliterative bronchiolitis.
the development of acute or chronic rejec- In 1993, a consensus statement suggested
tion. Computed tomography (CT) scans using the term “bronchiolitis obliterans syn-
can be helpful in assessing for changes asso- drome,” defined by changes in pulmonary
ciated with rejection. Lung biopsy remains function as a possible surrogate marker for
the only accurate method of diagnosing obliterative bronchiolitis.82 These recommen-
acute and chronic rejection; however, the dations were later modified to use forced mid
utility of lung biopsy is limited by sampling expiratory flow in addition to changes in
error (small samples obtained with the pedi- forced expiratory volume in 1 second (focus-
atric biopsy forceps and skip areas). Rejec- ing on early changes in small airways), and
tion is diagnosed on the basis of standard to use percent predicted values in addition to
histopathologic markers, and immunosup- absolute values (to account for lung growth
pressive therapy is adjusted accordingly.80 in small children).83 Other surrogate clinical
Obliterative bronchiolitis (formerly bronchi- markers of obliterative bronchiolitis have
olitis obliterans) is rare in healthy children, but been investigated, including cytokine mea-
its incidence is markedly increased in the con- surements, measurement of cell surface recep-
text of lung transplantation or SCT. Oblitera- tors, and soluble cytokines and receptors in
tive bronchiolitis is characterized by partial or bronchoalveolar lavage (BAL).79 BAL neutro-
complete occlusion of the lumens of terminal philia in the absence of detectable infectious
and respiratory bronchioles by inflammatory agents has been shown to be a reproducible
and fibrous tissue. The initiating event in the marker of obliterative bronchiolitis in adult
chain of events that leads to obliterative bron- and pediatric transplant patients.79
chiolitis is unclear. The primary trigger is The optimal therapy for obliterative bron-
thought to relate to epithelial injury in the chiolitis in lung transplant and SCT patients
small airways leading to transient derange- is controversial. Alteration of immunosup-
ments in epithelial cell function or local necro- pressive agents (see Table 3-8), inhaled cyclo-
sis. This local necrosis leads to the generation sporine, extracorporeal phosphophoresis,
of fibrinopurulent exudates that induce and the use of macrolide antibiotics have been
ingrowth of myofibroblasts, cellular prolifera- studied in small groups of patients with vari-
tion, capillary immigration, and the develop- able results.79 Despite these therapies, it is esti-
ment of an intraluminal polyp. Ongoing mated that 35% to 60% of long-term survivors
injury to the airway epithelium perpetuates of lung transplantation develop obliterative
this process, leading to narrowing or oblitera- bronchiolitis, which is the most common
tion of the airway lumen. cause of death in this patient population.79
Although injury and infection likely play a
role in the changes that lead to obliterative Stem Cell Transplantation
bronchiolitis, the high incidence of oblitera- SCT presents an even greater challenge to
tive bronchiolitis in lung transplant and the host defenses against pneumonia and
lung injury because of the combined chal- embolism. Chronic obstructive pulmonary
lenges of the initial conditioning regimen disease can be detected in 20% of long-term
and the need for the recipient to develop a survivors of SCT; this is mainly associated
functional immune system from donor- with chronic GVHD, but other risk associa-
derived stem cells. Serious infection occurs tions include the preparatory regimen (total
in the first 2 years after SCT in 50% of reci- body irradiation (TBI), methotrexate) and
pients with uncomplicated transplants from infection.34,86 Mortality can be high, partic-
histocompatible sibling donors and in 80% ularly if there is an early onset and rapid
to 90% of recipients from matched unre- decline in forced expiratory volume in 1 sec-
lated donors. ond. Immunosuppressive therapies may be
The immune deficits after SCT can be beneficial, but less than 50% of patients
categorized into three phases. In the pre- receiving such therapies show improvement
engraftment phase (0 to 30 days post-trans- in lung function or symptoms. Late-onset
plant), infections arise primarily as a result pulmonary disease includes obliterative
of prolonged neutropenia and breaks in bronchiolitis, cryptogenic organizing pneu-
the mucosal barriers resulting from muco- monia (formerly bronchiolitis obliterans–
sitis from the induction regimen before organizing pneumonia87,88), diffuse alveolar
transplant. Myelosuppressive drugs can pro- damage, and interstitial pneumonia.34,86
long this period. Repopulation of the lungs PTLD is often associated with T cell dys-
by donor-derived alveolar macrophages and function in the presence of EBV. The mean
recovery of circulating neutrophil counts interval to development of PTLD was 5 to
occur during this period. Recovery of 6 months post-transplantation, with a
lymphocyte counts takes longer (the post- cumulative incidence of 1% at 10 years.
engraftment phase, 30 to 100 days post- The use of quantitative polymerase chain
transplant), and cellular immunity remains reaction for EBV DNA has improved diagno-
impaired. Response to alloantigens may sis dramatically. Using the EBV viral load,
not return for at least 6 months after SCT, patients can be identified with low tumor
and return of B cell function and humoral burden. Use of rituximab (anti-CD20 mono-
antibody production may take 1 year (late clonal antibody) has shown promise in the
phase, >100 days post-transplant).34,61,84 treatment of PTLD in SCT patients.86
The temporal sequence of the immuno- Obliterative bronchiolitis develops in
logic recovery and immunosuppressive ther- 10% of SCT recipients who develop
apy determines SCT recipients’ susceptibility GVHD.79 As with obliterative bronchiolitis
to pulmonary infection at any given time in lung transplant recipients, immunologic
point. During the pre-engraftment phase, and nonimmunologic factors are believed
patients are most susceptible to bacterial to play a role in the development of obliter-
infections and viral infections, including her- ative bronchiolitis in SCT recipients. These
pes simplex virus, CMV, and RSV. After neu- nonimmunologic factors include the pre-
trophil recovery (postengraftment phase), SCT conditioning regimen, intercurrent ill-
T cell and B cell immunity remains abnormal, ness (particularly viral pneumonitis), the
predisposing the patient to infections use of immunosuppressive medications,
with fungi, viruses, mycobacteria, and para- and the underlying disease that necessitated
sites. Patients can remain susceptible to the SCT. Viral agents, such as CMV, adenovi-
encapsulated organisms because of inability rus, influenza, parainfluenza, and RSV, have
to generate specific antibody responses. The been implicated in the development of
development of GVHD further increases sus- obliterative bronchiolitis. Several medica-
ceptibility to infection.34,61,84-86 tions have been used in SCT recipients for
Several noninfectious complications the treatment of chronic GVHD and obliter-
occur after SCT, including airway obstruc- ative bronchiolitis; however, response was
tion by mucositis, diffuse alveolar hemor- usually limited to skin, soft tissue, and oral
rhage, pulmonary edema, and pulmonary mucosa.
Diagnosis and Treatment Histoplasma) infection, and pulmonary

of Respiratory Abnormalities edema or early obliterative bronchiolitis,
in a Child with Secondary rejection, and GVHD. Consolidation can
arise from bacterial infections (S. pneumoniae,
Immunocompromise Owing to H. influenzae, S. aureus, gram-negative organ-
Cancer or Transplantation isms, M. tuberculosis, or atypical mycobac-
teria) and fungal infections (Cryptococcus,
In an immunocompromised child, aspects of Nocardia, Aspergillus, Mucor), and pulmonary
the medical history, physical examination, thromboembolic disease, pulmonary hemor-
and routine microbial surveillance (or previ- rhage, and pulmonary edema. Nodular infil-
ous antibody titers) are important first steps. trates arise from bacterial infections, fungal
Timing of the symptoms relative to drug infections, P. jiroveci pneumonia, and M.
therapies or changes in immunosuppressants tuberculosis. The early changes of obliterative
could point to the infection or noninfectious bronchiolitis manifest as hyperinflation with
complications. The presence of sinusitis, oti- clear lung fields. There is considerable over-
tis media, and rhinitis would point to respira- lap between these basic radiographic patterns
tory virus infections as an important and their causes, so more aggressive diagnos-
consideration. The presence of severe muco- tic studies are indicated to show the cause
sitis or evidence of skin GVHD could point and direct appropriate therapy.34,65
to anaerobic organisms, oral flora, or gut CT scan of the chest is particularly useful
enterics as causes for the respiratory symp- when the chest radiograph is negative, or
toms or infiltrates on chest x-ray. The history when findings on chest x-ray are nonspe-
and physical examination can only suggest cific. CT is useful in defining areas of lung
the causes of lung complications or lung involvement for more invasive studies (e.g.,
symptoms and physical findings, however. biopsy, BAL). Spiral CT and ventilation/per-
Because there is a good probability of full fusion studies can be diagnostic if pulmo-
recovery if the pathogen is uncovered, early nary thromboembolism is a consideration.
and aggressive diagnostic studies are war- A “mosaic” pattern of lung hyperinflation
ranted to direct appropriate antimicrobial or and infiltrate can suggest the development
antiviral therapy. This is particularly true in of obliterative bronchiolitis.
the context of fever in a neutropenic patient.
Sputum and Nasopharyngeal

Radiography Washes, and Other Indirect Methods
for Pathogen Detection
Pulmonary changes on chest radiographs
may be delayed or modified in an immuno- Spontaneous or induced sputum samples can
compromised patient because of the inability be studied by culture and special stains for pul-
to generate an inflammatory response. Still, monary pathogens: Gram stain, fungal stains,
the time course, evolution, and appearance acid-fast bacillus stain, and silver stains can be
of the pneumonias can provide important performed to diagnose bacterial and fungal
diagnostic clues. Radiographic changes in causes of pulmonary infiltrates. Blood cultures
an immunocompromised child can be classi- are rarely positive, but can be diagnostic for
fied according to their appearance: (1) diffuse bacterial pneumonias. In addition, nasal aspi-
alveolar or interstitial pneumonias, (2) loca- rates can be studied by immunologic methods
lized alveolar lobar or lobular consolidation, or culture to identify common viral pathogens
(3) nodular infiltrates or abscesses, or (4) (RSV, influenza, parainfluenza viruses, adeno-
hyperinflation.34,65 Interstitial/alveolar infil- virus) that can cause pulmonary infections in
trates can arise from viral (CMV, RSV, vari- immunocompromised patients. Viral cultures
cella-zoster virus, adenovirus) and fungal can be useful in detecting the common viral
(P. jiroveci pneumonia, Cryptococcus, Candida, pathogens in addition to members of the
herpesvirus family (CMV, herpes simplex invasive Aspergillus), in addition to helping

virus). Genetic probes are available to detect to identify acute rejection (lung transplant),
CMV and EBV in blood samples, and quantita- GVHD, and obliterative bronchiolitis (SCT
tive polymerase chain reaction can provide a and lung transplant).34,80 Most centers have
measure of viral load. Probes also are available a protocol for surveillance post-transplanta-
for detecting P. jiroveci, Legionella, Mycobacte- tion to screen for rejection. Open biopsy is
rium, and Mycoplasma. These studies also can usually needed to make the diagnosis of oblit-
be applied to samples obtained by more inva- erative bronchiolitis.
sive methods (bronchoscopy and lung biopsy) Lung lavage can be done in intubated
as described subsequently. patients by passing a catheter through an
existing endotracheal tube and performing
saline washes. This technique is “blind,”
Flexible Bronchoscopy but can provide important diagnostic mate-
rial in a critically ill child too sick to tolerate
Flexible fiberoptic bronchoscopy can provide standard BAL techniques.
BAL or bronchial lavage samples and biopsy
materials for diagnosis of pulmonary compli-
cations in immunocompromised patients.
Transthoracic Needle Aspiration
Bronchoscopy with lavage performed early in
Biopsy
the course of evaluation of an immunocom- Needle aspiration of the lung under CT or
promised patient can enhance the probability fluoroscopic guidance can have high yields
of identifying a pathogen in the lung. BAL in sampling peripheral lung lesions (particu-
can provide materials for culture (i.e., bacte- larly suspected fungal lesions) that cannot
rial, viral, fungal, acid-fast bacillus), cytology, be reached by standard flexible fiberoptic
and immunohistochemistry, potentially iden- bronchoscopy techniques. The major risks
tifying pathogens in the lung. In addition, of transthoracic biopsy are pneumothorax
bronchoscopy can identify endobronchial and bleeding. In addition, because of the
obstruction owing to infection or tumor. Pro- small needle size, sampling error can occur
tected brush specimens can decrease the (“missing” nearby involved areas).
potential for BAL samples to be contaminated
by upper airway flora during passage through
the nasopharynx. Although bronchoscopy Open Lung Biopsy
with BAL can provide important diagnostic
information, it has limitations. BAL cultures Open lung biopsy remains the gold stan-
in patients already on broad-spectrum anti- dard for diagnosis of pulmonary abnormal-
biotics are often negative. Pathogens present ities in an immunocompromised patient. It
in small numbers (e.g., P. jiroveci, mycobacteria) allows the surgeon to obtain adequate quanti-
may be missed on stains or cytology, although ties of lung tissue for analysis, provides the
more sensitive polymerase chain reaction tech- opportunity to sample multiple sites, and
niques may increase the yield. Invasive patho- allows the surgeon to visualize and select opti-
gens (Aspergillus) may be missed by lavage mal sites for biopsy. The use of a mini-thora-
when obvious on biopsy samples. cotomy or video-assisted thoracoscopic
Bronchoscopy also can be used to perform surgery allows for a smaller incision. Although
transbronchial lung biopsies.34,80 Transbron- open lung biopsy provides the most definitive
chial biopsy can be difficult in young children information in an immunocompromised
because the size of available bronchoscopes patient, timing of the biopsies and the poten-
and their small suction channel (1.2 mm) tial need for repeated biopsies (particularly if
require obtaining several samples for ade- rejection and obliterative bronchiolitis are
quate material for histology and culture. In considerations) limit the use of this tech-
older children, small adult bronchoscopes nique. A patient who does not respond to
can be used with standard size biopsy forceps. therapy based on other diagnostic techniques
These biopsy samples can help in identifying (including bronchoscopy and needle biopsy)
pathogens missed by standard BAL (e.g., usually would benefit from open biopsy.
Summary in common variable immunodeficiency. Curr Opin

Allergy Clin Immunol 5:496-503, 2005.
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CHAPTER 4
of Cardiac Diseases
MARLYN S. WOO AND JACQUELINE R. SZMUSZKOVICZ
Overview of the Cardiovascular Vascular Anomalies That Cause Airway

Circulation 79 Obstruction 89
Pulmonary Circulation 79 Lesions with Increased Venous Admixture 92
Bronchial Circulation 80 Idiopathic Pulmonary Arterial
Lymphatic Circulation 80 Hypertension 95
Cardiovascular Lesions That Increase Other Pulmonary Conditions Associated with
the Work of Breathing 80 Cardiac Disease or Surgery 96
Large Volume Left-to-Right Shunts 81 Summary 96
Outflow or Inflow Obstruction of the References 97
Systemic Ventricle 87
Sharing the same body cavity, the heart and Overview of the
lungs are closely interconnected by Cardiovascular Circulation
the pulmonary vasculature. An increase or
decrease in pulmonary vascular pressures The cardiopulmonary vascular system com-
leads to changes in the blood vessels, which prises two components: the pulmonary cir-
directly affect the airways, lung interstitium, culation and the bronchial circulation. The
alveoli, and pleura. Heart disease often leads bronchial circulation constitutes a very
to respiratory failure as a result of its impact small portion of the output of the left ven-
on gas exchange, water/solute exchange, tricle, and it supplies part of the tracheo-
and pulmonary mechanics. The appearance bronchial tree with systemic arterial blood.
of lung disease secondary to cardiac disease The pulmonary circulation constitutes the
depends on whether the changes in the pul- entire output of the right ventricle, and it
monary vascular pressures are acute or supplies the lung with the mixed venous
chronic. Clinical manifestations of cardiac blood draining from all the tissues of the
disease include pulmonary edema, pleural body. This blood undergoes gas exchange
effusion, hypoxemia, pulmonary hyperten- with alveolar air in the pulmonary capil-
sion, atelectasis, and plastic bronchitis. laries. Under normal circumstances, these
Noninfectious pulmonary complications, systems change with the maturational stage
such as bronchiectasis, prolonged postoper- of the individual. It is important to under-
ative mechanical ventilation, extubation stand the vascular changes that occur with
failure, airway complications (e.g., tracheo- normal growth over time. A brief review of
bronchomalacia, subglottic stenosis, bron- the cardiovascular circulation follows.
chial stenosis), and obstructive sleep apnea,
have been extensively described in pediatric
patients after cardiac surgery.1-4 Although Pulmonary Circulation
many of the physiologic mechanisms are
similar, this chapter concentrates on pediat- The normal mature pulmonary circulation
ric heart diseases and disorders that have an is a low-resistance system compared with
impact on the pulmonary system. the general systemic circulation.5 Despite
79
receiving about the same amount of blood do the other systemic arteries (dilation in
flow, the pulmonary arterial pressure is only response to hypoxia). Conversely, the pulmo-
about 20% of the systemic circulation pres- nary arteries constrict to hypoxia. The bron-
sure. The plasticity of the pulmonary circu- chial arteries arise from the aorta and the
lation can be attributed to two related intercostal arteries, and then divide along
factors: (1) the pulmonary vessels are thin- with the bronchial divisions. Despite the
walled and dilate with mild increases in differences between the pulmonary and bron-
pressure, and (2) this augmentation of the chial circulations, there are intricate intercon-
vessel radius passively recruits underper- nections between them. Anastomotic vessels
fused vessels, which leads to an increase in connect the bronchial arteries to the pulmo-
overall cross-sectional area. nary arterioles and to the pulmonary veins.
In contrast to the mature pulmonary circu- These anastomotic connections permit flexi-
lation, the fetal pulmonary resistance is bility of flow to and from pulmonary and
higher than the systemic resistance. The high bronchial circulations. The drainage of the
pulmonary system resistance in the fetus per- bronchial arteries to a vascular plexus permits
mits shunting of blood from the systemic great flexibility of bronchial venous drainage.
venous to the systemic arterial circulation via The bronchial venous drainage can move to
the ductus arteriosus to the aorta and through either the right or the left side of the heart.
the foramen ovale to the left atrium. The fol- Extrapulmonary bronchial vessels supplying
lowing three factors contribute to the high large airways drain to the right atrium
fetal pulmonary circulation resistance: (1) In through the azygos and hemiazygos veins.
the fetus, the pulmonary arteries are exposed The intrapulmonary vessels drain to the pul-
to the full systemic blood pressure via the duc- monary veins and to the left atrium. The
tus arteriosus, and their walls are very muscu- venous drainage permits flexibility in drain-
lar. (2) The fetal lung exists in an airless state. age route, depending on changing hemody-
(3) There is hypoxic vasoconstriction within namic pressures.
the intrauterine environment.
With the onset of air breathing and infla-
tion of the lungs, the pulmonary circulatory Lymphatic Circulation
resistance decreases with the loss of the pla-
The pulmonary lymphatic circulation lies in
cental circulation. The inflation of the lungs
the connective tissue of the lung. There is
causes expansion of the pulmonary vessels,
continuous filtration of liquid and protein
and the increase in oxygenation results in
through the lung microcirculation. Passive
vasodilation. With subsequent involution
flow of liquids proceeds along a pressure
of the arterial muscle, there is remodeling
gradient to reach the lymphatic capillaries
of the pulmonary arteries. This remodeling
and is returned via active pumping to the
involves thinning of the arterial muscular
systemic circulation. Disruption of the intra-
wall and the normal branching and growth
vascular pulmonary pressures also alters the
of the airways and alveoli. Although the pul-
lymphatic circulation.5,7
monary veins have thinner walls compared
with the arteries, veins do have a muscular
layer, which can become hypertrophied in
response to elevated pulmonary pressure.5,6 Cardiovascular Lesions That
Increase the Work of
Breathing
Bronchial Circulation
Generally, three types of cardiovascular prob-
In contrast to the pulmonary circulation, the lems cause disturbances in mechanical func-
bronchial circulation is small, carrying only tion of the lungs and increase the work
1% of the cardiac output. The bronchial of breathing: (1) large volume left-to-right
arteries carry oxygenated blood to the lungs shunts, (2) outflow or inflow obstruction
as part of the general systemic circulatory sys- of the systemic ventricle, and (3) vascular
tem. Bronchial arteries respond to stimuli, as anomalies that obstruct the airways.
Chapter 4—Pulmonary Manifestations of Cardiac Diseases 81
Large Volume Left-to-Right Shunts declines postnatally, signs of pulmonary con-

gestion develop quickly.
Lesions that allow communication between Numerous factors have been identified
the systemic and pulmonary circulations and that influence the decrease in pulmonary
cause a large left-to-right shunt are the most vascular resistance associated with the tran-
frequent congenital cardiac anomalies. These sition to extrauterine life. In the immediate
include common problems such as ventricular postnatal period, the expansion of the
septal defect (VSD), atrial septal defect (ASD), alveoli, the increase in alveolar PO2, and
and patent ductus arteriosus (PDA), and the decrease in the alveolar PCO2 cause
defects with similar physiologic conse- recruitment of pulmonary capillaries and
quences, but more complex anatomy, such as dilation of pulmonary arterioles, decreasing
single ventricle, aorticopulmonary window, pulmonary vascular resistance. As the
and truncus arteriosus. These lesions are char- arterial musculature becomes thinner, and
acterized by the recirculation of oxygenated new vessels gradually grow in the lungs,
blood through the lungs and pulmonary vas- pulmonary vascular resistance decreases
cular congestion. The shunt produces exces- even further. Finally, the postnatal decline
sive pulmonary blood flow and increased in hematocrit—so-called physiologic ane-
return of pulmonary venous blood to the left mia—also contributes significantly to the
side of the heart. In addition, when the abnor- decrease in pulmonary vascular resistance
mal communication is large and occurs at the by reducing blood viscosity.
level of the ventricles or great vessels, the high Left-to-right shunts can cause increased
pressure of the left side of the heart is transmit- symptoms after the decrease in the pulmo-
ted to the pulmonary circulation, causing nary arterial pressure and pulmonary vascular
pulmonary artery hypertension. resistance that normally occurs after birth. As
The volume of blood traversing the pul- mentioned before, these shunts can be intra-
monary circulation in the presence of an cardiac (ASD, VSD, or atrioventricular septal
anomalous intracardiac communication or defect) or extracardiac (PDA or aorticopul-
between the great arteries depends on the monary window). Intracardiac shunts usually
size of the communication and the relative are associated with increased pulmonary
resistances of the pulmonary and systemic blood flow without an increase in pressure in
circulations. When the communication is the early stage of the disease. Extracardiac
small, it offers a high resistance to the passage shunts (depending on their size) may expose
of blood. As a result there is a large pressure the pulmonary vascular circulation to sys-
decrease between the high-pressure chamber temic pressures that would cause earlier devel-
and vessel (usually, the left ventricle or aorta) opment of vascular changes. Shunt lesions,
and the low-pressure chamber or vessel such as a VSD, ASD, or PDA, may not cause a
(usually, the right ventricle or pulmonary significant murmur in a neonate because of
artery), and the left-to-right shunt is limited. the normally elevated pulmonary vascular
When the communication is large, there is resistance at birth causing the shunting to be
virtually no resistance to the flow of blood low velocity. As the pulmonary vascular resis-
from the systemic to the pulmonary side of tance decreases to normal levels over the first
the circulation. Consequently, the pressures 1 to 2 months of life, the shunt becomes more
become equal in both sides, and the size of prominent. The normal systemic vascular
the shunt is no longer governed by the size resistance is about 25 Wood units/m2, and
of the communication, but rather by the normal pulmonary vascular resistance is
relative magnitudes of the systemic and pul- about 3 Wood units/m2, so blood shunts from
monary vascular resistances. Because the the left (systemic) circulation to the right (pul-
pulmonary vascular resistance of the term monary) circulation.
newborn is very high, it is not surprising that
even large communications such as those Pathophysiology of Pulmonary Edema
caused by a large VSD or PDA produce little and Pleural Effusion
left-to-right shunt for days, or even weeks, One of the main pathophysiologic effects of
after birth. As pulmonary vascular resistance the left-to-right shunt is to redistribute part
of the left ventricular output from the sys- of this fluid buildup, or edema, is the accumu-
temic to the pulmonary circulation (Fig. 4-1). lation of fluid around the bronchovascular
When this occurs, pulmonary blood flow bundles. This accrual of bronchovascular bun-
increases, increasing the right ventricular dle fluid can be seen on chest radiographs,
afterload, left ventricular preload, left atrial particularly in the fissures.
pressure, and the work performed by the heart When the pulmonary lymphatic system
muscle. In normal circumstances, the venous cannot clear the interstitial fluid, the fluid
pressure in the lung is low and varies only a lit- accumulation must leave by other means.
tle during the cardiac cycle. An increase in left One route is to form a transudate through
ventricular end-diastolic or left atrial pressure the interlobular septa and then to the pleu-
can cause increased pressure in the pulmo- ral space, which leads to pleural effusion.
nary veins, however, with subsequent pres- When in the pleural space, the liquid is
sure increases in the capillary vessels and absorbed into the parietal pleural lym-
then in the pulmonary arteries. As a result, phatic system. Transport of interstitial fluid
fluid starts to accumulate in the interstitium to the pleural space reduces the possibility
and alveoli, causing pulmonary edema. of alveolar edema, which is associated with
Edema usually forms in response to increased altered gas exchange and pulmonary
pulmonary venous pressures. As the intravas- mechanics. In contrast, pleural effusion
cular pressure increases, more extravascular alone generally is not associated with
fluid is filtered through the pulmonary inter- severe derangements in pulmonary func-
stitium to the lymphatic system. When this tion. Alterations in blood flow and in pul-
microvasculature filtration system becomes monary vascular pressures are associated
overwhelmed, there is accumulation of fluid with pathologic changes in the pulmonary
in the interstitial lung tissue.8 An early feature arteries (Table 4-1).
↑ Pulmonary blood flow and

↑ PA, PV pressure
O2 Pulmonary edema and
• Pulmonary edema
• Large airway obstruction airway obstruction
• Small airway obstruction ⋅ ⋅
• Areas of V/Q = 0
• ↓ PO2
• ±↑ PCO2
↓ Systemic flow and

↑ adrenergic tone
• Redistribution
Large L → R shunt
systemic flow
• ↑ Pulmonary blood flow • ↑ O2 extraction
• ↑ PA, PV, LA pressures • ↓ Respiratory muscle
• ↑ RV afterload, LV preload perfusion
O2
Postnatal ↓ [Hb]
• ↓ O2 transport
• ↑ L → R shunt
Figure 4-1. Pathophysiology of a large left-to-right shunt. Proceeding in a clockwise direction, this schema shows the
factors that contribute to respiratory and circulatory compromise. With a large left-to-right (L ! R) shunt, pulmonary
blood flow and pulmonary arterial (PA), pulmonary venous (PV), and left atrial (LA) pressures increase, as does right ven-
tricular (RV) afterload and left ventricular (LV) preload. These changes promote pulmonary edema formation, and cause
large or small airway obstruction. The restrictive and obstructive lung disease creates areas of the lung with true intrapul-
monary shunt (V/ _ Q
_ ¼ 0), and can depress arterial PO2 and increase arterial PCO2. Because of the reduced systemic perfu-
sion and increased adrenergic tone, systemic blood flow is redistributed, O2 extraction increases, and respiratory muscle
perfusion is diminished. The postnatal decline in hemoglobin concentration [Hb] further aggravates the circulatory imbal-
ance by decreasing O2 transport and increasing further the left-to-right shunt. (From Lister, and G Perez Fontan JJ. Congenital
Heart Disease and Respiratory Disease in Children. Loughlin G and Eigen H. Eds. Baltimore, Williams & Wilkins, 1994, p 603.)
Diagnoses Associated with

Table 4-1 Increased Pulmonary Arterial
Pressure
Aorta
Patent ductus arteriosus
Aorticopulmonary window
Truncus arteriosus
Postsurgical shunts
Blalock-Taussig (subclavian artery to ipsilateral
pulmonary artery)
Potts (descending aorta–left pulmonary artery)
Waterston (ascending aorta–right pulmonary
artery)
Atrium Figure 4-2. Plexiform lesion on lung biopsy specimen of
Atrial septal defect a patient with severe pulmonary arterial hypertension.
Common atrium
Total or partial anomalous pulmonary venous resistance with a right-to-left shunt is
connection defined as Eisenmenger syndrome.
Transposition of the great arteries with atrial septal
defect Clinical Findings of Acute Increased
Ventricle Pulmonary Venous Pressure
Ventricular septal defect Patients with acute pulmonary edema may
Single ventricle be asymptomatic in the early stages. On aus-
Atrioventricular canal cultation, the lung sounds can be normal, or
Associated lesions with ventricular septal defect there may be mild wheezing. As the condi-
Transposition of the great arteries tion progresses with alveolar edema, the
Double-outlet right ventricle patient may experience tachypnea and possi-
Tricuspid atresia without pulmonary stenosis ble cough productive of foamy secretions. At
Mitral atresia this stage, coarse crackles (rales) are usually
heard. Conditions associated with acute
increase of pulmonary venous pressure are
The earliest change to increased pressure
outlined in Table 4-2.
in the pulmonary arteries is medial thick-
The chest radiograph is more sensitive
ening, which is the response to increased
than the history or physical examination in
intramural vascular pressure. The medial
detecting acute elevation of pulmonary
thickening may come about from hypertro-
venous pressure (Fig. 4-3). The chest radio-
phy and hyperplasia of smooth muscle cells.
graph shows increased vascular markings
The next change is an increase in intimal
and changes in the cardiac silhouette,
thickening. Intimal thickening can be due
depending on the underlying heart disease.
to an increase in the number of cells or an
Kerley B lines are seen in the periphery of
accumulation of dense fibrous tissue. The
the lungs, indicating accumulation of fluid
development of irreversible change is her-
alded by the formation of plexiform lesions
Diagnoses Associated with Acute
(Fig. 4-2). Increase of Pulmonary Venous
Table 4-2
As the pulmonary vascular disease gradu- Pressure
ally worsens from the increased pressure,
Aortic regurgitation
the pulmonary vascular resistance also
Left atrium
increases and results in decreased pulmo-
Mitral regurgitation
nary blood flow. When the pulmonary vas-
Mitral stenosis or obstruction
cular resistance becomes higher than the
Left ventricular failure
systemic vascular resistance, the shunt flow
Myocarditis
(initially left-to-right shunt) reverses direc-
Pericardial tamponade
tion, leading to a right-to-left shunt. At this
Tachyarrhythmia
point, the elevated pulmonary vascular
in the interlobular septa. Alveolar edema is lobe bronchus).9 In addition, there is usually
represented radiologically as fluffy infiltrates. compression of small intraparenchymal air-
Pleural effusion may also appear, usually ways by engorged peribronchial vessels or
bilaterally beginning with blunting of the by bronchial wall or peribronchial edema.
costophrenic angles (Fig. 4-3). The term “cardiac asthma” is often applied
Even with interstitial edema and pleural to describe the wheezing caused by compres-
effusion, pulmonary function changes little sion of large and small intrathoracic airways.
in patients with acute increased pulmonary Affected infants often may have respiratory
venous pressure. Alveolar edema is associated symptoms so prominent that they over-
with significant decreases in the PaO2, how- shadow or mask the underlying cardiac dis-
ever. With increased alveolar flooding, there ease. The shunt may be recognized only
is also a decrease in lung volume and compli- when a clinician notes the coexistence of
ance. Airway resistance increases because of cardiomegaly and air trapping on a chest
the decrease in lung volume and liquid filling radiograph. Bronchial compression at these
the airway lumen. locations also can produce lobar emphysema
Pulmonary edema renders the alveoli or atelectasis. This complication is seen most
unstable, and it makes the lung stiff, frequently in 2 to 9-month-old infants. The
increasing the work that the respiratory age range predilection may be linked to the
muscle must perform to maintain adequate gradual decrease of pulmonary vascular resis-
ventilation. Pulmonary edema is not the tance over the first few months of life that
only mechanism, however, by which the results in an increase in pulmonary blood flow
work of breathing becomes greater in sub- and the small airway caliber and less cartilagi-
jects with a left-to-right shunt. These patients nous airway support in infants.6 Evaluation
can also develop extrinsic airway com- for underlying cardiac disease also should be
pression. Pulmonary “overcirculation” along part of the assessment of an infant or young
with pulmonary hypertension may cause child with atelectasis or lobar emphysema.
extrinsic compression of the main and lobar Pulmonary edema, and the mechanical
bronchi by enlarged pulmonary arteries (usu- disturbances that it produces, also impairs
ally affecting the right main stem bronchus, gas exchange within the lung. In the pres-
the lingular and left upper lobe bronchi, or ence of a left-to-right shunt, overall ventila-
the left main stem bronchus) or by distention tion to perfusion is low, and there are areas
of the left atrium (affecting the left lower that are perfused but not ventilated (true
right-to-left intrapulmonary shunt). How-
ever, the recirculation of arterial blood
through the lung and the high saturation of
pulmonary arterial blood (owing to the
left-to-right shunt) minimize the effects,
of intrapulmonary right-to-left shunting on
arterial oxygen saturation. Arterial PO2 and
PCO2 are usually near-normal, unless there
is respiratory fatigue caused by increased
respiratory rate and effort.
Patients with ASD are usually asymptom-
atic in early life, although they may have
an increased incidence of respiratory tract
infections. With the onset of pulmonary
hypertension (usually in adulthood), dys-
pnea and fatigue may occur. Patients with
left-to-right shunts at the aortic and ventric-
ular levels may develop biventricular con-
gestive heart failure in infancy. Symptoms
Figure 4-3. Pleural effusion in a child with severe con- include dyspnea, grunting, apnea, and poor
gestive heart failure. feeding. The early congestive heart failure
also predisposes these infants to respiratory accumulation of pulmonary edema. In par-

infections and poor growth. When the disease ticular, the combination of diuretics and
has progressed to Eisenmenger syndrome, all inotropic drugs can decrease filling pressure
patients have cyanosis (at rest and during in the left atrium and reduce pulmonary
exercise) and dyspnea. The clubbing that is microvascular pressure, attenuating edema
apparent is due to chronic hypoxia; the formation. Depending on the specific lesion
peripheral tissue capillaries dilate to increase and the size of the patient, often interven-
the oxygen supply, causing digital swelling. tional cardiac catheterization offers an alter-
Other symptoms that occur after disease pro- native to cardiac surgery. These less invasive
gression to Eisenmenger syndrome are chest techniques are currently widely used for the
pain, syncope, and hemoptysis. The hemop- closure of secundum ASDs and PDAs.
tysis can be caused by pulmonary infarction
from low pulmonary blood flow or conges- Clinical Manifestations of Chronic
tion, polycythemia, or bronchial arterial Increased Pulmonary Venous Pressure
bleeding. Several conditions are associated with
Patients with PDA characteristically have chronic increased pulmonary venous pressure
a continuous murmur. When the disease (Table 4-3). The gradual onset of increased pul-
progresses to Eisenmenger syndrome, a monary venous pressure leads to an almost
patient with an uncorrected PDA has differ- imperceptible onset of symptoms. These early
ential cyanosis (upper body is pink and symptoms may include dyspnea, fatigue, and
lower body is blue owing to right-to-left decrease in endurance or exercise tolerance.
shunt beyond the left subclavian artery).
Isolated digital clubbing of the toes without
clubbing of the fingers may occur because of
the difference in upper versus lower body
Diagnoses Associated with
oxygenation. Chronic Increase of Pulmonary
Table 4-3
Venous Pressure
Treatment of Large Volume
Aortic Valve
Left-to-Right Shunts
Aortic regurgitation
Although corrective or palliative surgery is the
Aortic stenosis
ultimate therapy for each of the conditions
Left Atrium
described in this section, initial medical man-
Atrial myxoma
agement is essential for stabilizing an infant
Ball-valve thrombus
with critical congestive heart failure. For an
Cor triatriatum
infant with large left-to-right shunt, treatment
Left Ventricle
traditionally has focused on improving myo-
Chronic heart failure
cardial function, removing excess fluid accu-
Congenital subaortic stenosis
mulated in the lungs, and, in some patients,
Constrictive pericarditis
providing assisted respiration. These infants
Hypertrophic cardiomyopathy
have increased caloric needs, and close assess-
Restrictive cardiomyopathy
ment of growth is an essential part of their
Mitral Valve
management and part of the decision-making
Mitral regurgitation
process in determining the timing of correc-
Mitral stenosis
tive surgery. They have increased energy
Pulmonary Veins
requirements and sometimes have difficulty
Congenital pulmonary vein stenosis
feeding secondary to shortness of breath.
Mediastinal fibrosis
In an acutely decompensated infant, an
Mediastinal neoplasms
intravenous inotropic agent, such as dopa-
Mediastinitis
mine, dobutamine, or isoproterenol, is most
Veno-occlusive disease
useful. For long-term use, a medication that
Thoracic Aorta
can be given enterally, such as digoxin, is
Coarctation of aorta
more appropriate. Diuretics can improve
Supravalvular aortic stenosis
respiratory function by controlling the
When these patients are otherwise stable,

symptoms may be minimal. Acute increases
in cardiac output (e.g., fever or exercise) or
decreases in filling time (e.g., tachyarrhy-
thmias) can lead to sudden worsening of
dyspnea (Fig. 4-4). Hemoptysis is a late com-
plication and is caused by rupture of the
dilated bronchial anastomotic vessels.
Pediatric patients can have a severe, rapidly
progressive form of veno-occlusive disease.10
This form of veno-occlusive disease can be
sporadic or familial. The initial chest radio-
graph may show only cardiomegaly with
mild lung changes, or may show pulmonary
effusion or edema (Fig. 4-5). These patients
present with progressive dyspnea and then
syncope. As a postcapillary form of pulmo-
nary hypertension, patients are often mis-
Figure 4-5. Chest radiograph of a child with pulmonary
diagnosed as having arterial hypertension. veno-occlusive disease.
Although cardiac catheterization and com-
puted tomography (CT) of the chest can be
diagnostic,11 a lung biopsy may be needed vascular congestion, atelectasis, and pleural
to confirm the diagnosis. On pulmonary func- effusion.14 Vasodilators should be used spar-
tion tests, there is reduction of vital capacity, ingly and extremely cautiously in pediatric
forced expiratory volume in one second, and patients with veno-occlusive disease. Consul-
arterial oxygen saturation or diffusing capac- tation with a lung transplant team is recom-
ity for carbon monoxide.12 There is no effec- mended at the time of diagnosis.
tive medical or surgical therapy for most of As with acute increased pulmonary venous
these cases. There have been some case reports pressure, the chest radiograph may be the
that immunosuppressant therapy may ame- most sensitive noninvasive test to alert the
liorate the disease progression.13 Although clinician to the possibility of chronic venous
gentle vasodilator therapy may be effective hypertension. On the radiograph, the pul-
in some cases, use of vasodilator therapy also monary arteries become attenuated initially
can lead to (sometimes acutely) increased at the bases and then toward the apex. Kerley
B lines appear due to the presence of dilated
lymphatics and interlobular fibrosis, rather
than owing to interstitial edema, as in the
patient with acute increased pulmonary
venous pressure. Diffuse nodularity resulting
from hemosiderin-laden macrophages may
fill the lower lobe alveoli. Rarely, ossified
nodules also may be found at the lung bases
(Fig. 4-6).
The chest radiograph also is useful in deter-
mining the level of the venous obstruction.
If the level of obstruction is preventricular
(atrial myxoma or cor triatriatum), the left
ventricular silhouette may be normal,
although the left atrium may show an
enlarged shadow. If the level of obstruction
is at the ventricle due to myocardial disease
Figure 4-4. Acute decompensation of a patient with
chronic pulmonary venous hypertension after sponta- or to valvular disease, the heart is likely to
neous left pneumothorax. appear enlarged on the chest radiograph.
Figure 4-6. High-resolution CT scan of the chest of a

patient with idiopathic/sporadic pulmonary veno-occlu- Figure 4-7. Photomicrograph of lung biopsy specimen
sive disease. taken from a child with pulmonary venous obstruction.
Note the thickened walls of the pulmonary vein with nar-
rowing of the lumen. Also note the dilated capillaries in
Initial changes in pulmonary function are the interstitium.
due to congestion of the lungs and interstitial
edema. Pulmonary congestion and interstitial
edema may lead to decreases in airway caliber aorta, interruption of the aortic arch, and
with a decrease in forced expiratory volume obstruction to pulmonary venous return.
in one second. With increasing years, chronic These anomalies generally are characterized
changes, including interlobular fibrosis by decreased systemic perfusion and pulmo-
develop and lead to a decrease in lung recoil nary venous congestion. Infants with
and volume. In time, the chronic hemody- obstruction of the left heart usually develop
namic and pulmonary functional limitation clinical manifestations at an earlier post-
may lead to changes in respiratory muscle natal age and have more severe respiratory
function as shown by decreases in maximal compromise because closure of the ductus
strength. arteriosus, which usually occurs within the
With the chronic interstitial edema, lym- first few days after birth, may substantially
phatic distention, and possible intermittent reduce blood flow through the aorta and
extravasation of blood into the interstitium, decrease systemic perfusion. When the pul-
interstitial fibrosis develops around septa and monary artery pressure is suprasystemic,
blood vessels. The pulmonary veins show as in total anomalous pulmonary venous
characteristic changes of medial hypertrophy. return and obstruction, ductus closure elim-
Later venous changes include intimal thick- inates a mechanism for amelioration of the
ening and fibrosis (Fig. 4-7). An external elastic pulmonary hypertension via right-to-left
membrane characteristic of arteries may shunting. The pulmonary and systemic
form—the so-called arterialization of the pul- venous congestion can occur precipitously.
monary veins. These venous changes are
pathognomonic of pulmonary venous hyper- Pathophysiology of Obstruction of the
tension but nonspecific as to the underlying Systemic Ventricle
causes. Calcium deposition and ossification The problems occurring with left heart
are the most extreme changes, however, which obstruction arise from its effects on systemic
are seen only in long-standing mitral stenosis. blood flow, ventricular loading, and pulmo-
nary function. For a better understanding of
the pathophysiology of left ventricular
Outflow or Inflow Obstruction of the obstruction, it is helpful to separate the
Systemic Ventricle lesions into outflow and inflow obstruction.
Anomalies that commonly cause left-sided Left Ventricular Outflow Obstruction.
(systemic ventricular) obstruction include These lesions cause an increased afterload of
aortic stenosis or atresia, coarctation of the the left ventricle, which is tolerated very
poorly if the obstruction is severe or if it occurs The findings on chest radiograph also vary
abruptly. The hemodynamic consequences of with the severity of the obstruction. Severe
outflow obstruction are increased ventricular obstruction may show edema on the chest
end-diastolic, left atrial, and pulmonary film, along with left ventricular enlargement.
venous and pulmonary arterial pressures, In most patients with mild or moderate aortic
which cause variable degrees of pulmonary stenosis, the heart size is normal or only
venous congestion and pulmonary edema mildly enlarged. Intervention for aortic ste-
(interstitial and alveolar) and obstruction nosis, when indicated, can be accomplished
of large and small airways, just as with the by percutaneous balloon valvuloplasty in
large left-to-right shunt. In the most severe the cardiac catheterization laboratory or by
forms of obstruction, usually found in neo- surgical valvulotomy or valve replacement.
nates, there are always signs of poor systemic
perfusion (increased capillary refill time, Coarctation of the Aorta
decreased or absent peripheral pulses, cool Coarctation of the aorta often manifests as a
extremities) accompanied by lactic acidosis. discrete stenosis in the proximal thoracic
aorta, just opposite the PDA insertion. There
Left Ventricular Inflow Obstruction. is a wide spectrum of this disease, however,
These anomalies (i.e., mitral atresia or steno- including long segment coarctation and
sis) impede left ventricular filling and increase abdominal coarctation. Associated lesions,
the afterload on the right ventricle. The pre- such as PDA, VSD, aortic stenosis, or mitral
load on the right ventricle also becomes stenosis, also affect the pathophysiology
increased by the excess blood flow entering and clinical presentation.
the right ventricle from the portion of the pul- The clinical presentation of isolated coarc-
monary venous return, which is shunted from tation of the aorta varies. Newborns with
the left to the right atrium through the fora- severe coarctation and PDA closure present
men ovale. The impairment of systemic perfu- with congestive heart failure and cardiogenic
sion depends on the amount if any, of shock or low cardiac output. If a right-to-left
anterograde (aortic) flow from the systemic ductal shunt is present, differential cyanosis
ventricle and the right-to-left shunt, through of the lower extremities is seen. On the other
the ductus arteriosus. When there is atresia end of the spectrum, coarctation can manifest
of the mitral or aortic valve, the left-to-right later in childhood when systolic hypertension
atrial shunt represents the only means for or a heart murmur is being evaluated. The sys-
blood to reach the systemic circulation (via tolic blood pressure in the upper extremity is
the right ventricle and through the ductus elevated proximal to the coarctation, and
arteriosus to the descending aorta). there is a gradient noted between the arm
and leg systolic blood pressures. The arterial
Aortic Stenosis pulse in the leg is diminished and delayed
Aortic stenosis causes a spectrum of disease when palpated at the same time as the arm
in children, based on the severity of the val- pulse. The blood pressure and pulse should
vular narrowing. The valvular pathology be evaluated in all four limbs.
involves thickening of the tissue and vary- The chest radiograph of an infant with
ing degrees of separation of the commis- severe coarctation of the aorta usually shows
sures. Clinical findings vary widely with cardiomegaly and pulmonary vascular con-
the severity of the valvular obstruction. gestion. In older children being evaluated
Most children with mild aortic stenosis have for a murmur or hypertension, the heart size
normal growth and development and come usually is not prominent, and in isolated
to a cardiologist’s attention when a heart coarctation, the pulmonary markings are
murmur is heard. On the other end of the normal. The contour of the aortic arch is
spectrum, infants with critical aortic steno- often abnormal, with an indentation seen
sis can be hemodynamically unstable and at the site of coarctation (the “3” sign). Rib
exhibit severe endocardial fibroelastosis at notching also can occur in older patients;
birth, requiring immediate relief of the this is caused by erosion of the inferior rib
obstruction through interventional cardiac by the collateral circulation or dilated inter-
catheterization or a surgical approach. costals arteries.
Treatment for many children consists of An example of the latter is the pulmonary
surgical repair of the coarctation. This is usu- artery sling. The left pulmonary artery arises
ally performed via a left thoracotomy. Some- from an elongated main pulmonary artery
times, when an associated lesion also is being or distally from the right pulmonary artery.
repaired, a sternotomy is performed.15 Percu- It crosses the midline between the trachea
taneous balloon angioplasty, stent placement, and the esophagus, sometimes with a cross-
or both, for a discrete coarctation or re- over segment of the left pulmonary artery
coarctation are other treatment options.16-18 supplying the right upper lobe. This condi-
tion also is strongly associated with long
segment congenital tracheal stenosis.
Vascular Anomalies That Cause The most likely types of vascular rings
Airway Obstruction include double aortic arch and right aortic
arch with aberrant left subclavian artery,
Compression of the trachea and bronchi can
which arises from the descending aorta and
be caused by developmental abnormalities of
passes behind the esophagus. The vascular
both of the major arterial branches of the
ring is completed by the left ligamentum
aorta or the pulmonary vessels (Table 4-4). arteriosum, which courses from the origin
These lesions, which generally arise from fail-
of the left subclavian artery to the left pulmo-
ure of normal regression of one or more seg-
nary artery (Fig. 4-8). The left subclavian
ments of the early fetal paired branchial
arches, can produce substantial distortion
of the trachea and large bronchi.19 The most
common types involve either complete
encirclement of the tracheoesophageal com-
plex by vascular structures (vascular rings)
or compression of the trachea or bronchi by
vessels that follow an anomalous trajectory.
Causes of Vascular Compression A

Table 4-4 of the Airway in Children
• Anomalies of the aorta
Double aortic arch
Interrupted aortic arch (after surgical repair)
Right-sided aortic arch
• With aberrant left subclavian artery
• With mirror-image branching and right
ligamentum arteriosum
Left-sided aortic arch
• With aberrant right subclavian artery and
right ligamentum arteriosum
• Right-sided descending aorta with right
ligamentum arteriosum
Cervical aortic arch
• Absent pulmonary valve syndrome
• Aberrant left pulmonary artery (‘pulmonary B
artery sling’)
• Acquired cardiovascular disease
Figure 4-8. A 5-year-old boy with a right-sided aortic
arch and aberrant left subclavian artery. A, Axial CT scan
Dilated cardiomyopathy of the thorax shows compression of the trachea by the
Aneurysm aberrant artery (arrow). B, Three-dimensional volume ren-
dered image (posterior view) shows the right-sided aortic
• Ascending aorta
arch (white arrow on right) and the aberrant left subclavian
Ductus arteriosus artery (white arrow) arising from the descending aorta.
Adapted from McLaren CA, Elliott MJ, Roebuck DJ: Vascular (Adapted from McLaren CA, Elliott MJ, Roebuck DJ: Vascular
compression of the airway in children. Paediatr Respir Rev compression of the airway in children. Paediatr Respir Rev
9:85-94, 2008. 9:85-94, 2008.)
artery often originates from an outpouching

of the descending aorta, called Kommerell
diverticulum. Other patterns of right aortic
arch include mirror-image branching and
right ligamentum arteriosum, anomalous
innominate arising farther to the left than
usual and passing anterior to the trachea,
anomalous left carotid artery arising further
to the right than usual and passing anterior
to the trachea, and aberrant right subclavian
artery.
As a group, vascular anomalies obstruct
the intrathoracic airways exclusively. Conse-
quently, their manifestations are predomi-
nantly expiratory and include wheezing
and lung hyperinflation. When the com-
pression is severe, inspiratory stridor also is
heard indicating the relatively fixed nature Figure 4-9. Lateral projection of a barium esophago-
gram in a 3-month-old infant with a double aortic arch
of the obstruction. Infants are often brought causing posterior compression of the esophagus.
to medical attention when an intercurrent
infection causes increased respiratory dis-
tress. Some patients are labeled as having
“recurrent bronchitis” or “steroid-resistant an uncommon radiographic finding is an
asthma” before the diagnosis of a vascular anterior esophageal indentation with a pos-
ring is made. In older children, a (often terior impression on the tracheal air col-
more “loose”) vascular ring can manifest umn. This combination is seen when the
with dysphagia or choking. Other patients left pulmonary artery originates from the
remain asymptomatic and are diagnosed right pulmonary artery (pulmonary artery
incidentally. sling). The anomalous left pulmonary artery
Barium esophagogram is an important tool must find its way to the left lung anterior to
for the initial evaluation of infants and chil- the esophagus and posterior to the trachea.
dren suspected to have airway compression In the process, it passes over the right main
by an anomalous vessel. A large posterior stem bronchus, behind the trachea, and
esophageal indentation in association with down over the left main stem bronchus,
an anterior notch in the tracheal air column and may compress any of these structures,
is usually caused by complete vascular rings frequently causing air trapping or atelectasis
(double aortic arch or a right aortic arch with in either lung.
an aberrant left subclavian artery or ligamen- The diagnosis of vascular rings and slings is
tum arteriosum or both) encircling the tra- confirmed by magnetic resonance imaging
chea and esophagus (Fig. 4-9). (MRI)20 and computed tomography (CT).
A complete vascular ring can be associated These are the most useful imaging techniques
with intracardiac defects, such as VSD, because they provide information about the
which can divert attention from the extra- tracheobronchial tree, the cardiovascular
cardiac anomalies. Another radiographic structures, and their relationship to each
finding is the presence of an isolated ante- other. CT data are generally useful to diagnose
rior tracheal indentation. This pattern the type and severity of airway compression,
occurs when there is an anomalous innomi- but multiplanar reconstruction and three-
nate artery that arises too far from its nor- dimensional volume rendered images provide
mal origin and has to cross the midline in further useful information. Virtual bronchos-
front of the trachea. In contrast to the com- copy images also can be generated from CT
plete vascular rings, anterior tracheal com- data but rarely add diagnostic information
pression may be an incidental observation and cannot yet be used as a substitute for flex-
and produce few to no symptoms. Finally, ible bronchoscopy. MRI has excellent contrast
resolution and multiplanar imaging capabil- stenosis, if present. Surgery does not usually
ities.20 Evaluation of cardiac anatomy and eliminate all the respiratory manifestations
physiology with MRI is usually superior to immediately, if ever, because the residual
CT. Most MRI studies for vascular compres- tracheal obstruction tends to persist for
sion are quite prolonged (>30 minutes), how- months. In some cases, it is unclear whether
ever, requiring sedation or general anesthesia the airway ever becomes normal.21
in young children. Sedation risks for children
with a compromised airway are significant. Congenital Absence of the Pulmonary
In practice, the increased speed and quality Valve
of multiplanar reconstruction provided by Congenital absence of the pulmonary valve
CT technology means that CT is used more is characterized by the presence of enlarged
often than MRI in most centers. A limitation pulmonary arteries and hypoplastic pulmo-
of MRI and CT is that obliterated vascular seg- nary valve cusps. This lesion often occurs
ments (e.g., the ligamentum arteriosum or an in association with tetralogy of Fallot, VSD,
atretic aortic arch) cannot be directly visual- and right ventricular outflow tract obstruc-
ized. Echocardiography is essential for the tion. There is also a strong association with
evaluation of associated congenital heart dis- DiGeorge syndrome.
ease and usually clearly shows abnormal vas- Regurgitation of blood through the pulmo-
cular structures. Echocardiography is useful nary outflow tract results in extremely
to the surgeon for understanding complex enlarged pulmonary arteries (Fig. 4-10). These
three-dimensional relationships. Cross-sec- arteries compress the trachea and main stem
tional imaging is probably much better than bronchi, causing lobar collapse or lobar
bronchoscopy at determining the nature of emphysema and severe respiratory distress.
the vascular compression of the airway. Yet, Airway compression can be unilateral or bilat-
current CT and MRI techniques do not eral. Respiratory difficulty occurs as the pul-
reliably distinguish, between dynamic and monary artery becomes gradually dilated
static airway narrowing. This is an important when the postnatal decrease in pulmonary
practical issue because many children with vascular resistance increases left-to-right
prolonged airway compression develop sec- shunting and pulmonary regurgitation. Surgi-
ondary malacia. Flexible bronchoscopy is cal repair of the cardiac anomaly and place-
currently the best technique for this purpose. ment of an artificial pulmonary valve are
Airway malacia should be assessed only when invariably necessary. As a result of the residual
the patient is breathing spontaneously. Diag- tracheomalacia, there is, in many patients, a
nostic catheter angiography has largely been need for mechanical ventilation for weeks or
replaced by cross-sectional imaging. months after surgical repair even if the hemo-
Surgery is advised for symptomatic dynamic function is near-normal, and there is
patients with diagnostic imaging evidence no regurgitation.
of tracheal compression. The left arch is
generally small, nondominant (hypoplas- Pathophysiology of Respiratory
tic), and often transected in patients with Manifestations
double aortic arch. Compression produced From a clinical point of view, all the cardio-
by a right aortic arch and aberrant left sub- vascular anomalies we have described until
clavian artery with a ligamentum arterio- now are characterized by the severity of
sum is relieved by transection of the latter. their respiratory manifestations. Regardless
Anomalous innominate or carotid arteries of the exact nature of the anomaly, these
cannot be divided; attaching the adventitia manifestations always include an increase
of these vessels to the sternum usually in the work that the respiratory system must
relieves the tracheal compression. An anom- perform to maintain adequate ventilation.
alous left pulmonary artery is corrected dur- The increased work takes a further toll on
ing cardiopulmonary bypass by division at the already limited energy reserves of most
its origin and reimplantation to the main patients and often leads to respiratory fail-
pulmonary artery with the simultaneous ure as the first indication of the presence
repair of a long segment congenital tracheal of the anomaly.
predominant respiratory abnormality.

Whether it is caused by direct compression
of the trachea and large bronchi by enlarged
vessels or heart chambers or by narrowing
of the small intraparenchymal airways by
edema, the obstruction is almost always
intrathoracic, and as such is exacerbated
during expiration. In these patients, respira-
tion tends to be slower and deeper, and the
physical examination reveals wheezing and
prolonged expiration. The chest x-ray shows
hyperinflation.
The increase in the work of breathing
represents a challenge for patients who are
A usually in a poor nutritional state and
whose respiratory muscles may have a
reduced ability to increase their blood flow
because of reduced systemic perfusion. In
addition, the mechanical abnormalities pro-
duced by the disease itself tend to decrease
the efficiency with which the respiratory
system uses its limited resources (Fig. 4-11).
The development of severe retractions
creates an extra burden on the diaphragm,
B which for the same amount of work per-
Figure 4-10. Tetralogy of Fallot and absent pulmonary formed by the lungs has to use more energy
valve syndrome with airway compression in a 15-month- to deform the rib cage. Likewise, flattening
old boy. A, CT volume-rendered image shows compres- of the diaphragm in the presence of airway
sion of the left main bronchus (arrow). B, Axial CT scan
of the thorax shows severe compression of the airway obstruction causes the muscle to generate
between the vertebral body and the grossly enlarged pul- less volume displacement for the same degree
monary arteries. (From McLaren CA, Elliott MJ, Roebuck DJ: of fiber shortening and diminishes its area of
Vascular compression of the airway in children. Paediatr
Respir Rev 9:85-94, 2008.) apposition to the rib cage. Under such condi-
tions, it is not unsurprising that the energy
cost of breathing becomes extraordinary.
The mechanisms responsible for the Such demands cannot always be fully met,
increase in work of breathing vary depend- particularly under stressful conditions. Respi-
ing on the mechanical alterations produced ratory failure then develops.
by each cardiovascular anomaly. Most
patients with a large left-to-right shunt or
a left ventricular obstruction develop pul- Lesions with Increased Venous
monary edema. As a result, their alveoli Admixture
become unstable and collapse, causing an
increase in the force that the respiratory Cyanotic children have defects that allow
muscles have to generate to overcome the venous blood to mix with arterial oxygenated
elastic recoil of the lungs. Under these cir- blood. Children may have an isolated right-
cumstances, intercostal and subcostal retrac- to-left shunt or obstruction to pulmonary
tions develop, and the respiratory pattern blood flow in addition to the right-to-left
becomes rapid and shallow. The patient fre- shunt. Another example of cyanotic heart dis-
quently tries to preserve lung volume by ease is when the great arteries are transposed,
closing the glottis at the end of expiration, causing the systemic venous blood to return
producing a grunt. directly to the aorta. Examples of each of these
A group of children with similar heart dis- types of cyanotic heart lesions are discussed
ease can develop airway obstruction as their subsequently.
↓ Muscle
blood
flow
↓ Energy
↓ Nutrition
transduction
Alveolar collapse
Pulmonary edema
Energy Compensation
available Airway obstruction
Work of
breathing
Rib cage distortion

↓ Diaphragmatic length Efficiency Respiratory
Fatigue failure
Figure 4-11. Schematic representation of the balance between the energy available to the respiratory muscles and the
work that these muscles do during breathing in the presence of mechanical alteration. Whether the balance tips toward
compensation or respiratory failure depends not only on the relative magnitudes of the energy available to the muscles
and the increased workload (represented by the weights on both sides of the balance) but also on the efficiency with
which the energy is transformed into work (represented by the position of the fulcrum). The presence of heart disease,
alveolar collapse, pulmonary edema, and airway obstruction can increase the workload; poor nutrition, decreased blood
flow, and, in general, the inability of the muscle’s contractile machinery to transduce energy into work can decrease the
energy available. Under such circumstances, decreased efficiency caused by rib cage distortion (retractions), a flattened
diaphragm, or muscle fatigue can easily displace the fulcrum to the left, precipitating respiratory failure. (From Lister, G
and Perez Fontan JJ. Congenital Heart Disease and Respiratory Disease in Children. Loughlin G and Eigen H. Eds. Baltimore,
Williams & Wilkins, 1994, p 603.)
Tricuspid Atresia the main underlying physiologic issue,

Infants with tricuspid atresia do not have a whether it is the need to increase pulmonary
normal pathway for blood to flow from the blood flow, decrease pulmonary overcircula-
right atrium to the right ventricle because tion, or eliminate interatrial obstruction.
the tricuspid valve is not patent. The blood
in the right atrium instead takes a path Tetralogy of Fallot
across an ASD to mix with the oxygenated When there is an obstruction to pulmonary
blood in the left atrium. Patients with tricus- outflow and a right-to-left shunt, the pulmo-
pid atresia can have normally related great nary blood flow can decrease to less than sys-
arteries, D-transposed great arteries, or temic flow (Table 4-5). The most common
L-transposition of the great arteries. Some cardiac anomaly associated with decreased
have pulmonary stenosis or atresia, and pulmonary arterial pressure is tetralogy of
some have VSDs of varying sizes. Associated Fallot.
cardiac anomalies may produce decreased, With low pulmonary blood flow, the bron-
increased, or normal pulmonary blood flow. chial circulation may assume a more promi-
Patients with decreased pulmonary blood nent role in supplying blood to the lungs
flow appear cyanotic, while patients with
excessive pulmonary blood flow develop
congestive heart failure. Patients with tricus- Diagnoses Associated with
pid atresia who present in the first days of life Table 4-5 Decreased Pulmonary Arterial
Pressure
are typically cyanotic, have a leftward supe-
rior axis and left ventricular hypertrophy Ebstein anomaly
on electrocardiogram, and have decreased Pulmonary valvular stenosis with patent foramen
ovale
pulmonary vascular markings on chest
Tetralogy of Fallot
radiograph. Surgical palliation is directed at
for gas exchange. With severe pulmonary D-Transposition of the Great Arteries
outflow obstruction, cyanosis appears early, D-transposition of the great arteries is a cya-
occurring when the patient is crying or notic heart lesion that occurs when the
straining. The mechanism is presumed to be aorta arises from the right ventricle, and
an increase in pulmonary vascular resistance the pulmonary artery arises from the left
by a Valsalva-like maneuver. The cyanosis ventricle (ventriculoarterial discordance).
becomes severe, and the children are usually A parallel circulation is set up, and a mixing
dyspneic. Their characteristic pose, squatting lesion (VSD, ASD, or PDA) is essential for
to relieve their shortness of breath, is believed survival.
to help increase systemic resistance, which Clinically, an infant who does not have
increases the pulmonary blood flow and adequate mixing appears severely cyanotic.
improves their oxygenation. On physical A hyperoxia test can be performed to distin-
examination, these children have cyanosis, guish cyanotic heart disease from severe
digital clubbing, and growth failure. Electro- pulmonary disease by placing the patient
cardiograms and echocardiograms show on 100% FiO2 for 10 minutes. If the PO2
right ventricular and atrial hypertrophy. On increases greater than 150mmHg, pulmo-
chest radiograph, there is a prominent right nary disease should be suspected. The classic
ventricle and a small pulmonary artery, chest radiograph is described as an “egg on a
which appears as the characteristic “boot- string” because the great vessels are in an
shaped” cardiac silhouette (Fig. 4-12). anteroposterior relationship (Fig. 4-13). The
Except for significant hypoxemia, there chest radiograph also can appear normal in
are minimal alterations in pulmonary func- these patients, or may exhibit increased pul-
tion. One study found reduced lung volumes monary vascular markings and enlarged car-
in young adults with congenital pulmonic diac silhouette if a large VSD is present.23 If
stenosis compared with normal controls. It mixing of the pulmonary and systemic cir-
has been proposed that low pulmonary culations is inadequate at birth, an atrial
blood pressures can cause pulmonary hypo- septostomy can be performed in the cardiac
plasia.22 Patients with tetralogy of Fallot catheterization laboratory to create an ASD.
undergo complete surgical repair; sometimes This palliative procedure is followed by the
severely ill cyanotic infants require a pallia- arterial switch surgery, with reimplantation
tive Blalock-Taussig shunt before definitive of the coronary arteries to restore normal
repair. circulatory flow.
Figure 4-12. Chest radiograph of a child with tetralogy Figure 4-13. Chest radiograph of a child with D-trans-
of Fallot. position of the great arteries.
Idiopathic Pulmonary Arterial

Pulmonary Hypertension
Hypertension Table 4-6 Diagnostic Classification
Although idiopathic pulmonary arterial Pulmonary Arterial Hypertension

hypertension (IPAH) is not a primary cardiac Familial
disease, children with IPAH are usually Sporadic
referred to pediatric cardiologists for evalua- Related to:
tion of their symptoms or cardiomegaly or Connective tissue disease
both (Fig. 4-14). Children with IPAH (previ- Congenital heart disease
ously known as primary pulmonary hyper- Portal hypertension
tension) have a worse prognosis than Human immunodeficiency virus infection
adults.24 The definition of pulmonary arte- Drugs and toxins
rial hypertension is the same for children Other—type 1 glycogen storage disease, Gaucher
disease, hemoglobinopathies, myeloproliferative
and adults: mean pulmonary arterial pres- disorders, hereditary hemorrhagic telangiectasia
sure greater than 25mmHg at rest or greater (Rendu-Osler-Weber disease)
than 30mmHg during exercise, with normal Pulmonary Arterial Hypertension with
pulmonary artery wedge pressure (i.e., <15 Significant Venule or Capillary Involvement
mmHg), and an increased pulmonary vas- Pulmonary veno-occlusive disease
cular resistance index (>3 Wood units/m2). Familial
The diagnosis of IPAH is made only when all Sporadic
other causes of pulmonary hypertension have Pulmonary capillary hemangiomatosis
been ruled out (Table 4-6).24,25 A careful fam- Persistent Fetal Circulation (Persistent
Pulmonary Hypertension of the Newborn)
ily history also must be obtained to rule out
Pulmonary Venous Hypertension
familial pulmonary arterial hypertension. Pulmonary venous obstruction (discrete)
Children with IPAH often have insidious Left-sided heart disease
onset of vague symptoms, including fatigue, Pulmonary Hypertension Associated with
decreased endurance, or abdominal pain Disorders of Respiratory System or Hypoxemia
(older children and adolescents may have Hyaline membrane disease
chest pain). They also may present with recur- Bronchopulmonary dysplasia
rent exertional or nocturnal syncope. If the Congenital diaphragmatic hernia
child with IPAH fails to respond to vasodilator Pulmonary hypoplasia
therapy or is not treated in this manner, the Alveolar capillary dysplasia
prognosis is poor. The pulmonary arteries Cystic fibrosis
become greatly dilated throughout the lung Chronic obstructive pulmonary disease
parenchyma (Fig. 4-15), and patients develop Interstitial lung disease
progressive right heart failure accompanied Sleep-disordered breathing
by hemoptysis. Alveolar hypoventilation disorders
Chronic exposure to high altitude
Pulmonary Hypertension due to Chronic
Thrombotic or Embolic Disease
Thromboembolic obstruction of proximal
pulmonary arteries
Thromboembolic obstruction of distal pulmonary
arteries
Pulmonary embolism (tumor, parasites, foreign
material)
Miscellaneous
Sarcoidosis
Histiocytosis X
Fibrosing mediastinitis
Adenopathy and tumors
Lymphangiomatosis
Figure 4-14. Chest radiograph of a child with idiopathic From Rosenzweig EB, Widlitz AC, Barst RJ: Pulmonary arterial
pulmonary arterial hypertension. hypertension in children. Pediatr Pulmonol 38:2-22, 2004.
Other Pulmonary Conditions

Associated with Cardiac Disease
or Surgery
Plastic Bronchitis
Plastic bronchitis can occur in children and
adults.26,27 The disease is characterized by
severe obstruction of the large airways by bron-
chial casts (Fig. 4-17). Affected patients are usu-
ally classified by the type of airway cast.26 Type I
or inflammatory casts have fibrin, eosinophils,
and Charcot-Leiden crystals. Type II or nonin-
Figure 4-15. Explanted lung from a young adolescent
girl with idiopathic pulmonary arterial hypertension. Note flammatory/acellular casts consist primarily of
the markedly dilated pulmonary arteries extending to the mucin with a paucity of cells. Type II casts usu-
peripheral portions of the lung. ally occur in children with cyanotic congenital
heart disease and after cardiac surgery. A new
classification scheme has been proposed that
Diagnosis generally starts with an echo- is based on the associated disease and the histol-
cardiogram with Doppler, to evaluate the ogy of the cast.27 Treatment usually consists
cardiac anatomy, and if a shunt is present, of urgent/emergency removal of the casts
to determine shunt flow direction and to from the large airways by means of flexible or
quantify the shunt velocity (Fig. 4-16). rigid bronchoscopy. Aerosolized medications
Patients proceed to cardiac catheterization (rhDNase, heparin, tissue plasminogen activa-
for measurement of pressures and evalua- tor) and other medications (corticosteroids,
tion of response to acute therapy (e.g., nitric low-dose azithromycin) also have been used
oxide, prostacyclin). If the child fails to in published case reports.28-31 Thoracic duct
respond to vasodilator therapy, the progno- ligation has been performed in two patients
sis is poor. with Fontan circuits who had recurrent epi-
Few pulmonary function changes other sodes of plastic bronchitis that failed to respond
than cyanosis occur with disease progres- adequately to medical management.32
sion. Until congestive heart failure occurs,
the lung parenchyma is relatively spared.
Increase in airway resistance with mild non- Summary
reversible airway obstruction has been
reported, in these patients, however. Because of the close proximity and in-
terconnected circulatory systems of the car-
diac and respiratory system, alteration in
cardiac function has profound effects on
RA LA
RV LV
Figure 4-17. Bronchial casts (“plastic bronchitis”)

Figure 4-16. Echocardiogram of a patient with severe removed by flexible fiberoptic bronchoscopy from a
pulmonary arterial hypertension. There is severe right ven- patient with congenital heart disease with acute airway
tricular and right atrial dilation. obstruction and respiratory failure.
the entire respiratory system. Understanding 15. Dittrich S, et al: Comparison of sodium nitroprus-
side versus esmolol for the treatment of hyperten-
the physiologic mechanisms of this interrela- sion following repair of coarctation of the aorta.
tionship and the early signs and symptoms of Interact Cardiovasc Thorac Surg 2:111-115, 2003.
dysfunction of the cardiopulmonary circula- 16. Weber HS, Cyran SE: Endovascular stenting for
native coarctation of the aorta is an effective alter-
tory systems can aid in the early detection native to surgical intervention in older children.
and initiation of best available treatment for Congen Heart Dis 3:54-59, 2008.
children with cardiac disease. 17. Lee CL, et al: Balloon angioplasty of native coarcta-
tion and comparison of patients younger and older
than three months. Circ J 71:1781-1784, 2007.
18. Mendelsohn AM, Lloyd TR, Crowley DC, et al: Late
References follow-up of balloon angioplasty in children with a
native coarctation of the aorta. Am J Cardiol
1. Ip P, Chiu CS, Cheung YF: Risk factors prolonging 74:696-700, 1994.
ventilation in young children after cardiac surgery: 19. McLaren CA, Elliott MJ, Roebuck DJ: Vascular com-
Impact of noninfectious pulmonary complications. pression of the airway in children. Paediatr Respir
Pediatr Crit Care Med 3:269-274, 2002. Rev 9:85-94ss, 2008.
2. Thomas B, et al: Chronic respiratory complications 20. Malik TH, et al: The role of magnetic resonance
in pediatric heart transplant recipients. J Heart imaging in the assessment of suspected extrinsic
Lung Transplant 26:236-240B, 2007. tracheobronchial compression due to vascular
3. Bandla HP, et al: Pulmonary risk factors compro- anomalies. Arch Dis Child 91:52-55, 2006.
mising postoperative recovery after surgical repair 21. Murphy TM, et al: Pulmonary function sequelae in
for congenital heart disease. Chest 116:740-747, children with operated vascular rings. Chest
1999. 86(2):295, 1984.
4. Weissman C: Pulmonary complications after car- 22. De Troyer A, Yernault J-C, Englert M: Lung hypo-
diac surgery. Semin Cardiothorac Vasc Anesth plasia in congenital pulmonary valve stenosis. Cir-
8:185-211, 2004. culation 56:647-651, 1977.
5. Broaddus VC: Cardiac disease. In Murray JF, ed: Pul- 23. Levin DL, et al: D-Transposition of the great vessels
monary Complications of Systemic Disease. New in the neonate: A clinical diagnosis. Arch Intern
York, Marcel Dekker, 1992, pp 149-190. Med 137:1421-1425, 1977.
6. Lister G, Pitt BR: Cardiopulmonary interactions in 24. Rosenzweig EB, Widlitz AC, Barst RJ: Pulmonary
the infant with congenital cardiac disease. Clin arterial hypertension in children. Pediatr Pulmonol
Chest Med 4(2):219-232, 1983. 38:2-22, 2004.
7. Bates DV: Inter-relationships between cardiac and 25. Simonneau G, et al: Clinical classification of pul-
pulmonary function. In: Respiratory Function in monary hypertension. J Am Coll Cardiol 43:
Disease, 3rd ed. Philadelphia, WB Saunders, 1989, 5S-12S, 2004.
pp 250-264. 26. Brogan TV, et al: Plastic bronchitis in children:
8. Remetz MS, Cleman MW, Cabin HS: Pulmonary A case series and review of the medical literature.
and pleural complications of cardiac disease. Clin Pediatr Pulmonol 34:482-487, 2002.
Chest Med 10(4):545-592, 1989. 27. Madsen P, Shah SA, Rubin BK: Plastic bronchitis:
9. Stanger P, Lucas R, Edwards J: Anatomic factors New insights and a classification scheme. Paediatr
causing respiratory distress in acyanotic congenital Respir Rev 6:292-300, 2005.
heart disease: Special reference to bronchial 28. Wang G, et al: Effective use of corticosteroids in treat-
obstruction. Pediatrics 47:760-769, 1969. ment of plastic bronchitis with hemoptysis in Chi-
10. Wagenvoort CA, Wagenvoort TN, Takahashi T: Pul- nese adults. Acta Pharmacol Sin 27:1206-1212, 2006.
monary veno-occlusive disease: Involvement of 29. Wakeman MK, et al: Long-term treatment of plastic
pulmonary arteries and review of the literature. bronchitis with aerosolized tissue plasminogen
Hum Pathol 16:1033-1041, 1985. activator in a Fontan patient. Pediatr Crit Care
11. Resten A, et al: Pulmonary hypertension: CT of the Med 6:76-78, 2005.
chest in pulmonary venoocclusive disease. AJR Am 30. Kamin W, Klar-Hlawatsch B, Truebel H: Easy
J Roentgenol 183:65-70, 2004. removal of a large mucus plug with flexible paedia-
12. Thadani U, et al: Pulmonary veno-occlusive disease. tric bronchoscope after administration of rhDNase
QJM 44:133-159, 1975. (Pulmozyme). Klin Padiatr 218:88-91, 2006.
13. Sanderson JE, et al: A case of pulmonary veno- 31. Schultz KD, Oermann CM: Treatment of cast bron-
occlusive disease responding to treatment with chitis with low-dose oral azithromycin. Pediatr Pul-
azathioprine. Thorax 32:140-148, 1977. monol 35:139, 2003.
14. Davis LL, et al: Effect of prostacyclin on microvas- 32. Shah SS, Drinkwater DC, Christian KG: Plastic
cular pressures in a patient with pulmonary veno- bronchitis: Is thoracic duct ligation a real surgical
occlusive disease. Chest 108:1754-1756, 1995. option? Ann Thorac Surg 81:2281-2283, 2006.
CHAPTER 5
of Gastrointestinal Diseases
JOSEPH LEVY
Gastroesophageal Reflux Disease 99 Diagnostic Approach 110

Pathophysiology 99 Clinical Management 110
Developmental Aspects 100 Hepatopulmonary Syndrome 111
Congenital Anomalies 100 Clinical Manifestations 111
Diagnosis 102 Pathophysiology 111
Diagnostic Approach 103 Diagnostic Approach 112
Reflux as Etiology of Pulmonary Clinical Management 113
Pathology 104 Pancreatitis 114
Gastroesophageal Reflux Disease and Etiology 114
Asthma 105 Pulmonary Manifestations 114
Apparent Life-Threatening Events 105 Pathophysiology 115
Heiner Syndrome 106 Diagnostic Approach 116
Diagnostic Approach 107 Clinical Management 116
Inflammatory Bowel Disease 108 Acknowledgments 117
Pulmonary Manifestations 108 References 117
Clinical Manifestations 110
This chapter addresses the pulmonary in- The pulmonary involvement concurrent
volvement observed in gastrointestinal dis- with gastrointestinal diseases is often clini-
eases, particularly gastroesophageal reflux cally subtle and requires a high index of suspi-
(GER), Heiner syndrome, inflammatory bowel cion. The radiologic manifestations might lag
disease (IBD), the hepatopulmonary syn- behind the establishment of respiratory com-
drome (HPS), and pancreatitis. Although the promise, and only specialized testing such as
purported mechanisms currently invoked to high-resolution computed tomography (CT),
explain their concurrent associations vary, permeability studies with labeled proteins, or
several general modes of involvement include comprehensive pulmonary function tests
(1) the direct effect of spillage of food or gastric (PFTs) may be sensitive enough to detect the
contents into the airway, resulting in aspira- evolving pathophysiology. Increased use of
tion pneumonia; (2) a secondary, immune- these techniques, in addition to bronchoal-
mediated process, inflaming specific elements veolar lavage and validation of various bio-
of the lung; and (3) injury to the lung from markers, would allow better definition of the
medications used to treat specific gastrointes- prevalence of these disorders and their natural
tinal disorders, such as sulfa derivatives or history. As in many fields of pediatrics, the
immunosuppressive agents integral to the data on pulmonary manifestations of gastro-
management of IBD. The true etiology of the intestinal diseases are limited by sample size
observed involvement is still unclear, and and general research investment. Much of
much work is being done to unravel the the data is extrapolated from adult studies or
molecular mechanisms at play. This is a fruit- animal models.
ful field for translational research and wide For the most part, management is support-
open for the development of novel pharmaco- ive and conservative. Increasing recognition
logic agents with precise targets. of specific entities such as immune-mediated
98
Chapter 5—Pulmonary Manifestations of Gastrointestinal Diseases 99
alveolitis or granulomatous involvement of chronic bronchitis/bronchiolitis, chronic

the airway would result in the implementa- cough, asthma, and apparent life-threatening
tion of therapies that can be lifesaving or sig- events (ALTEs).3,4 Neonatal conditions that
nificantly improve the patient’s prognosis. are associated with a heightened risk of
GER include prematurity, postrepair eso-
phageal atresia with or without associated
tracheoesophageal fistula, congenital dia-
Gastroesophageal Reflux phragmatic hernia, and chronic lung disease
Disease of infancy.
GER, defined as the passage of gastric con-

tents into the esophagus, is a common phys- Pathophysiology
iologic event of little consequence in most
infants. It occurs throughout the day, and is It is now believed that the primary mecha-
most frequent in the immediate postprandial nism responsible for reflux in children is
period. In the first 3 months of life, more an inappropriate relaxation of the lower
than 50% of full-term infants regurgitate esophageal sphincter.5 In contrast to in
more than once a day, and 15% regurgitate adults, the resting pressure of the sphincter
more than four times a day. These numbers is rarely abnormally low in children. Other
increase from 4 to 6 months of age, when factors contributing to reflux in this patient
greater than 80% regurgitate. By the time population include reduced esophageal
the child is 18 months old, the prevalence capacitance and increased intra-abdominal
of reflux decreases to 5%.1 pressure. Important developmental factors
In contrast to GER, gastroesophageal reflux also play a role, including decreased fundic
disease (GERD) refers to the significant clinical compliance, discoordination of gastric emp-
manifestations of excessive reflux, which tying, and the shorter length of the intra-
manifest in a wide spectrum of settings, in- abdominal esophagus. Esophageal peristal-
cluding failure to thrive, irritability, feeding sis and mucosal protective factors are less
difficulties (especially feeding aversion), bleed- efficient in infants, especially when born
ing, and anemia. Extraesophageal manifes- prematurely, and this helps explain the
tations include chronic hoarseness, upper increased occurrence of pathologic reflux
airway obstruction owing to vocal cord ede- in this vulnerable population.5
ma, recurrent bronchitis or pneumonia, and Experimental work in animals and some
exacerbation of reactive airway disease.2 studies in humans suggest that pulmonary
The pulmonary manifestations of GERD involvement in the presence of acid reflux
are controversial. Pathophysiologically, it is can be the result of at least two very different,
often impossible to ascribe a causal relation- but potentially complementary or synergistic
ship to these two phenomena, presenting mechanisms. Exposure of the lower esophagus
a which-came-first conundrum: Are the pul- of kittens to hydrochloric acid has been asso-
monary complications observed in children ciated with a mild increase in measured bron-
with reflux a direct result of the exposure of chial smooth muscle tone.6-9 Similar results
the airway to acid or gastric contents, or are have not been consistently documented in
the cough, bronchospasm, and deranged dia- adults or in children, although evidence sug-
phragmatic mechanics the primary causes of gests that there is a loss of protective lower
the suspected reflux? Acid spillage into the esophageal sphincter tone in the presence of
distal esophagus may trigger increased vagal established esophagitis. A second mechanism
tone resulting in bronchospasm and worsen- considered pertinent to the pathophysiology
ing reflux as the infant mobilizes abdominal of reactive airways in the presence of reflux is
muscles to aid in exhalation against the the stimulation, through vagal mediators, of
bronchospasur constricted airways. receptors in the upper airway by microaspira-
The clinical manifestations of airway tion of acid or other irritants.10,11
disease in which reflux is suspected as an eti- Loss of the protective reflexes, which nor-
ologic factor include recurrent pneumonia, mally prevent aspiration from above, would
aggravate pulmonary manifestations in any A particularly dangerous form of aspiration

patient with concomitant risk factors. The occurs when stool softeners and laxatives
most vulnerable children presenting with containing mineral oil are administered
pulmonary signs and symptoms suggestive orally for management of chronic constipa-
of GERD are children with associated neuro- tion. Medium-chain triglycerides (MCT) oil
muscular handicaps that place them at risk used to increase the caloric density of formu-
for aspiration.12,13 las also may cause a lipoid pneumonia when
aspirated. Lipoid pneumonia can manifest
insidiously from continued microaspiration,
Developmental Aspects but also can have a sudden onset when a
large aspiration of lipid occurs. Oropharyn-
The mechanisms that coordinate breathing geal discoordination, loss of protective cough
and swallowing are not fully developed until reflexes, and airway penetration all contrib-
34 weeks gestation.14 Premature infants are ute to the development of lipoid pneumonia.
often treated for apnea suspected to be The pulmonary injury can manifest insidi-
caused by reflux; however, acidic and non- ously over months or years with tachypnea
acidic events occur frequently in this popula- and unexplained fever, but little cough or
tion, and they are not always causally related congestion.21 The findings on radiologic
to the respiratory irregularities or apnea that studies can be impressive (Fig. 5-1).
occurs regularly in this setting of central ner-
vous system immaturity.15-17 The technique
of intraluminal electrical impedance, which Congenital Anomalies
is limited to institutions with a research inter-
Infants born with congenital anomalies
est, allows identification not only of the
direction and volume of the bolus (antegrade affecting the oropharynx and other midline
structures (e.g., cleft palate, laryngotracheal
or retrograde), but also the effectiveness of
cleft) and infants with disproportionately
the esophageal clearance mechanisms.18
When paired with a pH sensor, this tech- large tongues or small mandibles (macroglos-
nique can shed light on important factors sia, as seen in various syndromes or in the
not otherwise detected with the more com- Pierre Robin sequence) are at a major disad-
monly used gold standard,—prolonged pH vantage with respect to their capacity to
intraesophageal monitoring.19 prevent aspiration from above and in the
As infants mature, the larynx descends and presence of reflux (Fig. 5-2).22,23 The presence
of abnormal communication between the
moves more effectively to provide a tight
esophagus and the airway (tracheoesophageal
seal during sucking and to close the trachea
with a well-developed epiglottis; the risk of
aspiration decreases significantly.20 For
many former premature infants, however,
the vulnerabilities can persist for years and
become a major challenge in their day-to-
day management; this is especially the case
with infants who have sustained intracranial
bleeds or injuries, infants with hydrocepha-
lus, infants with anoxic encephalopathy,
and infants who have required prolonged
respiratory support and artificial orogastric
or gavage feedings.3 In children who are fed
by gastrostomy tube, GER is common even
when studies before gastrostomy tube place-
ment are negative for GER. Figure 5-1. Aspiration of mineral oil resulted from treat-
In children with spastic cerebral palsy and ment of constipation in a 14-year-old child with profound
mental retardation and seizure disorder. Extensive, severe,
other syndromes that may include men- bilateral basilar chronic pneumonia is documented in this
tal retardation, constipation is common. chest CT scan.
Children with neuromuscular disorders,

including children with certain forms of
spastic cerebral palsy, spinal muscular atro-
phy, or bulbar involvement, can have recur-
rent aspiration because of their inability to
coordinate the five muscle groups that form
the intrinsic muscles of the larynx. These
groups are innervated by the trigeminal,
facial, hypoglossal, and vagus nerves, along
with the important branches, the superior
and recurrent laryngeal nerves. Sensory
abnormalities and autonomic dysfunction
(such as encountered in children with familial
and nonfamilial dysautonomic syndromes)
can result in prominent and life-threatening
lung disease (Fig. 5-3; see Fig. 5-2).25
Figure 5-2. CT scan of a patient with nemaline myopathy Another at-risk group for chronic reflux
and compromised chest motion secondary to his paralytic
thorax shows extensive basilar atelectasis and pneumonia and pulmonary disease are children with
resulting from recurrent aspiration. Bronchiectasis also is congenital diaphragmatic hernia.26,27 The
present bilaterally. presence of the herniated viscus during the
development of the lung often becomes
the most life-threatening component of
fistulas) results in spillage of saliva and the defect because it profoundly affects lung
particulate food into the airway. Even after development and results in pulmonary
repair of the fistula, most children with hypertension.28 The pulmonary compro-
these anomalies have a dysmotility of mise poses the most serious prognostic
their foregut, with more severe GER, and implications for the child. The effects on
increased likelihood of associated tracheoesophageal motility can be serious; often
malacia or laryngomalacia.24 there is an associated delayed gastric empty-
Serious respiratory and gastrointestinal ing and severe feeding intolerance.26 Infants
complications, such as recurrent pneumo- born with congenital diaphragmatic hernia
nia, obstructive airway disease, airway
hyperreactivity, GERD, and esophageal ste-
nosis, are frequent in patients with a history
of esophageal atresia/tracheoesophageal fis-
tula, although the frequency of such events
seems to decrease significantly with age.
Because chronic aspiration can lead to recur-
rent pneumonia and impaired pulmonary
function, it is essential in patients with a his-
tory of esophageal atresia/tracheoesophageal
fistula that these recognized respiratory
complications be excluded before respiratory
symptoms are simply attributed to “asthma.”
Common etiologies of respiratory symptoms
in patients with a history of esophageal
atresia/tracheoesophageal fistula include
retained secretions owing to impaired muco-
ciliary clearance secondary to tracheomala- Figure 5-3. Chest x-ray in a patient with familial dysauto-
cia, and aspiration related to impaired nomia (Riley-Day syndrome) shows hyperinflation, extensive
esophageal peristalsis or esophageal stricture right upper lobe and parahilar areas of atelectasis, and pneu-
monia. Oropharyngeal and gastroesophageal reflux also
or both, recurrence of the tracheoesophageal were documented. The patient’s x-rays improved after a
fistula, or GERD. Nissen fundoplication was performed.
often also have various degrees of pulmo-

Differential Diagnosis of Vomiting
nary hypertension, which is usually propor- Table 5-1 in Pediatric Patients
tional to the extent of lung hypoplasia. GER
Structural/Anatomic
is a major problem after surgical repair of
Pyloric stenosis
the diaphragm because with the stomach
Malrotation
in the chest during fetal development, these
Intestinal stenosis/atresia
infants fail to develop a cardiac sphincter,
Intussusception
and their esophagus tends to be short and
Hirschsprung disease
intrinsically dysmotile, as is the rest of the
Infections
foregut. After surgery (even if an antireflux
Pyelonephritis/cystitis
procedure is performed at the initial sur-
Pneumonia
gery), recurrence of GER is common when
Central nervous system infections
there is a paraesophageal hernia or slippage
Gastroenteritis
of the antireflux wrap. This is a common
Otitis
event when the diaphragm is repaired with
Sepsis
a Gore-Tex patch owing to stretch of the
Metabolic Disorders
patch with growth of the infant allowing
Organic acidurias
slippage of the stomach through the wrap.
Galactosemia
There is also an increased risk of reflux in
Hereditary fructose intolerance
esophageal atresia because even after esoph-
Urea cycle defects
ageal anastomosis, these infants are at very
Fatty acid oxidation defects
high risk for esophageal stricture at the site
Central Nervous System Disorders
of the anastomosis and poor distal esopha-
Hydrocephalus
geal motility. Similar to infants with con-
Ventricular or intracerebral hemorrhage
genital diaphragmatic hernia, these infants
Chronic subdural hematoma
rarely have a competent gastroesophageal
Tumors
sphincter.
Gastrointestinal Etiologies
Penetration of gastric contents, acid, or
Acute appendicitis
nasal or oral secretions into the airway has
Gastritis
deleterious effects on the surface epithe-
Pancreatitis
lium, triggering the production of mucus,
Allergic enteropathies
the recruitment of inflammatory cells, and
GERD
the activation of inflammatory pathways.
Cholelithiasis/cholecystitis
Surfactant damage, alveolar obliteration,
Hepatitis (infectious, autoimmune, metabolic,
atelectasis, and progressive parenchymal drugs)
damage result. As a result, interstitial fibrosis Miscellaneous
can develop with secondary changes in the Medication side effects
pulmonary circulation.29 Lead toxicity
Dysautonomic crisis
Diagnosis
The differential diagnosis of vomiting in vomiting is typically projectile and nonbilious.

a child is multifactorial (Table 5-1), and a The presence of bilious vomiting is always an
diagnosis of “reflux” should not be consid- emergency because it can result from malrota-
ered seriously until other important reasons tion or intussusception. Delay in diagnosis of
for vomiting are ruled out by a thorough his- volvulus can have catastrophic consequences,
tory and physical examination. When neces- with ischemic damage to the midgut. Vomit-
sary, ancillary tests help define potentially ing also is a common clinical manifestation
serious etiologies of vomiting. of an underlying infection in infants and chil-
Vomiting in an infant is often the presenting dren, including central nervous system in-
symptom for an underlying structural prob- fection, urinary tract infection, otitis media,
lem or obstruction. In pyloric stenosis, the and pneumonia. Inborn errors of metabolism
often manifest with vomiting and failure to to answer a specific clinical question. A
thrive. In specific disorders, intolerance to cer- guiding principle in the choice of test to
tain carbohydrates (galactose, fructose) or to identify reflux is to consider how the results
proteins (urea cycle disorders) can confuse would help guide or change management.30
the clinical picture and result in inappropriate Radiologic visualization of the esophagus
management for presumed reflux. Because the and stomach is neither particularly sensitive
child is vomiting, tests designed to identify nor specific to identify reflux, but radiogra-
reflux of gastric contents into the esophagus phy is an excellent and widely available
would invariably be positive, reinforcing the screening test for detecting anatomic de-
false assumption of reflux as the underlying fects, such as the critical conditions of
primary pathology. obstruction or malrotation.
The modified barium swallow, performed
Diagnostic Approach under videofluoroscopic control with the
guidance of a feeding or speech therapist
Given the numerous tests available to iden- who works closely with the radiologist, can
tify reflux (Table 5-2), it behooves the practi- provide extremely useful information
tioner to choose the most appropriate test regarding the mechanics of suck and
Diagnostic Tests Used in the Investigation of Gastroesophageal Reflux–Associated

Table 5-2 Pulmonary Involvement
TEST ADVANTAGES LIMITATIONS

Barium swallow/upper Commonly available; inexpensive; best suited Poor specificity; procedure performed
GI series to identify anatomic abnormalities supine; easy to elicit reflux in
frightened, crying infant
Modified barium Allows accurate definition of phases of Requires collaboration between
swallow swallow and abnormal structural positions experienced speech/feeding and
of involved structures; physiologic posture; radiology services; not widely
helps in the management of infants and available
children with dysphagia and other feeding
difficulties
Prolonged pH probe Accurate capture of acid reflux events; allows Does not identify nonacidic reflux
monitoring correlation with symptoms; reflects events; difficult to perform in
esophageal acid clearance; presents children receiving nasogastric or
physiologic events over time (18-24 hr), continuous feedings; not useful in
and their timing during the day and night; the identification of GER-related
helps in titration of antacid therapy ALTEs (see text)
Milk scan Affords a more physiologic setting to Insensitive to detect aspiration,
determine gastric emptying compared with unless it occurs while isotope is still
inert barium in the stomach; requires child to be
completely immobile for >1 hr
under the gamma camera
Salivagram High concentration of isotope allows better Not commonly performed; no
demonstration of aspiration from above; standards available
helps in visualizing retropharyngeal
pooling and esophageal clearance
Intraluminal Best test available to show bidirectional fluid Available only in a very limited
impedance movement in the esophagus; acid and number of centers at present;
nonacid events can be identified analysis is time-consuming and
dependent on experience of reader
Polysomnography Provides a wealth of physiologic data Only performed in a few pediatric
reflective of most systems potentially centers in the U.S.; requires
involved in ALTE episodes—EEG, air flow, overnight hospitalization (home
end-tidal CO2, EMG, abdominal and chest monitoring sometimes available
wall motion, saturation, ECG video through commercial services)
recording, and pH probe; allows temporal
correlation between variables
ALTE, apparent life-threatening event; ECG, electrocardiogram; EEG, electroencephalogram; EMG, electromyogram; GER,
gastroesophageal reflux; GI, gastrointestinal.
swallow and the safety of oral feedings performed with slender probes that have
(Fig. 5-4).31,32 This study is performed with proximal and distal sensors; this allows
the infant in a more physiologic position determination of the level reached by the
(sitting up, as opposed to lying down, as is acid refluxate in the esophagus. It also is use-
the case for a routine upper gastrointestinal ful in determining the adequacy of acid-
series) while various textures and barium suppressive therapy, a recurrent and very
consistencies are offered via a nipple or relevant clinical issue that arises when
cup. In addition to delineating the appropri- symptoms persist despite what is believed
ateness of lip and tongue coordination, to be an appropriate dose of H2-blocker or
bolus propulsion, and traverse through the proton pump inhibitor.
retropharynx and into the upper esophagus, A gastric scintiscan using a Tc 99m–
the test allows an appreciation of the esoph- labeled meal also can be performed. This
ageal sweeping peristaltic waves and the study allows detection of reflux and quanti-
effective relaxation of the lower esophageal fies gastric emptying over 2 hours. In some
sphincter during swallows. cases, markedly delayed gastric emptying
Monitoring of the changes in acidity appears to contribute to the reflux.
occurring in the esophagus is still consid-
ered one of the most valuable diagnostic
tests to quantify acid reflux and to deter- Reflux as Etiology of Pulmonary
mine its correlation to symptoms such as Pathology
irritability, neck posturing and arching,
feeding refusal, or nocturnal cough.33 The Determining the possible contribution of
pH probe monitoring test can now be reflux to pulmonary disease remains a formi-
dable challenge. As already noted, no single
test can help make the distinction between
aspiration or reflux of food and saliva from
above, or of acid and gastric contents from
below. Correlation with respiratory events,
including apnea, bronchospasm, and cough,
requires the simultaneous recording of multi-
ple variables, usually best performed in a
sleep laboratory or similarly specialized test-
ing facility. Polysomnography allows mea-
surement of airflow and chest movements
and cardiovascular parameters and oxygen
saturation, while also capturing REM sleep
and, if indicated, swallowing movements.
Correlating events that are separated by
milliseconds and trying to determine cause-
and-effect relationships can be a daunting
task and can help explain the dearth of
“definitive” studies pertaining to this topic.
Theoretically, labeling of saliva with nuclear
isotopes should provide a sensitive way to
detect aspiration of secretions from above.34,35
The “salivagram” has never been validated as a
useful tool for this indication, however.36 It
sometimes provides information on esopha-
geal clearance and even gastric emptying,
similar to a formal gastric emptying test per-
Figure 5-4. Direct tracheal aspiration documented dur- formed with labeled formula or solids.37 Iden-
ing a modified barium swallow in a patient with bulbar
dysfunction. Retention of the contrast material at the level tifying aspiration of gastric contents during
of the vallecula also can be appreciated. a gastric emptying test depends on the
aspiration event occurring while there is still patients documented the presence of abnor-
sufficient isotope left in the stomach. It does mal pH monitoring studies in more than
not easily or reliably duplicate the clinical 60% of infants and children with asthma.
setting of nocturnal aspiration. Nevertheless, only half of the patients with
chronic asthma and abnormal pH studies ever
reported gastrointestinal symptoms (includ-
Gastroesophageal Reflux Disease
ing vomiting, regurgitation, and heartburn)
and Asthma
suggestive of underlying reflux disease. No
The etiologic role of GERD in some patients clinical features of asthma predicted which
with the more refractory forms of asthma has children had abnormal pH scores.
not been firmly established, although there There is no pediatric experience that helps
is evidence (albeit controversial) to suggest predict which children with asthma but with-
that aggressive management of GERD can out GER symptoms might benefit from empiric
change the natural history of unremitting antireflux therapy, or how to approach patients
steroid dependency and severe bronchial with severe asthma who have negative pro-
inflammation in some patients.38 For most longed esophageal pH probe studies. Regarding
patients with uncomplicated asthma, how- surgery, a review of six case series involving
ever, it is unclear to what degree stimulation 258 patients with steroid-dependent asthma
of esophageal vagal mediators plays a role in showed that 85% of patients who under-
triggering or aggravating bronchospasm, or went an antireflux operation (fundoplica-
even whether reflux exerts its deleterious tion) were reported to have a decrease in
effects in this population through (micro) the frequency and intensity of their asthma
aspiration and airway penetration.39 attacks and were able to reduce their bron-
chodilator and anti-inflammatory medica-
Clinical Management tion dose. The American Thoracic Society
Typical acid reflux symptoms are often and the National Institutes of Health Expert
absent in patients with asthma referred to Panel on the Diagnosis and Management
a pediatric gastroenterologist for evalua- of Asthma have issued recommendations to
tion. Severe bronchospasm and cough can investigate reflux as a possible cause of
result in chest pain, epigastric discomfort, poorly controlled asthma (in adults), includ-
and nausea indistinguishable from GERD. ing documenting reflux with pH probe
Increased secretions promote triggering of studies, if indicated.41,42
the gag reflex and nausea, adding to the There is some evidence that GER is a pos-
diagnostic difficulties. In practical terms, sible trigger or aggravating factor in a sub-
the possibility of GERD-aggravated asthma group of patients with severe asthma. In
is considered when response to appropriate patients who have frequent exacerbations,
therapy is inadequate, and when asthma nocturnal attacks or cough, frequent need
symptoms seem to worsen at night or recur for steroids, or steroid dependence, a trial
without obvious explanation. Steroid de- of aggressive acid suppression (preferably
pendence and difficulties in maintaining with a proton pump inhibitor) and lifestyle
airway quiescence while receiving anti- modifications for at least 3 months can be
inflammatory and bronchodilator therapy beneficial and should be recommended.
should be a “red flag” pointing to GERD For patients without any GER symptoms,
as a possible contributor to the refractory but with a positive pH study or a clinical
nature of asthma. A positive pH probe is profile that includes recurrent pneumonia,
more likely in patients with severe asthma nighttime wheezing, and steroid dependence,
than in patients without severe asthma. 40 the same recommendations apply.
In 2001, the North American Society for
Pediatric Gastroenterology and Nutrition Apparent Life-Threatening Events
published clinical practice guidelines for eval-
uation and treatment of GER in infants and In the spectrum of pulmonary complications
children.30 In this evidence-based review, a related to reflux disease, ALTEs hold a special
meta-analysis of 13 case series involving 668 place, given the high anxiety generated
by the episodes and the costly evaluation to first hour postprandially, and if the infant
which many of these infants are subjected was awake (or semiawake) and supine.44
when they are admitted to the hospital Changes in position are known to pro-
for investigation of the episode.43 ALTEs mote relaxation of the lower esophageal
are defined as frightening events affecting sphincter, and the presence of a full stom-
infants who, during the episode, appear to ach in the recumbent position favors
require resuscitation (usually mouth-to- regurgitation.
mouth breathing for perceived apnea) and
look cyanotic (or pale) and lifeless, and Clinical Management
who were sometimes observed to have had Management of ALTEs associated with
a preceding gasping, choking, or gagging reflux focuses on measures geared to
trigger.44 In the typical case, an otherwise decrease the likelihood of reflux; avoidance
healthy infant has an ALTE episode when of the supine position within 1 hour of feed-
placed supine on a changing table soon after ings and thickened feedings have been
a feed or a bottle. It is not unusual to elicit a recommended. If there is a history of symp-
history of finding formula in the infant’s tomatic reflux, acid suppression and
mouth, or noticing the infant cough just improvement in the degree of esophagitis
as the airway clears and the long episode would optimize sphincter function. Diag-
(15 to 40 seconds) subsides. Characteristi- nostically, a pH monitoring study rarely is
cally, by the time emergency personnel helpful because the ALTEs are so random
arrive at the home and bring the infant to that capturing a whole GER-obstruction-
the emergency department, there is little to apnea sequence is seldom successful or
support the parents’ concerns about a life- worth the effort. Conservative treatment is
threatening event. recommended for most infants with ALTEs.
In addition to certain infections (e.g., respi- This recommendation represents a signifi-
ratory syncytial virus in premature infants), cant change in the indication for surgery
the differential diagnosis of ALTEs includes (fundoplication), which used to be the stan-
cardiac arrhythmias, central nervous system dard of care in some centers for manage-
disorders (including seizures), and metabolic ment of GERD-related ALTEs.46
derangements. It is important to consider All parents, and especially parents whose
defects of fatty acid oxidation and other, less infants have had an ALTE, should be
common entities because they can be diffi- instructed on back to sleep, the recommenda-
cult to diagnose unless there is a high index tion to encourage sleeping in the supine
of suspicion and specific tests are obtained position. This recommendation has been
shortly after the event.45,131,132 associated with a major reduction in the inci-
GER plays a role in a large proportion of dence of sudden infant death syndrome.
children with ALTEs (80% can have abnor- Severe GERD has been considered a special
mal pH monitoring studies, although they circumstance, however, in which a semi-
seldom are found to correlate with ALTE epi- prone position can be allowed, provided that
sodes). Frequent regurgitation is elicited the infant is carefully observed and moni-
in the history of 60% to 70% of infants tored, and the infant’s face rests against a
presenting with ALTEs.43 firm mattress. In addition, bottle propping
The understanding of the sequence of or bottle in bed is recognized as a risk factor
events leading to apnea in this setting is for ALTE and aspiration and chronic bronchi-
that the activation of protective reflexes in tis from aspiration as the infant falls asleep
the upper airway leads to airway obstruction with the bottle in the mouth.
when refluxate reaches the upper larynx or
is about to penetrate the airway. Vagally
mediated reflexes can explain the vasomo- Heiner Syndrome
tor and cardiorespiratory changes after the
obstructive episode. The likelihood of GER Heiner syndrome is a very rare form of pul-
being responsible for the ALTE episode monary hemosiderosis, believed to be due
increases if the event occurred within the to cow’s milk allergy because in the initial
report all infants had precipitins to cow’s milk presents with recurrent or chronic respira-
proteins in their serum.47 The symptoms tory symptoms. A history of chronic cough,
in these children were not the symptoms nor- pneumonia, bronchitis, and bronchiolitis
mally expected in idiopathic pulmonary is often elicited, and a history of frequent
hemosiderosis48 (recurrent hemoptysis or visits to the emergency department for
intermittent blood-streaked sputum, varying wheezing and a suspected diagnosis of
degrees of anemia, and radiographic find- asthma. Hemoptysis can occur when the in-
ings of symmetric diffuse alveolar infiltrates flammation and alveolar damage progress to
predominant in perihilar regions and lower intrapulmonary bleeding.48,51 Some children
zones), and all had nonspecific complaints can have transient hives and other urticarial
of chronic lung disease and upper respiratory rashes, periorbital edema, and allergic shin-
tract disease. These patients apparently im- ers. As a result of the chronic nature of the
proved on a milk-free diet. pulmonary involvement, many children are
In more recent decades, enthusiasm for debilitated and have poor weight gain and
cow’s milk allergy as the cause of idiopathic failure to thrive.52 Gastrointestinal manifes-
pulmonary hemosiderosis has waned. In a tations are nonspecific and include vomiting
very large series of patients with idiopathic and abdominal pain. Diarrhea is more com-
pulmonary hemosiderosis, no such associa- mon than constipation, although in some
tion was present. Some patients with pul- cases, both may be present.
monary hemosiderosis did not have milk
precipitins, whereas many children with
milk precipitins did not have pulmonary Diagnostic Approach
hemosiderosis. Because of the reported asso-
ciation between cow’s milk allergy and pul- The chest x-ray findings are nonspecific and
monary hemosiderosis, many children reflect the underlying interstitial changes
with idiopathic pulmonary hemosiderosis and air trapping caused by small and large
are placed on milk-free diets, but unless airway obstruction. Diffuse and variable
there is unequivocal evidence of true milk infiltrates, patchy pneumonia, interstitial
allergy, this approach is unjustified.49,50 lung disease, and fibrosis can be document-
The possible role played by exposure to ed at various times during the course and
foreign food proteins should be actively progression of the condition. Chronic intra-
elicited during the history. The onset of pulmonary bleeding results in a microcytic,
symptoms depends on the time of introduc- hypochromic anemia and iron deficiency
tion of milk and solid foods and varies in that can be severe and debilitating.
different geographic areas and cultural back- The precipitins against cow’s milk protein
grounds. As mentioned, cow’s milk seems fractions can be identified by the micro-
to be the major offender, but individual Ouchterlony technique; their appearance
experiences suggest soy, eggs, and pork also and concentration can vary depending on
can play a role.47 the state of sensitization and the temporal
The reported clinical improvement that proximity of the exposure to the offending
results from withdrawal of the offending protein.50 These circulating IgG antibodies
protein seems to be marked. It also is fol- are not pathognomonic, however, because,
lowed by radiologic improvement, which as mentioned previously, they have been
can lag behind symptomatic relief. Demon- reported in children who do not manifest
stration of the causal relationship with pulmonary hemosiderosis. Identification of
cow’s milk protein exposure is not always iron-laden alveolar macrophages in bron-
feasible because parents might be reluctant choalveolar lavage is good evidence that
to allow re-exposure after they have wit- bleeding has occurred recently, and that
nessed the dramatic resolution of chronic the disease process is still active. The finding
symptoms and the resumption of normal of hemosiderin in macrophages from gastric
weight gain and growth. aspirates also is suggestive of the diagnosis,
Heiner syndrome may be considered in but is less direct than bronchoalveo-
any atopic infant or young child who lar lavage. Nevertheless, their presence—
notwithstanding the suspected specific pro- Inflammatory Bowel Disease

tein exposure trigger—should raise the
possibility of other entities responsible Inflammatory bowel disease (IBD) refers to
for pulmonary hemorrhage/hemoptysis in the two most common forms of chronic,
children (Fig. 5-5).49,53,54 idiopathic inflammation affecting the intes-
Heiner syndrome remains a controversial tinal tract: Crohn disease and ulcerative coli-
entity because circulating precipitins, al- tis. These conditions presently are believed
though necessary, are insufficient to pre- to be due to the intersection of predisposing
dict clinical symptoms. The role of genetic genetic factors, environmental triggers, and
and environmental factors has not been a dysregulation of immune control resulting
elucidated in most reported cases of pulmo- in varying degrees of damage.57 In the case
nary hemosiderosis, but it is important to of Crohn disease, the inflammation is trans-
consider alternative, or concurrent, triggers mural and segmental, involving any portion
resulting in iron deposition in the lungs.55,56 of the small or large bowel, and often
progressing to cicatricial stricture. In con-
trast, the involvement in ulcerative colitis is
limited to the large bowel. The inflammation
is mucosal, begins at the rectum, and is
contiguous, without skip lesions. At worst,
ulcerative colitis affects the whole colon
(universal colitis), but sometimes only the
rectum (proctitis) or left colon is affected.
The clinical manifestations depend on
the severity and location of the inflamma-
R L tion and range from mild, intermittent
abdominal pain to severe bloody diarrhea
with or without extraintestinal involve-
A ment. In a quarter of children, the gastro-
intestinal manifestations can be subtle;
delayed growth and pubertal development
is more prominent.58 Fatigue, low-grade
fever, and night sweats sometimes can be
confused for hematologic or oncologic etiol-
ogies; rheumatologic manifestations also are
common.59
The multisystemic involvement in IBD has

long been recognized, and the extraintes-
tinal manifestations are believed to reflect
the effects of deranged immunologic regula-
tion.60 Changes in intestinal permeability
B that allow translocation of bacteria, fungal,
Figure 5-5. A, Chest CT scan of a 2-year-old patient or viral products (including endotoxin)
with hemosiderin-laden macrophages in bronchoalveolar can stimulate the formation of antibodies
lavage shows multiple nodular masses involving the upper targeting similar epitopes. Also, a common
and lower lobe fields. B, Chest x-ray shows bilateral nodu-
lar masses of varying sizes. The appearance of the chest embryologic origin (as is the case with the
radiographs improved between attacks of febrile respira- gut and the lung or with elements of the
tory distress. Although this patient was initially diagnosed eye or the joints) can result in distant
with idiopathic pulmonary hemosiderosis, her subsequent
benign course suggests that she might have had Heiner inflammation in conjunction with or inde-
syndrome. pendent of the bowel disease.61
The involvement of the lung is perhaps the most commonly as the development of bron-
least recognized of the extraintestinal mani- chiectasis and suppurative bronchitis.63,67
festations of IBD, and there are no reliable fig- The spectrum of involvement includes bron-
ures to describe true incidence and prevalence chial and bronchiolar inflammation, bron-
rates.133 It is possible that a systematic study chiolitis obliterans organizing pneumonia,67
would bring to light many cases that are mild and severe upper airway stenosis.69,70 In
and subclinical, or that would be identifiable Crohn disease, metastatic granulomatous
only by abnormalities in PFTs, including the involvement of the larynx, trachea, and bron-
diffusing capacity for carbon monoxide, or chi has been reported.69 Most of the published
by increased lung permeability as identified series involve adults, although single case
by Tc 99m DTPA clearance.62 It is believed that reports have shown that children also can
as a whole, extraintestinal manifestations are develop these complications.71 In the spec-
more common in Crohn disease than in ulcer- trum of extraintestinal manifestations, pul-
ative colitis, although pulmonary complica- monary disease is much less common than
tions in particular seem to be more common joint, skin, or eye involvement.
in ulcerative colitis.63 Also, when a patient The presence of lymphocytes in the
has one extraintestinal complication, gener- bronchoalveolar lavage of some patients
ally there is a higher likelihood of involve- with Crohn disease suggests an immune-
ment in another organ. mediated damage. Along these same lines,
Parenchymal and Pleural Disease the changes observed histologically in
Ascribing an etiologic role to the immune instances of small airway disease have been
mechanisms that underlie IBD may be similar to those found in patients with a
difficult because reactions to drugs used in its graft-versus-host disease after bone marrow
management can confound the picture. or lung transplantation. In patients with
Hypersensitivity pneumonitis with eosino- ulcerative colitis, pulmonary complications
philia is a known complication of exposure to can occur 1 to 2 years after colectomy
certain drugs, including sulfa and some of its (Fig. 5-6). One study suggests that colec-
derivatives—a class of drugs that is commonly tomy might represent an independent risk
used in the long-term treatment of IBD factor for the onset of the lung disease.72
patients.64,65 Clinical manifestations of drug- In some patients, there is no correlation
related pneumonitis are nonspecific and between the degree of inflammatory activity
include fever, dyspnea, chest pain, and produc- in the bowel and the timing of appearance
tive cough. A mixed obstructive-restrictive of the respiratory disease.63
lung disease pattern is often shown on PFTs.
Confirming the presence of eosinophilic
pleural effusions or alveolar fibrosis and res-
olution of clinical symptoms and signs or
radiologic findings is sometimes the only
way that a presumptive diagnosis of a
drug-induced complication can be consid-
ered. Response to drug withdrawal and ster-
oids can be lifesaving, particularly in cases
in which the inflammation potentially
could progress to pulmonary fibrosis.65 For
the most part, the offending agent is
believed to be the sulfapyridine moiety of
sulfasalazine, although there have been
isolated reports of eosinophilic pneumonia Figure 5-6. A 16-year-old patient, who underwent
in patients receiving only mesalamine.66-68 colectomy for ulcerative colitis, developed bronchiectasis
in the right mid-lung field 1 year later. Clinical manifesta-
Airway Disease tions included recurrent fever, productive cough, and dys-
pnea on exertion. Management included antibiotics for
Airway damage in IBD has been document- acute exacerbations and prophylactically, postural drain-
ed at all levels of the tracheobronchial tree, age, and inhaled bronchodilator.
Clinical Manifestations
The most common manifestations of pul-

monary disease in IBD are cough and dys-
pnea. In bronchiectasis, the cough is
productive, and the secretions are copious
and thick—although there are reports of
well-documented bronchiectasis with nei-
ther cough nor sputum production. In B
patients with few (if any) symptoms, pul-
monary disease can only be surmised on
the basis of abnormal radiologic findings or
abnormal PFTs. In more severe cases of sup-
purative disease, dyspnea and hypoxemia
can be significant.73
Diagnostic Approach
The airway and interstitial changes that

occur as a result of the immune-mediated A
damage are not always accompanied by
identifiable radiologic changes in plain
chest films, even when the clinical situation
has progressed, and the patient is clearly Figure 5-7. “Tree in bud” pattern on high-resolution
CT. (From Mahadeva R, et al: Clinical and radiological char-
symptomatic.63 A more representative pic- acteristics of lung disease in inflammatory bowel disease. Eur
ture is obtained through the use of high- Resp J 15:41-48, 2000.)
resolution CT, particularly if care is exercised
in obtaining full inspiration and expiration
views.74 The presence of bronchiectasis is
identified by the discrepant caliber of the in bud” pattern (Fig. 5-7).75 Air trapping
bronchus in relation to its corresponding can be prominent and can be reversible
artery. The bronchus appears of a homoge- with steroid treatment. Pathophysiologi-
neous diameter even in images that extend cally, this pattern often seems to be asso-
to the periphery, where the size would be ciated with more severe coughing, much as
expected to diminish. The presence of secre- bronchiectasis is often accompanied by pro-
tions in the dilated bronchial tree reflects ductive cough.
the stasis and suppuration occurring during
the inflammatory process.
Changes in the diameter of the larger air- Clinical Management
ways have been described in isolated instances
of glottis and tracheal stenosis in patients Systemic steroids are the mainstay of treat-
with ulcerative colitis. In these instances, the ment for inflammatory lung disease when
trachea can appear as a long, rigid channel. it occurs in the context of IBD. The inflam-
Mucosal swelling can be identified promi- matory changes in the lungs do not always
nently in magnetic resonance imaging scans parallel the degree of activity of the under-
with gadolinium enhancement.71 lying intestinal disease and need to be man-
Parenchymal characteristics on high-reso- aged in their own right, regardless of
lution CT reflect the inflammatory exudates whether the intestine is quiescent or not.
present in various portions of the lung and In some instances of suppurative bronchial
appear in a ground-glass pattern. Centrilob- or bronchiolar disease, the response to ster-
ular nodules and branching linear opacities oids can be dramatic and has been the indi-
can give what has been described as a “tree cation for recurrent courses of treatment
during the course of the illness. Similarly, pulmonary vasoconstriction leads to compro-
patients with stenosing airway presen- mised oxygenation in the presence of portal
tations, in which airway wall edema is hypertension.82
prominent, have benefited greatly from HPS is found in 30% to 40% of patients
steroids. In some instances of interstitial with chronic liver disease (range 13% to
pneumonia, methylprednisolone has been 47%).83 PPHTN is much less common, diag-
administered directly in the form of bron- nosed in about 5% of patients with chronic
chial lavages.76 In this respect, the thera- liver disease. The symptoms of PPHTN are
peutic response is similar to what is seen in those of hemodynamic compromise, with
immune-mediated lung disorders, including right ventricular dysfunction and cor pul-
autoimmune and vasculitic syndromes, or in monale. PPHTN is associated with mortality
graft-versus-host disease. rates of 40% within 15 months of diagno-
sis.80 In contrast to HPS, PPHTN is much
less likely to reverse after successful liver
Hepatopulmonary Syndrome transplantation.
HPS is a recognized complication of cirrhotic

and noncirrhotic liver disease that is accom- Clinical Manifestations
panied by portal hypertension. HPS is charac-
Initially, patients with HPS can be asymp-
terized by the clinical triad of (1) chronic liver
tomatic, although as the alveolar-arterial
disease, (2) arterial hypoxemia, and (3) for-
gradient increases, dyspnea and cyanosis
mation of abnormal intrapulmonary vascular
inevitably ensue. In addition, digital club-
dilations.77 The initial description of HPS
bing can be prominent. In some patients,
dates to the turn of the 19th century, but the
orthodeoxia—the decrease in arterial oxyge-
pathophysiologic processes underscoring the
nation caused by pooling of blood in the
intrapulmonary shunting, and the molecular
dilated capillary vasculature when a patient
mechanisms responsible for those changes,
stands up (as blood moves with gravity to
have begun to be appreciated only in the past
the lower lobes of the lungs)—develops.84
2 decades.78
Patients also have clinical signs of the
HPS has a profound impact on the sur-
underlying chronic liver disease, most com-
vival of patients who develop it. It raises
monly hyperbilirubinemia, spider angio-
the Model End-Stage Liver Disease score
mas, splenomegaly, and other signs of
for patients awaiting liver transplantation
portal hypertension.
because orthotopic liver transplantation
remains the only proven therapy at this
time.79 Liver transplantation brings about a Pathophysiology
resolution of the pulmonary findings in
greater than 80% of patients. The reversibil- New insights into the possible mechanisms
ity of the syndrome reinforces the notion of development of HPS have been gained
that HPS is secondary to functional abnor- from detailed studies in a mouse model of
malities occurring in the endothelium of common bile duct ligation. After ligation
the pulmonary vasculature.80 These abnor- of the common bile duct, progressive
malities seem to be mediated by various changes in the pulmonary vasculature are
key circulating molecular species released consistent with the changes shown in the
into the venous circulation, particularly concentrations of nitric oxide in the lung:
nitric oxide and carbon monoxide, which hypoxia results.81 The postulated mecha-
contribute to the vasodilation and subse- nism is a chain reaction triggered by produc-
quent microvascular changes.81 tion of the mediator endothelin-1 (ET-1) by
It is important to distinguish between HPS cholangiocytes, which become hypertro-
and portopulmonary hypertension (PPHTN) phic after the ligation. Overexpression of
because these two entities are pathophysio- endothelial endothelin B (ETB) receptor pro-
logically distinct. Their underlying mechani- moted by the shear stress in the pulmonary
sms are diametrically opposed. In PPHTN, circulation increases the production of nitric
oxide in the lung. This cascade possibly is

initiated by absorption of bacterial endo-
toxin in the gut, triggering tumor necrosis
factor-a release, which upregulates cyclic
adenosine monophosphate and the intrin-
sic nitric oxide synthesis pathway.85
Factors playing a role in the formation of
pulmonary arteriovenous shunts and dilated
microcapillaries differ from the factors that
are involved in the hyperdynamic circulation
most characteristic of patients with cirrhotic
liver disease. In all patients with cirrhosis,
systemic vasodilation occurs uniformly as a
function of time, whereas HPS is seen in only
about one third of this population, pointing
to other mechanisms involved in the patho-
genesis.86 It also has become clear that, in
rare instances, HPS can develop even when
cirrhosis is not firmly established, suggesting
that activation of nitric oxide–mediated
pathways can occur in the presence of pre-
served hepatic synthetic function84 or tran-
siently, in the setting of acute or chronic
hepatitis.87,88
In the above-described experimental Figure 5-8. Patient with cystic fibrosis, established bili-
model of common bile duct ligation, ET-1 ary cirrhosis, and portal hypertension shows arteriovenous
shunting by right and left selective pulmonary arterio-
plays an important role in producing an grams. Findings are characteristic of the hepatopulmonary
overexpression of the ETB receptor, which syndrome and resulted in hypoxemia and orthodeoxia
brings about vascular dilation.85 It is para- (see text).
doxical that ET-1, a well-recognized vaso-
constrictor, would result in vasodilation in
the pulmonary circulation. The explanation of the capillary bed interrupts the normal
seems to lie in selective activation of ETB physiologic steady state characterized by
receptors on the luminal surface of the vas- the movement of single red blood cells
cular endothelial cells in the lung by ET-1, through the capillary bed with highly effi-
which is the final mediator of vasodilation. cient oxygen transfer to hemoglobin. This
ETB receptor expression was found to be transfer cannot occur when four or five
significantly increased in the presence of red blood cells are traversing the capillary
portal hypertension secondary to biliary or bed simultaneously, as has been shown in
nonbiliary cirrhosis. The increase in ETB pathologic preparations.82 Depending on
receptor concentration mediates the sensiti- the extent of the phenomenon, a pressure
zation of the pulmonary vasculature to the difference between the oxygen in the
vasodilating effects of ET-1, with activation alveoli and the arteries can result in either
of the endothelial nitric oxide synthase no symptoms or in severe dyspnea, with
pathway.81 consequent hypoxemia.
One consequence of this vasodilation is
the development of a perfusion/ventilation
mismatch, owing in part to increased perfu- Diagnostic Approach
sion in under ventilated areas where the
abnormal dilation has developed. In addi- The diagnosis of HPS depends on identifica-
tion, there are direct shunts between the tion of dilated capillary channels in the
arterial and venous plexuses creating a periphery of the lung. Four common methods
bypass physiology (Fig. 5-8).86 The dilation of identifying this process are (1) contrast-
enhanced echocardiography, (2) Tc 99m– From a structural point of view, high-reso-

labeled macroaggregated albumin (MAA) lution CT may facilitate determining the
scan, (3) pulmonary angiography, and (4) ratio of the pulmonary artery (main pulmo-
high-resolution CT. nary trunk, right and left main pulmonary
In contrast-enhanced echocardiography, arteries) and the diameter of pulmonary vas-
indocyanine green or normal saline is culature. These changes can be shown best
injected intravenously while a transthoracic on the “parenchymal” windows on the
echocardiogram is performed. In the pres- CT scan, in contrast to the “mediastinal”
ence of a dilated capillary bed in the lungs, windows, which seem better suited for the
the 8 to 15mm bubbles are noted to appear vascular measurements. The ratio of the
in the heart after five or six cardiac cycles diameter of the right lower lobe basal seg-
owing to the “escape” of the microbubbles mental pulmonary artery to the diameter
through the dilated channels, which may of the lumen of the accompanying bron-
be 500 mm in diameter.89 The delayed opaci- chus, known as the pulmonary artery/
fication seen after three to six cardiac cycles bronchus ratio, can be calculated. In high-
is a reflection of the time it takes for the resolution chest CT, there is a correlation
microbubbles to permeate through the pul- between the diameter of the right lower lobe
monary capillaries, and is a specific sign of basal segmental artery and the partial pres-
the intrapulmonary shunting that is taking sure of oxygen in HPS. An increased pulmo-
place. The presence of a positive contrast- nary artery/bronchus ratio may be helpful
enhanced echocardiography study is not in diagnosing HPS in patients with liver dis-
enough, however, to ensure a diagnosis of ease and hypoxemia. High-resolution CT
HPS. In some instances, some patients have also can identify the presence of pleural or
been found to have a positive contrast- direct arteriovenous communications in
enhanced echocardiography study, but nor- dilated channels, and provide information
mal alveolar-arterial gradient. These patients on the lung parenchyma.92 More experience
would not technically qualify for a diagnosis with this technique is needed because these
of HPS. findings have been inconsistent.93
A similar principle applies to the passage of The appearance of the chest x-ray in HPS is
Tc 99m MAA molecules through the dilated usually nonspecific. Some chest radiographs
channels in a Tc 99m MAA study. The sen- might show “mottled” shadows bilaterally,
sitivity of these tests is not high, but they are which have been suspicious enough to war-
specific in the absence of intracardiac shunt- rant treatment for suspected tuberculosis.
ing.90 The oxygenation in the pulmonary Increased bilateral interstitial markings also
artery when 100% oxygen is inspired has been have been described. It is believed that these
shown to be significantly worse in HPS when markings are a result of the intrapulmonary
pulmonary nonvascular comorbidities are vascular dilations.
present. This finding is of clinical significance
because mortality is increased when decreased
oxygenation is present while breathing room Clinical Management
air and when there is an increase in the shift
of Tc 99m MAA to the brain. The presence of HPS is associated with
Echocardiography, especially if the trans- increased mortality in patients with liver
esophageal approach is used, has better disease. It is important to evaluate periodi-
sensitivity for distinguishing between intra- cally the presence and progression of the
pulmonary and intracardiac shunting than gradient and the presence of hypoxemia in
the regular transthoracic echocardiogram. any patient with chronic liver disease.
Because it requires anesthesia, however, trans- Because HPS is reversible only by trans-
esophageal echocardiography poses practical plantation, it constitutes at present an
risks in the setting of compromised liver func- indication for early liver transplantation.
tion and the possible presence of esophageal Transplantation results have been positive;
varices.91 greater than 80% of transplant recipients
have near-complete resolution of pathologic

Table 5-3 Etiology of Pancreatitis in Children
changes.94 The return to normal occurs over
months in patients surviving the transplant. Idiopathic (20%-30% of cases)
As mentioned, it is important to ensure Trauma (including child abuse)
beforehand that no pulmonary comorbid- Drugs*
ities are present, particularly the presence Thiazides
of PPHTN. Azathioprine
Asparaginase
Antiretrovirals
Pancreatitis Valproic acid
Infections (congenital and acquired)
Acute pancreatitis is often a self-limited Viral/bacterial—mumps, rubella, coxsackievirus,
influenza, hepatitis A and B, Mycoplasma
condition characterized by abdominal pain pneumoniae
and elevation in the serum concentrations Parasitic—Ascaris, Echinococcus, Clonorchis sinensis
of amylase and lipase. Inflammation of the Metabolic disorders
pancreas is the result of activation of Hyperparathyroidism
the digestive enzymes normally maintained Hyperlipidemia types I, IV, V
in an inactive proform in the exocrine Hypercalcemia
portion (the acini) of the gland. Autodiges- Vitamin D deficiency
tion is potentially a serious consequence, Hereditary conditions
although self-limited mild inflammation is Cystic fibrosis
more common than fulminant, necrotizing Shwachman-Diamond syndrome
pancreatitis.95 Familial recurrent pancreatitis
The hallmarks of pancreatitis include Collagen vascular disorders
abdominal pain and abnormalities in the Systemic lupus erythematosus
measured circulating pancreatic enzymes, Periarteritis nodosa
principally amylase and lipase.96 The abdom- Congenital anatomic abnormalities
inal pain—typically referring to pain in the Choledochal cyst
back and epigastrium—can be excruciating, Enteric duplications
requiring narcotics for management. Nausea, Cholelithiasis
vomiting, and the sensation of bloating
often accompany the pain. In many cases, *List is not comprehensive.
pancreatitis can be asymptomatic, however,

and can be suspected only from the presence
of biochemical abnormalities.
handlebar injuries are notorious in this
regard,99 but the possibility of child abuse
Etiology needs to be considered.100
The most common triggers for pancreatitis
in adults are gallstones and alcohol inges- Pulmonary Manifestations
tion. In children, the etiology often remains
elusive or idiopathic; Table 5-3 lists the Lung involvement in the course of acute
broad categories to be considered in the dif- pancreatitis has long been recognized as a
ferential diagnosis. In addition to infections potentially extremely serious complication,
and medications, some metabolic disorders manifesting in 5% of cases as acute respira-
and hereditary forms of recurrent pancre- tory distress syndrome (ARDS) with high
atitis are now being increasingly recog- mortality rates of 50% to 75%. In adults,
nized as possible causes, with mutations in the incidence of lung complications has
genes involved in the stability of trypsino- been reported to be 15% to 55%.101 Data
gen and other protective mechanisms.97,98 for pediatric patients are unavailable, and
An important cause of pancreatitis in chil- only anecdotal case reports have been
dren is blunt abdominal trauma; bicycle published.102,103
The changes leading to pleural effusions Damaged acini release the powerful mem-
and to alveolar damage are not fully under- brane and cellular digestive enzymes nor-
stood, but intensive work in several animal mally kept in their proenzyme granular
models of pancreatitis has helped expand storage form. Elastase and phospholipase A
understanding of the pathophysiologic are considered key players in this process.110
steps involved in the process. Cystic fibrosis When the inflammatory cascade is trig-
also can manifest as recurrent pancreatitis. gered, upregulation of the genes encoding
These patients often have similar CFTR gene for nuclear factor kB and tumor necrosis fac-
mutations, class IV (abnormal conductance) tor-a has been shown.111
and class V (reduced synthesis or traffick- Important changes occur in the pulmo-
ing). In these two classes, lung dysfunction nary capillary bed, resulting from recruit-
is often recognized only after complete ment of neutrophils and translocation of
genetic evaluation.134 serum proteins into the lung interstitium
Early in the course of the attack of acute (this can be shown with the use of chro-
pancreatitis, changes can occur in the lung mium-labeled albumin or transferrin). Pul-
ranging from asymptomatic hypoxemia to monary infiltrates are seen radiologically.
fulminant respiratory failure. The degree of Thickening of basement membranes and
hypoxemia is not correlated to the severity lysis of the surfactant proteins and phos-
of the underlying pancreatic involvement. pholipids results in the clinical picture of
Tachypnea, dyspnea, and shallow breathing ARDS and profound hypoxemia.112
can be present, with the last-mentioned Various adhesion molecules, such as intra-
reflecting the presence of diaphragmatic irri- cellular adhesion molecule-1, are synthe-
tation secondary to accumulated pleural effu- sized in higher quantities in the presence
sions. Effusions have been shown in more of inflammation.111 They play a role in the
than 15% of patients and are preferentially activation of lymphocytes, macrophages,
left-sided, for unclear reasons, but perhaps and neutrophils; they further contribute to
related to direct irritation of the dia- the endothelial damage and the leaking of
phragm.101 The effusion fluid is usually rich proteins into the lung parenchyma. The role
in amylase, and the enzyme concentrations of endotoxemia is strongly suspected as
can remain elevated even after the circulating another important promoter of progressive
pancreatic enzymes have normalized.104 damage and multiorgan failure because
severe pancreatitis is frequently associated
with infection of the necrotic gland; the
Pathophysiology most common organisms are enteropatho-
gens believed to have translocated as a result
Experimental pancreatitis, induced in rats of the above-described diffuse capillary per-
either by intraperitoneal injections of cerulein meability changes.113
(an analogue of cholecystokinin) or by intra- Structural changes in the alveolar integ-
biliary ductal injection of the bile acid tauro- rity parallel severe impairment in oxygen
cholate, has allowed identification of several diffusing capacity and bronchial reactivity.
important mechanisms participating in the Vital capacity piratory volume in 1 second
observed multiorgan dysfunction.105,106 are diminished, although the functional
As autodigestion of the gland occurs, che- residual capacity does not seem as
mokines and cytokines are released into the affected.114 On the basis of results provided
circulation, resulting in recruitment of acti- by labeled transferrin studies, it has been
vated cellular mediators capable of producing established that the main drive for the patho-
intense changes in the alveolar endothelium physiologic changes in the lung results from
and the pulmonary vasculature.105 Among the changes in vascular permeability
the cellular mediators, mast cells and macro- and protein exudation into the peribronch-
phages are believed to play central roles, iolar and parenchymal space.115 After this
whereas activated trypsinogen generates tryp- process takes place, mortality increases
sin, a potent protease.107-109 significantly.116
The most dreaded complication of pan- infiltrates, and atelectasis all can be present
creatitis is the progression to fulminant nec- during the evolution of the pulmonary de-
rotizing destruction of the gland. As noted, terioration. High-resolution CT can help
this occurs via autodigestion and activation demarcate the alveolar damage and the exu-
of inflammatory pathways by virtue of a dative process that ultimately result in the
wide variety of mediators capable of affect- picture of ARDS.125 The pulmonary picture
ing the circulation in profound ways, with is similar to the one observed in shock, or in
rapid progression to systemic inflammatory what is now termed “systemic inflammatory
syndrome, capillary leak, and irreversible response syndrome.”
shock. The pulmonary changes are mani-
fested by subclinical hypoxia or by frank
ARDS, with serious implications for the Clinical Management
patient’s prognosis.117
Management of pancreatitis is conservative,
addressing the following factors: (1) support
Diagnostic Approach of cardiovascular homeostasis, (2) judicious
use of antibiotics when infected collections
In addition to the biochemical abnormal- or peritonitis is believed to be imminent or
ities, pancreatitis is characterized by radio- established, and (3) nutritional support.
logically identifiable changes in the gland, More recent evidence suggests improved
best documented by abdominal CT with survival with early introduction of enteral
oral and intravenous contrast enhance- feedings (intragastric or transpyloric) and
ment. The presence of glandular edema avoiding reliance on intravenous alimenta-
and peripancreatic fluid accumulation are tion, which carries a high risk for serious
common in the acute phase of the process, bacteremia and fungemia.126-128 Patients
whereas calcifications, fat necrosis, and scar- benefit from the expertise of tertiary centers
ring are sequelae of chronic pancreatitis.118 with excellent intensive care units and
Ultrasonography is useful in identifying access to important ancillary services such
concomitant gallbladder pathology, bile as intervention radiology, gastroenterology,
duct dilation, and cholelithiasis, but the and surgery.
presence of intraluminal gas makes it an Experimental approaches aimed at inhib-
unreliable examination to visualize the pan- iting the inflammatory cascade triggered by
creas.119 Newer techniques using magnetic noxious cytokines have not changed the
resonance (magnetic resonance cholangio- natural course of the disease, and much
pancreatography [MRCP]) can accurately work continues in this field of clinical
visualize the pancreatic and biliary tree, research. The interruption of systemic ab-
often obviating the need for the more inva- sorption and widespread distribution of
sive endoscopic retrograde cholangiopan- toxic vasoactive and proteolytic substances
creatography (ERCP).120,121 ERCP is more by ligation or external draining of the tho-
commonly used in adults, but advances in racic duct has been promising, but has not
equipment design and miniaturization of been confirmed by additional studies.101 In
video processors have made ERCP applica- an attempt to decrease pancreatic secretion,
ble in infants and children.122,123 Concur- the somatostatin analogue octreotide and
rent improvements in the magnetic signal the platelet-activating factor antagonist lexi-
acquisition and processing have reduced pafant have been tried with mixed results,
the resolution of MRCP and expanded its although the exact mechanism of the pur-
usefulness for pediatric patients.120,121,124 ported beneficial effect could not be deter-
Radiologically, the lung changes during mined with certainty. In addition to its
acute pancreatitis are nonspecific and are effects on exocrine and endocrine pancreatic
often mild or unappreciated, even when secretion, it is believed that somatostatin
pulmonary function abnormalities are pres- has a direct immunomodulator effect, which
ent. The presence of effusions already has could play a part in the observed decreased
been alluded to, and increased markings, progression to ARDS.129,130
The complexity of the processes at play, 10. Herve P, et al: Intraesophageal perfusion of acid
increases the bronchomotor response to methacho-
the variety of cellular and chemical media- line and to isocapnic hyperventilation in asthmatic
tors, and the individual genetic predisposi- subjects. Am Rev Resp Dis 134:986-989, 1986.
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lescents with chronic cholestasis. Pediatr Pulmo- pancreatic elastase. Exp Mol Pathol 42:44-59,
nol 33:374-379, 2002. 1985.
90. Abrams GA, et al: Use of macroaggregated albumin 111. Hartwig W, et al: Membrane-bound ICAM-1 is up-
lung perfusion scan to diagnose hepatopulmonary regulated by trypsin and contributes to leukocyte
syndrome: A new approach. Gastroenterology migration in acute pancreatitis. Am J Physiol Gastro-
114:305-310, 1998. intest Liver Physiol 287:G1194-G1199, 2004.
91. Aller R, et al: Diagnosis of hepatopulmonary syn- 112. Frossard J-L: Pathophysiology of acute pancreati-
drome with contrast transesophageal echocardi- tis: A multistep disease. Acta Gastroenterol Belg
ography: Advantages over contrast transthoracic 66:166-173, 2003.
echocardiography. Dig Dis Sci 44:1243-1248, 113. Pastor CM, et al: Role of Toll-like receptor 4 on
1999. pancreatic and pulmonary injury in a mice model
92. Lee KN, et al: Hypoxemia and liver cirrhosis of acute pancreatitis associated with endotoxemia.
(hepatopulmonary syndrome) in eight patients: Crit Care Med 32:1759-1763, 2004.
114. Ates F, Hacievliyagil SS, Karincaoglu M: Clinical sig- 125. Puneet P, Moochhala S, Bhatia M: Chemokines in
nificance of pulmonary function tests in patients acute respiratory distress syndrome. Am J Physiol
with acute pancreatitis. Dig Dis Sci 51:7-10, 2006. Lung Cell Mol Physiol 288:L3-L15, 2005.
115. Foitzik T, et al: Persistent multiple organ microcir- 126. Kaushik N, et al: Enteral feeding without pancre-
culatory disorders in severe acute pancreatitis: atic stimulation. Pancreas 31:353-359, 2005.
Experimental findings and clinical implications. 127. O’Keefe SJD, McClave SA: Feeding the injured
Dig Dis Sci 47:130-138, 2002. pancreas. Gastroenterology 129:1129-1130, 2005.
116. Steer ML: Relationship between pancreatitis and 128. Eatock FC, et al: A randomized study of early naso-
lung diseases. Resp Physiol 128:13-16, 2001. gastric versus nasojejunal feeding in severe acute
117. Bhatia M, et al: Pathophysiology of acute pancrea- pancreatitis. Am J Gastroenterol 100:432-439,
titis. Pancreatology 5(2-3):132-144, 2005. 2005.
118. Graziani R, et al: The various imaging aspects of 129. Heinrich S, et al: Evidence-based treatment of
chronic pancreatitis. J Pancreas 6(1 Suppl):73-88, acute pancreatitis: A look at established para-
2005. digms. Ann Surg 243:154-168, 2006.
119. Gupta V, Toskes PP: Diagnosis and management of 130. Hoogerwerf WA: Pharmacological management of
chronic pancreatitis. Postgrad Med J 81:491-497, pancreatitis. Curr Opin Pharmacol 5:578-582,
2005. 2005.
120. Pamuklar E, Semelka RC: MR imaging of the pan- 131. McGovern MC, Smith MBH: Causes of apparent
creas. Magn Reson Imaging Clin N Am 13:313-330, life threatening events in infants: A systematic
2005. review. Arch Dis Child 89:1043-1048, 2004.
121. Arcement CM, et al: MRCP in the evaluation of 132. Kozzi DA, et al: Pathogenesis of ALTE in infants
pancreaticobiliary disease in children. Pediatr with esophageal atresia. Pediatr Pulmonol
Radiol 31:92-97, 2001. 41:488-493, 2001.
122. Cheng C-L, et al: Diagnostic and therapeutic 133. Black H, Mendoza M, Murin S: Thoracic manifes-
endoscopic retrograde cholangiopancreatography tations of inflammatory bowel disease. Chest
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123. Rocca R, et al: Therapeutic ERCP in paediatric cystic fibrosis: Correlation with pancreatic status
patients. Dig Liver Dis 37:357-362, 2005. and genotype. Pediatrics 115:463-469, 2005.
124. Hamada Y, et al: Magnetic resonance cholangio-
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20:43-46, 2004.
CHAPTER 6
Renal Diseases
NELSON L. TURCIOS
Role of the Kidney in Fetal Lung Pulmonary Calcifications 126

Growth 121 Urinothorax 126
Physiologic Connections Between the Sleep Apnea 127
Lungs and the Kidneys 121 Anemia 127
Diseases That Affect Lungs and Pulmonary Embolism 128
Kidneys 123 Hemodialysis-Related Hypoxemia 129
Wegener Granulomatosis 123 Respiratory Effects of Acute Renal
Systemic Lupus Erythematosus 124 Failure 130
Goodpasture Syndrome 124 How Critical Illness and Mechanical
Respiratory Effects of Chronic Renal Ventilation Can Damage the
Failure 124 Kidneys 131
Pulmonary Edema 125 Summary 132
Fibrinous Pleuritis 125 References 132
Tuberculosis 125
The relationships between the kidneys and Role of the Kidney in Fetal
the lungs are clinically important ones in Lung Growth
health and disease. This chapter first reviews
the role of the kidney in fetal lung develop- Lung development continues during the
ment and the interactions between respiratory middle trimester with branching morpho-
and renal function under normal conditions. genesis and is completed postnatally with
Then a brief overview is provided of the large the development of alveoli. Fetal urine is an
group of diseases that affect the lungs and the important component of the amniotic fluid
kidneys. Most of these conditions are uncom- during late gestation and contributes to lung
mon in pediatric patients, although three of growth. During fetal development, the kid-
them—Wegener granulomatosis, systemic ney also is a major source of proline. Proline
lupus erythematosus, and Goodpasture syn- aids in the formation of collagen and mesen-
drome—may be encountered frequently by chyme in the lung, explaining the severe pul-
clinicians. They are discussed in detail else- monary hypoplasia secondary to prolonged
where in this book. This chapter describes or severe oligohydramnios (amniotic fluid
how chronic renal failure may affect res- index <4 for >2 weeks) seen in fetal renal
piratory function and the intrathoracic agenesis, urinary tract obstruction, bilateral
structures, and provides a brief review of renal dysplasia, and bilateral cystic kidneys.
the corresponding manifestations of acute
renal failure and the ways in which they
affect respiratory care in children. The phe- Physiologic Connections
nomenon of dialysis-related hypoxemia is Between the Lungs and the
described and explained. Finally, the ways Kidneys
in which critical illness and its manage-
ment may adversely affect kidney function Lung and kidney function are intimately
are summarized. related in health and disease.1 Respiratory
121
changes help modulate the systemic effects of thought of as respiratory compensation for
renal acid-base disturbances, and the reverse is metabolic acidosis. The stimulus to increase
also true, although renal compensation oc- the ventilation is chiefly the action of Hþ
curs more slowly than its respiratory counter- ions on the peripheral chemoreceptors.
part. Under normal circumstances, the lungs An increase in HCO3 concentration
and kidneys work together to maintain acid- (metabolic alkalosis)5 causes an increase in
base balance in the body, according to the arterial pH (alkalemia), which tends to
relationship described by the Henderson- decrease alveolar ventilation (respiratory
Hasselbalch equation1,2: acidosis).6 In this instance, respiratory com-
pensation is usually less vigorous, however,
pH ¼ pK þ log ðbase concentration= because the respiratory stimulant effect of
acid concentrationÞ hypercapnia is much stronger than the
According to this equation, the overall respiratory depressant effect of alkalemia.
acidity or alkalinity of the blood, which is The familiar clinical presentation of diabetic
quantified by the negative logarithm of the ketoacidosis is an example of respiratory
hydrogen ion concentration (or pH), is compensation for severe metabolic acidosis.
determined by the relationship between Patients with this disorder may hyperventi-
the amount of base and the amount of acid late to PaCO2 levels of 10 mm Hg or less,
present, also expressed logarithmically, as which diminishes (but does not completely
modified by a mathematical constant (pK) correct) their severe acidemia. In both
for the particular acid involved. The bicar- instances, the respiratory changes are imme-
bonate-carbonic acid system is the major diate (within a few minutes) because of the
buffering system of the extracellular fluid. rapidity of equilibration between alveolar
Bicarbonate (HCO3) dissociates into CO2 gas and pulmonary capillary blood.
and water in the presence of the enzyme In the less frequent situation of primary
carbonic anhydrase, so that the acid-base metabolic alkalosis, as is seen with pro-
quotient in the previous equation can be tracted vomiting or the ingestion of excess
thought of as the HCO3 concentration alkali, patients typically present with only
divided by the CO2 concentration. The modest hypercapnia (e.g., PaCO2 48 to 50
CO2 concentration is related to the partial mm Hg) despite pH greater than 7.60.
pressure of CO2 (PaCO2) in the arterial An increase in PaCO2 stimulates the kidneys
blood by the solubility constant 0.03, so to retain HCO3, producing metabolic al-
the Henderson-Hasselbalch equation can kalosis, which tends to normalize arterial
be rewritten in terms of what clinicians typ- pH. Conversely, hypocapnia prompts an
ically measure: increased loss of HCO3, causing a compen-
satory metabolic acidosis that decreases arte-
pH ¼ 6:1 þ log ½HCO
3 concentration= rial pH. The renal responses to respiratory
ðPaco2 0:03Þ
acid-base disturbances occur much more
Because the kidneys normally determine slowly, however—over a few days—than do
the concentration of the HCO3, and the respiratory adjustments to metabolic distur-
alveolar ventilation regulates the PaCO2, bances. As a result, because carbonic acid/
the relationship also can be rewritten con- HCO3 buffering acts immediately, but is
ceptually as: relatively weak, sudden alterations in respi-
ratory acid-base status cause more sudden
pH ¼ pK þ ðkidneys=lungsÞ
and severe changes in arterial pH than do
A decrease in HCO3 concentration (met- their primary metabolic counterparts. An
abolic acidosis),3 whether from an increase example of the more gradual adjustment of
in acids in the blood or an overall loss of metabolic status with changes in ventilatory
HCO3, provokes an increase in alveolar status is respiratory acidosis in patients
ventilation (respiratory alkalosis),4 which with cystic fibrosis. When such patients
tends to restore the balance between the present with a severe exacerbation, they
two and bring the low arterial pH (acidemia) may be severely acidemic if hypercapnia
back toward normal. This process may be has developed rapidly, whereas the same
Chapter 6 — Pulmonary Manifestations of Renal Diseases 123
Table 6-1 Renal Compensation for Respiratory Acidosis

Normal Acute Respiratory Acidosis* Chronic Respiratory Acidosis{
pH 7.40 7.24 7.38
PaCO2 (mm Hg) 40 56 56
HCO3 (mEq/L) 24 25 33
*Minutes to hours; no renal compensation.

{
Days to weeks; renal compensation present.
Adapted from Pierson DJ: Respiratory considerations in the patient with renal failure. Respir Care 51:413-422, 2006.
PaCO2 in a clinically stable patient tends to

Diseases That Affect Lungs
be associated with a much more normal pH Table 6-2 and Kidneys
(Table 6-1).
A more comprehensive discussion of the Diseases that cause alveolar hemorrhage in the
presence of pulmonary capillaritis
different types of acid-base disturbance, Wegener granulomatosis
their effects on respiratory and renal func-
Henoch-Schönlein purpura
tion, and their management is beyond the
Microscopic polyangiitis
scope of this brief review. More recent
Immune complex–associated glomerulonephritis
reviews of these topics are available, how-
Pauci-immune glomerulonephritis
ever.3-8 The kidneys also regulate fluid bal-
Mixed cryoglobulinemia
ance in the body,1 and derangements in
Diseases that cause alveolar hemorrhage with
overall volume status can affect pulmonary pulmonary capillaritis variably present
function, as discussed subsequently. Systemic lupus erythematosus
Other connective tissue diseases
Goodpasture syndrome
Diseases That Affect Lungs Diseases that cause alveolar hemorrhage without
pulmonary capillaritis
and Kidneys
Thrombotic thrombocytopenic purpura
Drug-induced (e.g., penicillamine)
There are many “pulmonary-renal syn-
Diseases in which alveolar hemorrhage is not a
dromes” that affect the lungs and the typical feature
kidneys.1,9-11 These disorders most com- Churg-Strauss syndrome
monly manifest with hemoptysis from dif-
fuse alveolar hemorrhage, along with renal Adapted from Pierson DJ: Respiratory considerations in the
patient with renal failure. Respir Care 51:413-422, 2006.
failure associated with either acute glomeru-
lonephritis or other vasculitis. Patients may
develop pulmonary hemorrhage without evi- distinction difficult.14 Three of the most
dence of renal involvement, however, with familiar diseases with pulmonary and renal
the latter appearing only later in the clinical manifestations are Wegener granulomatosis,
course. The reverse sequence may also occur. systemic lupus erythematosus, and Goodpas-
Many of these diseases have overlapping and ture syndrome (see Chapter 11).
variable features, prompting investigators to
classify them in various ways. Schwarz and Wegener Granulomatosis
colleagues12,13 have used the presence or
absence of pulmonary capillaritis as a means Wegener granulomatosis is a clinical syndrome
of categorizing these diseases (Table 6-2). consisting mainly of necrotizing granuloma-
Another classification of patients with pul- tous vasculitis of the upper and lower respira-
monary hemorrhage and nephritis uses the tory tract, along with glomerulonephritis.9,15
presence or absence of anti–glomerular base- The eyes, ears, heart, skin, joints, and central
ment membrane antibody; antineutrophil nervous system also may be involved. It is the
cytoplasmic antibody; or small, medium, or most common vasculitis involving the lungs
large vessel vasculitis, although overlapping and most frequently affects school-age chil-
features in different cases often make clear dren and adolescents. Sinusitis is the most
common clinical manifestation, followed by Goodpasture Syndrome

fever, arthralgias, cough, rhinitis, hemoptysis,
otitis media, epistaxis, and ocular inflamma- Goodpasture syndrome is a disorder of
tion.9,15 Although Wegener granulomatosis unknown etiology, manifested by diffuse alve-
may be confined to the kidneys, the lungs are olar hemorrhage and glomerulonephritis. It is
involved in more than 80% of all patients with also known as anti–glomerular basement
the disease. Likewise, some patients have pul- membrane antibody disease because the pres-
monary but not renal involvement. The pul- ence of such antibodies is characteristic and
monary involvement varies, but localized believed to account for at least some of its
infiltrates or nodules or both, either bilateral manifestations. It is most common in young
or unilateral, are most common. men, particularly in the fourth decade of life,
Cavitations may occur in 10% to 20% of and manifests with cough, hemoptysis, and
cases. The cause of the disease is unknown, fatigue. Alveolar hemorrhage seems to be
but it is characterized by the presence of pos- more common among patients who smoke.
itive tests for antineutrophil cytoplasmic Although either pulmonary or renal involve-
antibody in at least 90% of affected patients. ment may be present in isolation, at least at
Wegener granulomatosis was almost always the time of presentation, most patients with
fatal within a few months before the advent Goodpasture syndrome have both. The diag-
of combination therapy with corticosteroids nosis is typically made with renal biopsy. The
and cytotoxic agents, but today more than disease is treated with plasmapheresis, corti-
three quarters of all patients achieve com- costeroids, and cytotoxic drugs, but the prog-
plete remission, with long-term survival.11,15 nosis is guarded at best, and dialysis or renal
transplantation is often necessary.
Systemic Lupus Erythematosus

Respiratory Effects of
Systemic lupus erythematosus is a multisys- Chronic Renal Failure
tem inflammatory disorder of unknown
cause, which is most common in young Numerous complications related to the respi-
women.16 It is characterized by the presence ratory system occur in patients with chronic
of antinuclear antibodies. Its many manifes- renal disease (Table 6-3).1,18-20 Some of these
tations include a characteristic but highly are related to alterations in volume status,
variable malar rash, photosensitivity, ar- plasma oncotic pressure, bone and mineral
thritis, various neuropsychiatric problems, metabolism, concomitant heart failure, and
and hematologic and immune defects. Pul- altered immune function in such patients,
monary and renal involvements are very although in other instances the precise
common. Thoracic manifestations include mechanisms are not well understood.
pleuritis, acute lupus pneumonitis, intersti-
tial pulmonary fibrosis, pulmonary vasculi-
tis, diffuse alveolar hemorrhage, pulmonary Respiratory Complications
Table 6-3 of Chronic Renal Failure
hypertension, organizing pneumonia, and
the “shrinking lung syndrome.”17 Pleuritis, Pulmonary edema
with pleuritic pain and effusions, is com- Fibrinous pleuritis
mon, as is acute pneumonitis. Although Tuberculosis
these usually occur in patients with an Pulmonary calcification
established diagnosis of lupus, either of Urinothorax
them, and any of the other intrathoracic Sleep apnea
processes listed, may be the initial manifes- Anemia
tation of the disease. Systemic lupus erythe- Pulmonary embolism
matosus has a highly variable course, and Dialysis-associated hypoxemia
the response to treatment and the overall Adapted from Pierson DJ: Respiratory considerations in the
prognosis may be difficult to predict. patient with renal failure. Respir Care 51:413-422, 2006.
Pulmonary Edema in inflammatory conditions such as acute

respiratory distress syndrome (ARDS).
Pulmonary edema (Fig. 6-1) is a common Left ventricular failure is common in
complication in acute and chronic renal fail- chronic renal failure, further complicating
ure.1 Its pathogenesis is not fully understood. attempts to clarify the nature of pulmonary
Uremia may be associated with pulmonary edema in patients with this condition. Pul-
edema as the result of overhydration, expan- monary congestion in patients with chronic
sion of the blood volume, and elevation of renal failure is associated with a restrictive
the pulmonary microvascular pressures, pattern on pulmonary function testing,
compounded by anemia and reduced colloid and reduced airflow rates can be observed
osmotic pressures. Hypoalbuminemia, char- on spirometry. These abnormalities have
acteristic of chronic renal failure, decreases been shown to improve or resolve with
plasma oncotic pressure and promotes move- hemodialysis.23-25 This observation would
ment of fluid out of the pulmonary capil- seem to strengthen the argument that
laries. The increased hydrostatic pressure increased lung water results primarily from
that occurs may result from the altered vascu- overall hypervolemia in the presence of low
lar permeability caused by the increased serum albumin levels in this condition, and
metabolic products of uremia, which also fos- accounts for the symptoms and signs tradi-
ters such movement. One would assume tionally associated with “uremic lung.”19
that the edema fluid resulting from these
processes would be low in protein, as is
characteristic of cardiogenic or hydrostatic Fibrinous Pleuritis
pulmonary edema. The finding of increased
protein concentrations in the edema fluid Pleural disease is common in patients with
of patients with renal failure21 suggests, chronic renal failure, being present in as many
however, that capillary permeability also is as 20% to 40% of autopsies on adult patients
altered. Such a suggestion is supported by with this condition.1,26,27 The most common
the occurrence of pulmonary edema in manifestation encountered clinically is pleu-
patients who are clinically normovolemic ral effusion, which was present in 3% of all
and do not have other features of heart fail- patients with end-stage renal disease in one
ure. Other studies of the edema fluid in series.28 The effusion is typically an exudate
patients with chronic renal failure22 have and may be hemorrhagic.27,29 Effusions are
found low protein levels, however, more con- typically unilateral and can be quite large.
sistent with those found in heart failure than Most patients with fibrinous pleuritis are
asymptomatic. Dyspnea is the most common
symptom, but this condition also can be asso-
ciated with fever and pleuritic chest pain,
sometimes with an audible friction rub on
auscultation. Fibrothorax also can occur.
Tuberculosis
The incidence of tuberculosis is increasing

worldwide. Compared with the general pop-
ulation, patients with chronic renal failure
and patients on long-term dialysis have at
least a several-fold greater risk of developing
tuberculosis.30 Patients with chronic renal
failure are immunocompromised. Because
of an impairment of cellular immunity,
patients with chronic renal failure are sus-
Figure 6-1. Pulmonary edema as seen in a chest x-ray of ceptible to reactivation of tuberculosis. Sev-
a 4-year-old child with nephrotic syndrome. enty patients were treated by continuous
ambulatory peritoneal dialysis in a pediatric implicated as causes of ischemic necrosis, car-

nephrology department during an 8-year diac arrhythmias, and respiratory failure. Soft
period.31 Tuberculosis was diagnosed in four tissue calcification has been regarded as rare,
patients, representing 5.7% of all continu- however, in pediatric renal patients. In a retro-
ous ambulatory peritoneal dialysis patients spective review of clinical, biochemical, and
in that study. One patient had extrapul- autopsy data of 120 patients with uremia, on
monary tuberculosis (tuberculosis osteomy- dialysis, or after renal transplantation,33 soft
elitis), and the others had pulmonary tissue calcification was found in 72 patients
tuberculosis. All patients were treated with (60%). Forty-three patients (36%) had sys-
antituberculous drugs. Two patients with temic calcinosis; the lung was the most fre-
pulmonary tuberculosis were cured. Symp- quent site of mineral deposition. By multiple
toms improved in the other two patients, logistic regression analysis, the use of vitamin
but they died at home of unknown causes. D or its analogues, the form of vitamin D med-
An 8-year-old boy receiving maintenance ication prescribed, the peak calcium phos-
hemodialysis for chronic renal failure devel- phorus product, the age at onset of renal
oped mediastinal lymph node tuberculosis. failure, and male sex were together associated
He showed only intermittent fever, recurring with calcinosis. Vitamin D therapy showed
every 2 weeks, with no other symptoms sug- the strongest independent association with
gesting tuberculosis. Although tuberculosis calcinosis, and the probability of calcinosis
skin test was negative, and staining and culture was greater in patients receiving calcitriol com-
of gastric aspirate specimens failed to provide pared with dihydrotachysterol and vitamin D2
evidence of tuberculosis, a lymph node biopsy or D3. The duration of renal failure, peak serum
specimen showed caseating granulomas. Anti- calcium, serum calcium and phosphorus at
tuberculous therapy with isoniazid, rifampin, death, and primary renal diagnosis were not
pyrazinamide, and ethambutol was given for statistically associated with calcinosis.
12 months, resulting in complete resolution The rapid administration of sodium bicar-
of the tuberculosis, with no subsequent recur- bonate to correct severe metabolic acidosis has
rence.32 It is recommended that all children been associated with soft tissue calcification.
with chronic renal failure in regions of high Acidosis increases while alkalosis decreases the
prevalence of tuberculosis should be investi- proportion of ionized calcium, and calcium
gated for tuberculosis, especially if they have deposition in soft tissues may occur during
a cough or fever of unknown etiology. the rapid correction or overcorrection of aci-
Renal insufficiency complicates the man- dosis or with alkalosis. Alkalinization or over-
agement of tuberculosis because the kidneys correction of an acidosis may facilitate the
clear some antituberculosis medications. development of ectopic calcification.34
Management may be complicated further When calcification occurs in the lungs, it is
by the removal of some antituberculosis frequently asymptomatic. Although some-
agents via hemodialysis. Some adjustment times not apparent on chest radiography,
in dosing is commonly necessary in patients pulmonary calcification usually can be de-
with renal insufficiency and end-stage renal tected on computed tomography (CT), or,
disease receiving hemodialysis. Increasing more specifically, on Tc 99m diphosphonate
the dosing interval, instead of decreasing scanning.35 When visible on the standard
the dose of the antituberculosis agent, is chest radiograph, pulmonary calcification
recommended and either estimating or mea- most often produces small nodular opacities,
suring creatinine clearance.30 which occasionally may coalesce into larger
infiltrates (Fig. 6-2).36,37
Pulmonary Calcifications
Urinothorax
Calcifications occur as a complication of
chronic renal failure in adult patients and Urinothorax, or collection of urine in the
may be found in various visceral organs and pleural space, is a very rare complication of
soft tissues. Calcifications have been obstructive uropathy.38 Most patients who
as restless legs syndrome and periodic limb

movement disorder, also are common in this
population.44 Several potential explanations
have been proposed, but the mechanism
remains unknown. There seems to be a strong
link between sleep apnea and nocturnal hy-
poxemia and cardiovascular complications in
patients with chronic renal failure.45,46 Hemo-
dialysis during the night is said to have an
ameliorating effect on sleep apnea,43,47,48
although the reason for this also remains
unclear. As in obstructive sleep apnea unasso-
ciated with renal disease, treatment with con-
tinuous positive airway pressure is effective.
Breathing disorders during sleep complicating
chronic renal failure in children is an area that
warrants investigation.
Anemia
Figure 6-2. Pulmonary calcifications on a chest x-ray of Normochromic normocytic anemia is a
a 4-year-old child with chronic renal failure.
common and important manifestation in
children with chronic renal failure when
their glomerular filtration rate is less than
are found to have urinothorax also have a 35 mL/min/1.73 m2 body surface area, but it
urine collection (urinoma) in the abdominal may develop earlier in some forms of renal
cavity or retroperitoneal space.39 Leakage disease. An inadequate erythropoiesis due
from the urinary tract may cause urinoma, to insufficient erythropoietin synthesis in
which can lead to urinothorax. The urino- the kidneys is the main cause of renal ane-
thorax usually disappears within a few days mia. Other reasons include reduced red blood
after adequate urinary drainage has been cell life span, chronic blood loss, iron
established. Reported underlying causes deficiency, inhibitors of erythropoiesis, and
include posterior urethral valves, nephro- malnutrition. The presence of anemia con-
lithiasis, blunt renal trauma, ureteral instru- tributes to many of the symptoms of uremia,
mentation, or ureteral surgery.39 The pleural including decreased appetite, decreased
fluid in urinothorax is a transudate, although energy, poor cardiac function, and poor
the lactate dehydrogenase level can be high, school performance.49,50
causing misclassification as an exudate.38 If the anemia is untreated, hemoglobin
The pH and glucose levels tend to be low. An concentrations typically decrease to less
elevated pleural fluid-to-serum creatinine than 10 g/dL, and frequently to half or less
ratio (which should be about 1, but may be of the normal value. With blood oxygen car-
10 in urinothorax) confirms the diagnosis. rying capacity markedly diminished, cardiac
output must increase to maintain normal
Sleep Apnea tissue oxygen delivery, and even in the
absence of pulmonary disease, patients are
Sleep apnea is common in adults with chronic vulnerable to tissue hypoxia during exertion
renal failure.1,40-42 Its prevalence is said to be and at times of acute illness. Correction of
10-fold higher in adults with end-stage renal anemia dramatically improves the quality
disease than in the general population,43 and of life of a child with chronic renal failure.
studies have found that at least 60% of Presently, the goal of anemia management is
patients on long-term hemodialysis have the to maintain hematocrit concentrations at
disorder.18,44 Other sleep disturbances, such 33% to 36% and a hemoglobin concentration
of at least 11 g/L. This objective can be ac- increase. Right ventricular dilatation leads to
complished by weekly intravenous or sub- tricuspid regurgitation and may eventually
cutaneous administration of recombinant compromise the filling of the left ventricle.
erythropoietin and iron preparations. If ade- In addition, right ventricular enlargement
quate iron stores cannot be maintained with causes leftward shift of the interventricular
oral therapy, intravenous iron should be con- septum, resulting in an impaired left ventricu-
sidered. Treatment with recombinant human lar filling during diastole. Cardiac output
erythropoietin corrects anemia, avoids the decreases, and the patient becomes hypoten-
requirement for blood transfusions, and sive. The increased right ventricular pressure
improves quality of life and exercise toler- compresses the right coronary artery, decreas-
ance.51 To optimize anemia management in ing subendocardial perfusion, and as a conse-
children with chronic renal failure, future quence, cardiac ischemia may develop.
research should concentrate on the normali- The clinical manifestations of pulmonary
zation of hemoglobin early in the course of embolism vary, and no group of physical
chronic renal failure, and the long-term findings yields a high positive predictive
effects on the child’s development. value. Pleuritic chest pain, dyspnea, appre-
hension, and cough are the most common
complaints, and tachypnea is the most
Pulmonary Embolism common physical finding. Other potential
findings include crackles, increased inten-
Pulmonary embolism is an uncommon sity of the pulmonary component of the
complication in children with renal dis- second heart sound, tachycardia, diapho-
eases, but a potentially serious and fatal resis, wheezing, and hemoptysis. Patients
disease. Children with nephrotic syndrome with severe pulmonary embolism can even
are at increased risk of thromboembolic present with hemodynamic instability, cor
events. The incidence of this complication pulmonale, and shock. Fever, chest pain,
in children is 2% to 5%, which represents and respiratory manifestations may suggest
a much lower risk than that of adults with heart disease, or masquerade as pneumonia;
nephrotic syndrome.72 Nephrotic syndrome however, significant hypoalbuminemia may
is primarily a pediatric disease. The charac- raise the index of suspicion.
teristic features of nephrotic syndrome are Because the clinical diagnosis lacks sensi-
heavy proteinuria (>40 mg/m2/hr), hypoal- tivity and specificity, objective diagnostic
buminemia (<2.5 g/dL), edema, and hy- imaging is necessary to establish or rule
percholesterolemia.73 Most children (90%) out the presence of pulmonary embolism.
with nephrotic syndrome have a form of An electrocardiogram and arterial blood
idiopathic nephrotic syndrome.74 The risk of gases are useful in ruling out other diseases.
thrombosis is related to increased prothrom- The measurement of the breakdown prod-
botic factors (fibrinogen, thrombocytosis, uct of cross-linked fibrin (D-dimer) in
hemoconcentration, relative immobilization) plasma is a sensitive but nonspecific test
and decreased fibrinolytic factors (urinary for suspected venous thrombosis. In adults,
losses of antithrombin III, proteins C and S).75 studies showed that it is safe to exclude pul-
The effects of pulmonary embolism depend monary embolism in patients with a normal
on the extent to which it obstructs the pulmo- D-dimer level. Chest radiographs are often
nary circulation, coexistent cardiopulmonary normal in patients with pulmonary embo-
disease, and vasoactive mediators. Acute pul- lism. Ventilation/perfusion imaging displays
monary embolism, obstructing more than regional blood flow and ventilation defects
50% of the pulmonary circulation, increases by noninvasive means and is safe and inex-
right ventricular afterload. Because the thin- pensive. A normal ventilation/perfusion
walled right ventricle is not accustomed to scan does not exclude a pulmonary embo-
working against a sudden obstruction, right lism, however. Helical (spiral) CT is becom-
ventricular dilatation occurs, and the right ing the first-choice diagnostic test for
ventricular and pulmonary artery pressures pulmonary embolism in many centers. An
iodinated contrast agent that is injected in a There are several techniques. Effective frag-
peripheral vessel visualizes the pulmonary mentation of central emboli and dislocation
vessels. Pulmonary embolism is seen as par- of the fragments to the periphery has been
tial or complete filling defects in pulmonary reported in children.
arteries. This scan is particularly useful in
patients with concomitant lung disease. Pul- Hemodialysis-Related Hypoxemia
monary angiography is the gold standard
diagnostic test for pulmonary embolism.76 Shortly after it was introduced in the treat-
The optimal treatment of hypercoagulabil- ment of renal failure, most patients un-
ity in nephrotic syndrome has not been dergoing hemodialysis were discovered to
prospectively investigated, and randomized develop hypoxemia while connected to the
trials to guide the therapy are lacking. Prophy- dialysis apparatus.1 This phenomenon has
lactic anticoagulation is not recommended in generated much interest among renal and
children unless they have had a previous respiratory clinicians as to its possible mech-
thromboembolic event. Overaggressive diure- anisms. Proposed explanations included a
sis should be avoided, and use of indwelling shift in the oxyhemoglobin dissociation curve
catheters should be limited because these because of the increased pH during dialysis,
factors may increase the likelihood of clot- depression of central ventilatory drive, im-
ting complications. Unfractionated heparin pairment of oxygen diffusion, leukostasis in
should be used in the initial phase of anticoag- small pulmonary vessels leading to mismatch-
ulation.76,77 It functions as an antithrombotic ing of ventilation and perfusion, and alveolar
agent by binding to and potentiating the hypoventilation because of diffusion of CO2
activity of antithrombin. Careful monitoring into the dialysate.18
of the activated partial thromboplastin time Studies in animals and humans showed
and platelets is important. Low-molecular- that leukocytes did accumulate in the lungs
weight heparin is an equally effective alterna- during hemodialysis, with activation of com-
tive to unfractionated heparin.76,77 Similar to plement and other events associated with
unfractionated heparin, the anticoagulant inflammation.54,55 For several years, “dialysis
activity of low-molecular-weight heparin lung” was a subject of intense interest at the
results from catalyzing the ability of anti- bedside and in the laboratory. It was shown
thrombin to inactivate coagulation factors. that PaO2 decreases within a few minutes of
Monitoring of the anti–factor Xa assay should the initiation of hemodialysis, usually by 10
be done. Warfarin (Coumadin), which sup- to 15 mm Hg, but sometimes considerably
presses vitamin K–dependent clotting factors, more, reaching a nadir after 30 to 60 minutes
should be started 24 to 48 hours after heparin and then returning to predialysis levels on ter-
therapy is begun. Generally, anticoagulation mination of the procedure.18,56 The magni-
therapy for a minimum of 6 to 12 months is tude of the decrease in PaO2 varies according
recommended.77 Some authors have sug- to the chemical composition of the dialysate
gested continuing anticoagulation for as long and the type of membrane used.57 Current
as the patient is nephrotic.77 understanding of dialysis-related hypoxemia
Thrombolytic agents such as plasminogen is based on the fundamentals of alveolar ven-
activators, including urokinase, streptoki- tilation, as taught in physiology class. Leuko-
nase, and tissue plasminogen activator, also stasis and complement activation do occur
are useful. In most centers, tissue plasmino- during dialysis, but they are almost certainly
gen activator is favored over the other throm- unrelated to the observed changes in PaO2.
bolytic agents because of fibrin specificity The hypoxemia is explained by decreased
and affinity and low immunogenicity.76 alveolar ventilation in response to diffusion
Thrombolytic therapy causes faster resolu- of CO2 into the dialysate (Fig. 6-3).
tion of the embolus than heparin therapy. As CO2 diffuses into the dialysate, the CO2
Open surgical embolectomy can be benefi- content in venous blood decreases. Because
cial in hemodynamically unstable patients ventilation is tightly controlled by the periph-
for whom thrombolysis is contraindicated.76 eral and central chemoreceptors in response
Diffusion of CO2 into dialysate decreased plasma oncotic pressure from

hypoalbuminemia and hemodilution pro-
motes leakage of fluid from pulmonary
↓CO2 content in venous blood capillaries. The restrictive effects of pulmo-
nary interstitial and alveolar edema, pleural
effusion, and chest wall edema increase the
↓Hypercapnic ventilatory drive work of spontaneous breathing and may
contribute to the development of acute ven-
tilatory failure. In addition, the metabolic
↓Minute ventilation to acidosis present in most instances of acute
maintain constant PaCO2 renal failure increases the demand for venti-
lation through compensatory respiratory
alkalosis, further disrupting the relationship
↓PaO2 secondary to between the patient’s ventilatory needs and
alveolar hypoventilation
capabilities. Pulmonary edema and ventila-
tion at low lung volumes can cause or
worsen hypoxemia.
↓PaO2
Acute renal failure may necessitate num-
Figure 6-3. Pathogenesis of dialysis-associated hypoxemia. erous adjustments to the management of
mechanical ventilation (Table 6-4). Higher
airway pressure is required to maintain the
to changes in PaCO2, this decrease in blood same level of ventilation in the presence of
CO2 content diminishes central ventilatory
drive and decreases minute ventilation.
Because some of the body’s CO2 production is Ways in Which Acute Renal Failure
being eliminated through dialysis, to maintain Table 6-4 Affects Ventilator Management
a normal PaCO2, less CO2 must be eliminated
Decreased Respiratory System Compliance
via the lungs. As alveolar ventilation falls and
Intrapulmonary causes
oxygen extraction remains the same, alveolar
Pulmonary edema
PO2 (PaO2) decreases, and PaO2 decreases.
Airway edema
That this basic physiologic sequence is
Extrapulmonary causes
responsible for dialysis-associated hypox-
Pleural effusion
emia was finally shown by a series of studies
Pericardial effusion
of ventilation and perfusion in several
Chest wall edema
laboratories.56,58,59 This mechanism is an
Clinical implication
example of alveolar hypoventilation with-
Requirement for higher airway pressure
out hypercapnia,60 something that is possi-
Increased Airway Resistance
ble only if CO2 is being removed from the
Causes
body by some route other than the lungs.
Airway edema
Decreased lung volumes
Clinical implication
Respiratory Effects of Acute
Increased likelihood of hyperinflation and auto-
Renal Failure PEEP
Metabolic Acidosis
Acute renal failure is common in the intensive Cause
care unit (ICU).1 An observational study of Impaired excretion of acid and metabolic products
nearly 30,000 adults admitted to the ICUs of Clinical implications
54 hospitals in 23 countries found that 5.7% Need for compensatory hyperventilation
of all patients had acute respiratory failure Worse acidemia with lung protective ventilation
during their stay, and that nearly 75% of these Increased minute ventilation requirement may
required some form of renal replacement ther- interfere with weaning
apy.52 Development of acute renal failure pre- Adapted from Pierson DJ: Respiratory considerations in the
disposes patients to overall fluid overload, and patient with renal failure. Respir Care 51:413-422, 2006.
pulmonary edema, pleural effusion, or total

Mechanisms by Which Critical
body fluid overload. Airway mucosal edema Table 6-5 Illness and Its Management Can
can reduce effective airway diameter, predis- Damage the Kidneys
posing to air trapping and endogenous posi- Systemic effects of sepsis
tive end-expiratory pressure, which can Intensive care unit–acquired urinary tract infection
reduce venous return, compromising cardiac Drug toxicity
function further and increasing the risk of Abdominal compartment syndrome
alveolar rupture.53 Ventilator-induced renal injury
The management of acute lung injury Adverse effects of permissive hypercapnia
(ALI) and ARDS using lung protective venti- and hypoxia on renal blood flow
lation is made more difficult in the presence Renal hypoperfusion owing to decreased cardiac
of metabolic acidosis, which increases venti- output (increased intrathoracic pressure)
latory drive and worsens acidemia related to Effects of systemic inflammatory mediators released
in response to mechanical ventilation
permissive hypercapnia. Because low tidal
volume, lung protective ventilation sub- Adapted from Pierson DJ: Respiratory considerations in the
stantially improves survival in ALI and patient with renal failure. Respir Care 51:413-422, 2006.
ARDS, its use should not be abandoned

because of acidemia in the face of acute renal failure, particularly in patients with
renal failure. Using a dialysate solution with underlying renal disease. A host of drugs used
a higher concentration of bicarbonate can in the ICU can cause or aggravate renal failure.
facilitate “compensation” for hypercapnia Shock from any cause is a known precipitant
and permit renal replacement therapy and of acute renal failure, as are conditions that
lung protective ventilation to be main- predispose to diminished renal perfusion.
tained. Weaning in the face of a metabolic One of the latter conditions that has
acidosis is challenging because of the received increasing attention in recent years
requirement that the patient be able to is abdominal compartment syndrome.62-64
maintain higher than usual minute ventila- In this syndrome, increased intra-abdominal
tion. Otherwise healthy patients may have pressure impairs venous return to the heart,
no trouble with this requirement, but in diminishes cardiac output, and causes venous
patients with severe obstructive lung disease congestion of the abdominal organs, includ-
or ARDS, weaning may have to be deferred ing the kidneys. Clinically, the abdominal
until either ventilatory function improves compartment syndrome is characterized by
or the required hyperpnea diminishes. hypotension, increased airway pressure, and
oliguria. In this clinical setting, its presence is
confirmed by measurement of pressure in
the urinary bladder. Although some authors
How Critical Illness and consider intravesical pressures greater than
Mechanical Ventilation Can 12 mm Hg to be associated with adverse
Damage the Kidneys effects,64 others use a pressure of 30 cm H2O
or greater to diagnose the syndrome.65
Patients may be admitted to the ICU because Although ventilator-induced lung injury is
of illness or injury causing acute renal failure. now a widely accepted entity and a much-
There are several ways, however, in which crit- investigated subject,66-68 until more recently,
ical illness not initially involving the kidneys, much less attention was focused on the poten-
and the management of that illness in the tial association between mechanical ventila-
ICU, can precipitate iatrogenic renal damage tion and renal injury. An increasing body of
(Table 6-5).1 Just as acute processes that precip- experimental evidence supports the concept
itate the systemic inflammatory response syn- that ventilatory support, particularly with high
drome predispose patients to ALI and ARDS, airway pressure and distending volume, can
these same processes are associated with the damage the kidneys and the lungs.69-71 In addi-
development of acute renal failure in the tion, permissive hypercapnia and permissive
ICU.61 Urinary tract infection, the most com- hypoxemia, although potentially protecting
mon hospital-acquired infection, can lead to the lungs from mechanical and biochemical
damage, may be associated with adverse effects 4. Foster GT, Vaziri ND, Sassoon CS: Respiratory alka-
losis. Respir Care 46:384-391, 2001.
on renal perfusion and excretory function.69 5. Khanna A, Kurtzman NA: Metabolic alkalosis.
The emerging concept of biotrauma,68 Respir Care 46:354-365, 2001.
through which mechanical events in the lungs 6. Epstein SK, Singh N: Respiratory acidosis. Respir
Care 46:366-383, 2001.
and airways initiate systemic processes that 7. Kraut JA, Madias NE: Approach to patients with
adversely affect other tissues and organs, may acid-base disorders. Respir Care 46:392-403, 2001.
apply to the kidneys and to the lungs.69 8. Madias NE, Adrogue HJ: Cross-talk between two
organs: How the kidney responds to disruption of
acid-base balance by the lung. Nephron Physiol
93:61-66, 2003.
Summary 9. Akikusa JD, et al: Clinical features and outcomes of
pediatric Wegener’s syndrome. Arthritis Rheum
57:837-844, 2007.
Awareness of the relationship of respiratory 10. Godfrey S: Pulmonary hemorrhage and hemoptysis
and renal function is important in managing in children. Pediatr Pulmonol 37:476-484, 2004.
11. von Vigier RO, et al: Pulmonary renal syndrome in
patients with diseases of the lungs and the childhood: A report of twenty-one cases and a review
kidneys. Among the disease processes with of the literature. Pediatr Pulmonol 29:382-388, 2000.
pulmonary and renal manifestations, Wege- 12. Schwarz MI, Collard HR, King TE Jr: Diffuse alveo-
lar hemorrhage and other rare infiltrative disorders.
ner granulomatosis, systemic lupus erythema- In Mason RJ, et al, eds: Murray and Nadel’s Text-
tosus, and Goodpasture syndrome may be book of Respiratory Medicine. Philadelphia, WB
commonly encountered in respiratory care. Saunders, 2005, pp 1656-1678.
13. Collard HR, Schwarz MI: Diffuse alveolar hemor-
Patients with chronic renal failure are subject rhage. Clin Chest Med 25:583-592, 2004.
to several important respiratory complica- 14. Niles JL, et al: The syndrome of lung hemorrhage
tions, including pulmonary edema, pleural and nephritis is usually an ANCA-associated condi-
tion. Arch Intern Med 156:440-445, 1996.
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nous pleuritis. In managing acute renal fail- clinical and therapeutic experience with patients for
ure, the clinician often must contend with 21 years. Ann Intern Med 98:76-85, 1983.
16. Gutiérrez-Suárez R, et al: A proposal for a pediatric
respiratory manifestations of volume over- version of the Systemic Lupus International Collab-
load and metabolic acidosis. Mechanical ven- orating Clinics/American College of Rheumatology
tilation in patients with renal failure can be Damage Index based on the analysis of 1,015
patients with juvenile-onset systemic lupus erythe-
especially challenging, particularly with matosus. Arthritis Rheum 54:2989-2996, 2006.
respect to lung protective ventilation and 17. Eid NS, Buchino JJ, Schikler KN: Pulmonary mani-
weaning. Although it was previously believed festations of rheumatic diseases. Pediatr Pulmonol
Suppl 18:91-92, 1999.
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tions in the nephrotic syndrome: Pathophysiology
CHAPTER 7
Hematologic and Oncologic Diseases
RAUL C. RIBEIRO*, CARLOS RODRIGUEZ-GALINDO, AND GUILLERMO CHANTADA
Oncologic Diseases 135 Complications of Treatment of

Complications Related to Disease and Acute Hematologic and Oncologic
Treatment 135 Disorders 154
Solid Tumors 141 Hematopoietic Stem Cell
Primary Lung Neoplasms 146 Transplantation 154
Inflammatory Pseudotumor 147 Transfusion-Related Acute Lung Injury 156
Hematologic Disorders 147 Chemotherapy-Induced Lung Toxicity 158
Sickle Cell Disease 147 Radiation Therapy 162
Histiocytic Disorders of the Lung 152 Acknowledgments 163
References 163
Pulmonary complications are a common side (erythroid, myeloid, lymphoid, and megakar-
effect of pediatric hematologic and oncologic yocytic) that result from the transformation
disorders and their treatment. Respiratory of immature progenitor cells of these hemato-
signs and symptoms can be the presenting poietic lineages. These disorders are grouped
manifestations of several types of pediatric in four broad categories: acute lymphoblastic
malignancies. The anatomic structures typi- leukemia (ALL), acute myeloid leukemia
cally affected by this group of disorders are (AML), non-Hodgkin lymphoma (NHL), and
the mediastinum, airways (trachea and bron- Hodgkin disease (HD). They are classified
chus), alveolocapillary units, lung paren- further by the type of specific progenitor
chyma, pleura, diaphragm, and chest wall. cells involved in the process.1 Because the
Many of these thoracic structures, as exem- hematopoietic system is functionally diverse
plified by the thymus, continue to develop and has a wide anatomic distribution, the
intensively after birth and are common tar- clinical and biologic characteristics of leuke-
gets of malignant transformation. This chap- mias and lymphomas in young patients vary
ter describes the pulmonary symptoms and substantially.
management of pediatric hematologic and In the United States, of the approximately
oncologic disorders that directly or indirectly 13,000 new cases of cancer diagnosed per
affect the respiratory system. year in children, adolescents, and adults
younger than 20 years old, 18.7% are ALL,
Oncologic Diseases 8.8% are HD, 6.5% are NHL, and 3.5% are
AML.2,3 Of the neoplasias in children and
Complications Related to Disease adolescents, 50% are hematologic malig-
and Acute Treatment nancies. The incidence of leukemias and
lymphomas varies with age. ALL represents
Pediatric acute leukemias and lymphomas are 17% of all cases of pediatric cancer in neo-
clonal disorders of the blood-forming cells nates and infants, 46% of cases of cancer
*This work was supported in part by Cancer Center Support (CORE) grant P30 CA-21765 from the National Insti-
tutes of Health, by a Center of Excellence Grant from the State of Tennessee, and by the American
Lebanese Syrian Associated Charities (ALSAC)
135
in children 2 to 3 years old, and 9% of cases vena cava (SVC) syndrome, or both. The
of cancer in individuals 15 to 20 years old. most common tumors in this area are HD
Although the incidence of AML also varies and NHL. Tracheal compression may cause
with age, the rates are highest in the first cough, stridor, dyspnea, or orthopnea. In
2 years of life, after which they decrease to these cases, chest radiograph may reveal an
a nadir at the end of the first decade, and anterior mediastinal mass, prominent hilar
then gradually increase during the second lymph nodes, posterior tracheal deviation,
decade of life. Conversely, the rates of NHL atelectasis, and pleural effusion. Tracheal
and HD increase with age. The incidence compression is not always obvious, how-
of HD increases with age, with 43.2 cases ever, from the physical examination or
per 1 million for individuals 19 years old. chest radiograph. It may become apparent
The pattern of age distribution among leu- when a patient is unable to lie supine
kemia and lymphomas suggests that etiologic because of increased dyspnea; the patient
factors differ in these diseases. Generally, the should be considered at high risk for com-
process of malignant transformation of a spe- plete tracheal obstruction.11,12 The SVC
cific hematopoietic progenitor cell is believed is particularly susceptible to compression
to occur during fetal development in acute because it is surrounded by lymph nodes
leukemias4 and postnatally in lympho- and is in direct contact with rigid anatomic
mas5—hence, the incidence of lymphomas is structures. It has a delicate vessel wall and
greatly affected by environmental factors. In low intraluminal pressure.
some areas of Africa, Burkitt lymphoma and Symptoms resulting from moderate to
Kaposi sarcoma are two common types of severe SVC compression include headache,
pediatric malignancy.6 dizziness, syncope, and cardiovascular col-
The intrathoracic cavity harbors primary lapse secondary to decreased venous return
(thymus) and secondary (lymph nodes and (Fig. 7-1).13 Physical examination may be
mucosa-associated lymphatic aggregates) unremarkable or may show facial and peri-
lymphoid organs; thoracic lymphoid struc- orbital edema, cyanosis, plethora, neck and
tures are commonly affected in lymphoid leu- chest vein distention, papilledema, and
kemias and lymphomas. Enlargement of the edema of the upper extremities. The severity
thymus or its associated lymph nodes is very of the clinical manifestations of SVC syn-
common in T cell ALL, lymphoblastic NHL, drome depends on how rapidly the obstruc-
and HD.7-9 Mediastinal involvement is tion arises, and whether sufficient time has
extremely rare in AML. Chest radiography is elapsed for new collateral blood vessels to
an effective screening tool to identify children develop.
with mediastinal mass and should be Children with tracheal compression or
obtained in any patient newly diagnosed with SVC syndrome are often anxious and dia-
leukemia or lymphoma. A large mediastinal phoretic. They resist efforts to be placed
mass in a child should be considered a medical in the supine position and should not be
emergency and managed in a tertiary care forced into this position. Assessment of air-
hospital by a multidisciplinary team. Depend- way patency with computed tomography
ing on the size, location, organ compression, (CT) scan or flexible bronchoscopy is ill-
and progression time, a particular constella- advised because patients do not tolerate
tion of clinical signs and symptoms indicates these procedures well and may be very
whether the airways, great vessels, or both difficult to resuscitate if they experience
are predominantly affected.10,11 A detailed cardiorespiratory collapse. Total airway
assessment of the patient’s medical history occlusion has been reported during the
and results of the physical examination can induction of general anesthesia, tracheal
provide clues regarding whether the compres- intubation or extubation, movement of a
sion is affecting the airways, great vessels, patient to a supine or flexed position (for
heart, or more than one of these structures. lumbar puncture), and conscious seda-
tion.14 Flow-volume loops have been used
Tracheal Compression and Superior to indicate the degree of central airway
Vena Cava Syndrome obstruction and may be helpful in distin-
Large tumors in the anterior mediastinum guishing fixed from variable intrathoracic
can cause tracheal compression, superior airway lesions.15
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 137
A C
Figure 7-1. An 11-year-old boy with lymphoblastic lymphoma. A, Posteroanterior chest radiograph shows large ante-
rior mediastinal mass and pleural effusion. B and C, Cytocentrifuge examination of the pleural effusion shows FAB L1 lym-
phoblasts (B) (Wright-Giemsa) of T cell origin (C) (anti-CD3 staining).
Whole-body positron emission tomogra- lower extremities because most of the venous
phy (PET) has been increasingly used to deter- return proceeds through the inferior vena
mine the extent of disease and response to cava. Although SVC syndrome per se does
therapy. NHL and HD are metabolically active, not represent a medical emergency, most
and so they can be detected with this method. children with SVC syndrome experience
Although PET/CT (Fig. 7-2) is still considered a some degree of airway compression. Therapy
research tool in disease staging and prognosis, with radiation to the mid-plane or cortico-
some studies have shown the superiority of steroids (hydrocortisone, 2 mg/kg every 6
PET/CT to PET or CT alone in the manage- hours) or both usually alleviates symptoms.
ment of NHL and HD.15 The least invasive Most mediastinal masses in children and
technique is used to obtain tissue for diagno- adolescents are highly sensitive to chemo-
sis. The diagnosis often can be made from therapy. These patients are at high risk of uric
bone marrow aspirate or peripheral lymph acid nephropathy and consequently kidney
node biopsy, which can be obtained with top- dysfunction.17,18 Hyperhydration and alka-
ical anesthesia. Similarly, if pleural effusion is linization used for patients at high risk of
present, thoracentesis can be used in making tumor lysis syndrome (hyperuricemia)17
a diagnosis (Fig. 7-3). should be avoided in patients with SVC
A proper regimen of chemotherapy should syndrome, however, because of the risk of
be started as soon as a diagnosis is established. respiratory insufficiency and worsening of
Intravenous access should be started in the existent pleural effusion. Rasburicase is very
Figure 7-2. A, A 14-year-old boy with

lymphoblastic lymphoma complicated
by vena cava compression syndrome.
The compression was predominantly
vascular; the patient had no signs of
respiratory distress. B, A 10-year-old
boy with lymphoblastic lymphoma,
superior vena cava syndrome, and tra-
cheal compression. In addition to having
increased collateral circulation in the
frontal and cervical regions, the patient
was plethoric and was experiencing A B
respiratory distress.
R L
B C
Figure 7-3. PET/CT images of a 15-year-old boy with non-Hodgkin lymphoma. A, CT image, transverse plane, shows large
mediastinal mass (top arrow) and large pleural effusion (bottom arrow). Collapse of the right lung and mediastinal shift to the
right are evident. B, PET image at same anatomic level as A shows irregularly increased uptake of fludeoxyglucose F 18
(FDG) in mediastinal mass (top arrow). The pleural effusion (bottom arrow) shows no uptake of FDG. Increased uptake of
FDG, which represents pleural involvement, is evident along the periphery of the effusion, however. C, Fused image of A
and B overlies the anatomic image in A and the functional image in B.
effective in rapidly decreasing plasma urate, for primary malignancy should be instituted
avoiding the need for hyperhydration and as soon as the diagnosis is established.
alkalinization.19
Doppler ultrasonography and echocardi- Pulmonary Leukostasis Syndrome
ography may be indicated for evaluating Approximately 50% of children with ALL
flow through the great vessels and myocar- and AML present with an abnormally ele-
dial function. If thrombosis is detected, use vated blood leukocyte count. Severe leuko-
of unfractionated or low-molecular-weight cytosis (defined as peripheral leukocytes
heparin should be considered to prevent 100,000/mm3) occurs in approximately
propagation of the thrombus. In rare cases, 20% of children with ALL and 15% of chil-
catheter-directed thrombolysis has been dren with AML.21,22 Most of these patients
performed to relieve obstruction.20 Most have no pulmonary signs or symptoms asso-
importantly, prompt specific chemotherapy ciated with this abnormality. Depending on
the number of leukocytes and the type of can lead to the misdiagnosis of pulmonary
leukemia, however, a constellation of signs embolism. Imaging studies are nonspecific
and symptoms, known as pulmonary leu- for pulmonary leukostasis.37
kostasis syndrome, may occur.23 Leukostasis Hypoxemia in patients with hyperleuko-
can affect any organ, but it most commonly cytosis can be a true or false finding. Causes
involves brain and lungs. Clinically, pulmo- of true hypoxemia in these patients include
nary involvement is characterized by short- infection, hemorrhage, pulmonary embo-
ness of breath, tachypnea, dyspnea on lism, pulmonary alveolar proteinosis (PAP),
exertion, and pleuritic chest pain. Mortality and occlusion of the pulmonary vasculature
in patients with leukostasis is approximately by leukocyte thrombi. False hypoxemia can
20%, usually secondary to pulmonary or result from technical inaccuracies in the
intracranial hemorrhage.24 measurement of PaO2, and often may reflect
Patients with AML tend to develop symp- that leukemic cells are metabolically active
tomatic leukostasis at much lower leukocyte in vitro.38-41 In this situation, low levels of
counts than do patients with ALL.25 Post- PaO2 reflect consumption of dissolved oxy-
mortem evidence of leukostasis in AML, gen by leukocytes or platelets after the
including extensive leukemic infiltration of arterial blood specimen is obtained, a phe-
the alveoli and parenchyma, and occlusion nomenon called “oxygen steal.”42 Consis-
of small pulmonary vessels, has been found tent with this concept is the observation
in patients presenting with a wide range of that PaO2 values are negatively correlated
leukocyte counts.26,27 Symptomatic pulmo- with the number of circulating leukocytes.
nary leukostasis occurs almost exclusively Because pulse oximetry measures capillary
in children with AML.28 oxygen instead of whole-blood oxygen
Respiratory distress and early death result- saturation, this method is considered the
ing from hyperleukocytosis (defined as leu- most accurate way to assess oxygenation in
kocyte counts 200,000/mm3) is more patients with hyperleukocytosis.43
common in children with AML, occurring Acute leukemia complicated by severe
in 6% of patients. A high initial white blood hyperleukocytosis should be considered a
cell count seems to be the only marker asso- medical emergency. Admission of the patient
ciated with the development of respiratory to an intensive care unit and proper manage-
complications.29 In addition, because myelo- ment of aggravating factors, such as dehydra-
blasts express adhesion molecules that attach tion, electrolyte or metabolic imbalances,
to the pulmonary vascular endothelium, infection, thrombocytopenia, and coagulop-
they are more tissue-invasive than lympho- athy, should be initiated immediately. Fluid
blasts. These factors apparently are more rele- balance is required to avoid excessive fluid
vant to the severity of pulmonary leukostasis retention. Transfusion of platelet concen-
syndrome than the number of leukemia cells. trate or fresh frozen plasma is used to reduce
The adverse interactions between leukemic the risk of bleeding. Prophylaxis of thrombo-
cells and organs such as lungs, brain, and embolic phenomena with heparin is not
kidneys seem to be worsened further in M5 indicated. Transfusion of packed red blood
AML and M4 AML because these subtypes of cells should be withheld or be given with
AML31-34 release many proinflammatory caution to prevent an increase in blood
cytokines and lysozymes.30,35 viscosity before the reduction of the leuko-
Chest radiographs can be normal, or they cyte count.44 Anemia in patients with hyper-
may reveal variable degrees of diffuse alveo- leukocytosis can be seen as an adaptive
lar-interstitial infiltrates and pulmonary ves- mechanism. Inhaled nitric oxide to produce
sel enlargement. Findings of chest CT scans pulmonary vasodilation and ventilation/
include bilateral thickening of the interlob- perfusion mismatch reduction has been used
ular septa with patchy areas of ground-glass by some investigators.45-47 Leukapheresis or
opacity that resemble that of interstitial exchange transfusion (for young children)
edema. A ventilation/perfusion lung scan is commonly considered as a temporary mea-
can show mismatched defects,36 but is not sure until specific antileukemia treatment is
specific for leukostasis, and reliance on it initiated.48-53 The efficacy of leukapheresis in
reducing mortality or life-threatening compli- evidence suggest that abnormality of the

cations has not been evaluated in controlled GM-CSF signaling in the lung is associated
clinical trials. with PAP pathogenesis. First, histologically
similar PAP lung changes occur in mice
Pulmonary Alveolar Proteinosis genetically deficient in GM-CSF or its
PAP can rarely be a cause of respiratory fail- receptor.76,77 Abnormal clearance of surfac-
ure in patients with acute leukemia, partic- tant lipids is impaired in GM-CSF–deficient
ularly AML.54 PAP is characterized by the mice, providing an explanation for the
intra-alveolar accumulation of surfactant intra-alveolar accumulation of PAS-positive
proteinaceous material, resulting in impaired material. PAP in GM-CSF–deficient mice
alveolocapillary gas exchange (Fig. 7-4).55-57 can be corrected by the local expression of
Three types of PAP have been recognized: GM-CSF in the lungs,78,79,84 or by bone
congenital,58-62 associated with or secondary marrow transplantation from a wild-type
to systemic disease,63-65 and idiopathic. The mouse.80 Second, PAP occurs in individuals
last-mentioned is the most common form harboring constitutional mutations in the
of PAP and believed to have an autoimmune genes encoding surfactant proteins B or C or
basis.66-68 the bc chain of the GM-CSF receptor.58-62
The mechanism of PAP has not been firmly Finally, autoantibodies that bind and neu-
established, although surfactant homeostasis tralize GM-CSF are found in broncho-
apparently is impaired in this disease.69 alveolar lavage (BAL) of patients with the
Although only 10% of surfactant comprises idiopathic form of PAP.66
proteins, denominated A, B, C, and D, they Imaging studies of the lungs suggest PAP.85
are crucial to surfactant metabolism, opsoni- The chest radiograph usually shows bilateral
zation of microorganisms, and stimulation airspace disease characterized as ground-glass
of alveolar macrophage.70-72 Alveolar type II opacities suggestive of pulmonary edema,
epithelial cells and alveolar macrophage con- but without other signs of left-sided heart dys-
trol surfactant synthesis, storage, and ca- function. There is no relationship between
tabolism. Alveolar macrophages, which are clinical and radiographic findings, with the
produced by bone marrow hematopoietic latter being disproportionately more severe.85
cells, internalize and catabolize surfactant High-resolution CT scans reveal a pattern
by a process believed to depend on granulo- referred to as “crazy-paving,” which is charac-
cyte-macrophage colony-stimulating factor terized by ground-glass opacifications with
(GM-CSF) signaling.73-75 Several lines of superimposed interlobular septal and intra-
lobular thickening.86
BAL specimens can be used to establish
the diagnosis.87 Lung biopsy is the gold
standard for the diagnosis of PAP, but it
sometimes can yield false-negative results.
The incidence of PAP associated with leu-
kemia is unknown, but a study by Cordon-
nier and colleagues63 suggested that it can
be 10% in patients with leukemia and respi-
ratory failure. Treatment of PAP consists of
overall supportive care because many of
these patients have severe neutropenia from
previous chemotherapy, and whole-lung
lavage for patients with severe respiratory
distress.88-93 Most cases of chemotherapy-
induced PAP usually improve with the reso-
Figure 7-4. Pulmonary alveolar proteinosis (accumula- lution of neutropenia.
tion of amorphous, eosinophilic, periodic acid-Schiff-posi- Because the mechanism of PAP has been
tive material) in pulmonary alveolar lumens. (Hematoxylin
and eosin, 40 original magnification.) Inset shows PAS associated with GM-CSF deficiency, adminis-
stain counterstained with hematoxylin. tration of GM-CSF has been proposed as a
treatment of PAP. In a study of 25 patients of diagnosis.95-98 Approximately 5% of all

with idiopathic PAP, subcutaneous adminis- osteosarcomas are multifocal (i.e., involving
tration of GM-CSF improved oxygenation two or more bones at the time of diagnosis).
and decreased alveolar-arterial oxygen gradi- Multifocal osteosarcoma has a more aggres-
ent in approximately 50% of the patients.94 sive clinical behavior, a higher incidence of
Whether GM-CSF has a therapeutic value pulmonary metastases, and a very poor
in children with leukemia and respiratory dis- prognosis.99
tress associated with clinical and laboratory When osteosarcoma is diagnosed, even the
features of PAP remains to be determined. most accurate staging procedures detect
Defective expression of GM-CSF/interleukin- metastases in only a few patients. Without
3/interleukin-5 receptor common b chain adequate treatment, however, most patients
has been shown to occur in children with with seemingly localized disease develop sec-
AML associated with respiratory failure.95 ondary metastases within 1 year.100 This
finding implies that micrometastases are
already present at diagnosis in most patients.
Solid Tumors With appropriate treatment, 60% to 70%
of patients with localized disease are ex-
Solid malignancies in children differ mark- pected to be cured. The outcome of pa-
edly from such tumors in adults; biology tients with clinically detectable metastatic
and histology define a very distinct group of disease at diagnosis is usually very poor; less
neoplasms, most of them of dysontogenetic than 30% of patients are expected to sur-
origin, with unique clinical manifestations vive.94,101-103 Care of these patients needs
and natural history. Epithelial malignancies to combine a multimodal approach, with
are extremely rare in children; sarcomas and intensive preoperative and postoperative
dysontogenetic tumors constitute most solid chemotherapy and resection of the primary
cancers. Generally, these groups of malignan- tumor and all the metastatic lesions.102-105
cies are aggressive, and systemic dissemina- Using these guidelines, more recent research
tion (microscopic or macroscopic) is present reports 2- to 5-year, progression-free survival
at the time of diagnosis. For this reason, an rates of 25% to 45%.102,106-108 Factors that
extensive metastatic work-up is necessary, affect outcome include number of metas-
and most malignancies require systemic ther- tases, laterality, and the ability to perform a
apy regardless of the local stage. complete resection.102,105
The lungs also are the most common sites
Osteosarcoma of treatment failure in patients with osteo-
Osteosarcoma, a malignant neoplasm derived sarcoma. For patients with recurrent disease,
from primitive mesenchymal cells and char- a surgical approach is recommended; the
acterized by the presence of osteoid-produc- 5-year postrelapse survival of patients in
ing spindle cell stroma, is the most common whom a complete resection of all macro-
malignant bone tumor in pediatric patients.92 scopic disease can be achieved is almost
Osteosarcoma accounts for 2.6% of all neo- 40%, whereas it is 0% for patients with unre-
plasms in children, with an estimated annual sectable disease.104,109 Prognostic factors for
incidence of 3.9 per 1 million in white survival after recurrence include isolated
children and 4.5 per 1 million in African- lung metastases, late (>24 months) recur-
American children.93 Most osteosarcomas rences, and small number of pulmonary
occur during the first 2 decades of life, a nodules.105,109,110
period characterized by rapid skeletal growth. Plain chest radiographs detect lung metas-
Overt macroscopic metastatic disease is seen tases in most cases. High-resolution CT of
in a significant proportion of patients, and the chest is the procedure of choice, how-
has a grave prognosis when present.94 The ever. False-positive results occur, particularly
most common site for metastatic spread with smaller lesions, and biopsy confirma-
is the lung; 14% to 24% of patients have tion of the lung disease is usually required.
macroscopic pulmonary disease at the time Osteoid matrix produced by osteosarcoma
cells forms bone and causes calcification in nodule in the site of a scar was malignant
pulmonary nodules. Seventy-five percent was 82%.111
of metastatic osteosarcoma nodules lack cal- The ability to control the pulmonary micro-
cification, however. Conversely, only 50% metastatic disease after completion of therapy
of calcified nodules in newly diagnosed would result in a significant improvement
patients with osteosarcoma are malignant, in outcome. Muramyl tripeptide phospha-
whereas 65% of noncalcified lesions are tidylethanolamine (MTP-PE), a synthetic lipo-
found to be metastatic osteosarcoma.111 philic analogue of muramyl dipeptide (a
Mediastinal adenopathies are very rare in component of the cell wall of bacille Calm-
patients newly diagnosed with osteosar- ette-Guérin), has been encapsulated in lipo-
coma, and their presence in the context of somes to deliver the agent selectively to
lung nodules favors the diagnosis of a non- monocytes and macrophages to activate their
malignant condition; 60% of patients with tumoricidal properties. In an animal model,
benign nodules have mediastinal disease the administration of liposome-encapsulated
compared with less than 20% of patients muramyl tripeptide (L-MTP-PE) resulted in
with metastases.111 activation of pulmonary macrophages and
CT is often unable to distinguish benign eradication of pulmonary micrometastases.113
from malignant pulmonary disease, and a In the cooperative Children’s Cancer Group
surgical procedure is often required for con- and Pediatric Oncology Group intergroup
firmation. CT can miss 40% to 50% of the INT0133 clinical trial, patients with localized
lesions that are found later during the surgi- osteosarcoma received standard treatment
cal procedure.112 This finding highlights the with methotrexate-cisplatin-doxorubicin reg-
importance of manual palpation during imen. Patients were first randomly assigned
open thoracotomy; minimal access proce- to receive ifosfamide, L-MTP-E, or a combi-
dures such as thoracoscopy should not be nation of both. Adding a combination ther-
the approach if the goal is resection. apy with ifosfamide and L-MTP-PE to the
In patients who have undergone thoracot- standard regimen resulted in a significantly
omy for metastatic disease, new nodules are better outcome than the other three regi-
likely to be metastatic, and surgical interven- mens.114 This improved outcome could be
tion is warranted. Surgical scarring often due to the synergistic effect of L-MTP-PE
makes the diagnosis of recurrent disease diffi- and ifosfamide.115
cult, however. McCarville and associates111 It also is possible to induce activation of
evaluated the imaging patterns of recurrent alveolar macrophages by nebulization of
nodules after thoracotomy in patients with GM-CSF. Based on encouraging preliminary
osteosarcoma. Pulmonary nodules recurred data, the Children’s Oncology Group is cur-
in 90% of patients who underwent thoracot- rently evaluating this approach in patients
omy, and metastatic disease was found in with metastatic osteosarcoma. Another simi-
90% of patients who underwent another sur- lar approach is the interleukin-12 gene trans-
gical procedure. Only one third of the fer by aerosol using a nonviral vector, such as
nodules appeared to be calcified on CT scans. polyethylenimine, a polycationic DNA car-
A consistent pattern suggestive of malig- rier. Interleukin-12 has a well-known activity
nancy was the presence of progressive pleural against various tumors. The systemic admin-
thickening. In contrast to newly diagnosed istration of interleukin-12 is limited by its
patients, in most patients who had under- toxicity. In animal models, aerosol therapy
gone thoracotomy, recurrent pulmonary dis- resulted in a significant decrease in the size
ease was associated with the presence of and number of metastatic nodules.116,117
mediastinal adenopathies. With subsequent Interleukin-12 also has been shown to
recurrence, the proportion of malignant enhance the sensitivity of osteosarcoma cells
lesions and the incidence of malignant medi- in vitro to 4-hydroxy-cyclophosphamide by
astinal disease increased.111 Also, half of the a mechanism involving the Fas pathway,
new lesions occurred in previous scars, and which suggests that this approach may act
the estimated probability that a recurrent synergistically with ifosfamide.115 The same
polyethylenimine transfer technology has metastases; most (50% to 60%) have extrapul-
been shown to provide an antitumor effect monary disease (usually of the bone and bone
using p53 transfection.117 marrow).122,125-127,131 Overall, approximately
Aerosolized technology also has been devel- 10% of patients have lung metastases at the
oped to deliver chemotherapeutic agents time of diagnosis (Fig. 7-5).129
directly to the lungs. In an animal model, The most important prognostic factor is
aerosolized 9-nitrocamptothecin liposome the presence of metastatic disease at diagno-
was administered to mice that had subcutane- sis.122 Advances in the treatment of ESFT
ous xenografts of various human cancers and have resulted in only a very modest improve-
to mice with lung metastases of osteosar- ment in the survival of patients with metas-
coma. The results were encouraging; a signi- tases.122,126,132 Even among patients with
ficant antitumor effect was noted in the metastatic disease, however, there is some
xenografts and in the pulmonary disease, heterogeneity. Patients with isolated lung
suggesting not only a local, but also a sys- metastases may have a better prognosis than
temic effect.118 Clinical trials to assess this patients with extrapulmonary metastases,
form of therapy are under way.119 with long-term survival rates approaching
40% to 45%.125,130,131 Among patients with
Ewing Sarcoma Family of Tumors lung metastases, patients with unilateral
The term “Ewing sarcoma family of tumors” disease130 and patients with good histologic
(ESFT) refers to a group of small round cell response to induction chemotherapy129
neoplasms of neuroectodermal origin. Ewing seem to have a survival advantage.
sarcoma of the bone is the least differentiated In approximately 50% of patients with
form, and primitive neuroectodermal tumor isolated lung metastases, treatment fail-
and peripheral neuroepithelioma are the ures occur as isolated pulmonary disease
most differentiated forms. Of all types of pedi- again,129,130 suggesting that further response
atric malignancy, 3% are ESFT; these tumors consolidation might improve the outcome
are rare in nonwhites.120 Approximately of these patients. In contrast to osteosar-
40% of all bone cancers in children are ESFT coma cells, ESFT cells are very sensitive to
of the bone, the second most common type radiation therapy, and lung radiation is an
of bone malignancy in children after osteo- alternative to lung surgery. In the first Amer-
sarcoma.120 Patients with ESFT commonly ican Intergroup Ewing Sarcoma Study, lung
present with symptoms during the second radiation was associated with a lower inci-
decade of life; 80% of patients with EFST are dence of lung (and distant) recurrences.133
younger than 18 years, and the median age With the development of more intensive
at diagnosis is 14 years.120-122 ESFT has a chemotherapeutic regimens, lung radiation
tendency to involve the shaft of long tubular of localized disease was abandoned. It
bones, the pelvis, and the ribs, but almost remains a therapeutic option, however, for
every bone can be affected. More than 50%
of the tumors arise from axial bones, with
the pelvis being the most commonly
involved (23% to 27%). Primary ESFT of the
chest wall, previously known as Askin tumor,
occurs in 12% of patients with ESFT.120-123
ESFT are aggressive neoplasms; systemic
manifestations including fever and anemia
are present in 10% to 15% of patients,124 and
approximately 20% to 25% of cases have clini-
cally apparent metastatic disease at the time
of diagnosis.125-127 Metastatic disease seems
to be associated with older age128 and large
tumors128-130 or with pelvic primary
tumors.125,126,129 Isolated lung disease, usually Figure 7-5. Chest CT scan shows multiple pulmonary
bilateral, occurs in 25% to 45% of patients with metastases (arrows) in a patient with Ewing sarcoma.
patients with metastatic disease. In this Approximately 10% to 15% of patients

regard, whole-lung radiation seems to pro- with RMS have metastatic disease at the
vide a modest survival advantage in patients time of diagnosis. The incidence of meta-
with metastatic disease.129 Preliminary data static disease is higher in patients with alve-
of the European Bone Marrow Transplant olar RMS (25% to 30%) than in patients
Registry134 suggest that an alternative ap- with embryonal RMS (5% to 10%).137-139
proach to the treatment of patients with Most cases of alveolar RMS are characterized
isolated lung metastases may be high-dose by the presence of the t(2;13)(q35;q14) or,
chemotherapy using a busulfan-based regi- less frequently, t(1;13)(p36;q14) transloca-
men and autologous stem cell rescue. tions, which result in the PAX3-FKHR or
Patients with primary ESFT of the chest PAX7-FKHR chimeric genes. Patients with
wall represent a distinct group. Many of these the PAX3 translocation have more wide-
patients have infiltration of the pleura, have spread metastatic disease and a worse out-
pleural effusion, or may develop intraopera- come. The PAX7 translocation seems to be
tive contamination of the pleural space. They associated with a lower incidence of lung
may be at high risk of disease relapse within metastases.140
the pleural compartment, and many groups Approximately 5% of patients with RMS
have used hemothorax radiation covering have lung metastases at the time of diagno-
the entire pleural space. The use of hemi- sis.138 Only 15% to 25% of patients with
thorax radiation seems to reduce systemic metastatic disease have isolated lung metas-
relapse rates (mainly in lung metastases) tases; in most cases, the presence of lung
and to provide a survival advantage.135 disease is a sign of more widespread meta-
static RMS.141,142 The presence of isolated
Soft Tissue Sarcomas lung metastases is associated with favorable
Pediatric soft tissue sarcomas (STS) are broadly features, such as embryonal histology and
divided into rhabdomyosarcoma (RMS) (40% negative nodal involvement. Patients with
to 45%) and non-RMS soft tissue sarcomas metastatic disease have a generally poor
(NRSTS) (55% to 60%), which include several prognosis, with long-term survival estimates
histologic subtypes, each one of which con- of less than 30%. Patients with isolated lung
stitutes less than 5% to 10% of STS. Alto- metastases seem to benefit from lung radia-
gether, STS represent approximately 6% to tion, however, and have a slightly better
7% of the cases of malignancy in individuals outcome, with 4-year overall survival rates
younger than 20 years. The incidence of of 40%.142
RMS is highest in infancy and during the first NRSTS comprise a very heterogeneous
years of life, and it decreases and levels out at group of neoplasms of mesenchymal origin.
later ages, whereas NRSTS have their highest The most common subtypes in children are
incidence in adolescence, although a peak is dermatofibrosarcoma protuberans, synovial
observed in infants.136 sarcoma, malignant fibrous histiocytoma,
RMS recapitulates the phenotypic and bio- fibrosarcoma, and malignant peripheral nerve
logic features of developing skeletal muscle. sheath tumor. Because each tumor is individu-
Two broad categories are identified: Embry- ally rare in pediatric patients, little is known
onal RMS with its botryoid and spindle cell about their biology and natural history in
variants accounts for two thirds of the cases, children. Most have clinical behavior similar
and alveolar RMS and undifferentiated RMS to tumors in adults; however, there are nota-
account for the remaining cases. RMS is clini- ble exceptions, such as infantile fibrosar-
cally heterogeneous; it can arise anywhere in coma and infantile hemangiopericytoma,
the body where mesenchymal tissue is found. neoplasms that are associated with character-
One third of the cases arise in the head and istically good prognosis despite aggressive
neck region (orbit, parameningeal, and non- histologic features.
parameningeal sites); 25% arise in the genito- Lung metastases are present in 5% to 10% of
urinary tracts, primarily bladder and prostate; the cases at diagnosis.143,144 Only 12% of chil-
and 18% arise in the extremities. RMS occur dren who have undergone gross tumor resec-
much less frequently in the trunk and pelvis. tion experience metastatic tumor recurrence.
Patients with large (5 cm), invasive, or high- lesions identified on CT only are not malig-
grade tumors have a significantly higher (25% nant.156 For these reasons, the role of lung
to 35%) risk of distant disease recurrence, radiation in this group of patients with CT-
however, usually in the lungs.145-147 If pa- only lung nodules is unclear. In such patients
tients are at high risk of distant metastases treated on the National Wilms Tumor Studies
after local control or have unresectable or met- 3 and 4, the 4-year event-free survival esti-
astatic tumors at presentation, chemotherapy mates were 89% for patients receiving radia-
must be considered. tion and 80% for patients treated with
Among all the histologic subtypes of chemotherapy only.157 Similarly, results of a
NRSTS, alveolar STS warrants special men- study by the International Society of Pediatric
tion. This rare tumor accounts for only 1% Oncology showed that patients with lung
of all STS. Of patients with this form of sar- nodules identified only on CT and who
coma, 65% have lung metastases at the time achieved a complete response to chemo-
of diagnosis, however. This sarcoma has a therapy had a 5-year overall survival esti-
very indolent course, and even in the pres- mate of 83%.158 These results contrast
ence of metastases, 5-year overall survival with the findings of the United Kingdom
rates exceed 70% to 80%.148 Children’s Cancer Study Group, which
indicated much lower (65%) survival rates
Wilms Tumor if no radiation was used.159
Wilms tumor is the most common childhood Because this issue remains unresolved,
renal tumor, accounting for approximately future trials by investigators in the Chil-
6% of all pediatric malignant disease. The most dren’s Oncology Group are expected to
common presentation is an asymptomatic assess the necessity of lung radiation for
abdominal mass in a young child (typically patients whose tumors have favorable bio-
<5 years old), although approximately one logic and histologic features and show rapid
third of such patients present with abdominal response to chemotherapy. It is possible that
pain, anorexia, and malaise. Hypertension is some children with stage IV favorable his-
present in 25% of the cases, and congenital tology Wilms tumor may be treated success-
anomalies, such as aniridia, genitourinary mal- fully without lung radiation.152 Finally, an
formations, or hemihypertrophy, are present important consideration is the frequent
in 10% to 20% of children.149 Histologic char- extension of Wilms tumor into the renal
acteristics are the most important prognostic vein and proximal inferior vena cava, which
indicators; anaplasia (which occurs in 10% of is sometimes associated with pulmonary
cases) is associated with an adverse outcome. embolism.160 In most cases, tumor throm-
Lung metastases are present in approximately bus can be removed en bloc with the kid-
10% of patients with favorable histology and ney. If the tumor extends to the hepatic
in 20% of patients with anaplasia.150,151 In level or into the atrium, however, the risk
contrast to most other types of pediatric malig- of operative morbidity is very high, and pre-
nancy, Wilms tumor with lung metastases operative chemotherapy is recommended.
has a good outcome, with 5-year overall sur-
vival estimates exceeding 80% for patients Neuroblastoma
with favorable histology.152 Lung radiation is Neuroblastoma is the most common extra-
an integral component in the management cranial solid tumor in children, accounting for
of these patients with lung metastases. 10% of all childhood cancers. Approximately
Plain chest radiographs have been used to two thirds of patients with neuroblastoma
define the presence of metastatic disease in have metastatic disease at diagnosis, typically
patients with Wilms tumor. In approximately of the bone or bone marrow, and their prog-
10% of patients with lung nodules, plain chest nosis is very poor, although it varies accord-
x-rays are normal, however, and the lesions ing to many clinical and biologic risk
are visible only on CT scan.153 Nonmalignant factors.161 Pulmonary involvement at diag-
nodular lesions are frequently identified on nosis is extremely rare, occurring in less than
chest CT scans, but not on plain radiographs 1% of patients.162 In patients with metastatic
in children.154,155 In adults, 50% to 60% of disease, lung metastases may be present in
4% of patients, are never isolated, and are

always found in the context of a very aggres-
sive clinical and biologic behavior. On radio-
graphs, these lesions appear as multiple,
small, bilateral, noncalcified nodules.163
Hepatoblastoma
Hepatoblastoma is a very rare malignancy in
the overall population, but it accounts for
75% of all liver cancers in children. Lung A
metastases are very common; 20% of pediat-
ric patients have pulmonary disease at diag-
nosis, and the lungs are the most common
site of recurrence.164-166 Metastatic hepato-
blastoma is curable if the tumor responds
to chemotherapy and the lung metastases
are resected. With this aggressive approach,
the 5-year overall survival estimates are
approximately 50%.164,166
Imaging Considerations
Multiple studies have shown that even in
B
children with tumors known to metastasize
to the lungs, a significant proportion of Figure 7-6. A and B, Chest CT scans show single pul-
lesions found on chest CT scans are monary nodules (arrows) of similar characteristics in
two patients with osteosarcoma. Both patients under-
benign.167,168 Although granulomas develop went a thoracotomy. Examination of a tissue specimen
less frequently in children than in adults, helped establish a diagnosis of histoplasmosis in the
several other benign conditions may develop patient shown in A and metastatic osteosarcoma in
the patient shown in B.
in the lungs of children, including the
growth of normal intrapulmonary lymph
nodes, hamartoma, round pneumonia, atel-
as PET/CT may allow us to assess more accu-
ectasis (particularly in children requiring
rately and noninvasively the metabolic activ-
sedation or anesthesia), and inflammatory
ity of pulmonary nodules.
pseudotumor. Distinguishing benign from
malignant pulmonary nodules may be diffi-
cult (Fig. 7-6). Primary Lung Neoplasms
The availability of helical CT has improved
the quality of the chest images by diminish- Pleuropulmonary blastoma (PPB) is a unique
ing the effect of breathing and cardiac dysontogenetic neoplasm of childhood that
motion on the readability of the scan. appears as a pulmonary or pleural-based mass,
McCarville and associates169 investigated with a primitive, histologically variable mixed
the imaging features of 81 pulmonary blastomatous and sarcomatous appearance. It
nodules in 41 patients with solid tumors usually manifests in the first 3 to 4 years of life
who had undergone a thoracotomy. The with respiratory distress, fever, cough, or chest
new chest CT scans were able to detect 75% pain. Cystic changes and pneumothorax are
of the nodules found at surgery; 44% of the common on CT scans. The lower lobes are
patients had benign lesions only. Sharply more commonly involved, and pleural inva-
defined nodules were more likely to be malig- sion and effusion are typical. PPB can be
nant in children than in adults.169 Although divided into three morphologic types or sub-
node size was not always a predictor of malig- types based on the cystic, cystic and solid, or
nancy, small (<5 mm) nodules were less solid appearance of the tumor, as determined
likely to be malignant, particularly small sol- by the gross and microscopic examination.
itary nodules.169,170 New technologies such The exclusively cystic or type I PPB is the least
complex, manifests at an earlier age than the Hematologic Disorders

other two forms, and is more readily resect-
able. The rhabdomyosarcomatous compo- Sickle Cell Disease
nent is a prominent feature of type II and
type III PPB, and it is the exclusive malignant Sickle cell disease (SCD) comprises a group
element in type I. PPB is an aggressive malig- of inherited hemoglobinopathies character-
nancy, and metastases to the brain are ized by a predominance of hemoglobin
common. (Hb) S. Included in SCD are sickle cell ane-
Type I PPB usually has a good prognosis mia (Hb SS, the homozygous state for the b
if complete resection is achieved. The out- S globin gene), Hb SC (Hb S and Hb C),
come associated with type II and type III sickle b-thalassemia syndrome (either Hb
PPB is much worse, with 5-year survival rates b0 thalassemia or Hb bþ thalassemia in com-
of less than 50%. These patients need a very bination with Hb S), and other combina-
aggressive treatment approach, with wide tions of Hb S and abnormal hemoglobins.
resection and systemic chemotherapy.171 These hemoglobinopathies result from the
Other, less common primary malignancies substitution of valine for glutamic acid at
of the lungs include carcinoid and primary position 6 of the b globin chain, which
sarcomas such as malignant peripheral nerve alters the quaternary structure of hemoglo-
sheath tumor and fibrosarcoma. bin and reduces the solubility of deoxyhe-
moglobin S to approximately 10% of that
of the normal deoxyhemoglobin A. After
Inflammatory Pseudotumor deoxygenation of the erythrocyte, Hb S
undergoes intracellular polymerization. As
Inflammatory pseudotumor (plasma cell the concentration of Hb S increases, the ery-
granuloma, inflammatory myofibroblastic throcytes collapse into a sickle shape, either
tumor) is a rare benign neoplasm consisting reversibly or irreversibly. Repeated cycles of
of histiocytes, myofibroblasts, plasma cells, polymerization induce a series of erythro-
and spindle-shaped mesenchymal cells. cyte abnormalities, including cytoplasmic
Inflammatory pseudotumor most often and membrane rigidity and cellular dehydra-
affects children and young adults, and it tion. Elevated blood viscosity and microvas-
can be found in pulmonary and extrapul- cular occlusion then develop. The clinical
monary locations, most commonly the features of the sickle cell syndromes include
abdomen. Despite its benign nature, it may chronic hemolytic anemia, frequent infec-
be difficult to differentiate from a malig- tions owing to loss of splenic function, and
nancy because of its local invasiveness and microvascular obstruction producing acute
its tendency to recur. Pulmonary pseudotu- and chronic anemia and organ damage from
mor is often encountered as an incidental infarction and fibrosis.174
finding in a chest radiograph. Patients with sickle cell anemia frequently
When a pseudotumor is symptomatic, experience acute pulmonary complications,
patients may present with nonspecific respi- such as asthma, thromboembolism, and acute
ratory symptoms, such as cough, shortness chest syndrome (ACS). Results of several
of breath, chest pain, hemoptysis, and club- studies suggest that asthma is a significant
bing. Laboratory findings consistent with contributing factor for acute pulmonary com-
inflammation are common. The etiologic plications, and 35% of children with SCD have
factors are not clearly established, although obstructive lung disease.175 Individuals with
an infectious cause is suspected. Although SCD seem to be at risk of thromboembolism
there are some anecdotal cases of spontane- because of a hypercoagulable state. The term
ous regression, the treatment of pulmonary “acute chest syndrome” reflects the difficulty
inflammatory pseudotumor is surgical. Local of establishing a definitive cause for these
recurrences are well described; for this rea- acute pulmonary episodes, particularly in dis-
son, an aggressive surgical resection at diag- tinguishing infection from pulmonary infarc-
nosis is always recommended.172,173 tion by microvascular occlusion (Fig. 7-7).
A B
Figure 7-7. An 18-month-old

girl with hemoglobin SS disease
and respiratory distress. A-C, Rad-
iographs reflect the rapid pro-
gression typical of acute chest
syndrome at the time of admission
(A), 24 hours later (B), and 72 C
hours later (C).
Acute Chest Syndrome vated steady-state white blood cell counts.

Definition. ACS is a clinical pulmonary Patients with Hb SC disease also are at risk,
exacerbation of SCD manifested by fever; a although the incidence and frequency of
new infiltrate on chest radiograph; and one vaso-occlusive episodes, including ACS, is
or more pulmonary signs or symptoms, lower.178
such as cough, dyspnea, and chest pain.177 Etiology. The etiology of ACS is complex
As with pneumonias in children without and heterogeneous. In addition to the
SCD, the initial radiograph may not show expected intravascular pulmonary thrombo-
a new infiltrate. The most common present- sis, ACS is marked by the co-occurrence of
ing signs are fever, cough, tachypnea, infection, fat embolism (presumably from
crackles, and hypoxemia. Fever is more bone infarcts), hypoventilation, edema, and
common in children with ACS, and pain is reactive airway disease, and by secondary
more common in adults. ACS is the second problems of mucus hypersecretion and atelec-
leading reason for hospitalization (after tasis. Pulmonary infarction is the presumed
vaso-occlusive painful crisis) and the lead- cause in 16% of cases, and fat embolism is
ing cause of death in patients with SCD.176 the presumed cause in 9%. Because multiple
Sudden death in the setting of ACS may be etiologic factors are usually involved, the diag-
associated with acute exacerbations of pul- nostic label of ACS is strongly preferred to
monary hypertension. pneumonia. A specific cause of ACS can be
Epidemiology. Vaso-occlusive painful identified in 50% of the cases.
crisis and ACS are the most common sickle In children with SCD, infections are more
cell–related events during the first decade commonly documented, as are associated
of life. The risk of vaso-occlusive painful cri- bacteremias. An infectious etiology can be
sis and ACS begins in the first year and identified in one third of the patients; the
increases steadily; ACS is experienced by most common agents are viruses, such as
half of all patients with Hb SS disease by 6 respiratory syncytial virus, parvovirus, and
years of age. Of patients with sickle cell ane- rhinovirus, particularly during winter
mia (Hb SS) experiencing a first ACS, 25% months. These can be diagnosed through
have a recurrent event in 6 months. The risk the immunofluorescent assessment of nasal
is decreased with greater levels of fetal secretions or by serial measurements of spe-
hemoglobin (Hb F) and is increased with cific antibody titers. Atypical bacteria, such
the magnitude of the anemia and with ele- as Mycoplasma pneumoniae and Chlamydia
pneumoniae, mostly cause bacterial infec- decrease after diagnosis, despite aggressive
tions. Pneumonia from these agents is more intervention. Hypoxia is common, but
severe in SCD than in normal children. In younger patients are less likely to require
the era of long-term antibiotic prophylaxis oxygen.174,177
and immunizations for Streptococcus pneu- Bronchoscopy and BAL provide adequate
moniae and Haemophilus influenzae, these material, and the diagnostic yield is high,
bacteria are less commonly responsible for but it is associated with risk of complica-
ACS than previously, and other causes such tions. The mean hospital stay is 10 days.
as community-acquired pneumonia have Adults are more likely to have complications
arisen.178 In 45% of the cases, an etiology during hospitalization; neurologic events
cannot be identified.177 occur in 10% of patients. The most com-
The vasculopathy of SCD progresses in mon is altered mental status, although cere-
the first years of life to render the spleen brovascular accidents also are common.177
incapable of performing its immune func- Pathogenesis. The pathogenesis of ACS
tions, including the generation of antibodies is the result of a complex series of reactions
to encapsulated organisms. In addition to involving activation of the endothelium,
this “functional asplenia,” there are abnor- often caused by an infection, and subsequent
malities of the complement defense system. adherence of sickle erythrocytes. This
Together, these deficits predispose patients, sequence of events leads to a partial obstruc-
especially children, to blood-borne infections tion of microcirculatory flow; prolonged
with encapsulated organisms. Antimicrobial transit allows extensive polymerization of
prophylaxis with penicillin and immuniza- Hb S with its resultant erythrocyte rigidity.
tion against these organisms (S. pneumoniae Trapping of poorly deformable sickle erythro-
and H. influenzae) are important strategies cytes results in transient or prolonged
to reduce episodes of bacterial sepsis and obstruction, ischemia, and further endothe-
recurrences of ACS. After age 6 months, lial activation.174 Various adhesive proteins
annual immunizations against influenza are expressed on the sickle erythrocyte mem-
recommended. brane interact with the corresponding mole-
Clinical Presentation. Nearly half of cules on the endothelial cell and are
patients with SCD are usually admitted with mediated by plasma ligands, such as throm-
a diagnosis other than ACS, usually a vaso- bospondin and von Willebrand factor.174
occlusive crisis; pain is a prodrome of ACS. Hb S polymerization generates reactive oxy-
The clinical presentation of ACS is similar to gen species, which activates the transcription
that of pneumonia. Cardinal features com- factor nuclear factor-kB, which upregulates
prise fever; a new infiltrate on radiograph; expression of the adhesion molecule
symptoms including cough, shortness of VCAM-1 on the endothelium, facilitating
breath, and chest pain; signs including erythrocyte adhesion.
tachypnea, crackles, and hypoxia; and pain, Granulocytes and monocytes also play an
including a greater frequency of chest, rib, important role in microvascular occlusion.
and abdominal pain in children, and a Additional vasoactive components also
greater frequency of extremity pain in adoles- may play a role in the ACS process.
cents and adults. The presenting chest ra- Endothelin is a potent vasoconstrictor of
diograph may be normal, as it may be with the pulmonary vascular bed, and its levels
clinical pneumonia, so a second radiograph are increased with hypoxemia. In patients
should be obtained as indicated by clinical with SCD, endothelin-1 levels are increased
suspicion. Multilobar involvement, espe- during the steady state, and increase sharply
cially of the lower lobes, and effusion are during the ACS. Nitric oxide, in addition to
present in two thirds of patients. Upper and providing vasodilation of the pulmonary
middle lobe involvement is more common vasculature, downregulates VCAM-1 and
in children, and isolated lower lobe involve- inhibits the adherence of normal sickle ery-
ment is more common in adults.177,178 throcytes to vascular endothelium.174
Abnormalities seen on radiographs tend Treatment. In the management of ACS,
to progress. Oxygenation and hemoglobin clinicians need to consider the evolving
nature of the ACS. Most patients present development of ACS and pulmonary hyper-
with pain or develop pain during admission, tension.181 The concurrent association of
and in many instances, chest pain may reactive airway disease and ACS is associated
result in hypoventilation, atelectasis, or with more severe exacerbation and prolonged
pneumonia. Incentive spirometry must be hospitalization. Reactive airway disease is
started early and be aggressively imple- associated with the release of a wider variety
mented. A judicious use of opioid analgesics of inflammatory mediators and cytokines
must be implemented early in management. than with ACS alone, and is associated with
Dehydration predisposes to vaso-occlusive airway edema and mucus hypersecretion, fac-
painful crisis and ACS, and commonly fol- tors known to worsen the course of ACS.
lows episodes of fever, tachypnea, or Treatment of reactive airway disease
anorexia. Aggressive rehydration is always exacerbations in the context of ACS is simi-
indicated in the management of vaso-occlu- lar to standard acute asthma care. There is a
sive crises. Rehydration is often accom- theoretical basis for steroid use because acti-
plished by the administration of fluids at a vation of the inflammatory cascade plays a
rate of 1.5 times maintenance, which is central role in ACS; however, its role is still
reduced to maintenance when the patient is unclear. A short course of steroids may
normovolemic. Overhydration should be reduce the length of hospitalization in chil-
avoided because pulmonary edema and wors- dren and the need for analgesics and oxygen
ening of the disease process might ensue. supplementation, but a rebound effect may
Empiric antibiotic therapy always must occur.179 Bronchoscopy is recommended
include a combination of a macrolide and a when patients do not respond to initial ther-
second-generation cephalosporin. Vancomy- apy. Aggressive mechanical ventilatory sup-
cin also is recommended if fever persists, and port, including extracorporeal membrane
there is history of infection with penicillin- oxygenation, may be necessary; nitric oxide
resistant S. pneumoniae, or if the patient resides also may be used.174,176,180
in an area with a high prevalence of resistance Secondary Complications. As with
of this organism. Oxygen supplementation community-acquired pneumonias, ACS is
also is indicated for decreases in pulse oxime- frequently associated with atelectasis or
try greater than 4% over baseline, or for values pleural effusions or both. The pleural fluid
less than 92%. is usually sterile and exudative, but may
Oxygenation significantly improves with develop empyema. The atelectasis may or
simple blood transfusion and exchange trans- may not be associated with retained airway
fusion. Early transfusions are indicated for mucus secretions. In some cases, the mucus
patients at high risk of complications; patients strings are extensive and dehydrated and
presenting with severe anemia, thrombocyto- may form bronchial casts. Because of their
penia, and multilobar pneumonia should firmness, the syndrome has been referred
receive a transfusion even before respiratory to as plastic bronchitis. In these cases, fiber-
distress develops. A post-transfusion increase optic bronchoscopy with washes of saline,
in hemoglobin levels greater than 11 g/dL DNase, or N-acetyl cysteine may be useful
must be avoided, however, because of the risk in clearing the airway obstruction and expe-
of sudden increase in blood viscosity that diting the resolution of the atelectasis.
could lead to thrombosis and ischemic epi-
sodes. Exchange transfusion is indicated if Chronic Sickle Cell Lung Disease
the patient’s baseline hemoglobin is elevated, Chronic sickle lung disease is a progressive dis-
or the patient has more severe disease, wors- order that is insidious in onset during child-
ening hypoxemia, neurologic abnormalities, hood and may be asymptomatic in the
or multiorgan failure. absence of frequent exacerbations of ACS.
Evidence is mounting that reactive airway The end stage of progression is characterized
disease may play a role as a cause and as a con- by persistent hypoxemia, radiographic evi-
sequence of ACS.174 Reactive airway disease dence of interstitial fibrosis, restrictive lung
may occur in almost half of SCD patients, disease on pulmonary function testing, pul-
and seems to be a risk factor for the monary hypertension, and cor pulmonale.
Pulmonary hypertension in patients with Much of the improved quality of life and
SCD has been associated with worsened sur- survival of patients with SCD is attributed
vival. Close pulmonary and cardiac follow- to the details of preventive health care.
up are essential to monitor the progression of Because the spleen is a victim of sickle cell
chronic sickle lung disease. vasculopathy in the first few years of life
(functional asplenia), functional immunity
Pulmonary Hypertension to encapsulated organisms is impaired, and
The obliterative vasculopathy of pulmonary the risk for sepsis from these organisms is
hypertension is evident in one third of post- increased. Protective strategies include peni-
mortem studies of patients with SCD, but cillin prophylaxis and immunizations to
the true prevalence is unknown. This disor- S. pneumoniae and H. influenzae. Penicillin
der is most frequently recognized in adults, (or erythromycin) is administered twice
but almost certainly originates earlier in daily from early infancy to age 5 years in
childhood. Although a worsened prognosis children with the more severe hemoglobi-
for chronic sickle lung disease and pulmo- nopathies (Hb SS and Hb S/b0 thalassemia)
nary hypertension is associated with recur- and through age 3 years in children with
rent episodes of ACS, the prevalence of less severe variants of SCD, such as Hb SC.
pulmonary hypertension also is high in Prophylactic antibiotics are given perma-
patients without a history of ACS. nently to patients who have undergone
This pathophysiologic predisposition is splenectomy or have experienced pneumo-
related to the combination of hemolytic ane- coccal sepsis. The 7-valent pneumococcal
mia and “functional asplenia.”181 Hemolysis vaccine is administered to infants beginning
in combination with inadequate splenic clear- at 2 months of age with four doses adminis-
ance results in the accumulation of iron-rich tered by the age of 15 months, and the
hemoglobin, which functions as a scavenger 23-valent vaccine is administered at ages
of nitric oxide and catalyzes the formation of 2 and 5 years and then every 5 to 7 years
oxygen radical species. Arginase is simulta- thereafter. The usual childhood schedule is
neously released from erythrocytes and serves followed for H. influenzae type B immuniza-
to limit the supply of arginine to nitric oxide tions. Immunizations to influenza virus are
synthase, limiting the synthesis of nitric administered annually after age 6 months.
oxide. The nitric oxide serves a crucial func- The usual childhood immunization sched-
tion in promoting pulmonary vasodilation ule for hepatitis B is emphasized to prevent
and limiting the impact of many factors this potential complication of recurrent red
contributing to the vascular remodeling of blood cell transfusions.
pulmonary hypertension. The functional Therapies to correct the basic genetic or b
asplenia contributes to the remodeling by globin protein defect of SCD and therapies
the failure to clear platelet-derived mediators to prevent the progression of SCD do not
and cytokines that promote adherence of ery- yet exist. The major current therapeutic
throcytes to the endothelium and cause strategies are designed to reduce the propor-
microthrombosis. tion of erythrocytes carrying predominantly
The diagnosis of pulmonary hypertension sickle hemoglobin (Hb S) and to delay the
in SCD is ominous, with a 10-fold increase in progression of pulmonary hypertension.
the risk for death and survival less than 50% Of all the new therapies for treating SCD,
within 4 years. The more recent validation of hydroxyurea is the most promising. Several
echocardiography as a diagnostic tool for pul- pediatric and adult trials have reported
monary hypertension in SCD should promote decreases in pain, the incidence of ACS,
earlier detection. Several studies have sug- and overall mortality.181 Hydroxyurea ther-
gested the potential role for oxygen therapy, apy was initiated because of the drug’s abil-
red blood cell transfusions, inhaled nitric ity to increase Hb F production. This
oxide, intravenous arginine, prostacyclin, increase in Hb F and a concomitant increase
and the newer vasodilators. Controlled long- in red blood cell volume effectively reduce
term studies are needed to determine the the intracellular concentration of Hb S and
effectiveness of these and other therapies.183 result in decreased sickling. Hydroxyurea
has other beneficial effects, including a Histiocytic Disorders of the Lung

decrease in neutrophils and monocytes
(intervening in the inflammatory cascade), The histiocytoses are a group of rare hemato-
an increase in red blood cell deformability, poietic disorders characterized by the clonal
and a decrease in the adhesive receptors in proliferation and pathologic accumulation
the erythrocyte membrane.181 Trials of of cells of the mononuclear-phagocyte system
increasing length of hydroxyurea therapy in tissues. The mononuclear-phagocyte sys-
in adults and children have shown safety tem is a system of cells whose primary func-
and clinical efficacy, including a reduction tions consist of phagocytosis of foreign
in the incidence of ACS.181 material, antigen processing, and antigen
Other options include therapy with eryth- presentation to lymphocytes. Mononuclear
ropoietin to increase Hb F, but its effective- phagocytes are subclassified into two major
ness has been suboptimal. Because of this classes, macrophages and dendritic cells,
and its substantial expense, use of erythro- based on morphologic and functional charac-
poietin has been limited. Its primary use is teristics. The most common pulmonary
as adjunctive therapy for patients whose phagocytes are the alveolar and the airway
response to hydroxyurea is suboptimal or macrophages. They are indistinguishable
for patients with religious objections to except for their location within the respira-
blood transfusions. tory tract. These cells are primarily responsible
Transfusion therapy of normal erythro- for the sequestering and disposal of inhaled
cytes serves to depress the bone marrow pro- particles and pulmonary surfactant. They play
duction of erythrocytes expressing sickle an active role in the maintenance and remod-
hemoglobin.182 The timing of transfusion eling of the extracellular connective tissue
may be acute, intermittent, or chronic. matrix through the secretion of cytokines that
Adverse effects of recurrent transfusions regulate matrix production and degradation.
include iron overload, blood-borne infec- Interstitial macrophages are the second group
tions, and alloimmunization, complications of pulmonary macrophages with an improved
that can be reduced by erythrocytopheresis, antigen-presenting capability. The second
highly specific crossmatching, and the class of mononuclear phagocytes, the den-
newer iron-chelating agents. Current indica- dritic cells, consist of dendritic cells of the
tions for red blood cell transfusion therapy lymphoid follicle and Langerhans cells of the
in SCD include severe cases of vaso-occlu- skin and other organs.
sive painful crisis, recurrent or severe ACS, The histiocytic disorders can be classified
severe or worsening anemia, and primary into three classes based on the pathologic cells
and secondary stroke prevention in patients present within the lesions: class I, dendritic
at increased risk. cell histiocytosis; class II, non-dendritic cell
Because of the potentially serious complica- histiocytosis, and class III, malignant histiocy-
tions of bone marrow transplantation, in the tosis. The rest of this discussion is dedicated to
United States it is offered primarily to patients the pathophysiology, clinical presentation,
who have had serious complications, such as diagnosis, and treatment of Langerhans cell
stroke or recurrent ACS, and to patients with histiocytosis (LCH) and histiocytic disorders
HLA-matched sibling donors. Its greatest involving the lung.
benefit is, however, to patients who have nei- LCH is the most common of the dendritic
ther experienced significant complications cell histiocytoses. It is a proliferative disorder
nor developed significant chronic sickle lung of activated Langerhans cells and is character-
disease. ized by variable biologic behavior and a spec-
Efforts to develop effective gene therapy trum of distinct clinical presentations.184 The
or b globin substitution have failed so far. pathogenesis of LCH is poorly understood.
The primary impediment has been the Because LCH has been shown to be a mono-
development of a vector suitable for the clonal condition, it has been considered a
delivery of the replacement of b globin neoplastic disorder.185,186 Different patterns
DNA to bone marrow precursors. of clinical involvement indicate other
pathogenetic mechanisms, however. The

benign histopathologic appearance of the
lesions, the occurrence of spontaneous remis-
sions,187 and the ability to respond to immu-
nomodulation188 suggest a reactive clonal
disorder, rather than a malignant process, at
least in some cases. Langerhans cells, similar
to other dendritic cells, have a crucial role in
the immune system, and it has been suggested
that LCH could be the result of immune dys-
regulation. Although no consistent immuno-
logic abnormalities have been described,
there is increasing evidence that LCH may be A
the result of an uncontrolled and abnormal
proliferation of Langerhans cells secondary
to immune dysregulation or after exposure
to an as-yet-undetermined stimulus.189,190
The diagnosis of LCH requires a biopsy
with the specimen showing typical patho-
logic features of Langerhans cell infiltrates
and confirmatory positive staining for
CD1a and S-100. Alternatively, the demon-
stration of Birbeck granules by electron
microscopy has been used for confirmation
of this diagnosis. The diagnosis of pulmo-
nary LCH in children with multisystem dis-
B
ease is usually clinical because the histologic
diagnosis is usually made from extrapul- Figure 7-8. Pulmonary involvement in Langerhans cell
monary lesions. In the rare cases of isolated histiocytosis (LCH). A, CT scan shows acute changes in an
infant with newly diagnosed LCH and multisystem involve-
lung disease, a morphologic confirmation ment. Multiple small nodular opacities and cystic changes
is required, and it can be obtained by lung are seen. Also note enlarged thymus with calcifications. B,
biopsy or by BAL. In the latter case, the pres- CT scan of a 6-year-old boy shows chronic fibrosis, air
trapping, and bullous disease. This child received treatment
ence of greater than 5% of CD1a-positive for LCH and had lung involvement during infancy.
cells in the BAL fluid is very suggestive of
LCH. BAL also is a good tool for monitoring LCH includes diffuse skin involvement and
response and follow-up.191 involvement of multiple bones. The oral cav-
The histopathology of the lesion is ity; lymph nodes; and, to a lesser extent,
uniform, regardless of the clinical severity lungs, liver, and brain are common sites of
of the disease. It consists of collections of involvement in this disease. Lung involve-
Langerhans cells, interdigitating cells, and ment has been reported to occur in 20% to
macrophages, accompanied by T lympho- 50% of patients with multisystem disease.
cytes with variable numbers of multinucle- Radiographic changes consistent with past
ated giant histiocytes and eosinophils.192 lung involvement are present in 15% to
In light of the pathologic basis of the diag- 20% of long-term survivors (Fig. 7-8A).193,194
nosis of LCH and the variable nature of clini-
cal presentations, LCH is now subclassified Primary Pulmonary Langerhans Cell
by the degree of organ involvement: loca- Histiocytosis
lized single-system disease, multifocal sin- Primary pulmonary LCH is a disorder that
gle-system disease, and multisystem disease. most frequently affects young white adults
Localized LCH, involving skin, lymph node, with an equal sex distribution. LCH in this
or bones, usually has a good prognosis. The age group is epidemiologically associated with
most common presentation of multifocal cigarette smoking; greater than 90% of patients
have a history of smoking, and the disease usu- involving the middle and upper lobes, sym-
ally responds to smoking cessation, although metrically. As the disease progresses, nodular
systemic chemotherapy also may be needed. lesions are less frequent, and cystic changes
An important defining factor is that, in adult are much more prominent, progressing to
cases, Langerhans cell proliferation in primary the appearance of honeycombing and
pulmonary LCH is usually not clonal; this advanced emphysema. Early changes are best
finding is in contrast to that associated with seen in high-resolution CT scans. The combi-
childhood LCH.195 Although primary pulmo- nation of diffuse cystic changes with small
nary LCH can occur at any age, it is rarely seen peribronchial nodular opacities on CT is
in patients younger than 15 years. Pulmonary highly suggestive of LCH.193-195
involvement as part of systemic LCH is a com- Treatment of pulmonary LCH in children
mon feature of multisystem LCH, however, needs to be discussed in the context of the
seen in one third of patients. degree of involvement of other organs. Lung
The pathogenesis underlying primary pul- involvement is considered a poor prognostic
monary LCH, similar to systemic LCH, is feature, however, so these patients need to be
not well defined, but thought to be the treated aggressively, usually with combina-
result of an abnormal immune reaction to tion chemotherapy, for approximately 12
an irritant (i.e., smoke). Primary pulmonary months. Different regimens have proven to
LCH is mostly seen in the third or fourth be effective, and different combinations of
decade of life. Twenty percent to 25% of prednisone, vinblastine, etoposide, mercap-
patients are asymptomatic at the time of topurine, and methotrexate have been
diagnosis, with the disease being detected used.193,194 The optimal therapy for primary
on a screening chest radiograph. Respiratory pulmonary LCH remains undefined. Smoking
symptoms may include chronic cough and cessation is the most important component of
dyspnea and, more rarely, hemoptysis or therapy. Successful smoking cessation, com-
chest pain. Chest pain may be due to pneu- bined with use of oral corticosteroids, usually
mothoraces or rib lesions. results in remission. In cases refractory to cor-
Histopathologically, primary pulmonary ticosteroids, systemic chemotherapy may be
LCH begins as a proliferation of Langerhans required.195
cells along the small airways. These cellular
lesions expand to form nodules that can mea-
sure 1.5 cm. These nodules include a mixed Complications of Treatment
population of cells with variable numbers of of Hematologic and
CD1a-positive Langerhans cells, eosinophils, Oncologic Disorders
lymphocytes, plasma cells, and fibroblasts.
There is progression from cellular nodules to Hematopoietic Stem Cell
fibrosis, leading to a distinctive honeycomb- Transplantation
like pattern and hyperinflation (Fig. 7-8B).
In later stages, fibrosis is the predominant Hematopoietic stem cell transplantation
feature, and Langerhans cells are absent from (HSCT) has been used as a lifesaving proce-
the lesions.195 dure in children who have many malignant
Clinically, acute lung involvement occurs hematologic, immunologic, and inherited
in the context of multisystem disease. Patients metabolic diseases. Allogeneic and autolo-
usually present during the first 2 years of life, gous HSCTs are increasingly used. Pulmonary
with involvement of multiple systems, such complications depend on various factors,
as the bones, skin, lymph nodes, liver, spleen, including pretransplant intensive chemo-
and hematopoietic system.193 Children most therapy combined with radiation therapy,
commonly develop nonproductive cough and post-transplant infectious and noninfec-
and dyspnea. Early in the disease, the chest tious complications. These complications
radiograph shows micronodular or reticulo- have been well studied in adults. The pediat-
nodular and interstitial infiltrates, with su- ric experience is limited, but includes the
perimposed cystic changes predominantly same respiratory complications.
In one retrospective analysis, severe pul- microbiologic results that exclude pulmonary
monary complications occurred in 17 of infection. Risk factors for the development of
138 patients, leading to death in 8 (7%) DAH include intensive conditioning chemo-
patients.196 Three important post-HSCT therapy, radiation toxicity, solid malignancy,
periods can be identified for lung compli- and age older than 40 years. Early diagnosis
cations: the first month post-transplant, of DAH and prompt intervention are crucial.
which is characterized by neutropenia; the High doses of corticosteroids may improve
second month, in which idiopathic pneu- survival and reduce the development of
monia syndrome can develop; and the late subsequent respiratory failure201; however,
phase, after the third month, which is the prognosis for DAH is very poor.
characterized by late-onset noninfectious
pulmonary complications. Second Phase
Between the first and third months post-
First Phase transplant, as the neutropenia resolves, idio-
The phase that precedes engraftment is typi- pathic pneumonitis syndrome (IPS) may
cally characterized by prolonged neutropenia develop. The diagnosis of IPS is made by
and disruption of the mucosal barrier. The exclusion of other causes, including infec-
combination of neutropenia and mucositis tious.202 The incidence of IPS after allogeneic
predisposes patients to infectious pulmonary HSCT in adult patients is approximately 10%
complications. Noninfectious complications to 15%, and the median time from trans-
(pulmonary edema, diffuse alveolar hemor- plantation is approximately 45 days.203 The
rhage) also may occur. histologic patterns of IPS are interstitial pneu-
Pulmonary edema usually occurs in the sec- monitis and diffuse alveolar damage.203 The
ond or third week after HSCT.197 The exact usual presenting symptoms include dyspnea,
incidence is unknown, but it is a common nonproductive cough, fever, hypoxemia, and
problem. Patients present with acute onset of diffuse pulmonary infiltrates. The risk factor
dyspnea and clinical findings that include for the development of IPS includes allogeneic
weight gain of rapid onset, bilateral pulmo- HSCT, high-dose radiation, increasing age,
nary crackles, and hypoxemia. The chest chronic myelogenous leukemia, previous
radiograph shows mild to severe vascular splenectomy, and graft-versus-host disease
redistribution and bilateral interstitial infil- (GVHD). There is no proven effective treat-
trates, with or without pleural effusion. These ment for IPS after HSCT, although corticoster-
findings are indistinguishable from other oids may be helpful in some patients. The
causes of cardiogenic and noncardiogenic pul- prognosis is poor.
monary edema. Overzealous hydration, blood Pulmonary complications occurring after
transfusion, and renal and cardiac insuffi- the third month post-transplant are usually
ciency from chemotherapy can contribute to due to chronic GVHD.205 The incidence of
the development of pulmonary edema.198 late-onset noninfectious pulmonary compli-
The management of post-HSCT pulmonary cations after HSCT has been reported to be
edema is similar to the management of pul- 10% to 23%.206,207 The only significant vari-
monary edema resulting from other causes. ables associated with such complications
Diffuse alveolar hemorrhage (DAH), a seri- were chronic GVHD and complications of
ous post-HSCT complication, usually occurs GVHD therapy. These obstructive or restric-
in the second and third week after transplan- tive pulmonary complications include bron-
tation.199 DAH has been reported in 5% of all chiolitis obliterans, cryptogenic organizing
patients who have undergone HSCT, and is pneumonia (COP), and toxicity syndrome.
more frequent in autologous HSCT recipi- Bronchiolitis obliterans, an obstructive
ents.200 DAH is characterized by dyspnea of pulmonary disease, affects the small airways
sudden onset, nonproductive cough, fever, and was first described as a late complica-
and hypoxemia; hemoptysis is rare. Chest tion of allogeneic HSCT, mostly in long-
radiograph abnormalities include bilateral term survivors who have chronic GVHD,
interstitial infiltrates. The diagnosis is made although it can occur at any time. The inci-
by BAL that shows a hemorrhagic fluid and dence of bronchiolitis obliterans has been
reported to be 2% to 14% in allogeneic HSCT radiographs are characterized by the presence

recipients who survive longer than 3 months of patchy pulmonary infiltrates in multiple
post-transplant.208 The cause is unknown. lobes. Bronchiolitis obliterans manifests with
An immunologic mechanism that includes hyperlucency. High-resolution CT shows
injury of the bronchial epithelia has been patchy consolidation, particularly with peri-
suggested, but other causes, such as viral in- bronchovascular or peripheral distribution
fections, also have been postulated. The in immunocompetent patients, in whom
pathogenesis is likely to be multifactorial.209 ground-glass attenuation and nodules are
Patients generally present with dyspnea, more frequent.211 Risk factors for COP
wheezing, and nonproductive cough. Chest include being the recipient of an allogeneic
radiograph findings may be minimal with HSCT and the development of GVHD. Corti-
occasional evidence of hyperinflation. High- costeroids are effective in 60% of patients
resolution CT scan of the chest shows bron- with COP, but infections should be carefully
chial wall thickening, peripheral vascular ruled out before initiating treatment with
pruning, and mosaic lung attenuation with corticosteroids.206
air trapping on expiratory scan.210 Recipients of autologous transplants who
Airflow obstruction is the hallmark of receive high-dose chemotherapy or radiother-
bronchiolitis obliterans. A reduction in the apy as conditioning for HSCT may experience
ratio of forced expiratory volume in 1 second pulmonary toxicity months to years after the
to forced vital capacity is commonly present transplantation procedure.212 Drug-induced
in patients with GVHD. An obstructive lung and radiation-induced lung toxicity is de-
disease pattern and the lack of response to scribed in greater detail subsequently. Pulmo-
bronchodilators form a sufficient basis for nary complications are important causes of
making a diagnosis of bronchiolitis obliter- morbidity and mortality. Chest radiographic
ans. Although open lung biopsy is required changes are nonspecific. High-resolution CT
to confirm the diagnosis of bronchiolitis of the chest increases the detection of pulmo-
obliterans, it is seldom needed in practice. nary abnormalities, even when results of chest
The diagnosis of bronchiolitis obliterans can radiographs are normal, and it can help in
be made based on clinical criteria, pulmonary establishing the diagnosis. It also is helpful
function test abnormalities, and high-resolu- in guiding lung biopsy.
tion CT scan without open lung biopsy. The
treatment consists of increasing immuno-
suppression, usually with prednisone and Transfusion-Related Acute Lung
other agents such as cyclosporine or azathio- Injury
prine. Bronchiolitis obliterans is often pro-
gressive and unresponsive to therapy. A Although uncommon, transfusion-related
rapid deterioration, as shown on pulmonary acute lung injury (TRALI) has been increas-
function test, and severe obstruction (forced ingly recognized as the leading cause of trans-
expiratory volume in 1 second <45%) are fusion-related death in the United States; its
associated with poor prognosis. development is associated with 1 in 5000 U
COP is a common late complication; in of transfused blood products.213 Patients in
most cases, the exact etiology is unknown. whom acute onset of bilateral chest infiltrates
COP was formerly known as “bronchiolitis develops during or within 6 hours of the com-
obliterans with organizing pneumonia.” This pletion of transfusion of plasma-containing
condition differs from that of bronchiolitis blood products should be evaluated for this
obliterans. The histologic changes associated condition. In most cases, signs of respiratory
with COP are proliferative bronchiolitis and distress develop within the first 1 to 2 hours
alveolitis, which affect the distal airways. after the transfusion is started. Affected
Patients with COP have a characteristically patients usually have hypoxemia (PaO2/FIO2
restrictive pattern on pulmonary function <300 mm Hg) and diffuse lung infiltrates on
tests. Patients with COP have nonproductive the chest x-ray suggestive of noncardiogenic
cough, low-grade fever, and dyspnea. Chest pulmonary edema.214,215
Blood products implicated in TRALI include normal or decreased pulmonary artery wedge
whole blood, red blood cells, platelet transfu- pressure and left atrial pressure, although these
sions (including platelet concentrates and are rarely measured in children.
plateletpheresis), fresh frozen plasma, and The pathophysiology of TRALI is not well
cryoprecipitate.216 Although less common, understood. Two hypotheses have been postu-
intravenous immunoglobulin preparations lated. The first one tries to explain TRALI as an
also have been implicated in TRALI.216 The antibody-mediated event.221 These antibodies
condition has been reported predominantly may bind to the corresponding HLA epitopes
in patients with cancer or other hematologic on the lung endothelium, resulting in capil-
diseases such as SCD and in patients under- lary leak and cell damage.222 Alternatively,
going solid organ or stem cell transplanta- some authors hypothesize that a two-event
tion.214 Other, less common settings where model may explain the occurrence of TRALI.
this adverse transfusion reaction may occur The first event would be host-related predis-
are complement-mediated hemolysis in par- posing factors, such as the ones described pre-
oxysmal nocturnal hemoglobinuria and lung viously, leading to lung sequestration of
damage associated with granulocyte transfu- polymorphonuclear neutrophils.222 The sec-
sions.214 Because pulmonary infiltrates may ond event includes the infusion of chemical
result from various causes, establishing the mediators, including antibodies against poly-
diagnosis of TRALI may be difficult. The differ- morphonuclear neutrophils, HLA, or cyto-
ential diagnosis includes ACS in sickle cell kines.222 Soluble CD40 (a member of the
anemia, infections, diffuse alveolar damage tumor necrosis factor family of receptors)
after bone marrow recovery, and lung hemor- ligands have been reported to accumulate in
rhage. Patients with TRALI often improve stored blood components, leading to priming
within 48 to 72 hours of onset, but occasional of CD40-dependent granulocyte activation,
patients die of acute respiratory failure. which ultimately may cause lung injury.223
TRALI is more common in adults; however, The management of TRALI is largely sup-
several well-documented pediatric cases have portive.214 Oxygen supplementation and
been reported. Neonates, who seem to be pro- occasional mechanical ventilation should be
tected from TRALI, may develop leukopenia provided. It is important that clinicians be
as a complication of transfusion, but not pul- aware of this potential complication because
monary problems.214,217,218 Pediatric oncol- patients usually do well without long-term
ogy patients require frequent and repeated sequelae, if they survive the initial insult.
transfusions, so it is not surprising that TRALI The blood bank also should be informed of
has been more frequently reported in this this complication to avoid repeated exposure
population.217 of the recipient to the same donor-derived
No single test can reliably help make the blood products, and if possible, the blood
diagnosis of TRALI, but some clinical clues bank can perform anti-HLA antibody detec-
may be helpful. Patients with TRALI often tion. These tests are expensive, however, and
present with fever, chills, and hypotension. are not available in many blood banks. If
Such patients often have transient leukopenia respiratory distress occurs during transfusion,
that resolves within a few hours; this condition the transfusion should be stopped immedi-
may be helpful in making a diagnosis.219 A ately. Preventing TRALI is a challenge because
complete blood cell count should be obtained no test is reliable enough to predict this poten-
in every case in which TRALI is suspected. In tial complication.
patients requiring ventilatory support, a bron- An increased awareness of this complica-
chial sample to measure the protein level tion may improve the knowledge of its clinical
should be obtained within 15 minutes of intu- and pathophysiologic features. At present,
bation to be reliable.220 An edema fluid pro- TRALI can be diagnosed only by excluding
tein-to-plasma protein ratio greater than 0.6 other causes, however. TRALI should be in-
is highly suggestive of TRALI. Ratios less than cluded in the differential diagnosis of acute
0.6 may indicate a cardiac source of pulmonary pulmonary problems in pediatric oncology
edema.220 Patients with TRALI also have patients.
Chemotherapy-Induced Lung nervous system-mediated mechanisms seem

Toxicity to play a role in the toxicity of certain agents.
Identified risk factors include patient age,
Numerous drugs can cause pulmonary or cumulative dose, prior or concurrent radia-
pleural reactions in children. The most com- tion, oxygen therapy, and use of other toxic
mon offenders are certain chemotherapeutic drugs. Most reactions to noncytotoxic drugs
agents used in pediatric oncology (Table 7-1). seem to develop idiosyncratically. When
Other agents with lung toxicity are increas- patients are treated with several potentially
ingly reported (Table 7-2). Diffuse interstitial toxic drugs or with a toxic drug plus irradia-
pneumonitis and fibrosis constitute the most tion to the chest or high oxygen concentra-
frequent clinical presentation. Hypersensi- tion, specific offenders cannot be identified.
tivity lung disease, noncardiogenic pulmo- There is little, if any, evidence that children
nary edema, pleural effusion, bronchiolitis are more susceptible to drug-related lung
obliterans, and alveolar hemorrhage also are injury, and they may be less susceptible to
encountered. some agents, such as bleomycin.
Although some drug-induced pulmonary Although better identification of chemo-
damage is reversible, persistent and even fatal therapy-induced lung toxicity has led to a
dysfunction may occur. Lung reactions occa- more judicious use of agents that might
sionally are temporarily remote from expo- cause lung toxicity, the widespread use of
sure to chemotherapeutic agents. Depending higher dose chemotherapy regimens preced-
on the agent involved, the reaction may or ing stem cell rescue has improved the
not be dose-related. The mechanism of toxic- chances of survival of high-risk patients
ity is thought to be direct injury to lung cells who receive a high cumulative dose of che-
in most cases, but immunologic and central motherapy and radiotherapy, and who have
Table 7-1 Lung Toxicity Associated with Chemotherapeutic Agents Used in Pediatric Oncology
PROPOSED
DRUG PEDIATRIC DISEASES MECHANISM TYPICAL FEATURES
Bleomycin Hodgkin disease Oxidative effect Most common cause of pulmonary
toxicity
Germ cell tumors Release of proteases Dose-related acute and chronic
lung toxicity
Busulfan Bone marrow Direct toxicity Late-onset pulmonary fibrosis
transplantation Radiation may increase toxicity
Carmustine Bone marrow Oxidative damage Same as bleomycin
transplantation
Cyclophosphamide Widely used in several Oxidative damage Lung toxicity is uncommon
malignancies Usually subacute
Methotrexate Hematologic Hypersensitivity Mild and reversible
malignancies or direct effect hypersensitivity lung toxicity
Osteogenic sarcoma Not related to cumulative dose
Cytarabine Hematologic Not well studied Capillary leak syndrome
malignancies BO associated with higher doses
Melphalan Bone marrow Similar to busulfan Similar to busulfan
transplantation
Fludarabine Acute myelogenous Not well studied Interstitial pneumonia reported
leukemia in adults
Bone marrow
transplantation
BO, bronchiolitis obliterans.

Data from references 224-229, 237, 238, 242.
Table 7-2 Newer Agents Used in Pediatric Cancer Treatment Associated with Lung Toxicity
DRUG PEDIATRIC DISEASE REPORTED LUNG TOXICITY

Rituximab Lymphoma, post-transplant Acute-onset interstitial pneumonia, lung fibrosis
lymphoproliferative disease
Imatinib Chronic myelogenous leukemia Rare cases of interstitial pneumonia
Filgrastim Various diseases, bone marrow Pleural effusion and noncardiogenic pulmonary
(G-CSF) transplantation edema and ARDS
Trans- Acute promyelocytic leukemia Diffuse pulmonary infiltrates in the setting
retinoic of retinoic acid syndrome
acid
ARDS, acute respiratory distress syndrome; G-CSF, granulocyte colony-stimulating factor.

Data from references 224, 226, 242-245.
a history of opportunistic infection. This These include (1) no other likely cause of
new generation of heavily pretreated survi- lung disease, (2) symptoms consistent with
vors constitutes a high-risk population for the suspected drug, (3) time course compat-
long-term toxicity, including lung toxicity. ible with drug-induced lung disease, (4)
The clinical manifestations of drug-induced compatible tissue or BAL findings, and (5)
lung disease include fever, malaise, dyspnea, improvement after the drug is discontinued.
and a nonproductive cough. Radiologic stud-
ies almost always show diffuse alveolar or Cytotoxic Drugs
interstitial infiltrates, or both. Segmental or Antibiotics—Bleomycin. Bleomycin has
lobar disease, particularly if unilateral, should been consistently associated with lung tox-
suggest another diagnosis. A restrictive lung icity, especially lung fibrosis, in children
pattern in pulmonary function testing may and adults.227 Although the drug is active
be found before the appearance of radio- against squamous cell carcinoma and germ
graphic lesions. CT of the chest also may reveal cell tumors, its major use in children is in
early evidence of parenchymal abnormalities. the treatment of HD and other lympho-
Hypoxemia is an early and clinically im- mas.231,232 Because of the high frequency
portant functional manifestation. Patho- of lung reactions and the utility of bleomy-
logic changes do not distinguish among most cin for generating animal models of lung
drugs and most often consist of interstitial fibrosis,230 this drug has been studied more
thickening with chronic inflammatory cell thoroughly than others. Bleomycin can
infiltrate in the interstitial or alveolar compart- cause early-onset and late-onset lung
ment, fibroblast proliferation, fibrosis, and injury.227 Late-onset lung injury, which is
hyperplasia of type II pneumocytes. With initially characterized by interstitial pneu-
hypersensitivity reactions, the interstitial infil- monitis potentially leading to pulmonary
trate includes numerous eosinophils. fibrosis, is the most common effect and
The manifestations of drug-induced lung may occur several months or years after
toxicity are usually nonspecific, and so estab- exposure to the drug. Early bleomycin toxic-
lishing a definitive diagnosis may be difficult. ity usually manifests as an acute hypersensi-
Other diagnoses, such as infection, pulmo- tivity reaction.227
nary hemorrhage, lung disease related to an Lung injury secondary to bleomycin
underlying disorder, and radiation damage, occurs in approximately 4% to 7% of all
must be considered in the differential diagno- patients receiving the drug,227 although the
sis. BAL is being increasingly done to provide reported incidence is 40%. The frequency of
microbiologic and cytologic information reactions in children is not well documented
essential to differential diagnosis and as a because few children receive this agent. Fol-
research tool to identify disease markers and low-up data analyses from the Childhood
potential pathogenetic mechanisms. Cancer Survivor Study indicated, however,
Practical criteria for diagnosing drug- that the use of bleomycin is significantly
induced lung disease have been suggested. associated with pulmonary fibrosis (relative
risk 1.7), bronchitis (relative risk 1.4), and Histopathologic features are nonspecific
chronic cough (relative risk 1.9) at 5 years and similar to the features seen in other
postdiagnosis. cases of diffuse alveolar damage owing to
Bleomycin is metabolized by bleomycin other causes. The diagnosis is established
hydrolase, which is lacking in the lungs by exclusion. Early features include acute
and skin; the active drug accumulates, giv- inflammation such as edema, intra-alveolar
ing rise to increased exposure in these tis- hemorrhage, desquamation of alveolar cells,
sues.233 Bleomycin lung toxicity occurs and hyaline membrane formation (Fig. 7-9).
mainly as a result of direct injury to cells At a later stage, features of interstitial pneu-
and by secondary immunologic reac- monitis can be seen, including angiitis
tions.227,233 Direct toxicity may be mediated and inflammatory infiltrates. Interstitial
by oxidant injury, either through the pro- fibrosis occurs as a final event (Fig. 7-10).
duction of reactive oxygen metabolites or The alveolar epithelium discloses mor-
through inactivation of antioxidants. phologic changes including hyperplasia of
Bleomycin-induced lung disease can begin type II pneumocytes, often with bizarre
insidiously. Asymptomatic patients may have features. Insult from chemotherapy also
decreases in arterial oxygen saturation and dif- may affect the bronchial wall, leading to
fusing capacity for carbon monoxide (DLCO). peribronchial fibrosis. Eosinophil infiltra-
As the illness progresses, there is a decline in tion and granulomatous inflammation have
vital capacity and total lung capacity, charac- been associated with the use of bleomycin.
teristic of restrictive lung disease.227,234 In Features of bronchiolitis obliterans also
interstitial pneumonitis and hypersensitivity may occur secondary to bleomycin toxicity.
lung reactions, patients often present with Lung biopsy is sometimes unavoidable in
a dry, hacking cough and dyspnea; these cases of lung fibrosis of unexplained etiol-
manifestations occur only on exertion in ogy. Some patients also may show pleural
mild cases, but significant respiratory distress thickening leading to fibrosis as a late
accompanies advanced illness. Fever suggests event.
a hypersensitivity reaction. Physical examina- Risk factors for bleomycin toxicity include
tion reveals tachypnea and crackles. Chest age, cumulative dose, and concomitant
radiographs in symptomatic patients most therapies.234 Children seem to be less prone
commonly show diffuse linear densities. CT to development of bleomycin lung toxicity
of the chest is more sensitive for detection of than older patients.227,234 There is evidence
early interstitial disease. in animal models and humans that the risk
A B
Figure 7-9. Early-onset pathologic

pulmonary changes associated with
treatment-induced toxicity (hema-
toxylin-eosin stains). A, Vascular
changes consisting of thickening of
the media and narrowing of the vas-
cular lumen. B, Intra-alveolar edema
and perivascular mononuclear infil-
trates. C, Hemorrhage and interstitial
mononuclear infiltrate. D, Hyaline C D
membrane formation.
A B
Figure 7-10. Late-onset patho-

logic pulmonary changes associated
with treatment-induced toxicity
(hematoxylin-eosin stains). A, In-
creased collagen content in the
alveolar septum and epithelial hyper-
plasia. B, Interstitial fibrosis. C, Bron-
chiolitis obliterans. D, Organizing
C D pneumonia. (See Color Plate)
of bleomycin lung toxicity increases with used in any pediatric therapy as a single
dose intensity.227 Cumulative doses greater agent, however. Other risk factors include a
than 500 U have been associated with a history of oxygen administration and
20% incidence of interstitial lung toxicity impaired renal function because bleomycin
in adults.227 Lung toxicity, including death is mainly excreted by the kidneys.234 There
resulting from toxicity, may occur with is no method to predict accurately which
lower doses, however. Patients receiving patients will develop lung toxicity. The most
bleomycin should be monitored by serial important actions for decreasing the risk of
determinations of DLCO.227,235 Bleomycin- bleomycin lung toxicity are to reduce the total
induced lung toxicity may occur 6 months cumulative dose and to encourage patients to
after discontinuation of the drug in patients avoid exposure to smoking. Current protocols
with normal DLCO test results during bleo- for HD attempt to reduce the total cumulative
mycin therapy. Although the results of this dose of chemotherapeutic drugs by giving
test can be affected by numerous factors, it alternating or hybrid regimens, limiting the
is recommended that bleomycin therapy use of radiotherapy, and reducing the doses.
be stopped when the DLCO decreases by No established therapy is available for
greater than 40% to 60% of baseline bleomycin lung toxicity. Therapy of bleo-
values.227 CT of the chest may be useful for mycin-induced pneumonitis consists largely
monitoring progression of disease. In addi- of supportive measures. Withdrawal of the
tion, administration of cumulative doses drug at the onset of toxicity must be consid-
greater than 400 U should be avoided. ered. Careful monitoring of oxygen therapy
Radiotherapy also can cause lung toxicity is imperative. The use of steroids is contro-
by oxidative injury. It may potentiate the risk versial, but reversal of severe toxicity has
of lung toxicity by bleomycin. It is currently been documented in some patients after
unknown, however, how much toxicity the use of high-dose steroids.227,236 It has
radiotherapy adds to chemotherapy in these been suggested that responding patients
cases. This is an important issue because pedi- may have hypersensitivity reactions, and
atric patients with HD usually receive both that patients with established lung fibrosis
treatment modalities at the same time. Bleo- may respond less favorably. Patients who
mycin toxicity also is more common when experience acute pulmonary symptoms,
bleomycin is combined with another drug and who probably have hypersensitivity
than when it is used alone. Bleomycin is not reactions, should be considered for steroid
therapy after infections or other causes of Although pulmonary toxicity is uncommon,

lung disease have been ruled out.236 Con- it does produce severe and even fatal lung
versely, steroids are of unproven value in damage. One documented mechanism of
patients with a more chronic clinical picture lung injury is a cytotoxicity-mediated oxida-
suggesting pulmonary fibrosis. tive process. In experimental animals, cyclo-
Other chemotherapeutic agents that have phosphamide exposure results in leak of
been associated with lung toxicity, but which proteins across damaged endothelium and a
are seldom used in pediatric oncology, include reduction in lung antioxidant levels. Onset
mitomycin, gemcitabine, paclitaxel, doce- of pulmonary toxicity is usually subacute
taxel, cetuximab, bevacizumab, and chloram- rather than insidious as with other alkylating
bucil. Gemcitabine may be used occasionally agents. Dry cough and dyspnea herald the
for pediatric patients with relapsed or resistant onset; malaise, anorexia, and weight loss fol-
HD.237 Pulmonary function should be evalu- low. Physical examination reveals tachypnea
ated carefully before gemcitabine is adminis- and diffusely decreased breath sounds. Chest
tered to these patients. Drugs often used in radiographs may show diffuse bilateral infil-
pediatric oncology, but which are seldom trates, sometimes with pleural thickening.
associated with lung toxicity, include anthra- Pulmonary function testing reveals hypox-
cyclines, dactinomycin, vinca alkaloids, and emia and restrictive lung disease. Withdrawal
irinotecan. of the drug, supportive therapy, and cortico-
Antimetabolites—Methotrexate. Metho- steroids are the recommended treatment.
trexate is a folic acid antagonist used in the
treatment of several childhood malignancies,
notably leukemias and osteogenic sarcoma, Radiation Therapy
and nonmalignant conditions, such as juve-
nile rheumatoid arthritis and psoriasis.238 The The lung is a crucial organ for radiation
clinical features of methotrexate are consistent injury.239 Clinically, interstitial pneumonitis
with a hypersensitivity pneumonitis. Com- can occur, and occasionally lung fibrosis.
mon symptoms include dyspnea and dry Most radiation lung damage data come from
cough. Physical examination reveals tachyp- adults with lung and breast cancer; experi-
nea, diffuse crackles, cyanosis, and occasionally ence in children is more limited. Common
skin eruptions. Hypoxemia is observed in 90% malignancies that may include treatment
to 95% of patients, and mild eosinophilia has with pulmonary radiotherapy include meta-
been reported in almost half of the patients. static Wilms tumor, HD with bulky mediasti-
Pulmonary function testing may show nal involvement, or, less frequently, Ewing
decreased DLCO. The most common chest sarcoma-peripheral neuroectodermic tumors
radiographic abnormalities are bilateral inter- of the chest wall and primary lung neo-
stitial infiltrates. Lung biopsy in adults reveals plasms. Children with these types of malig-
interstitial pneumonitis with lymphocytic nancy often receive a limited dose of lung
and sometimes eosinophilic infiltrates, bron- radiotherapy. Children receiving total body
chiolitis, and granuloma formation consistent irradiation before HSCT also are at risk of lung
with a hypersensitivity reaction. Diagnosis of toxicity, despite shielding techniques usually
methotrexate-induced pneumonitis is difficult undertaken.240 Severe toxicity may be less
because this condition may mimic other condi- frequent in children than in adults.
tions. Therapy consists of withdrawal of the Risk factors for radiation pneumonitis
drug and administration of corticosteroids. include dose, lung volume irradiated, fraction-
Clinical improvement precedes radiographic ation, and radiation planning techniques.239
and pulmonary function improvement. Radiation pneumonitis seldom occurs when
Alkylating Agents—Cyclophosphamide. less than 10% of the lung is irradiated. When
Cyclophosphamide is widely used in the treat- doses greater than 20 Gy are used, the risk of
ment of leukemias, lymphomas, and nonma- radiation pneumonitis increases proportion-
lignant illnesses. It frequently produces ally, becoming highly likely when doses
severe alopecia and hemorrhagic cystitis. greater than 60 Gy are used.241 In contrast to
conventional radiotherapy planning, three- Acknowledgments

dimensional radiotherapy planning effec-
tively allows radiologists to avoid irradiation The authors thank Margaret Carbaugh, for
of surrounding tissues. Fractionation of radia- her expert editorial review, and Monica Simi-
tion also may influence the occurrence of novich, for providing the pathology illustra-
pneumonitis; the greater the number of fractions and comments on the manuscript.
tions, the lower the likelihood for lung
injury.241
Radiation can damage the lung through References
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CHAPTER 8
Endocrine and Metabolic Diseases
CARLOS MILLA
Specific Disorders 170 Hypoparathyroidism 177

Diabetes 170 Disorders of the Reproductive System 177
Growth Hormone Disorders 172 Obesity-Hypoventilation Syndrome and
Adrenal Disorders 172 Respiratory Complications of Obesity 177
Pseudohypoaldosteronism 172 Summary 181
Hypothyroidism 174 References 181
Hyperthyroidism 175
Although hormones and growth factors have Specific Disorders

an influence on the proliferation of lung tis-
sue, especially during early development, Diabetes
there are no significant alterations in lung
function or respiratory morbidity associated Lung disease is not a major complication for
with the most prevalent endocrine conditions children with diabetes. Barring an infection,
in pediatric patients. Numerous hormones, it is not a likely threat even when the diabe-
including corticosteroids and the thyroid hor- tes has reached a point where other compli-
mone, have been shown during the later cations are present.2 Nonetheless, several
stages of lung development to stimulate dif- cross-sectional studies in patients with dia-
ferentiation of type II alveolar epithelial cells betes have found mild abnormalities in dif-
and to produce architectural rearrangements ferent lung function parameters. In one
of lung connective tissue elements that facili- population cross-sectional study, Lange and
tate gas exchange. Glucocorticoids in the peri- colleagues3 found that forced vital capacity
natal period delay Clara cell differentiation,1 and forced expiratory volume in 1 second
elevate surfactant protein mRNA, and have a were significantly lower in individuals with
stimulatory effect on pulmonary cytochrome diabetes than in nondiabetic controls. This
P-450. These effects translate into the known finding was especially prominent among
maturational changes induced by corticoster- patients with insulin-dependent diabetes.
oids, and consequently they are used antena- Sandler and coworkers4,5 found mild but
tally to prevent premature births. significant decreases in lung elastic recoil,
This chapter reviews how endocrine dis- diffusing lung capacity, and capillary blood
orders affect the respiratory system. Emphasis volume in a group of patients with type 1
is placed on the pulmonary manifestations of diabetes compared with healthy controls.
diabetes, pseudohypoaldosteronism (PHA), The degree of pulmonary dysfunction corre-
hypothyroidism, hyperthyroidism, and obe- lated with the duration of the disease. Other
sity-hypoventilation syndrome. Clinicians investigators also have reported mild
should be aware of the potential relationships decreases in measures of lung function in
between endocrine disorders and pulmonary patients with diabetes,6-9 but these results
dysfunction. are hardly unanimous.10
170
Chapter 8—Pulmonary Manifestations of Endocrine and Metabolic Diseases 171
Experimental data from animal models of diabetic condition has features of type 1
diabetes suggest that there are abnormalities and type 2 diabetes, it has been named CF-
in the lung connective tissue synthesis and related diabetes to distinguish it as a sepa-
turnover that are especially prominent in rate entity. Multiple studies have shown a
the absence of insulin replacement. Thick- clear correlation between the presence of
ening of the alveolar wall from increased CF-related diabetes and shortened survival
deposition of collagen fibers and a reduced and increased pulmonary morbidity. Finkel-
degradation of connective tissue have been stein and associates18 reported a signifi-
observed in rats made diabetic by treatment cantly shortened survival in CF patients
with streptozocin.11,12 This thickening also with diabetes,18 with less than 25% surviv-
has often been noted in the alveolar and ing to age 30 years. In addition, clinical
endothelial epithelial basement membranes deterioration, as assessed by National Insti-
of humans.13 Such abnormalities in the tutes of Health score, was apparent 2 years
molecular composition of epithelial base- before the diagnosis of diabetes was made.
ment membranes are well-known complica- Epidemiologic and registry studies concur
tions of diabetes, and they have been in observing greater mortality and pulmo-
extensively studied in the renal glomeruli, nary morbidity among patients with CF-
with excessive glycosylation of the colla- related diabetes. These patients are more
gen-like material that confirms the theory likely to be malnourished and to have sig-
being proposed as the underlying patho- nificant pulmonary dysfunction than CF
physiologic mechanism.14 As it pertains to patients without diabetes.19-21
the lung, it is possible that hyperglycemia The underlying causes are still not well
leads to excessive nonenzymatic glycosyla- understood, but these studies raise the ques-
tion of lung connective tissue, but the con- tion whether it is more likely that a pre-
sequences of this remain unclear. Animal diabetic state develops insidiously and then
studies have reported discordant results. contributes to clinical decline, or, alterna-
Some studies have described irreversible tively, that sicker patients are simply more
cross-linking of collagen15 (a form of the susceptible to diabetes. Further longitudinal
protein that is resistant to proteolysis), and studies have shown a direct relationship
a decreased activity of the enzyme calmod- between abnormal glucose tolerance and
ulin16 (which is involved in the regulation deteriorating pulmonary function. The
of connective tissue remodeling), whereas annual rate of decline in pulmonary func-
others have shown interference with the tion over a 4-year observation period was
molecular cross-linking of elastin and colla- found to have a direct correlation with the
gen fibers.15,17 Regardless, this abnormal degree of glucose intolerance at baseline.22
accumulation of collagen and elastin fibers Notably, the rate of pulmonary decline was
alters the lungs’ mechanical properties, pos- inversely related to the magnitude of insulin
sibly explaining the decrease in lung tissue secretion at baseline; this suggests a rela-
elasticity reported in clinical studies. tionship between insulin deficiency and
Notwithstanding the potential effects of clinical deterioration.22 Because subjects at
diabetes on the lung, children with diabetic baseline were no different in terms of pul-
ketoacidosis who present with altered con- monary function and nutritional status,
sciousness and vomiting are at an increased these data strongly support the concept that
risk for aspiration. Because aspiration can the insulin-deficient state leads to progres-
lead to greater morbidity, the placement of sively declining pulmonary function. In
a nasogastric tube and intubation in the addition, female patients with CF-related
presence of altered mental status should be diabetes have been reported to have worse
approached with extra caution. pulmonary outcomes and an overall disad-
Diabetes is a common complication for vantage in survival. The current recommen-
patients with cystic fibrosis (CF), typically dation is that CF patients older than age 13
manifesting in the adolescent and adult should have annual screening for CF-related
years, although its occurrence has been diabetes through oral glucose tolerance
reported in infancy. Because this particular testing.25
Infants born to mothers with diabetes are at Pseudohypoaldosteronism

increased risk for intrauterine or perinatal
asphyxia.26 Maternal vascular disease, mani- The content of body fluid Naþ is tightly
fested primarily by nephropathy, may con- regulated by the epithelial Naþ channel
tribute to the development of fetal hypoxia (ENaC), which is present in apical mem-
and subsequent perinatal asphyxia. In addi- branes of many Naþ-absorptive epithelia,
tion, respiratory distress syndrome occurs such as the renal tubules, distal colon, and
more frequently in infants born to mothers lungs (Fig. 8-1). ENaC is specifically inhib-
with diabetes than in normal infants at each ited by the diuretic amiloride, and it also is
gestational stage, especially before 38.5 called the amiloride-sensitive Naþ channel.
weeks.27 Hyperinsulinemia causes the delayed The major physiologic role of ENaC is to
maturation of surfactant synthesis; a possible maintain Naþ homeostasis, blood volume,
mechanism for this is by interfering with the and blood pressure by providing an apical
induction of lung maturation by glucocorti- entry pathway for Naþ ions to permit rapid
coids.28,29 Infants born to mothers with diabe- transport of Naþ from the luminal to the
tes also are at risk for respiratory morbidity interstitial compartment. ENaC consists of
from pneumonia, hypertrophic cardiomyopa- three homologous subunits, a, b, and g.
thy, and transient tachypnea of the newborn, The a subunit is essential for the formation
which occurs two to three times more com- of a functional ion channel, whereas the b
monly in this group than in normal infants.30 and g subunits can greatly potentiate the
level of expressed Naþ currents.
ENaCs belong to the Degenerin/ENaC
Growth Hormone Disorders superfamily of ion channels. The human
ENaC genes have been cloned, and using
An increase in lung size has been reported genetic linkage analysis, it was found that
in patients with acromegaly;31 however, this the involvement of ENaC gene mutations
is not associated with any significant respi- results in two distinct human diseases. The
ratory dysfunction. Obstructive sleep apnea autosomal dominant form affects the kidneys
(OSA) is most common in adult patients only (Liddle syndrome). It is characteristically
with either active or treated acromegaly. free from any significant pulmonary involve-
This condition is believed to be primarily a ment and is due to a defect in the function of
consequence of upper airway obstruction the aldosterone receptor.35 The autosomal
owing to hypertrophy of the tongue and recessive form is a systemic syndrome that
pharyngeal tissues. In addition, growth affects the kidneys, colon, sweat and salivary
hormone-induced changes in central respi- glands, and lungs. As mentioned before, this
ratory control have been proposed as a pos-
sible mechanism for the disordered sleep
pattern found in these patients.32
Lumen Interstitium
Na+
Adrenal Disorders Na+
K+
Only one case has been reported of Cushing

syndrome in an infant secondary to a pitui-
tary adenoma who also presented with multi-
ENaC
cystic lesions in the lungs and kidneys.33 This
α
infant had elevated serum cortisol levels and β γ
nonsuppressed adrenocorticotropic hormone α Lumen
levels and increased urinary steroids. The lung
cysts were surgically removed and diagnosed
as congenital benign lung cysts.34 This multi- Interstitium
cystic lung disease could simply be a coin-
Figure 8-1. Schematic illustration showing the localiza-
cidental finding because no other similar tion of epithelial Naþ channels (ENaCs) in the collecting
presentations have been described. duct of the kidney.
syndrome arises from abnormalities in the with frequent episodes of cough and lung
activity of ENaC. This channel is involved in crackles, who had a forced expiratory volume
the apical exchange of Naþ and movement in 1 second of 91% predicted; an 8-year-old
of water across mucosal surfaces, such as girl with recurrent lower respiratory tract
the airway surface.36 The state of hyper- infections and left lower lobe pneumonia,
reninism and hyperaldosteronism in patients but normal pulmonary function; and twin
with systemic PHA type 1 is the result of sus- 4-month-old boys with recurrent episodes
tained extracellular fluid volume depletion of lower respiratory tract infection and
and is not due to peripheral resistance to wheezing. These patients had sweat chloride
mineralocorticoids. values ranging from 70 to 132. The authors
noted that up to 4 years of age, respiratory
Epithelial Naþ Channel Mutations infections usually occurred at times of dehy-
Schaedel and associates37 looked for ENaC dration. Later in life, the patients’ main
mutations in four patients with PHA type 1 symptoms were moderately severe cough,
and negative cystic fibrosis transmembrane wheezing, and crackles.
regulator (CFTR) gene analyses: a 2-year-old Marthinsen and coworkers40 described a
girl with recurrent bronchopneumonia; an 8- 6-year-old boy with PHA type 1. He had a
year-old boy with frequent pneumonia colo- sweat chloride value of 110, and a history
nized with Pseudomonas aeruginosa, normal of recurrent bronchopneumonia associated
pulmonary function tests, and a normal rest- with dehydration. Since 18 months of age,
ing nasal potential difference; his deceased sputum cultures were positive for P. aerugi-
7-week-old brother; and a 9-year-old boy with nosa. A computed tomography scan of his
recurrent bronchopneumonia. All four pa- chest showed no evidence of bronchiectasis,
tients had mutations of the ENaC a subunit and his pulmonary function tests were nor-
(1449delC, 729delA, C1685!T). The authors mal. He was treated with chest physiother-
suggested that an increase in the Naþ concen- apy and inhaled antibiotics. MacLaughlin41
tration in the airway surface liquid probably noted the similarities between CF and PHA
promotes the growth of P. aeruginosa and type 1, in terms of pulmonary bacterial
reduces its killing, leading to P. aeruginosa lung infection and sweat chloride concentration.
disease. Lung involvement in patients with Clinically, PHA type 1 can be indistinguish-
PHA type 1 seems to be related to mutations able from CF, unless serum aldosterone,
in the a subunit of ENaC, at least based on cur- plasma renin activity, and urinary electrolytes
rent evidence. Lung disease seems milder than are measured, and genetic studies are per-
in CF, however, with no reports of bronchiec- formed to rule out the presence of CFTR muta-
tasis in patients to date. tions.36 These similarities are highlighted by
The clinical syndrome consists of urinary the interaction of CFTR and ENaC. One of
salt wasting, hyperkalemia, and metabolic the physiologic functions of CFTR is to inhibit
acidosis associated with elevated plasma the ENaC.101 If CFTR is absent or expressed in
renin activity and aldosterone levels. These reduced quantity, luminal Naþ absorption
manifestations can be present in the neona- through ENaC is enhanced (Fig. 8-2).
tal period and lead to death from severe Naþ absorption is osmotically drawing water
dehydration and electrolyte imbalance. Fail- from the airway surface liquid, contributing
ure of lung fluid reabsorption at birth has to depletion of airway surface liquid. Naþ
been associated with neonatal respiratory hyperabsorption could be an important factor
distress syndrome in patients with PHA type in CF pathophysiology because mice overex-
1 and related to ENaC, which is involved in pressing the b subunit of ENaC do exhibit
this process.38 Additional clinical character- signs of CF lung disease, such as mucous
istics beyond the neonatal period include plugging and neutrophilic inflammation.102
persistent clear nasal discharge, frequent An alternative approach to CFTR phar-
lower respiratory infections associated with macotherapy would be to inhibit the
wheezing and crackles, and failure to thrive. enhanced Naþ absorption through ENaC.
Hanukoglu and colleagues39 reported four In the nasal mucosa, the defect in Naþ
patients with PHA type 1: an 8-year-old girl reabsorption can be shown by the absence
CYSTIC FIBROSIS addition, airway colonization with pathogens

SYSTEMIC PSEUDOHYPOALDOSTERONISM TYPE I is not as problematic as in patients with CF,
ENaC CFTR which may explain the more benign course
Na+ Cl− of their pulmonary disease.
Lumen At present, treatment of these patients is
quite similar to the treatment of CF patients.
TM1 TM2 Further research, looking particularly into
Interstitium the electrolyte composition of the airway sur-
NBD1 NBD2 face liquid in CF patients, is needed to deter-
mine whether airway colonization with
R P. aeruginosa in these two conditions is related
to common abnormalities in the electrolyte
Figure 8-2. Cystic fibrosis and systemic pseudohypoal- composition of the airway surface liquid or
dosteronism type 1. Interaction of CFTR and epithelial other host-related abnormalities in these
Naþ channel (ENaC). two conditions. Whether patients with PHA
type 1 and P. aeruginosa lung disease have
of amiloride-sensitive Naþ transport during mucoid Pseudomonas, and whether conver-
nasal transepithelial potential difference sion to mucoid also is related to host and
measurements (Fig. 8-3). environmental factors is unknown.
The pulmonary phenotype seems to be
related to the absent or severely reduced Naþ
transport in airway epithelia, with failure to Hypothyroidism
reabsorb fluid from the airway surface and
presence of watery secretions.42 Despite fre- Many of the manifestations of hypothy-
quent respiratory manifestations with respira- roidism are a consequence of the hypo-
tory exacerbations, patients with PHA type 1 metabolic state and accumulation of matrix
do not experience the destructive process that glycosaminoglycans (myxedema) that are
patients with CF manifest as they age. In induced by the lack of thyroid hormone.
Cl− Cl−
Na+Cl− Cl− Cl− Cl−
Normal
Cl−
Na+ Cl−
CF
Cl− Cl−
Cl− Cl− Cl− Cl−
PHA
0
CF
−20
mv
PHA
Normal
Figure 8-3. Nasal potential difference −45
(PD) in a patient with cystic fibrosis (CF),
a patient with pseudohypoaldosteronism
(PHA), and a normal subject, illustrating Amiloride
the response to perfusion with amiloride, Low Cl− solution
followed by the addition of chloride-free Isoproterenol
solution and then isoproterenol.
The hypometabolic state is primarily mani- hypothyroidism. The nature of these effu-
fested by weakness, fatigue, cold intolerance, sions (transudate or exudate) and their
constipation, weight gain, abnormalities in causes is controversial. Changes in capillary
muscle tone, and bradycardia. Myxedema permeability in the hypothyroid patient
leads to coarseness and induration of the skin, may be related to the development of pleu-
puffy facies, enlargement of the tongue, and ral effusions, however.
hoarseness. Specifically, from a respiratory The prevalence of hypothyroidism is high
perspective, respiratory muscle weakness among patients with idiopathic pulmonary
manifests as hypoventilation with shortness arterial hypertension, although hypothy-
of breath and decreased exercise capacity,43-45 roidism is not currently believed to be a risk
although the presence of cardiovascular dis- factor for the condition.51 The basis of the
ease also could play a role. Abnormal ventila- observed association of the two disorders is
tory responses to hypoxia and hypercapnia unclear.
can be shown in these patients as well, with Hypothyroidism can cause abnormally
the reduction in the ventilatory response to high sweat electrolyte levels.52 The presence
hypoxia being more pronounced.46,47 Thy- of elevated sweat electrolyte levels may lead
roid hormone replacement therapy restores to the misdiagnosis of CF during the evalua-
the normal response to hypoxia promptly, tion of children with chronic illness.53-55
whereas the hypercapnic drive is slower to The elevated chloride concentrations return
return to normal.44,47 The reason for the to normal with the start of replacement
impairment of ventilatory responses in some therapy.55 The abnormality in the ability of
hypothyroid patients is unknown, but may the sweat gland to secrete normal sweat is
be related to the decrease in oxygen consump- believed to be due to infiltration of the
tion associated with hypothyroidism. secretory coil with granular material.56,57
Muscle weakness, impaired ventilatory
responses, and potential upper airway ob-
struction determine the conditions for the Hyperthyroidism
development of significant sleep-disordered
breathing. Multiple studies have shown the The hyperthyroid state does not affect the
presence of sleep apnea with central or lung directly, but the increase in metabolism
obstructive components. The obstructive and the development of a hyperthyroid
form seems to be more common in these myopathy can affect lung function and car-
patients. OSA may be caused by an enlarged diopulmonary performance. The hypermeta-
tongue or reduced oropharynx owing to bolic state induced by hyperthyroidism
mucopolysaccharide and protein deposition increases the basal metabolic rate and has an
or by a myopathy involving the muscles of associated increase in oxygen consumption
the upper airway. Overweight seems to com- and carbon dioxide production.58 Hyperthy-
pound this problem.48 Based on these find- roid patients are typically dyspneic, and show
ings, it has been proposed that screening significantly lower resting arterial PCO2 and
for hypothyroidism should be considered tidal volume with increased ventilatory
during the evaluation of patients with sleep- responses to carbon dioxide and hypoxia.59
disordered breathing.49 In the absence of clin- With exercise, even correcting for carbon
ical manifestations of hypothyroidism (i.e., dioxide consumption, further increases in
subclinical hypothyroidism), the prevalence ventilatory responses are noted, which are
of sleep disorders is no different from euthy- believed to be secondary to an increased cen-
roid patients, and this needs to be taken into tral drive and can be blocked by b-blockers.60
consideration to avoid unnecessary testing. A smaller increment in heart rate between rest
The sleep-disordered breathing is reversible and anaerobic threshold, a reduced oxygen
with the institution of appropriate therapy,50 consumption at anaerobic threshold, and a
although the obstructive component may reduced oxygen pulse at anaerobic threshold
take some time to revert completely.48 also have been reported.61,62
Bilateral and unilateral pleural effusions A small study in children with untreated
have been reported in association with hyperthyroidism found no significant
differences at rest compared with a control

group in oxygen uptake, minute ventilation,
or respiratory rate. During exercise, there were
significant differences, however, in oxygen
uptake, heart rate, minute ventilation, and
respiratory rate.63 Patients with thyrotoxicosis
also have an increased resting reflex hypoxic
drive to respiration.64 These findings suggest
an inappropriate increase in respiratory drive,
possibly secondary to increased adrenergic
stimulation.60
Abnormalities in lung function also have Figure 8-4. Twin boys with neonatal hyperthyroidism
been reported in hyperthyroid patients, but confirmed by abnormal thyroid function tests. Clinical fea-
tures include lack of subcutaneous tissue owing to a
a lack of correlation between the severity hypermetabolic state and a wide-eyed, anxious stare.
of dyspnea and abnormalities in lung func- They were given the diagnosis of neonatal Graves disease,
tion suggests that the dyspnea is probably but their mother did not have Graves disease; they had
persistent, not transient, hyperthyroidism. At age 8 years,
due to extrapulmonary causes.65,66 The they were treated with radioiodine. They are now
development of myopathy in the hyperthy- believed to have had some other form of neonatal hyper-
roid state is known also to affect the respira- thyroidism, such as a constitutive activation of the
thyroid-stimulating hormone receptor. (From Kliegman
tory muscles. This muscle weakness, in RM, et al: Nelson Textbook of Pediatrics, 18th ed. Philadel-
addition to the above-noted abnormalities, phia, Saunders, 2007.)
leads to an impaired exercise capacity and
increases in breathing effort.67 In patients
with thyrotoxicosis, a linear relationship
has been shown between respiratory forces consequent respiratory distress.75 Thyromega-
(maximum inspiratory pressure, maximum ly is almost always present and sometimes
expiratory pressure) and levels of thyroid may cause tracheal compression and added
hormones (triiodothyronine, thyroxine). In respiratory distress.76 Persistent pulmonary
thyrotoxicosis, respiratory muscle weakness hypertension of the newborn with the
affects inspiratory and expiratory muscles characteristic severe respiratory failure also
and contributes to the dyspnea and exercise has been reported in these infants.77-79 It
abnormalities noted in these patients.65,68-70 has been postulated that thyrotoxicosis
Most of these abnormalities are reversible has effects on pulmonary vascular matura-
with therapy, although the pattern of breath- tion and the metabolism of endogenous
ing may not return to normal immediately.71 pulmonary vasodilators, contributing to
Although animal studies suggested an effect the development of persistent pulmonary
of thyroid hormone on bronchial smooth hypertension of the newborn.80
muscle tone and contractility,72 hyperthyroid- It also is recognized that some patients
ism might protect against carbachol-induced with hyperthyroidism may present with var-
bronchospasm.73 In a study with normal iable degrees of pulmonary hypertension
volunteers with induced hyperthyroidism by and isolated right heart failure.80 This is
administration of exogenous triiodothyronine reversible when the appropriate therapy for
for 3 weeks, no effect on airway reactivity or the hyperthyroid state is established.81,82
lung function was noted.74 The presence of elevated pulmonary pres-
Neonatal Graves disease must be consid- sures in otherwise asymptomatic hyperthy-
ered in any infant born to a woman with a roid patients also has been reported and is
history of Graves disease. Affected infants reversible after restoration to a euthyroid
are often preterm or low birth weight, state.83 Proposed mechanisms include high
appear anxious, and are restless and irritable cardiac output–induced endothelial injury,
(Fig. 8-4). They may be febrile, and often the increased metabolism of intrinsic pulmo-
skin is flushed and warm. Tachycardia is a nary vasodilating substances resulting in
consistent finding and may be accompanied elevated pulmonary vascular resistance,
by cardiomegaly and heart failure, with and autoimmune phenomenon.84
Hypoparathyroidism granulosa cell tumors, Sertoli-Leydig cell

tumors, and choriocarcinoma. Ovarian carci-
Hypoparathyroidism is an inherited or noma may manifest with pleural effusions.
acquired deficiency of the parathyroid hor- In addition, patients with benign ovarian
mone or its action. Parathyroid hormone tumors may present with unilateral pleural
secretion by the parathyroid glands (prime effusion (more often right-sided), although
regulators of serum calcium concentration) bilateral pleural effusions also may occur as
maintains serum calcium within a strict part of the Meigs syndrome. Rarely, endome-
range. Biochemical hallmarks of parathyroid triosis tissue can deposit in the pleural space.
hormone insufficiency are hypocalcemia During menstruation, this problem may lead
and hyperphosphatemia. Complications of to recurrent pneumothorax (catamenial
hypoparathyroidism are largely due to pneumothorax) usually on the right side.
hypocalcemia. Laryngospasm, a form of tet-
any, can lead to stridor and significant air-
way obstruction and prolongation of the Obesity-Hypoventilation Syndrome
Q-Tc interval. Hypocalcemia also leads to and Respiratory Complications
neuromuscular irritability. Affected patients of Obesity
may experience paresthesias, muscle cramp-
ing, tetany, or seizures.85 Obesity in children is a complex disorder. Its
Newborns may present with hypoparathy- prevalence has increased so significantly in
roidism, but it can manifest in individuals of recent years that many consider it a major
almost any age. Typically, patients with health concern of the developed world. In
DiGeorge syndrome present during the first the United States, 20% to 27% of all chil-
few weeks of life. DiGeorge syndrome, which dren and adolescents have obesity. Many
is one manifestation of the 22q11 deletion factors, including genetics, environment,
syndrome, is associated with recurrent infec- metabolism, lifestyle, and eating habits, are
tions related to T cell abnormalities and cono- believed to play a role in the development
truncal defects, such as tetralogy of Fallot and of obesity.86 Obesity-hypoventilation syn-
truncus arteriosus. Affected individuals also drome is an uncommon finding in children
may have a history of speech delay from velo- with obesity, with an estimated frequency of
pharyngeal insufficiency. Patients with auto- 1% to 3%. Stated from a different point of
immune and parathyroid hormone view, 10% of patients with OSA are obese.
resistance syndromes tend to present in ado- No firm diagnostic criteria to define obesity-
lescence. Transient hypoparathyroidism is hypoventilation syndrome exist; this fact,
common during the first few days of life in limited pediatric studies, and discrepant defini-
preterm infants, infants of mothers with dia- tions of obesity and abnormal pediatric
betes mellitus, infants of mothers with polysomnographic findings make the litera-
hypercalcemia, and infants with prolonged ture difficult. Obesity, sleep-disordered
delay in parathyroid gland responsiveness. breathing, and hypercarbia during wakefulness
Hypocalcemia that produces symptoms, are features generally described with obesity-
such as seizure, tetany, and laryngospasm, hypoventilation syndrome. Other features
requires intravenous calcium and continu- include excessive daytime sleepiness, hyperac-
ous monitoring for cardiac arrhythmias. tivity, poor school performance with difficulty
Oral calcium and vitamin D are initiated as attending to tasks and impaired memory,
soon as possible (e.g., when the patient is hypoxia, and signs of cor pulmonale.
tolerating oral feeds). In adults, male sex and obesity are common
risk factors for OSA. Witnessed apnea, loud
Disorders of the Reproductive disruptive snoring, and daytime sleepiness
System are frequent presenting complaints. In chil-
dren, neither these risk factors nor the symp-
Disorders of the reproductive system rarely tom profile is as predictive for OSA except in
manifest with respiratory abnormalities. Pul- children with obesity. Twenty-seven percent
monary metastases are known to occur with of children with OSA have failure to thrive.
In one study, daytime sleepiness occurred is only 30% to 50% compared with the over-
with the same overall frequency as in control night polysomnogram. Symptoms during
subjects; in another study, daytime sleepiness sleep89 include enuresis (this symptom alone
was found to be more frequent in obese chil- has a predictive value for OSA of 46%) and
dren with OSA. Mental retardation also has snoring intensity greater than 30 dB (this
been associated with obesity-hypoventilation symptom has a predictive value for OSA of
syndrome. 60%). Characteristically, snoring tends to
The exact mechanism for development worsen during flare-ups of nasal allergies and
of obesity-hypoventilation syndrome is during upper respiratory infections. Approxi-
unknown; however, it is believed to be related mately 10% of children who snore have signif-
primarily to abnormalities in ventilatory drive icant sleeping and breathing problems. Other
and response to hypoxia and hypercarbia, significant symptoms include restless sleep;
rather than the mechanical factors related to parasomnias, especially nightmares and sleep
excessive body weight.87 Other authors walking; witnessed apneas; irregular breathing
believe that body weight and, more impor- patterns in sleep; sweating at night; and
tantly, the distribution of body fat, hormones, sleeping with head extended.
and upper airway size and dynamics play During wakefulness, symptoms may
important roles. include chronic mouth breathing and day-
Associated upper airway obstruction is time sleepiness (this symptom occurs much
important in the occurrence of OSA/hypoven- less frequently in children with OSA than
tilation or hypopnea because OSA/hypoventi- in their adult counterparts except in the
lation or hypopnea is observed more case of children with obesity). Other impor-
frequently when the two conditions occur tant manifestations89 include hyperactivity
together compared with the simultaneous (younger children are more likely to show
presentation of OSA/hypoventilation or symptoms of sleep deprivation than excessive
hypopnea and simple obesity.88 Other factors daytime sleepiness), morning headaches,
that may play a role in the development of air- cardiac rhythm disturbances, systemic or
way obstruction during sleep include rapid pulmonary hypertension (or both), poor
eye movement (REM) atonia, increased soft school performance, poor memory, and poor
tissue and fatty infiltration around the neck, concentration.
decreased chest wall compliance, and Sleep apnea and daytime sleepiness can be
decreased lung volumes (especially in the aggravated by the use of alcohol, sedating
supine position) secondary to the upward dis- antihistamines, central nervous system
placement of the diaphragm caused by depressants, and some over-the-counter cold
increased abdominal fat.88 In children, tonsil- preparations. Increased incidence of hyperre-
lar hypertrophy added to obesity seems to be active airways (i.e., asthma) is observed in
more predictive of abnormal polysomno- children with obesity (30%). Decreased exer-
graphic findings. cise tolerance also is observed in children
Higher rates of morbidity and mortality with obesity.
are associated with childhood obesity. Pulmonary function studies may reveal a
Pulmonary consequences observed in chil- flow-volume loop with a saw-tooth pattern
dren and adolescents include an increased associated with upper airway obstruction.
frequency of reactive airway disease, poor Most children (58%) in the study by Mal-
exercise tolerance, increased work of lory and colleagues90 had abnormal pulmo-
breathing, and increased oxygen consump- nary function studies, primarily obstructive
tion. The few individuals who develop obe- in nature. The data by Fung and associates91
sity-hypoventilation syndrome experience showed significant changes in forced vital
right-sided heart failure with right ventric- capacity of overweight boys but not girls.
ular hypertrophy. These data are consistent with the finding
Although pediatricians have long valued a that fat distribution in overweight and
good history and physical examination, stud- obese adolescents differs from that of
ies have indicated that the predictive value of adults and is gender-specific. Boys tend to
the recorded history and physical examination accumulate fat in the abdominal area,
whereas girls tend to accumulate fat in the children, nasal continuous positive airway
subscapular area. pressure ventilation has been performed.
Maximum voluntary ventilation may be Surgical treatment includes tonsillectomy,
decreased. As mentioned, patterns of fat dis- adenoidectomy, or adenotonsillectomy (may
tribution differ in overweight and obese be successful even when weight loss alone
adolescent boys and girls. Because of the does not produce satisfactory resolution of
impact of the abdominal fat on the dia- symptoms). Other considerations include tra-
phragm, the expiratory reserve volume is cheostomy, uvulopalatopharyngoplasty, and
decreased, and consequently the forced vital mandibular advancement surgery. In children
capacity is decreased. Adult studies show the with apnea, there is an increased risk of post-
expiratory reserve volume to be decreased operative complications after relief of upper
severely with extreme and morbid obesity. airway obstruction when the patient history
Biring and coworkers92 found expiratory includes young age (<2 to 3 years old), morbid
reserve volume to be the most sensitive obesity, hypotonia, cor pulmonale, or severe
indicator of obesity. Many reasons have OSA. In such patients, one should strongly
been offered in addition to the mass effect consider cardiorespiratory monitoring in a
on the position of the diaphragm. These pediatric recovery or special care unit. Postop-
include decreased diaphragmatic mobility, erative pulmonary edema may be observed.
decreased respiratory compliance, decreased Prader-Willi syndrome is a specific condi-
respiratory muscle strength, and fatty infil- tion resulting from either paternal deletion
tration of the respiratory muscles. of 15q11-13 or maternal disomy for chromo-
Inselman and colleagues93 reported chil- some 15. It is characterized by neonatal hypo-
dren with decreased diffusing capacity for tonia, early childhood obesity, characteristic
carbon monoxide and normal inspiratory facial appearance, mental deficiency, hypogo-
and expiratory pressures. By contrast, Bir- nadism, short stature, and behavioral disor-
ing’s group,92 in subjects 13 to 78 years ders with increased appetite. Restrictive
old, showed the diffusing capacity for car- ventilatory impairment resulting primarily
bon monoxide and diffusing capacity for from respiratory muscle weakness has been
carbon monoxide/alveolar volume ratio to reported. REM sleep-related oxygen desatura-
be normal except in subjects with extreme tions with or without apneas are common
obesity. Airway resistance may be increased. sometimes with hypercapnia. Typical obe-
In the case of children and adolescents, sity-hypoventilation syndrome also has been
overnight polysomnogram shows morbid reported. Hypothalamic dysfunction is proba-
obesity can be associated with hypoventila- bly partly responsible for the sleep abnormal-
tion, hypoxia, and hypercarbia during sleep. ities observed in this syndrome.
Others may present with evidence of OSA.
The multiple sleep latency test can be use- Obesity and Asthma Interactions
ful in the evaluation of patients complain- The relationships, interactions, and associa-
ing of excessive daytime sleepiness. The tion between obesity and asthma are com-
multiple sleep latency test is performed on plex, and active sources of hypotheses and
the day after the overnight polysomnogram. research. An association between obesity
Its findings can be used to assess pathologic and asthma incidence or asthma severity or
sleepiness and contribute to a diagnosis of both has been reported in many studies,
narcolepsy. Cardiac dysrhythmias and right although there is still considerable discus-
bundle branch block have been reported. sion about the existence of the association
Weight loss is recommended, but often is and its meaning.94 Being overweight has
difficult to achieve and sustain. In addition, been associated with an increased risk of
although weight loss remains a cornerstone new-onset asthma in boys and nonallergic
to the treatment of obesity, it may not children.95 Asthma is a risk for obesity in
always improve the symptoms of OSA/ urban minority children and adolescents.96
hypoventilation or hypopnea. Progesterone, In an extensive review of the association
theophylline, protriptyline, and buspirone between asthma and obesity, Tantisra and
have been used in limited studies. In some Weiss97 described potential and causal
relationships that rely on genetics, im- an obese individual, which produces lower
mune system modulation, and mechanical than normal functional residual capacity.
mechanisms. Based on current evidence, Dynamic factors include the tidal action of
they reported the following: spontaneous breathing imposing tidal
1. Obesity has been associated with strains on airway smooth muscle. An obese
increases in the incidence and prevalence individual breathes at higher frequencies
of asthma in several epidemiologic stud- but smaller tidal volumes compared with a
ies in children. lean individual, resulting in a compromise
2. Weight loss in obese subjects results in in the bronchodilating mechanism and pre-
improvement in the overall pulmonary disposing to increased airway reactivity com-
function and asthma symptoms and pared with a lean subject (Fig. 8-5).
decreases in asthma medication usage. The second possibility is related to differ-
3. Obesity may directly affect the asthma ences in anatomy of the lungs and airways.
phenotype by mechanical effects, includ- In children, the mechanical load of obesity
ing airway reactivity; cytokine modula- might affect lung growth. Obesity also
tion via adipose tissue; common genes might lead to more accelerated airway re-
or genetic regions; or sex-specific effects, modeling with each asthma exacerbation.
including the hormone estrogen. The third possibility for the relationship
4. Obesity also may be related to asthma by of obesity to airway hyperreactivity is the
genetic interactions with environmental inflammatory microenvironment.99 White
exposures, including physical activity adipose tissue, which represents most adi-
and diet. pose tissue in humans, is no longer consid-
In a review of obesity, smooth muscle, and ered an inert tissue devoted to energy
airway hyperreactivity, Shore and Fredberg98 storage, but is emerging as an active partici-
suggested three possibilities that relate obe- pant in regulating physiologic and patho-
sity to airway hyperreactivity. The first possi- logic processes, including immunity and
bility consists of simple mechanical static inflammation. Adipose tissue is now consid-
and dynamic factors. Static factors include ered the largest endocrine organ in the
increased abdominal and chest wall mass in human body.
PRESSURE-VOLUME CURVES IN NORMAL AND OBESE SUBJECTS
Normal Obese
Chest wall
Respiratory system
Lung
1.0 1.0
Lung volume Lung volume
(% total lung (% total lung
capacity) 0.8 capacity) 0.8
Functional
residual capacity
0.6
Change in functional
Expiratory residual capacity
0.4 reserve Expiratory
volume reserve
0.2 0.2 Functional volume
Residual Residual residual capacity
volume volume
220 210 0 10 20 30 40 220 210 0 10 20 30 40

Recoil pressure (cm H2O) Recoil pressure (cm H2O)
Figure 8-5. Lung, chest wall, and respiratory system pressure-volume curves in normal and obese subjects. Note the
effect of the rightward shift in the chest wall curve on the respiratory system pressure-volume curve and on the functional
residual capacity and the expiratory reserve volume (as the residual volume is unchanged). (From Albert RK, Spiro SG, Jett
JR: Clinical Respiratory Medicine, 2nd ed. Philadelphia, Mosby, 2004.)
Exercise Fitness in Overweight Children reduction in the central respiratory drive,

and Adolescents upper airway obstruction, or associated restric-
A more recent study100 reported that over- tive pulmonary function from pleural effu-
weight and nonoverweight adolescents had sions or intrinsic decrease in lung volumes.
similar absolute oxygen consumption at Hyperthyroidism can have dyspnea as a
the lactate threshold and at maximal exer- major clinical manifestation because of the
tion, suggesting that overweight adolescents increase in central respiratory drive associated
are more limited by the increased cardiores- with the hypermetabolic state. High-output
piratory effort required to move their larger cardiac failure associated with hyperthyroid-
body mass through space than by cardiores- ism can lead to pulmonary edema in some
piratory deconditioning. The higher percent- patients.
age of oxygen consumed during submaximal Hypoparathyroidism may occur associated
exercise indicates that overweight adolescents with hypocalcemia, acute tetany, laryngeal
are burdened by the metabolic cost of their stridor, and muscle weakness.
excess mass. Their greater oxygen demand Benign and malignant ovarian tumors
during an unloaded task predicted poorer per- may manifest with unilateral or bilateral
formance during sustained exercise. pleural effusions.
A large part of the exercise intolerance The interplay between asthma and obesity
observed in overweight adolescents seems is clear, but the association between asthma
to be related to the increased metabolic and obesity is less clear regarding cause and
demands of moving excess mass. Cardiac effect. The increasing prevalence of both
constraints also may play a role and warrant conditions and the significant morbidity
closer, more detailed evaluation. The clinical and mortality from both make it imperative
implication of understanding how increased that practitioners stress the importance of
load from excess body mass affects exercise weight management in children and adoles-
tolerance is important for exercise prescrip- cents with and without asthma. Sustained
tions for overweight adolescents. Exercise weight loss is difficult. In children with obe-
prescriptions may require careful planning sity, exercise tolerance also may be limited.
to decrease overall body mass in addition
to targeting cardiorespiratory conditioning.
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CHAPTER 9
of Neuromuscular Diseases
JOHN R. BACH
Physiology 184 Physical Medicine Respiratory Muscle

Assessment of Respiratory Muscle Aids 194
Function 185 Goal One—Maintenance of Lung and Chest
Clinical Evaluation 185 Wall Mobility 194
Laboratory Evaluation 186 Goal Two—Maintain Normal Alveolar
Clinical Manifestations of Respiratory Ventilation 195
Muscle Fatigue 187 Goal Three—Facilitate Airway Clearance 196
Neurologic versus Muscular Disease 188 Mechanical Insufflation-Exsufflation 197
Clinical Entities 188 Extubation and Decannulation 197
Sleep Evaluation in Neuromuscular Glossopharyngeal Breathing 198
Diseases 193 Perioperative Management 198
Cardiac Involvement 194 Outcomes 198
Management 194 End-of-Life Care 199
References 199
Children with neuromuscular disorders have and concludes with a discussion of the pre-
primarily ventilation rather than oxygena- vention of respiratory failure caused by neu-
tion impairment as a result of inspiratory romuscular disease.
muscle insufficiency. When the respiratory
muscles are not assisted, this leads to hyper-
capnic ventilatory failure or acute respiratory Physiology
failure mostly owing to ineffective cough
during otherwise benign upper respiratory The three basic components of the respira-
tract infections. Most patients with Du- tory control system are as follows: (1) sensors,
chenne muscular dystrophy (DMD), infan- which gather afferent information and feed it
tile spinal muscular atrophy (SMA), and to (2) a central controller in the brain, which
other pediatric neuromuscular diseases die processes afferent information and sends
prematurely because of failure to use respira- efferent impulses to the (3) effectors (respira-
tory muscle aids. In large part for this reason, tory muscles), which cause ventilation or
respiratory failure continues to be the most cough.1
common cause of death for children with The afferent information for ventilation
severe myopathies, anterior horn cell disor- comes from central chemoreceptors located
ders, and high-level spinal cord injury. The in the medulla, carotid and aortic bodies,
use of inspiratory and expiratory muscle aids and stretch receptors in the lungs. The brain-
can prevent or reverse ventilatory failure, stem is the primary center for the central con-
preserve quality of life, and prolong survival trol of respiratory muscle activity. This
for most of these patients. This chapter control occurs at a subconscious level. The
briefly reviews clinical physiology, presents cortex can temporarily override the auto-
a diagnostic approach to these diseases, matic nature of this mechanism if voluntary
describes some common clinical entities, control is desired.
184
Chapter 9—Pulmonary Manifestations of Neuromuscular Diseases 185
For the central commands controlling respi- quiet breathing. The lungs and chest wall are
ration to operate the ventilatory mechanism, elastic and tend to return to their equilibrium
the motor units of the respiratory muscles also positions after being actively expanded during
must be functioning properly. A motor unit inspiration. The abdominal muscles are not
consists of an anterior horn cell, its peripheral used during quiet expiration to functional
nerve axon, the neuromuscular junction, and residual capacity. These muscles are contracted
the muscle fibers it innervates. Normally, during forceful exhalation that deflates lungs
when an anterior horn cell fires, the peripheral to residual volume.
nerve causes the release of acetylcholine at the
terminal axon. Acetylcholine diffuses across
the neuromuscular junction, where it binds
to receptors on the postjunctional membrane Assessment of Respiratory
and opens channels for the passage of calcium Muscle Function
and sodium ions. The ion influx depolarizes
the muscle membrane, which triggers contrac- Clinical Evaluation
tion of the myofibrils. Neuromuscular diseases
are caused by disorders of the anterior horn Clinical and laboratory evaluation of the chest
cells, peripheral motor nerves, myoneural wall can provide essential information with
junction, and muscle fibers. regard to chest wall function in a particular
The muscles of respiration include four patient (Table 9-1). The chest wall configura-
groups: the diaphragm, the chest wall mus- tion and pattern of spontaneous breathing,
cles, the abdominal muscles, and the muscles
of the upper airway (bulbar-innervated). The
diaphragm is the principal muscle of inspira- Guidelines for Assessment of
Table 9-1 Respiratory Muscle Function
tion. The phrenic nerves from cervical seg-
ments 3, 4, and 5 supply it. The chest wall
Clinical Evaluation
muscles consist of the internal and external
□ Chest wall configuration (e.g., scoliosis,
intercostals (T1-T12); the parasternal intercos- overdistention)
tals (T1-T12); the scalenes (C4-C8); and the □ Pattern of spontaneous breathing:
accessory inspiratory muscles, including the ○ Rate and amplitude of breathing
sternocleidomastoids (cranial nerve XI, C1- ○ Thoracic and/or abdominal breathing
C2), trapezoids (cranial nerve XI, C2-C3), ○ Coordination or paradoxic thoracic and
and pectoralis major (C5-C7). The abdominal abdominal expansion
respiratory muscles include the rectus and □ Specific maneuvers:
transverse abdominis and the external and ○ Maximal variation in thoracic circumference
internal obliques (T7-L1). They are the most ○ Maximal excursion of diaphragm (inspection
important muscles of expiration. and percussion)
The muscles of the upper airway include the ○ Cough maneuver–feeble or strong then
objective assessment?
muscles of the mouth (cranial nerves IX and
Laboratory Evaluation
X), uvula and palate (XI), tongue (IX and
□ Electromyographic studies of various respiratory
XII), and larynx (C1). Although these muscles muscles
do not have a direct action on the chest, they □ Roentgenograms (in supine position):
are essential for keeping the upper airway ○ Cinefluoroscopic studies of diaphragmatic and
patent, and they affect airway resistance and rib cage movements
airflow. ○ Plain roentgenograms in full expiration and
During normal respiration, the most impor- inspiration
tant muscles for breathing in addition to the □ Real-time ultrasonography
diaphragm are the parasternal intercostals. □ Pulmonary function tests:
Postural muscles such as the external and ○ Flows: assisted and unassisted peak cough flows
(PCF)
internal intercostals and the accessory muscles
○ Lung volumes
such as scalenes and sternocleidomastoids
○ Coordination of breathing (respiratory
affect breathing significantly only at high rates inductance plethysmography)
of ventilation. Expiration is passive during
including rate and amplitude of breathing, neuromuscular conditions have paradoxical

thoracic or abdominal breathing, coordinated breathing with a seesaw type of thoracoab-
or paradoxical thoracic and abdominal expan- dominal motion owing to severe intercostal
sion, maximal variation in chest circum- muscle weakness. This is true for all children
ference, maximal diaphragmatic excursion with SMA type 1 and about 40% with SMA
during inspiration, and cough effectiveness, type 2 and for many with severe congenital
are evaluated. myopathies and muscular dystrophy.
Careful bedside observation of an at-risk Respiratory rate is important to monitor. As
patient usually allows the recognition of clin- the work of breathing increases, the patient
ical signs and symptoms indicating progres- may opt to use less force per breath, reducing
sive respiratory muscle fatigue. These signs tidal volume with shallow breaths and com-
and symptoms include loss of nonbreathing pensating by taking more breaths per minute
functions of the respiratory system, increased to avoid fatigue. A very rapid breathing rate
respiratory rate, and pattern of breathing, cannot be sustained indefinitely, however,
and other warning signs (Table 9-2). and can lead to respiratory muscle exhaus-
For an infant and small child, inspection is tion. The pattern and regularity of breathing
the most important, and usually the only, eval- also are helpful to observe for risk of fatigue.
uation tool that is necessary. The normal Breathing that becomes increasingly more
movement of chest and abdominal wall is rapid and shallow and is interrupted by a deep
directed outward during inspiration. Inward breath with a brief pause to rest the muscles
motion of the chest wall during inspiration is can be a sign of fatigue for certain patients
called “paradoxical breathing.” This motion is with central nervous system disorders. Al-
seen when the thoracic cage loses its stability though pauses are normal in healthy chil-
and becomes distorted by the action of the dren, they can signal respiratory distress, as
diaphragm. Most infants who present with does nasal flaring, nocturnal flushing, and
perspiration. Cyanotic spells or cyanosis with
brief cough or brief pause, sustained paradox-
Clinical Manifestations of ical thoracic/abdominal movement, drooling
Table 9-2 Respiratory Muscle Failure
in the absence of airway obstruction (cannot
Inability to Perform Nonventilatory Functions pause to swallow), and confusion also can be
Inability to eat/drink/cry signs of impending respiratory arrest.
Reluctance to pause breathing voluntarily
Major Use of Accessory Muscles
Sternocleidomastoids and pectoral muscles Laboratory Evaluation
Increase in Respiratory Rate to Critical Level
Adolescents 55 breaths/min Longitudinal evaluation of lung function
Children, 4-10 years 70-75 breaths/min should be obtained in patients older than 6
Infants, 1-3 years 90 breaths/min years of age. Measurements of lung function
Neonates 120 breaths/min include forced spirometry, static lung volumes,
Signs Reflecting Options Taken to Relieve Fatigue end-tidal carbon dioxide (CO2), and oximetry.
Reduced inspiratory time (TI) and decreased Pdi: Measuring maximal inspiratory and expiratory
very shallow breathing pressures at the mouth also can assess respira-
Deep breaths with a brief pause to rest the muscles tory muscle strength, whereas cough efficacy
Respiratory alternans can be evaluated by measuring peak cough
Signs Indicating Impending Respiratory Arrest flows (PCFs) using a simple peak flowmeter.
Cyanotic spell The forced vital capacity (FVC) should be
Cyanosis with brief cough or brief pause measured in the sitting position. If FVC is less
Inappropriate pause than 80%, it should be measured again in the
Sustained paradoxic thoracic/abdominal supine position to investigate for diaphragm
movement weakness.2 A greater than 20% decrease in
Drooling in absence of airway obstruction (cannot FVC when going from sitting to supine indi-
pause to swallow)
cates diaphragm weakness out of proportion
Central nervous system signs (confusion)
to chest wall muscle weakness. Although
FVC less than 60% indicates a low risk for noc- volumes of air consecutively delivered from a
turnal hypoventilation, FVC less than 40% or volume-cycled ventilator or manual resuscita-
diaphragm weakness indicates a significant tor. The MIC–vital capacity difference is a
risk for nocturnal hypoventilation. Continu- direct function of glottic integrity and an
ous overnight pulse oximetry and end-tidal objective measure of bulbar-innervated mus-
or transcutaneous CO2 should be obtained cle function. Unassisted PCFs are measured.
annually in children too young to perform Then the patient air stacks as deeply as possi-
the FVC maneuver or when FVC is less than ble, and an abdominal thrust is applied, timed
60%, or more often when FVC is less to the glottic opening of a cough effort.
than 40%. Other qualitative and quantitative mea-
Full overnight polysomnography should sures of respiratory muscle function can be
be obtained when overnight pulse oximetry obtained, although they are rarely needed
is not diagnostic in the presence of symp- (see Table 9-1). These include electromyo-
toms suggestive of hypoventilation or sleep- graphic studies of various respiratory muscles,
disordered breathing, and a trial of nocturnal chest radiographs in supine position, and real-
noninvasive ventilation (NIV) is clearly war- time ultrasonography.4 Chest radiographs are
ranted. Polysomnograms are programmed useful for diagnosing pneumonia and gross
to interpret all abnormalities as being due atelectasis, but they lag behind oximetry as
to central/obstructive apneas and not due to an indication of these problems (see later).
respiratory muscle weakness. For these Diaphragmatic strength also can be invasively
patients, this is similar to “blaming the brain assessed by measuring transdiaphragmatic
and throat for what the diaphragm cannot pressure5 and by using a manometer for mea-
do.” It too often results in patients being pre- suring maximum inspiratory and expiratory
scribed continuous positive airway pressure pressures at the mouth. The measurement of
or bilevel positive airway pressure (BiPAP) at maximum voluntary ventilation, when possi-
inappropriately low spans, rather than suffi- ble, can be helpful in determining respiratory
cient pressure or volume support to correct muscle endurance.6 The most important and
hypoventilation and rest inspiratory muscles practical measures continue to be spirometry
more fully. A nocturnal desaturation pattern, for FVC and MIC, peak flowmeter for unas-
often a smooth one, may indicate alveolar sisted and assisted PCFs, end-tidal CO2, and
hypoventilation. When the patient has a pulse oximetry. The last two also are useful
respiratory tract infection, a sudden noctur- for nocturnal monitoring because they relate
nal or diurnal severe desaturation usually to inspiratory muscle dysfunction.
indicates mucous plugging.
Arterial blood gases are not routinely needed
because of the adequacy of end-tidal CO2/ Clinical Manifestations of
transcutaneous CO2 measurement. Pulse Respiratory Muscle Fatigue
oximetry should be reserved for intensive care
management only. Acute respiratory muscle fatigue is character-
PCF also should be measured annually dur- ized by exhaustion leading within minutes
ing a steady state and at any episode of respi- or hours to respiratory failure. Chronic fatigue
ratory infection; values less than 160 to is not as easily identified. Symptoms of
200 L/min may indicate that cough is inef- chronic fatigue are often subtle, and the diag-
fective and may place patients at risk for nosis is frequently missed unless specifically
recurrent respiratory infections and respira- considered. Infants with severe neuromuscu-
tory failure. The assisted PCF–unassisted lar disorders often present with tachypnea,
PCF difference also is an excellent measure nocturnal flushing, profuse perspiration, and
of glottic integrity.3 frequent arousals. After 6 months of age, these
Spirometry is equally important for the infants develop otherwise benign respiratory
measurement of maximum insufflation tract infections that result in airway mucous
capacity (MIC). The MIC is the measure of plugging because of their ineffective cough.
the maximum volume of air that the glottis This mucous plugging causes decreases in
can hold in the lungs by “air stacking” oxyhemoglobin saturation (SaO2) to less than
95%, which, if not quickly reversed by effec- tomography, magnetic resonance imaging,
tive assisted coughing, results in pneumo- and myelography.
nia and respiratory failure with persistent The lower motor neuron system includes
hypoxemia. the anterior horn cell, the peripheral nerve,
In older children, symptoms and signs of the neuromuscular junction, and muscle.
chronic respiratory insufficiency include gen- Manifestations of lower motor neuron
eral fatigue and dyspnea on exertion. The first involvement include flaccidity, depressed
manifestations of chronic respiratory muscle reflexes, fasciculations, and muscle atrophy.
impairment often are symptoms of sleep Anterior horn cell diseases cause distal weak-
hypoventilation, however, either nocturnal ness without sensory symptoms, whereas dis-
(frequent nightmares, enuresis, perspiration, orders of peripheral nerves are almost always
frequent awakenings) or daytime symptoms accompanied by sensory loss secondary to
(morning headaches, hypersomnolence, chro- the involvement of sensory nerves, hypore-
nic fatigue, impaired concentration, dyspnea, flexia, and usually distal weakness. Peripheral
tachycardia, difficulty awakening in the morn- nerve weakness can result from damage to
ing, right ventricular failure, peripheral edema, either the core axon (axon neuropathies) or
irritability, polycythemia, impaired cognition, the myelin sheath that coats the nerve (demy-
anxiety, depression, weight changes, muscle elinating neuropathies). Disorders of the neu-
aches, memory impairment), and poor control romuscular junction are characterized by
of upper airway secretions and exacerbation of fluctuating weakness and frequently involve
swallowing difficulties.7 Often, because many the extraocular and bulbar-innervated mus-
of these patients are wheelchair-bound and cles. Sensory symptoms are lacking.
inactive, only fatigue, anxiety, and sleepless- Muscle disorders usually manifest with
ness are noted. Small children exhibit proximal weakness manifested by inability to
increased paradoxical breathing and tachyp- rise from a chair or to comb the hair. Sensory
nea and nasal flaring, and appear distressed. symptoms are absent, and reflexes are usually
decreased. Serum levels of creatine kinase are
frequently elevated. Electrodiagnostic testing
Neurologic versus Muscular Disease may be used to differentiate between anterior
horn cell disorders, peripheral neuropathies,
Some neuromuscular diseases include upper neuromuscular junction disorders, and mus-
motor neuron involvement. Upper motor cle diseases.
neuron lesions result from pathology in the
cerebral cortex, brainstem, or spinal cord and
Clinical Entities
are signaled by an increase in muscle tone
(spasticity), hyperreflexia, and the persistence Table 9-3 lists causes of respiratory muscle
or reappearance of primitive reflexes, such as dysfunction.
the extensor plantar response (Babinski sign).
These patients also may have reflex deep Upper Motor Neuron
breaths (“sighs”) and coughs despite having Quadriplegia and respiratory compromise can
very low vital capacity and PCFs. Lesions result from acute cervical spinal cord trauma,
above the foramen magnum also may pro- spinal artery infarction, or compression by
duce contralateral hemiplegia. Lesions in the tumor. Injuries at or above C3 to C5 involve
cortex or subcortical areas often are associated the phrenic nerves and can cause partial to
with disorders of speech or other cortical func- complete bilateral hemidiaphragmatic paraly-
tions. Lesions in the brainstem usually affect sis. Intercostal muscle paralysis below the
cranial nerve function ipsilateral to the lesion level of the lesion limits the normal outward
and contralateral hemiplegia. Abnormalities expansion of the middle and upper rib cage,
in the spinal cord typically cause bilateral compromising inspiration further. Expiration
weakness because of the close proximity of also can be reduced because of paralysis of
the descending tracts. Upper motor neuron the abdominal and other expiratory muscles.
disorders can be identified and differentiated High-level quadriplegics may be unable to
further by imaging studies such as computed generate adequate tidal volumes, and the
capacity, maximum inspiratory pressure, and

Causes of Respiratory Muscle
Table 9-3 Dysfunction maximum expiratory pressure are reduced.
As the initial phase of spinal injury passes,
SITE OF DEFECT CAUSES chest wall flaccidity is replaced with spasticity,
Central Drive of Congenital or acquired and there is an improvement in the vital
Breathing capacity as the more rigid chest wall resists
Upper Motor Hemiplegia collapse.
Neuron Cerebral palsy
Quadriplegia Anterior Horn Cell Disorders
Lower Motor Poliomyelitis SMAs comprise a group of autosomal-reces-
Neuron Spinal muscular sive degenerative disorders of lower motor
atrophies neurons classified as type I (Werdnig-Hoffman
Guillain-Barré syndrome disease), type II, and type III (Kugelberg-
Tetanus Welander disease), based on the age of onset
Friedreich’s ataxia of muscle weakness and clinical severity.
Traumatic nerve lesions These disorders often manifest in infancy
Phrenic nerve paralysis and childhood with an estimated incidence
Neuromuscular Myasthenia gravis of 1:5000. SMAs are due to a mutation of the
Junction Congenital myasthenic survival motor neuron gene located on chro-
syndromes
mosome 5q13. This mutation is responsible
Botulism
for primary degeneration of the anterior horn
Drugs
cells of the spinal cord and often of the bulbar
Respiratory Muscles Muscular dystrophies
motor nuclei, which leads to skeletal muscle
Congenital myopathies
paralysis and atrophy.
Metabolic myopathies
Werdnig-Hoffman disease manifests in the
Steroid myopathy
first 6 months of life. Infants with this disease
Connective tissue disease
lack head control and are nearly always
Diaphragmatic
malformation unable to sit and walk. There is severe hypo-
Nonmuscular, Chest Scoliosis tonia, generalized weakness, and thin muscle
Wall Structures Congenital rib cage mass. All of these patients have paradoxical
abnormality inward rib cage movement with each inspira-
Overinflated rib cage tion, the diaphragm being relatively spared.
Connective tissue disease Unless provided with nocturnal high-span
Thoracic burns BiPAP, they develop pectus excavatum and
Obesity severe undergrowth of the lungs and chest
Giant exomphalos wall, showing on chest radiography reduced
lung volume and a bell-shaped thorax.
Unless supported by respiratory muscle aids
(described later), more than 90% of patients
accompanying hypoventilation and atelecta- die by 2 years of age.
sis can result in hypoxemia. Low-level cervical In SMA type 2, affected patients are usually
quadriplegics with intact phrenic nerves are able to suck and swallow, and respiration is
able to contract their diaphragms. They, too, adequate in early infancy. Swallowing difficul-
lack the intercostal muscle activity necessary ties or choking with feeds becomes apparent
to stabilize the rib cage for optimal inspiratory in the preschool years, predisposing these
function, however. These patients also may patients to recurrent pneumonia and chronic
lose the use of the abdominal and other expi- suppurative lung disease. These patients can
ratory muscles. Combined inspiratory and sit but not walk. About 40% of these patients
expiratory weakness can prevent them from have paradoxical breathing and require noc-
effectively coughing and clearing secretions turnal high-span BiPAP.
and place them at high risk for pneumonia. Kugelberg-Welander disease is the mildest
Initially, with spinal cord injury, the vital SMA (type 3), and patients may appear normal
in infancy. The progressive weakness is proxi- Acute idiopathic polyradiculitis, also known
mal in distribution, particularly involving as Guillain-Barré syndrome, is the most com-
shoulder girdle muscles. In the adult-onset mon peripheral neuropathy causing respira-
form, SMA type 4, patients can walk for some tory failure. It is considered to be an
period of time. An X-linked adult-onset type 5 autoimmune disease precipitated by a pre-
SMA (which affects only men), otherwise ceding viral or bacterial infection, such as
known as Kennedy disease, is associated with cytomegalovirus, Epstein-Barr virus, Myco-
gynecomastia, temporal atrophy, and endo- plasma pneumoniae, and Campylobacter jejuni.
crine disturbances and hypospermia. In 80% of these patients, there is a history of a
Preliminary data obtained from phase 1 nonspecific viral illness preceding weakness
human studies have suggested that sodium by 2 to 3 weeks. Diagnosis is mainly based
valproate may improve anterior horn cell on clinical grounds. It usually begins with
function in SMA. Pharmacologic therapy or fine paresthesias in the toes or fingertips fol-
gene therapy is unlikely to have a major lowed by progressive muscle weakness in
effect on the course of the disease in older the lower extremities, trunk, upper limbs,
patients with advanced disease, but NIV is and, finally, bulbar-innervated and respira-
effective in many of these patients and tory muscles. Muscle involvement is relatively
may buy time for medical therapies to take symmetric. Facial and oropharyngeal weak-
effect or even undergo development. ness are often impending signs of respiratory
Poliomyelitis is a poliovirus infection of failure. Muscle pain is common in the initial
young children that begins with fever and stages. Daily bedside evaluation of vital
upper respiratory symptoms that are followed capacity and arterial blood gases is essential
by signs of meningeal irritation and asymmet- for appropriate decisions regarding the need
ric, flaccid paralysis that can involve the of mechanical ventilatory support, which is
skeletal, respiratory, and bulbar-innervated required in 20% of affected children. Acute
musculature. The respiratory motor nuclei respiratory failure can be avoided with the
can be directly involved, resulting in dia- use of noninvasive aids when bulbar-inner-
phragmatic and accessory respiratory muscle vated muscle function is adequate to prevent
dysfunction. Involvement of lower cranial continuous aspiration of saliva or oxyhemo-
nerve nuclei can result in upper airway globin desaturation. Otherwise, patients need
obstruction, pooling of secretions, and aspira- to be intubated for ventilator use and airway
tion. The medullary respiratory center also secretion management. Early use of high-
can be affected, resulting in irregular respira- dose intravenous immunoglobulins or
tions and apnea. Many of these patients plasma exchange induces a more rapid
require ventilatory and hemodynamic support resolution of the disease. Corticosteroids are
during the acute phase of the illness. Although now used sparingly because they seem to pre-
most patients show substantial muscle recov- dispose to the chronic relapsing form of the
ery over time, they gradually relapse to require disease.
ventilatory assistance again later in life with Among other peripheral neuropathies lead-
the senescent aging and dropping out of over- ing to respiratory failure, Lyme disease
worked anterior motor neurons with aging.8 can manifest with a syndrome identical to
Guillain-Barré syndrome. In endemic areas,
Disorders of Peripheral Nerves serologic testing for Lyme disease is indicated.
Hereditary motor and sensorimotor neuropa- Acute intermittent porphyria can cause a neu-
thies are common. The former is often con- ropathy severe enough to result in respiratory
fused with and can be as severe as SMA. The failure. Postdiphtheritic neuropathy, toxic
most common is Charcot-Marie-Tooth disease, neuropathies (thallium, phosphate, and lead)
a demyelinating neuropathy. Almost 15% of avitaminosis, paralytic shellfish (saxitoxin)
patients are left with residual weakness, and poisoning, and the polyneuropathies asso-
an additional 5% experience chronic relapsing ciated with systemic lupus erythematosus and
(dysimmune) polyneuropathy. Some patients polyarteritis nodosa also can cause ventilatory
are never weaned from ventilatory support.8 failure.
Disorders of the Neuromuscular problems causing aspiration pneumonia,

Junction upper airway obstruction owing to inability
Myasthenia gravis is the most common disor- to handle oropharyngeal secretions, or respi-
der of the neuromuscular junction. It affects ratory muscle weakness. Some patients may
any age group, although clusters of cases are require ventilatory support during this
found in adolescent girls. Myasthenia gravis is period. After the abnormal antibodies disap-
characterized by fluctuating weakness with a pear, the infants have normal strength and
predilection for the ocular muscles (ptosis, dip- are not at increased risk for developing myas-
lopia, blurred vision) and bulbar-innervated thenia gravis in later childhood. The syn-
muscles (dysphagia, dysphasia, and aspira- drome of transient neonatal myasthenia
tion). The pupillary response to light is pre- gravis is to be distinguished from a rare, often
served. Similar to the adult form, juvenile hereditary, and often permanent, congenital
myasthenia gravis is an acquired immuno- myasthenia gravis not related to maternal
logic disorder of neuromuscular transmission myasthenia gravis. This disorder is character-
associated with circulating antibodies against ized by an abnormality of the acetylcholine
postsynaptic acetylcholine receptors. These receptor, manifested as high conductance
antibodies can be detected in the serum of and excessively fast closure, and is probably
90% of patients with generalized myasthenia due to a mutation affecting a single amino
gravis. acid residue. Therapy for acute attacks (myas-
Diagnosis of juvenile myasthenia gravis is thenia crisis) includes mechanical ventila-
based on clinical symptoms, electrophysio- tion in combination with plasma exchange,
logic studies, a positive finding of circulating acetylcholinesterase inhibitors (pyrido-
acetylcholine receptor autoantibodies, and stigmine), and corticosteroids or other
transient improvement with anticholinester- immunosuppressants.
ase medication. Most patients in whom this Botulism is a rare disorder of the neuro-
disease is suspected but undiagnosed show a muscular transmission blockade caused by
dramatic response to intravenous edropho- the binding of one of the neurotoxins (A,
nium chloride, a short-acting acetylcholines- B, E, and F) produced by Clostridium botuli-
terase inhibitor. Benign thymic hyperplasia num. The toxin that is carried in the blood-
or thymoma occurs in 90% of these patients. stream prevents the release of acetylcholine
Management is primarily based on anticho- from the presynaptic terminal and affects
linesterase medication (pyridostigmine bro- nicotinic and muscarinic synapses. Botulism
mide). Improvement with anticholinesterase occurs in three forms: infantile botulism,
medication is often incomplete, however, the most common, in which the organism
and most patients require further therapeutic and its spores are ingested in honey or other
measures, including thymectomy, which foods, or from the environment; food-borne
results in improvement or remission in 80% (classic) botulism, in which preformed toxin
of patients without thymomas. Immunosup- is ingested in nonacidic home-canned or
pressive drugs (prednisone, azathioprine, or factory-canned vegetables or meat; and
cyclosporine) are frequently recommended. wound botulism (very rare), in which C. bot-
Other autoimmune diseases, such as rheuma- ulinum and its spores contaminate traumatic
toid arthritis, systemic lupus erythematosus, or surgical wounds.9
and thyrotoxicosis, commonly complicate Infant botulism is most commonly seen
the clinical picture. in the first 4 months of life. Constipation
Transient neonatal myasthenia gravis is a is usually the first symptom; thereafter, neu-
syndrome that affects 30% of infants born romuscular dysfunction results in progressive
to mothers with autoimmune myasthenia descending muscle weakness, with early bul-
gravis. Clinical features are usually noted bar involvement and hypotonia. Acute respi-
within hours of birth and include feeding ratory failure develops in 90% of affected
and respiratory difficulties, hypotonia, weak infants. Respiratory failure results from respi-
cry, facial weakness, and palpebral ptosis. ratory muscle weakness and paralysis, causing
Respiratory difficulties are related to feeding hypoventilation; bulbar palsy and upper
airway muscle weakness, leading to aspiration births. The gene responsible for DMD and
pneumonia or upper airway obstruction; and Becker muscular dystrophy has been loca-
inability to clear secretions, resulting in pneu- lized on the short arm of the X chromosome
monia and atelectasis. Endotracheal intuba- (Xp21). The dystrophin gene regulates the
tion is performed as soon as depression of expression of dystrophin, a protein that links
the gag reflex is noted. the normal contractile apparatus to the sarco-
In older children with food-borne or lemma in skeletal muscle. DMD usually man-
wound botulism, the onset of neurologic ifests in boys with proximal muscle weakness
symptoms follows a characteristic pattern of at 2 to 4 years of age. Poor head control in
diplopia, blurred vision, ptosis, dry mouth, infancy may be an early sign of weakness.
dysphagia, dysarthria, decreased gag reflex, Clinical diagnosis is made after consideration
and decreased corneal reflex followed by of history, physical findings, and elevated
flaccid descending paralysis that often pro- serum creatine kinase level. Diagnosis is con-
gresses to affect the respiratory muscles. The firmed by finding an abnormality in the dys-
diagnosis should be considered if a previ- trophin gene by mutation analysis of blood
ously healthy infant, usually younger than leukocyte DNA. By inducing specific exon
6 months, has a history of constipation and skipping during messenger RNA splicing, anti-
then acutely develops weakness with diffi- sense compounds were shown to correct the
culty in sucking, swallowing, crying, or open reading frame of the DMD gene and to
breathing. It is suggested by electromyo- restore dystrophin expression in vitro and in
graphic changes of brief, small, abundant animal models in vivo.32
motor unit potentials in response to high rates Respiratory disease in DMD is the major
of stimulation similar to that seen in amino- cause of morbidity and mortality. Loss of lung
glycoside toxicity. The diagnosis is confirmed function progresses linearly after the initia-
by showing neurotoxin in the serum, stool, tion of wheelchair use; increasing hypoxemic
or contaminated food. Treatment includes dips are seen during sleep in subsequent
positioning the head backward to open the teenage years, and respiratory failure occurs
airway and improve respiratory mechanics. between 18 and 20 years of age. Unless prop-
Respiratory muscle aids are often required, erly managed with respiratory muscle aids,
and pneumonia is a common complication these patients invariably die before age 30.
and a major cause of death. Antibiotic therapy The deterioration in pulmonary function in
is not part of the treatment of uncomplicated DMD parallels the progression of the disease.
infantile or food-borne botulism because the A FVC of less than 1 L is a predictor of poor
toxin is primarily an intracellular molecule. outcome, with a 5-year survival rate of only
Antibiotics are reserved for the treatment of 8% if assisted ventilation is not provided.
complications. Wound botulism requires Death is due to respiratory failure in 80% of
aggressive use of antibiotics and antitoxin. cases or to cardiac failure in 10% to 20% of
The neuromuscular junction is perhaps the cases.10
most common site adversely affected in drug- A restrictive syndrome secondary to muscle
induced neuropathies. Several drugs have been weakness characterizes the pulmonary com-
reported to produce or potentiate unwanted promise in patients with DMD. When day-
neuromuscular blockade, including aminogly- time hypercapnia develops in DMD patients,
cosides, clindamycin, polymyxin, colistin, pro- life expectancy without noninvasive ventila-
pranolol, calcium channel blockers, quinidine, tory assistance is approximately 9 to 10
lidocaine, corticosteroids, chlorpromazine, months. Chest wall muscle weakness and
and lithium. contractures, spinal deformity, and vertebro-
costal ankylosis also occur. When assisted
Disorders of Muscles PCF decreases to less than 300 L/min, a pulse
DMD is the most common and severe of the oximeter and Cough-AssistTM (JH Emerson
muscular dystrophies that affect humans. Company, Cambridge, MA) are prescribed
Inherited as an X-linked recessive trait, it for the oximetry protocol as described sub-
has an estimated incidence of 1:3000 male sequently. Patients with DMD eventually
require 24-hour use of noninvasive inspira- (ventilatory assistance) make these patients
tory muscle aids, but can live well into their very prone to chronic hypoventilation and
40s using them.21 cor pulmonale.
Congenital myotonic dystrophy is the sec-
ond most common muscular dystrophy. Myo-
tonic dystrophy is an autosomal dominant Sleep Evaluation in Neuromuscular
inherited disease that occurs with an esti- Diseases
mated frequency of 1:7500 to 1:18,500. The
mutation responsible is an expansion of trinu- Neuromuscular diseases are frequently asso-
cleotide (CTG) repeats in the region of the ciated with sleep-disordered breathing and
myotonic dystrophy protein kinase (DMPK) alveolar hypoventilation. Onset of respiratory
gene, on the long arm of chromosome 19. insufficiency can be subtle. Symptoms of sleep
Myotonia, a very slow relaxation of muscle hypoventilation include gradually increasing
after contraction, and muscle weakness are headache, somnolence, and, rarely, vomiting.
the prominent clinical features, but many Patients with some neuromuscular disorders
organ systems can be affected, including the also are at risk for upper airway obstruction.
cardiac, endocrine, and ophthalmologic sys- Children with DMD may go through an
tems. Involvement of the respiratory system early phase of latent or occult nocturnal
is the major contributor to morbidity and hypoxemia before there is evidence of day-
mortality. time respiratory impairment. Such episodes
Neonatal myotonic dystrophy is a severe of hypoxemia can result in a disrupted sleep
form of myotonic dystrophy that develops in pattern and impair daytime cognitive per-
a few infants born to mothers, and rarely to formance. The sleep laboratory is an ideal
fathers, with myotonic dystrophy. Prominent site to diagnose occult episodes of nocturnal
manifestations include hypotonia without hypoxemia in patients with most types of
myotonia, feeding difficulties, and respiratory significant restrictive lung disease.
distress. Respiratory failure is common and The timing and necessity of polysomnog-
may result in death in the neonatal period. raphy to detect sleep hypoventilation have
Examining the parents and finding the repeat not been determined in patients with neuro-
segment of DNA on the myotonic dystrophy muscular disorders. Sleep hypoventilation
gene can confirm the diagnosis.11 Polyhy- correlates with an awake PaCO2 of 45 mm
dramnios and decreased fetal movements Hg or greater and a base excess 4 mmol/L or
are common. Prematurity, hydrops fetalis greater. Ambulatory monitoring at home
with pleural effusions, and pulmonary hypo- with recording of cardiac and respiratory
plasia can increase respiratory difficulties variables has been suggested as the first diag-
owing to diaphragmatic weakness at birth. nostic step in testing for sleep-disordered
Fifty percent of neonates with congenital breathing in patients with DMD. These
myotonic dystrophy need respiratory support devices can detect the presence of decreases
at birth. in sleep-related oxyhemoglobin saturation.
The diagnosis of this disease is suspected A negative test result does not rule out the
when the newborn is recognized to be diffi- diagnosis of sleep-disordered breathing and
cult to wean from the ventilator for unknown must be followed by polysomnography.
reasons. Thin ribs and an elevated right dia- It is recommended to review sleep quality
phragm on the chest radiograph may hint and symptoms of sleep-disordered breathing
at the diagnosis. The breathing pattern of at every patient encounter, and an annual eval-
these patients is similar to that of any patient uation for sleep-disordered breathing should
with a restrictive syndrome secondary to be obtained in patients with DMD starting
respiratory muscle weakness—increased rate from the time they are wheelchair users or
with small tidal volumes at rest. Myotonia when clinically indicated. Overnight pulse
and weakness of the respiratory muscles and oximetry with continuous CO2 monitoring
the muscles of deglutition, decreased ventila- provides useful information about nighttime
tory drive, and failure of myotonic muscles gas exchange, although central or obstructive
to benefit from inspiratory muscle support events not associated with desaturation or
CO2 retention would not be detected. A simple As mentioned earlier, numerous neuromus-
capillary blood gas measurement on arousal cular disorders are associated with cardiomy-
in the morning can show CO2 retention, opathy or conduction defects or both. The
although not as sensitively as continuous consequences of cardiac disease are worsened
capnography. by hypoxemia and hypercapnia. NIV therapy
may have direct cardioprotective effects.
Cardiac Involvement
Cardiac involvement is universal in indi-

Physical Medicine Respiratory
viduals with DMD. Cardiac disease is the sec- Muscle Aids
ond most common cause of death in
Inspiratory and expiratory muscle aids are
individuals with DMD.16 Dilated cardiomy-
devices and techniques that involve the appli-
opathy primarily involves the left ventricle,
cation of forces to the body or pressure
and can lead to dyspnea and other symptoms
changes to the airway to assist inspiratory or
of congestive heart failure. Conversely, right
expiratory muscle function. Body ventilators
ventricular failure can result from respiratory
act on the body to assist inspiration just as an
failure and pulmonary hypertension. Indi- abdominal thrust can assist coughing. Nega-
viduals with DMD also are at risk for ventric-
tive pressure applied to the airway during expi-
ular arrhythmias. Although some studies
ration also assists the expiratory muscles for
have suggested that the respiratory and
coughing, just as positive pressure applied to
peripheral muscle weakness tend to be
the airway during inhalation, or noninvasive
inversely related to the risk of cardiac failure,
intermittent positive-pressure ventilation
other studies suggest that left heart and respi-
(NPPV), assists the inspiratory muscles. Con-
ratory failure tend to occur in parallel. It is
tinuous positive airway pressure assists neither
recommended that all individuals with inspiratory nor expiratory muscles and should
DMD obtain regular cardiac evaluation with
rarely, if ever, be used for these patients.
annual electrocardiograms and echocardio-
grams, starting at least by school age.
Goal One—Maintenance of Lung
and Chest Wall Mobility
Management
As the vital capacity decreases, the largest
The three goals of management are to (1) pro- breath can expand only a small fraction of
vide insufflations to expand the lungs and the lungs. Similar to limb articulations, the
chest walls optimally to maintain compliance lungs and chest wall require regular mobili-
and promote lung growth in children, (2) zation. Use of incentive spirometry or deep
maintain normal alveolar ventilation around- breathing can expand the lungs no greater
the-clock, and (3) maximize PCF. The use of than the vital capacity and is useless. Lung
inspiratory and expiratory muscle aids attains mobilization can be achieved by air stack-
these goals. Many patients become continuing, by providing deep insufflations, or by
ous ventilator users for years without ever nocturnal high-span (inspiratoryexpira-
being hospitalized.12-14 tory positive airway pressure >10) BiPAP
It is surprising that a treatment applied at for infants (Fig. 9-1).13
night can have the sustained effect of correct- The patient uses a mouthpiece to “air
ing arterial blood gas tensions during the day. stack” consecutively delivered volumes from
Over the years, it has been hypothesized that a volume-cycled ventilator or a manual resus-
this improvement is mediated by many possi- citator multiple times, three times daily. If
ble mechanisms. It has been suggested30 that the lips or cheeks are too weak to permit air
NIV may work by (1) improving ventilatory stacking via a mouthpiece, it is done via a
mechanics; (2) resting fatigued respiratory nasal interface or Bennett Lipseal (Puritan-
muscles, improving strength and endurance; Bennett Inc. Boulder, CO) (Fig. 9-2). Most
or (3) enhancing ventilatory sensitivity to patients can learn to use glossopharyngeal
CO2. breathing (GPB) for lung expansion to or
Lung expansion can increase MIC, maxi-

mize PCF, improve pulmonary compliance,
prevent atelectasis, and provide mastery of
NIV. Anyone who can air stack can use NIV
as opposed to requiring tracheotomy.
The chest wall develops abnormally in
patients with some congenital neuromuscular
diseases, such as type 1 SMA and some inher-
ited myopathies. In patients with type 1
SMA, the relative preservation of diaphragm
strength in the face of marked weakness of
the intercostal muscles commonly leads to a
characteristic sternal recession and a small
chest. These chest wall deformities restrict
pulmonary development. Over and above
this effect on thoracic configuration, lung
growth is heavily influenced by chest wall
respiratory motion. Although infants cannot
air stack, nocturnal use of high-span BiPAP
has been shown to prevent pectus excavatum
and promote lung and chest wall growth for
infants with SMA.17
Some experts have advocated for many years
the use of NIV therapy to hyperinflate the
chest wall to preserve mechanical function.
Figure 9-1. This 25-year-old man with Duchenne mus- This stretching action of NIV may have an
cular dystrophy and severe scoliosis required 24-hour non- additional effect on chest wall expansion and
invasive intermittent positive-pressure ventilation (NIPPV) compliance and on underlying pulmonary
for more than 5 years. Here he is seen using mouthpiece
NIPPV for daytime ventilatory support. expansion and growth.
Any patient capable of air stacking who loses
breathing tolerance during chest colds can use
NIV continuously or be extubated directly to
it. This is extremely important for avoiding
a tracheotomy because such patients are
extubated without being ventilator weaned.
Goal Two—Maintain Normal

Alveolar Ventilation
Inspiratory Muscle Aids

NPPV, delivered via volume-cycled machines,
can be noninvasively delivered via Lipseals,
Figure 9-2. This 30-year-old Duchenne muscular dys- Oracles, and nasal and oronasal interfaces
trophy patient has required 24-hour ventilatory support for ventilatory support during sleep, with
since he was 14 years old. He uses simple mouthpiece
intermittent positive-pressure ventilation during daytime the patients trained and equipped in the
hours and mouthpiece with lip seal retention (seen here) outpatient setting. Lipseals and Oracles
for nocturnal ventilatory support. (Fisher-Paykell, Laguna Hills, CA) can provide
essentially closed systems of ventilatory
beyond the MIC.15,16 If the bulbar-innervated support.17
muscles are too weak for deep air stacking, Patients requiring around-the-clock support
single deep insufflations are provided via a use simple 15- or 22-mm angled mouth-
Cough-AssistTM (Philips Respironics) at 40 to pieces (4-730-00, Puritan-Bennett Inc, Boulder,
70 cm H2O three times daily. CO) held between the teeth for NPPV
drive is not depressed, even patients with

little or no measurable vital capacity can be
safely ventilated day and night by nasal or
oral ventilation.
Besides continuous dependence on NIV,
benefits from part-time use include respira-
tory muscle rest, increased tidal volumes,
improved alveolar ventilation and blood
gases, improved lung compliance and chemo-
tactic sensitivity, and possibly improved ven-
tilation/perfusion matching by reducing
atelectasis and small airway closure. A reason-
able peak inspiratory pressure to start with is
8 cm H2O, with the expectation to increase
this in increments as necessary to reduce the
work of breathing. Peak inspiratory pressure
levels of 10 to 16 cm H2O suffice for most chil-
dren. Positive end-expiratory pressure should
be set at a level to accomplish two goals:
increase functional residual capacity and
maintain the patency of the upper airway at
end expiration. The positive end-expiratory
pressure setting is generally adjusted in the
range of 4 to 10 cm H2O. To accomplish opti-
Figure 9-3. This patient with spinal muscular atrophy mal rest, high volumes or pressure spans
required nocturnal noninvasive intermittent positive-pres- should be used—inspiratory to expiratory
sure ventilation (NIPPV) for 18 years. She switched from
lip seal to nasal NIPPV in 1984. positive airway pressure spans of 10 to 12 for
BiPAP users. Patients vary the volume of air
taken to adjust tidal volume, speech volume,
(Fig. 9-3) during the day. To use mouthpiece and cough flows, and to air stack.
NPPV effectively and conveniently, adequate Respiratory impairment initially manifests
neck rotation and oral motor function are nec- as sleep hypoventilation. When symptom-
essary to grab the mouthpiece and receive atic and treated, pulmonary hypertension
NPPV without air leakage. and right ventricular failure can be pre-
When the lips are too weak to grab a mouth- vented. There are no significant complica-
piece, the patient can use an intermittent tions of NPPV and continuous users who
abdominal pressure ventilator18 or continue learn GPB need not worry about accidental
nocturnal nasal NPPV through daytime hours, disconnection or ventilator failure.
alternating nasal interfaces to vary skin pres-
sure. A popular interface for daytime use is
the Nasal-Aire (InnoMed Technologies, Boca Goal Three—Facilitate Airway
Raton, FL) because this interface permits the Clearance
use of glasses and does not obstruct vision.
The use of oronasal interfaces seems to be Chest percussion and vibration are not
unnecessary. Using a Lipseal and placing substitutes for coughing. Bulbar-innervated
cotton pledgets in the nostrils, and then inspiratory and expiratory muscles and
sealing the nostrils with a Band-Aid can pro- respiratory aids are needed for coughing.
vide a closed system of ventilatory support. The oximetry feedback respiratory aid pro-
It is crucial to avoid the depression of venti- tocol consists of using a pulse oximeter for
latory drive by the use of sedative medica- feedback to maintain SaO2 greater than
tions or oxygen, or daytime hypercapnia 94% by maintaining effective alveolar venti-
that results in oxyhemoglobin desaturation lation and airway secretion elimination by
to less than 95%. As long as ventilatory using inspiratory or expiratory aids, or
both—up to continuous NPPV and assisted One treatment consists of about five cycles
coughing. This is most important during of mechanical insufflation-exsufflation fol-
respiratory tract infections and when extu- lowed by a period of normal breathing or
bating patients with little or no breathing ventilator use for 20 to 30 seconds to avoid
tolerance. hyperventilation. Five or more treatments
are given in one sitting, and the treatments
Normal Cough are repeated until no further secretions are
Adequate expiratory muscle function is cru- expelled, and mucous plug-triggered hemo-
cial for creating the PCF necessary to clear air- globin desaturations are reversed. Mechani-
way secretions and bronchial mucous plugs. A cal insufflation-exsufflation sessions can be
normal cough requires a precough inspiration repeated every 5 to 10 minutes as needed.
or insufflation to about 85% of total lung Although usually applied via oronasal inter-
capacity.22 This is followed by the develop- face, mechanical insufflation-exsufflation
ment of thoracoabdominal pressures suffi- also can be applied via endotracheal or trache-
cient to generate an explosive decompression ostomy tubes to clear secretions without the
of the chest at glottic opening and PCF exceed- airway irritation and discomfort caused by tra-
ing 5 L/sec.23 Total expiratory volume during cheal suctioning. Also, in contrast to most
normal coughing is about 2.3 0.5 L.24 Nor- attempts at bronchial suctioning,25 mechani-
mal values are unavailable for small children. cal insufflation-exsufflation eliminates airway
secretions from the bronchial tree. Trans-
Assisted Coughing
tracheal use of mechanical insufflation-
Patients with less than 5 L/sec of unassisted
exsufflation rather than suctioning seems to
PCF benefit from assisted coughing. Tech-
be associated with a decrease in the produc-
niques of manually assisted coughing involve
tion of airway secretions caused by the irrita-
the use of a manually applied abdominal
tive effects of invasive airway suctioning.
thrust, which may be combined with an ante-
The use of mechanical insufflation-exsuffla-
rior chest wall compression timed to glottic
tion permits clinicians to extubate consistently
opening.22 For small children, one hand or
patients with little ventilator-free breathing
only a few fingers can be used. For adolescents
ability, and convert them to the use of NPPV.
or adults with less than 1.5 L of vital capacity,
It also permits clinicians to avoid intubation,
a maximal insufflation or air stacking pre-
or to extubate quickly patients with neuro-
cedes the manual assist. Manually assisted
muscular diseases with profuse airway secre-
coughing is less effective in the presence of
tions in acute respiratory failure during
scoliosis, marked obesity, or abdominal dis-
intercurrent respiratory tract infections. No
tention, and should not be used for 1 hour
significant pulmonary complications have
after meals. Abdominal thrusts are not used
been reported with the use of mechanical
for patients after abdominal trauma or sur-
insufflation-exsufflation.26
gery, and anterior chest compression is
avoided in elderly patients.
Extubation and Decannulation

Mechanical Insufflation-Exsufflation
Patients who are intubated and who then
Currently available mechanical insufflator- undergo tracheotomy during an acute hos-
exsufflators can cycle automatically between pitalization can be evaluated for possible
positive and negative pressure, or the cycling transition to NPPV.27 Although 94% of con-
can be done manually. The insufflation ventionally managed children with SMA
and exsufflation pressures are usually set at type 1 fail extubation, the success rate using
þ40 cm H2O to 40 cm H2O. Similar pressures a noninvasive extubation protocol is about
have been used without untoward effects on 90%.13 In this protocol, children are extubated
children 4 months old, although children are only when SaO2 remains greater than 94% in
often not optimally cooperative with it until ambient air, and they are extubated directly
age 2½ years. An abdominal thrust applied to high-span BiPAP. Manually and mechani-
during exsufflation increases PCF.3 cally (Cough-Assist) assisted coughing is used
Perioperative Management
Patients with vital capacity less than 40% to

60% of normal or hypercapnia have a risk of
failing ventilator weaning in the postopera-
tive period. These patients should be trained
in NPPV via simple 15-mm angled mouth-
pieces and nasal interfaces preoperatively.
Patients with assisted PCF less than 300 L/m
have a high risk of developing pneumonia
and other complications because of difficul-
ties in postoperative airway secretion expul-
sion. They should be trained in manually
and mechanically assisted coughing. These
patients can be routinely extubated and
decannulated with no autonomous ability
to breathe whether in the postoperative
period or otherwise. Extubation of untrained
patients to NIV who are unable to sustain
their breathing autonomously often results
in panic and extubation failure.
Figure 9-4. This 11-year-old boy with Duchenne mus-

cular dystrophy was extubated after spinal instrumenta- Outcomes
tion for scoliosis reduction despite requiring continuous
ventilatory support. He was switched to 24-hour noninva-
sive intermittent positive-pressure ventilation and required NPPV is overwhelmingly preferred over tra-
aggressive mechanical insufflation-exsufflation (seen here) cheotomy for speech, sleep, swallowing, com-
to clear his airway secretions.
fort, appearance, security, and use of GPB.19
NIV also has favorable impact on respiratory
infectious complications in children with
neuromuscular disorders.33 Another study
aggressively after extubation.13 Although chil-
showed 200% cost savings by using NIV sup-
dren can be decannulated and switched to
port methods for patients with no ventilator-
using NIV 24 hr/day, because of anxiety and
free breathing by facilitating community liv-
inability to cooperate, we have not done this
ing.12 Infants with SMA type 1 who undergo
for any continuously ventilator-dependent
tracheotomy lose all ability to breathe unaided
patients younger than age 12 (Fig. 9-4).
and do not develop the ability to speak,
whereas infants with the same disease severity
Glossopharyngeal Breathing who are maintained by noninvasive methods
usually require only nocturnal high-span
Inspiratory and, indirectly, expiratory mus- BiPAP and develop the ability to speak.20
cle activity can be assisted by GPB.15 This Many patients have become continuous
technique involves the glottis projecting ventilator users for years without ever being
air into the lungs. One breath usually con- hospitalized.21 Hundreds of hospitalizations
sists of six to nine gulps of 60 to 100 mL have been avoided by using continuous venti-
each. GPB can provide an individual who latory support along with mechanical insuf-
has little or no measurable vital capacity flation-exsufflation and assisted coughing at
with normal lung ventilation throughout home.12,13,17,18,21
daytime hours and perfect safety in the Virtually all patients with neuromuscular
event of ventilator failure day or night. The disease can be managed without resorting
safety and versatility afforded by GPB are to tracheotomy. The exceptions are patients
key reasons to eliminate tracheotomy in who are unable to cooperate because of
favor of noninvasive aids. coma or mental retardation and patients
whose bulbar-innervated musculature is so 5. Kelly BJ, Luce JM: The diagnosis and management
of neuromuscular diseases causing respiratory fail-
severely impaired that speech and swallow- ure. Chest 99:1485-1494, 1991.
ing have become impossible, and saliva is 6. Bennett DA, Black TP: Recognizing impending
continuously aspirated. The latter situation respiratory failure from neuromuscular causes.
J Crit Illness 3:46-60, 1988.
is rare in pediatric neuromuscular disease. 7. Bach JR, Alba AS: Management of chronic alveolar
Even patients with severe SMA type 1 (who hypoventilation by nasal ventilation. Chest 97:52-
can never breathe autonomously or swal- 57, 1990.
8. Bach JR, et al: Mouth intermittent positive pressure
low) can be managed safely without resort- ventilation in the management of post-polio respi-
ing to tracheotomy.13 Patients can become ratory insufficiency. Chest 91:859-864, 1987.
continuously dependent on NPPV without 9. Thilo EH, Townsend SF, Deacon J: Infant botulism
at 1 week of age: Report of two cases. Pediatr
ever being hospitalized, intubated, tracheot- 92:151, 1993.
omized, or bronchoscoped.21 These meth- 10. Smith DE, et al: Practical problems in the respira-
ods enhance quality of life; permit the use tory care of patients with muscular dystrophy.
N Engl J Med 316:1197-1204, 1987.
of GPB for security in the event of ventilator 11. Bergoffen JA, et al: Paternal transmission of con-
failure; and can drastically decrease morbid- genital myotonic dystrophy. J Med Genet 31:
ity, mortality, and cost.12,28,29 518-520, 1994.
12. Bach JR, et al: The ventilator individual: Cost anal-
ysis of institutionalization versus rehabilitation and
in-home management. Chest 101:26-30, 1992.
End-of-Life Care 13. Bach JR, et al: Spinal muscular atrophy type 1:
Management and outcomes. Pediatr Pulmonol
34:16-22, 2002.
Care for someone in the late stages of a pro- 14. Bach JR, et al: Neuromuscular ventilatory insuffi-
gressive chronic illness focuses on enhance- ciency: The effect of home mechanical ventilator
use vs. oxygen therapy on pneumonia and hospital-
ment of quality of life for the patient and ization rates. Am J Phys Med Rehab 77:8-19, 1998.
their family. A multidisciplinary approach is 15. Bach JR, et al: Glossopharyngeal breathing and
required, including primary and specialist non-invasive aids in the management of post-polio
respiratory insufficiency. Birth Defects 23:99-113,
physicians, hospice/palliative care specialists, 1987.
and social services, and spiritual care, family 16. Kang SW, Bach JR: Maximum insufflation capacity.
members, and others appropriate to the Chest 118:61-65, 2000.
17. Bach JR: Prevention of pectus excavatum for chil-
patient’s cultural or religious background.31 dren with spinal muscular atrophy type 1. Am J
The goals of end-of-life care for patients Phys Med Rehab 82:815-819, 2003.
with neuromuscular disorders include the 18. Bach JR, Alba AS: Intermittent abdominal pressure
ventilator in a regimen of noninvasive ventilatory
following: support. Chest 99:630-636, 1991.
1. Treating conditions (pain, dyspnea) that 19. Bach JR: A comparison of long-term ventilatory
cause distress (palliative care) support alternatives from the perspective of the
patient and care giver. Chest 104:1702-1706, 1993.
2. Attending to the psychosocial and spiri- 20. Bach JR, Chaudhry SS: Management approaches in
tual needs of the patient and family muscular dystrophy association clinics. Am J Phys
3. Respecting the patient and family’s Med Rehab 79:193-196, 2000.
21. Gomez-Merino E, Bach JR: Duchenne muscular
choice concerning testing and treatment dystrophy: Prolongation of life by noninvasive
respiratory muscle aids. Am J Phys Med Rehab
81:411-415, 2002.
References 22. Leith DE: Cough. In Brain JD, Proctor D, Reid L,
eds: Lung Biology in Health and Disease: Respira-
tory Defense Mechanisms, Part 2. New York, Marcel
1. West JB: Respiratory Physiology—The Essentials. Dekker, 1977, pp 545-592.
Baltimore, Williams & Wilkins, 2005. 23. Bach JR, et al: Airway secretion clearance by
2. Kang SW, Bach JR: Maximum insufflation capacity: mechanical exsufflation for post-poliomyelitis ven-
The relationships with vital capacity and cough tilator assisted individuals. Arch Phys Med Rehab
flows for patients with neuromuscular disease. Am 74:170-177, 1993.
J Phys Med Rehabil 79:222-227, 2000. 24. Aldrich JK, et al: Weaning from mechanical ventila-
3. Praud J-P, Canet E: Chest wall function and dys- tion: Adjunctive use of inspiratory muscle resistive
function in children. In Chernick V, et al, eds: Ken- training. Crit Care Med 17:143-147, 1989.
dig’s Disorders of the Respiratory Tract in Children, 25. Fishburn MJ, Marino RJ, Ditunno JF: Atelectasis
7th ed. Philadelphia, WB Saunders, 2006. and pneumonia in acute spinal cord injury. Arch
4. Bach JR: Mechanical insufflation-exsufflation: Phys Med Rehab 71:197-200, 1990.
Comparison of peak expiratory flows with manu- 26. Bach JR: Update and perspectives on noninvasive
ally assisted and unassisted coughing techniques. respiratory muscle aids, part 2: The expiratory mus-
Chest 104:1553-1562, 1993. cle aids. Chest 14:158-174, 1991.
27. Bach JR: Alternative methods of ventilatory support 31. Wolfe L: Should parents speak with a dying child
for the patient with ventilatory failure due to spinal about impending death. N Engl J Med 351:1251-
cord injury. J Am Paraplegia Soc 105:1538-1544, 1253, 2004.
1994. 32. Van Deutekom JC, et al: Local dystrophin restora-
28. Tzeng AC, Bach JR: Prevention of pulmonary mor- tion with antisense oligonucleotide PRO051. N
bidity for patients with neuromuscular disease. Engl J Med 357:2677-2686, 2007.
Chest 118:1390-1396, 2000. 33. Dohna-Schwake C, et al: Non-invasive ventilation
29. Bach JR: The Management of Patients with Neuro- reduces respiratory tract infections in children with
muscular Disease. Philadelphia, Elsevier, 2003. neuromuscular disorders. Pediatr Pulmonol 43:
30. Simonds AK: Recent advances in respiratory care 67-71, 2008.
for neuromuscular disease. Chest 130:1879-1886,
2006.
CHAPTER 10
of Rheumatoid Diseases*
C. EGLA RABINOVICH, EDWARD FELS, JOSEPH SHANAHAN, J. MARC MAJURE,
AND THOMAS M. MURPHY
Systemic Lupus Erythematosus 202 Pneumonitis Resulting from

Drug-Induced Lupus 211 Antirheumatic Therapy 232
Mixed Connective Tissue Disease 212 Methotrexate Pneumonitis 232
Sjögren Syndrome 215 Tumor Necrosis Factor-a Blockade and
Juvenile Rheumatoid Arthritis 217 Tuberculosis 233
Scleroderma 220 Other Rheumatology Medications Associated
Juvenile Dermatomyositis 225 with Pulmonary Disease 233
Ankylosing Spondylitis 226 Summary 233
Sarcoidosis 228 Acknowledgments 234
References 234
Arthritis is the most commonly recognized inflammatory expression. Although the

manifestation of rheumatic disease, but pul- mechanisms of the pulmonary inflammation
monary manifestations can occur in nearly of rheumatologic disorders differ by etiology,
all disorders and are found in various age common patterns of sequence and expression
groups in children. Symptoms of pulmo- are seen. The initial inflammatory lesions usu-
nary disease in children may be subtle or ally lack an identifiable etiology and behave
absent, and children at elevated risk should as though the child’s pulmonary tissue is
be screened for pulmonary involvement. foreign (hence the term “autoimmunity”).
The combination of well-developed vascu- Genetic susceptibility or genetic modifiers are
larity, exposure to external stimuli and toxins now well established for many disorders.
in ambient air, and a covering (the pleura) that Although acute expression with resolution
shares structures and functions analogous to sometimes occurs, chronic and relapsing sce-
joint synovia contributes to the susceptibility narios are more common. The general
of the lungs to rheumatic and vasculitic sequence is as follows:
Acute inflammation Amplification Failure of repair, resolution Relapse
Genetic predisposition Cellular Chronic vasculitis
Humoral Remodeling
Lytic enzymes Chronic interstitial pneumonitis
Oxidant stress Fibrosis
Immune complexes
In some disorders, such as systemic lupus

erythematosus (SLE), bleeding and infection
are integral participants in the expression of
the chronic inflammation. The cycle of
immune-mediated inflammation, vascular
*This chapter is dedicated to the life and contributions
leakage, and attempts at repair recurs with pro-
of Deborah Kredich, MD, a founder and developer of
the field of pediatric rheumatology and holder of certif- gressive organ damage, leading to loss of organ
icate number one from the American Sub-Board of function. Available pharmacologic therapies
Rheumatology of the American Board of Pediatrics. directed at alleviating the inflammation in
201
these disorders inhibit, but do not yet arrest adults.9 These and other studies confirm
the inflammatory process enough to prevent that the more uncommon cases of chronic
further organ damage. lung disease develop in children as well,
The list of childhood rheumatologic disor- including symptomatic chronic interstitial
ders is long. This chapter reviews the most lung disease (ILD) and shrinking lung syn-
common conditions and their associated drome. Drug-induced lupus (DIL) is often
pulmonary manifestations. characterized by lung involvement. Infec-
tion remains a leading cause of death in
patients with SLE, however. In view of the
Systemic Lupus risk of pulmonary infection associated with
Erythematosus immunosuppressive treatments for SLE, the
clinical approach to patients with pulmo-
SLE is an autoimmune disease characterized nary complaints should always include a
by multisystem inflammation and tissue dam- thorough search for infection. Initial treat-
age. It commonly develops in young women, ment regimens for acutely ill patients
but patients of either gender or any age may should incorporate empiric antibiotic ther-
be affected. In pediatric populations, SLE prev- apy until the precise cause of the pulmo-
alence is similar in prepubescent boys and nary disease is ascertained.
girls, but female predominance increases Noninfectious pulmonary complications of
steadily after puberty.1 The prevalence of SLE SLE are summarized in Table 10-1. Pleuritis is
increases with age, and SLE can develop in the most common pulmonary manifestation
individuals of any race or ethnicity. Neonatal of SLE. Symptoms include pleuritic chest pain
lupus occurs rarely and is caused by the and dyspnea in association with other features
passage of autoantibodies (anti-Ro, SSA and of lupus disease activity, such as fever, fatigue,
anti-La, SSB) across the placenta that cause rash, and arthritis. Chest radiographs may
congenital heart block or a self-limited lupus show small to moderate pleural effusions.
rash that manifests shortly after delivery and Large effusions are unusual (Figs. 10-1 and
persists until maternal antibodies disappear, 10-2). When pleural effusion is noted in SLE,
usually in the first year of life. diagnostic thoracentesis for pleural fluid aspi-
Pulmonary manifestations are common. ration and analysis is indicated. These effu-
Excluding common pulmonary infections, sions are typically serous or serosanguineous
the pleura is the most frequently involved exudates. Hemorrhagic effusions associated
tissue of the pulmonary system.2-4 Other with hypoxemia can occur with pulmonary
parenchymal complications—acute lupus infarcts and infection. These entities should
pneumonitis (ALP), alveolar hemorrhage always be considered in the differential diag-
(AH), pulmonary embolism, and pulmonary nosis of pleuritis, particularly in the absence
arterial hypertension (PAH)—occur less fre- of coexisting features of systemic lupus activ-
quently, but are potentially lethal. ity. Pleural pathology in SLE consists of local
Although the clinical literature of SLE is inflammation with immunoglobulin and
focused on adult studies, the reported pedi- complement deposition.10 In some cases, pleu-
atric literature suggests similar arrays of ral fibrosis is observed, although the fibrosis is
pulmonary manifestations and clinical infrequently considered clinically important.
syndrome courses.1,5,6 The prevalence of Mild pleuritis is usually treated effectively
pulmonary involvement is difficult to esti- with nonsteroidal anti-inflammatory drugs
mate because of selection bias related to (NSAIDs). In more severe cases, such as large
methodologies that are retrospective or symptomatic effusions, corticosteroids are
case-series in nature.5-8 Pediatric data are indicated. If the pleural effusions are not
insufficient to draw inferences regarding associated with significant multisystem
the variation in disease expression based activity, efforts should be made to limit cor-
on age or physical development. A large ticosteroid exposure, especially in children,
histopathologic study of lung involvement by using short pulses of therapy instead of
with SLE in children suggests that these prolonged tapers. Recurrent episodes of
lesions do not differ from the lesions in pleurisy may respond to treatment with
Table 10-1 Noninfectious Pulmonary Complications of Systemic Lupus Erythematosus
Chapter 10—Pulmonary Manifestations of Rheumatoid Diseases

PULMONARY ESTIMATED PRESENTING SIGNS RADIOGRAPHIC DIFFERENTIAL
MANIFESTATION PREVALENCE ONSET AND SYMPTOMS CHANGES PROGNOSIS TREATMENT DIAGNOSIS
Pleuritis 50-80% Acute Pleurisy, dyspnea, Pleural effusion Good NSAIDs, corticosteroids Infection, PE,
orthopnea, pleural ALP, AH,
rub PTX, drug
toxicity
ALP 10% Acute Dyspnea, cough, Patchy acinar Poor; mortality Corticosteroids, Infection, PE,
fever, chest pain, infiltrates with 50% plasmapheresis, CYC, AH, pleuritis
pleurisy, bibasilar AZA
hemoptysis; often predominance
preceded by or
associated with
infection,
hypoxemia
AH 2% Acute Dyspnea, cough, Patchy acinar Mortality 50% Corticosteroids, Infection, ALP,
chest pain, infiltrates with plasmapheresis, CYC, PE, vasculitis,
decrease in bibasilar AZA Goodpasture
hemoglobin, predominance syndrome,
pleurisy, IPH
hypoxemia
Acute reversible <1% Acute/chronic Dyspnea, low FVC, Normal Good Corticosteroids Infection, PE,
hypoxemia low DLCO early ALP or
AH,
shrinking
lung
syndrome
Chronic 3% Chronic, may be Dyspnea, cough, CXR—reticular Poor to good Corticosteroids, CYC, Infection, LIP,
interstitial long-term low FVC, low interstitial AZA drug toxicity,
pneumonitis complication of DLCO, fibrosis infiltrates: chronic
ALP ground glass, aspiration
honeycombing
(Continued)
203
204
Table 10-1 Noninfectious Pulmonary Complications of Systemic Lupus Erythematosus—Cont’d
PULMONARY ESTIMATED PRESENTING SIGNS RADIOGRAPHIC DIFFERENTIAL

MANIFESTATION PREVALENCE ONSET AND SYMPTOMS CHANGES PROGNOSIS TREATMENT DIAGNOSIS
Shrinking lung <1% Chronic Dyspnea, Normal or basilar Good Corticosteroids Respiratory
disease orthopnea, low atelectasis, muscle
FVC, low DLCO elevated weakness
diaphragm from
myopathies
Thromboembolic — Acute Dyspnea, pleurisy, CXR—normal Variable Anticoagulation Infection,
disease hemoptysis, fever, or effusion pleurisy, PTX,
pleural rub AH or ALP
Pulmonary 5-14% Chronic Dyspnea, chest CXR—normal Variable Pulmonary vasodilators Infection,
hypertension discomfort, right or perfusion (ETRA, prostanoids, interstitial
heart failure, phosphodiesterase lung disease
pericardial type 5 inhibitors,
effusion, elevated anticoagulants; CYC
BNP, low DLCO and corticosteroids in
with stable FVC select cases
AH, alveolar hemorrhage; ALP, acute lupus pneumonitis; AZA, azathioprine; BNP, brain natriuretic peptide; CXR, chest radiograph; CYC, cyclophosphamide; DLCO, diffusing capacity for carbon
monoxide; ETRA, endothelin receptor antagonist; FVC, forced vital capacity; IPH, idiopathic pulmonary hemosiderosis; LIP, lymphocytic interstitial pneumonia; NSAIDs, nonsteroidal anti-
inflammatory drugs; PE, pulmonary embolus; PTX, pneumothorax.
Chapter 10—Pulmonary Manifestations of Rheumatoid Diseases 205
hydroxychloroquine or methotrexate. More

aggressive immunosuppressants are needed
infrequently.
ALP is a rare complication of SLE, com-
monly manifesting with an acute, profound
loss of respiratory function. ALP occurs in
1% to 4% of patients and accounts for nearly
4% of SLE hospital admissions.2-3 Although
ALP may be a forme fruste of SLE, it most fre-
quently occurs in patients with established
disease.11 The clinical presentation includes
acute onset of dyspnea, cough, fever, and
hypoxemia. Coexisting infection is a com-
mon observation, suggesting that bacterial
or viral infections may trigger ALP. Many
patients report pleuritic chest pain. Hemop-
Figure 10-1. A 15-year-old girl with systemic lupus
erythematosus. Posteroanterior chest radiograph shows tysis occurs occasionally, but less frequently
left-sided pleural effusion (arrows). The remainder of the than the AH syndrome of pulmonary lupus.
examination was normal. Chest radiographs show a diffuse or patchy
acinar infiltrate with lower lobe predomi-
nance. With a rapidly progressive respiratory
A B
C
Figure 10-2. A 17-year-old girl with systemic lupus erythematosus. A, Posteroanterior chest x-ray shows bilateral ill-
defined nodular opacities, two of which (arrows) are evident in the left lung. B and C, Axial high-resolution chest CT scans
at the level of the carina (B) and slightly more inferiorly (C) show peripheral patchy fibrotic changes with scattered nod-
ular opacities; note subtle bronchiectasis (arrows in B).
decline, many patients require mechanical of SLE, most patients have an established diag-
ventilation. Bronchoscopy is suggested to nosis. AH most often occurs in patients who
exclude underlying infection, but because of have high anti-dsDNA titers. Coexisting renal
the frequent coexistence of pulmonary infec- disease is seen in 60% to 90% of patients with
tion with ALP, the discovery of a pathogen AH. Most patients are young women who
does not obviate the need for aggressive present with dyspnea, sometimes fever and
immunosuppressive therapy. Culture and pleurisy, and acute hypoxemia. Frank hemop-
antimicrobial sensitivity testing of broncho- tysis occurs in more than 50% of patients.
scopic or open lung biopsy specimens is help- Most patients with AH exhibit hemoptysis at
ful in directing antibiotic therapy. some point during their illness, helping to dif-
The histopathologic features of ALP appear ferentiate AH from ALP. Pulmonary bleeding
similar to diffuse alveolar damage. Inflamma- is usually substantial with an average hemo-
tory cellular infiltrates involve the interstitium globin decrease of approximately 7%.15 Chest
and alveolar wall.11-13 Nonspecific features, radiographs show diffuse, bilateral acinar
including edema, hemorrhage, and hyaline infiltrates that may progress rapidly over
membranes, are commonly observed. Com- hours and in some cases just as rapidly
plement and immunoglobulin deposition resolve. The respiratory compromise in more
may be shown by direct immunofluorescent than half of patients is rapid and profound,
staining, but vasculitic lesions are uncommon. resulting in a need for supplemental oxygen
Treatment of ALP is based primarily on ret- and assisted ventilation. With assisted venti-
rospective analyses of clinical cohorts, case lation, the addition of positive end-expiratory
series, and anecdotal reports.2,13,14 Typical pressure should theoretically be beneficial,
treatment incorporates high dose, intrave- impeding alveolar bleeding and maintaining
nous corticosteroids (1 to 2 mg/kg/day of alveolar expansion. Occasional cases of mild
prednisone or equivalent, usually to a maxi- AH may be managed more conservatively.
mum of 60 mg/day) and supportive respira- Because of the propensity for acute decom-
tory care. Because mortality rates approach pensation, all suspected cases of AH should
50%,11 rapidly progressive respiratory decline be managed with caution, preferably with
indicates a need for more aggressive interven- hospitalization. Mortality rates with AH are
tions, such as pulse intravenous methylpred- 40% to 90% in published series, with many
nisolone (30 mg/kg/day up to 1000 mg/day fatalities occurring early.2,3,15,16
for 3 days) and plasmapheresis. Additional Pulmonary infection may coexist in some
immunosuppressive agents, including azathi- cases.15 The relevance of infection as a causal
oprine and cyclophosphamide, should be con- agent is uncertain. The frequency of coexist-
sidered in patients who have persistent or ing infection makes bronchoscopy a useful
recurrent disease. Some centers advocate early approach to the evaluation of these patients,
initiation of azathioprine or cyclophospha- however. As in ALP, the presence of a pulmo-
mide in patients who are seriously ill. nary pathogen in bronchoalveolar lavage
ALP is usually expressed as a severe, but self- (BAL) or biopsy specimens does not obviate
limited, monophasic inflammation. Chronic the need for immunosuppression, but it helps
interstitial disease11 may rarely develop in sur- guide the choice of antibiotics. Most patients
vivors of the acute illness, however. The inci- have evidence of frank hemorrhage on BAL.
dence of chronic progression of ALP seems to In patients without bloody lavage fluid, the
be low enough that prolonged corticosteroid presence of hemosiderin-laden macrophages
or immunosuppressive use is not usually nec- is evidence of recent hemorrhage.16,17 Bron-
essary in patients who recover quickly from choscopic and open lung biopsy specimens
the initial onset of ALP. These patients should show nonspecific interstitial and alveolar wall
be monitored closely for pulmonary decline infiltrates of lymphocytes and neutrophils,
by determining serial pulmonary function edema, and hyaline membranes.15 Hemosid-
every 3 to 6 months. erin-laden macrophages or inflammation of
AH in SLE occurs rarely,6 but it may account small pulmonary arterioles or capillaries
for 3.7% of all SLE-related hospitalizations.15 (known as capillaritis) helps distinguish AH
Although AH can be the initial manifestation from ALP. Direct immunofluorescent staining
may show granular interstitial or endothelial patients with chronic ILD presenting typi-
staining for complement and immunoglobu- cally with cough, dyspnea, radiographic
lins.18 This differentiates AH from Goodpas- interstitial infiltrates or honeycomb changes,
ture syndrome, in which the histopathology and restrictive lung disease pattern on PFTs.
is characterized by a pattern of linear Histologic data are sparse, but include
immunofluorescence. nonspecific interstitial inflammation with
The prognosis of AH is similar to ALP changes of fibrosis.10-12,21 Some patients with
and relates proportionately to the severity at chronic ILD apparently respond to cortico-
presentation.2,3,15-17,19 Treatment recommen- steroids, rarely with marked improvement.
dations are based on case series and anecdotal In our center, we have observed patients
reports, although the early use of plasmaphe- with two different histologic patterns of
resis in severe cases is based on the success of ILD. A young African-American woman
this therapy in Goodpasture syndrome, which with a history of antiphospholipid antibody
is similarly characterized by recurrent AH. The syndrome presented with persistent dys-
core initial therapy is aggressive intravenous pnea and cough over 12 months. Repeated
corticosteroid dosing (1 to 2 mg/kg/day of high-resolution computed tomography (CT)
prednisone or equivalent) or may begin with scans performed during this period showed
intravenous pulse methylprednisolone (1000 transient patchy interstitial infiltrates. Ini-
mg/day 3 days). Early initiation of cyclo- tially, the concern was for recurrent pulmo-
phosphamide is advocated by some centers. nary emboli, even though she was being
Even the addition of this potent immunosup- aggressively anticoagulated. Lung tissue
pressant is not uniformly effective at reversing obtained by video-assisted thoracoscopy open
respiratory failure, however. Some patients lung biopsy showed changes consistent with
hemorrhage recurrently at variable intervals. nonspecific interstitial pneumonitis, however,
Plasmapheresis may be indicated in patients without any evidence of thrombosis or of
who have recurrent hemorrhages even after fibroblastic foci or honeycomb changes. This
starting corticosteroids because this may pro- patient was treated with oral corticosteroids
vide a more rapid onset of immunosuppres- for several months. Her respiratory symptoms
sion than cyclophosphamide. Nonetheless, and scan findings completely resolved.
efficacy data for plasmapheresis therapy are In a second case, an older white woman
lacking. Even the published data for cyclo- with inflammatory arthritis and subacute
phosphamide are conflicting. Some analyses cutaneous lupus presented with progressive
have suggested that cyclophosphamide use is dyspnea, chronic cough, and restrictive lung
a risk factor for AH-associated mortality; how- disease pattern on PFTs. High-resolution CT
ever, these results probably reflect referral bias scan revealed patchy ground-glass findings
because cyclophosphamide is more likely to and honeycomb changes with a peripheral
be used in patients who are more seriously ill. and basilar predominance. A lung biopsy
The frequency and range of expression performed by video-assisted thoracoscopy
of chronic ILD in patients with SLE is not revealed changes consistent with nonspe-
well documented. Chronic ILD probably cific interstitial pneumonia with fibroblastic
affects less than 2% of lupus patients, and foci. In addition, areas of heterogeneous
many of these patients probably have clini- honeycomb scar were noted on lower lobe
cally mild illness.20-22 Some authors have specimens. The patient was treated with cor-
reported chronic ILD developing as a conse- ticosteroids and 12 months of intravenous
quence of ALP.11,14 In some cases, intersti- pulse cyclophosphamide because the lung
tial scarring and restrictive changes on pathology was most characteristic of ILD
pulmonary function tests (PFTs) probably seen in scleroderma (systemic sclerosis).
reflect injury from the acute pulmonary Substantial improvements in respiratory
inflammation. Progressive dyspnea and pul- function (including elimination of her ini-
monary function decline in a subset of tial dependence on supplemental oxygen)
patients, however, probably reflecting more in addition to reductions in ground-glass
classically chronic progressive ILD. Reports opacities on scanning were observed. After
from other authors have described a few a course of cyclophosphamide, the patient
was transitioned to oral azathioprine for the risk.28 In rare cases, chronic thromboembo-
maintenance therapy and has not experi- lism can lead to the development of PAH. In
enced relapse of ILD after 1 year. patients presenting with PAH complicating
Although chronic forms of ILD are rare SLE, careful ventilation/perfusion scanning is
in SLE, they occur occasionally and may necessary to exclude chronic pulmonary
be misdiagnosed as manifestations of SLE. thromboembolic disease.
Careful evaluation, including serial PFTs PAH is not as rare in SLE as previously
and using prone imaging, can increase thought, and is characterized by progressive
diagnostic sensitivity. Most patients should dyspnea and hypoxemia that progresses rap-
undergo open lung biopsy to confirm the idly to right heart failure. PAH may be an
diagnosis; determine the degree of fibros- idiopathic condition typically occurring in
ing interstitial disease; and exclude other healthy young women or may develop sec-
pathology, such as thrombosis, malignancy, ondary to other conditions, including auto-
and chronic infection. Treatment may be lim- immune disease (most commonly seen in
ited to a course of corticosteroids in patients scleroderma), chronic venous thromboem-
with pathology limited to nonspecific intersti- bolism, congenital heart defect resulting in
tial pneumonitis,22 but prolonged courses of arterial-to-venous shunts, human immuno-
cyclophosphamide,23 methotrexate,24 or aza- deficiency virus (HIV), sickle cell disease,
thioprine should be considered in patients prior history of anorexigenic weight loss
with changes of fibrosis on biopsy. drugs, and portopulmonary disease of liver
Patients with SLE are at risk for the failure. Originally considered a rare SLE
development of venous thrombosis and complication, PAH is now recognized to
thromboembolism. Approximately 30% to develop in 1% to 14% of patients.3,29,30 As
40% of patients with SLE have circulating with scleroderma patients, lupus-associated
antiphospholipid antibodies. These anti- PAH has a poor prognosis, with mortality
bodies are associated with an increased risk rates of 50% within 2 years of diagnosis.2
for venous and arterial thrombosis and PAH often is unrecognized in early stages.
pregnancy wastage, particularly late first- Patients typically present with dyspnea on
trimester and second-trimester pregnancy exertion. By the time more alarming signs
loss.25 In patients with antiphospholipid and symptoms develop, most patients have
syndrome (defined as the presence of anti- progressed to substantial, and in some cases
cardiolipin antibodies or lupus anticoagu- irreversible, right heart failure. Risk factors
lant and thrombosis or defined pregnancy for the development of PAH in SLE patients
loss), recurrent thrombosis is common.26,27 are not well defined, although a greater per-
Treatment following a thrombosis requires centage of these patients with PAH report
lifelong anticoagulation, and subsequent preg- Raynaud phenomenon and have measur-
nancies after a loss should be managed with able antiphospholipid antibodies. Signifi-
heparin through 3 to 6 months postpartum. cant right heart failure is suggested by a
Venous thrombosis and thromboembolism constellation of any of the following signs:
are the most common thrombotic complica- syncope, ascites, lower extremity edema,
tions of antiphospholipid antibody syndrome. right ventricular heave, or a right-sided S3
Lupus patients presenting with acute dyspnea, auscultatory sound. Careful evaluation of
with or without pleurisy or hemoptysis, should diagnostic testing increases the sensitivity
undergo immediate evaluation for pulmonary for detecting early PAH. Echocardiogram is
embolus, including ventilation/perfusion or the primary screening tool and should be
spiral CT and lower extremity Doppler ultra- performed in all SLE patients presenting
sound to detect deep vein thrombosis. The with dyspnea. Estimated peak right ventric-
absolute risk for clot in patients with antiphos- ular pressures are often elevated. Signs of
pholipid antibodies and no prior history of right heart strain, such as right atrial or ven-
thrombosis is unknown. Procoagulant risk fac- tricular enlargement and dyskinetic septal
tors, including cigarette smoking, estrogen- motion, strongly suggest PAH, but are
based contraceptive use, and nephrotic-range more common in advanced disease. PFTs
proteinuria from renal disease, likely increase may show a disproportionate decrease in
diffusing capacity for carbon monoxide scleroderma. In the scleroderma group, no

(DLCO) compared with decreases in lung benefit has been observed from the use
volumes.31 In scleroderma patients, serum of immunosuppressive therapy.33 Evidence
brain natriuretic peptide seems to be a sensi- from case reports and retrospective studies
tive and specific marker of PAH in patients in SLE suggest, however, that a subset of
with normal left ventricular function.32 His- patients improve or experience reversal of
topathologic remodeling in PAH in SLE PAH with aggressive immunosuppressive
patients is nonspecific. Vascular lesions therapy incorporating corticosteroids and
include intimal thickening, medial smooth cyclophosphamide.33,34
muscle hypertrophy, and plexiform pathol- In our adult rheumatology clinic, all
ogy, lesions also seen in scleroderma and patients with SLE who develop PAH, exclud-
idiopathic PAH.3 ing PAH resulting from congenital heart
The diagnosis of PAH is suggested by dys- disease or chronic venous thromboembolic
pnea (in the absence of an alternative disease, are treated with six monthly doses
cardiopulmonary explanation) in conjunc- of intravenous pulse cyclophosphamide
tion with an elevated peak right ventricular (1 g/m2/dose) and tapering doses of corti-
systolic pressure on echocardiogram, accom- costeroids. Concomitant treatment with
panied by possible elevations of the forced standard PAH drugs is initiated in all
vital capacity (FVC)-DLCO ratio and serum patients with significant clinical symptoms
brain natriuretic peptide levels. The confir- (World Health Organization class III and
matory diagnostic test that is considered a IV) or with 6-minute walk distance test less
gold standard is a right heart catheteriza- than 320 meters. In patients with mild dis-
tion. The catheterization findings outlined ease (World Health Organization class I
in Table 10-2 confirm the diagnosis of and II) who have good 6-minute walk dis-
PAH. Because of the co-occurrence of shunts tance test, PAH drugs may be held while
resulting from congenital heart disease in the patient is treated with immunosuppres-
children, an experienced pediatric cardiolo- sion, provided that the patient is followed
gist or critical care specialist should perform carefully with monthly visit, quarterly echo-
the right heart catheterization. Echocardio- cardiograms, and 6-minute walk tests.
grams are insensitive instruments to detect Shrinking lung syndrome is a rare com-
shunts; a careful right heart catheterization plication of SLE, although it is possible
is crucial in all patients with suspected PAH. that mild cases may go undiagnosed.35,36
When SLE patients are diagnosed with Patients characteristically present with pro-
PAH, chronic venous thromboembolic dis- gressive dyspnea and a restrictive lung
ease should be carefully considered. Stan- pattern on PFTs.36 Orthopnea is a unique
dard treatment of all SLE patients with clinical feature of shrinking lung syndrome.
PAH includes anticoagulation, but the DLCO may or may not be decreased. Chest
level of anticoagulation may need to be radiographs reveal elevated diaphragms
increased for patients with antiphospho- and bibasilar atelectasis. This finding may
lipid antibodies who have developed clots. be present, however, even when there is
Treatment for SLE-associated PAH differs no evidence of parenchymal or pleural dis-
from treatment of PAH in patients with ease. The differential diagnosis includes
Table 10-2 Diagnostic Features of Pulmonary Artery Hypertension on Right Heart Catheterization
RIGHT HEART CATHETERIZATION RESULT CONFIRMING PULMONARY

MEASUREMENT ARTERY HYPERTENSION*
Elevated mean pulmonary arterial pressure >25 mm Hg at rest (>30 mm Hg with exercise)
Normal pulmonary capillary wedge pressure <15 mm Hg
Elevated pulmonary vascular resistance >3 Wood units
*All features are necessary to confirm diagnosis of pulmonary artery hypertension.

ILD; this does not show inflammatory or the diagnosis. Treatment typically is initiated
fibrotic changes, however. ILD is not a fea- with corticosteroids, which are usually effec-
ture of shrinking lung syndrome. The cause tive.2,41 The etiology of BOOP in SLE is uncer-
of shrinking lung syndrome is likely to be tain, but may be induced by infection.
multifactorial. In a few cases, progressive Primary upper airway disease in SLE is
pleural fibrosis results in restrictive lung extremely rare. A few authors have sug-
disease. More recent studies suggest that gested an increased risk for postintuba-
at least some patients have reduced lung tion subglottic stenosis. Extra care may be
volumes secondary to diaphragmatic and required for SLE patients after extubation.
intercostal muscle weakness.37,38 Obstructive lung disease is uncommon in
Although this condition was previously SLE. Some patients develop esophageal dys-
considered relentlessly progressive, most motility, however, similar to that seen in
cases of shrinking lung syndrome seem to scleroderma. As a result, the lower esopha-
have a good prognosis, stabilizing or some- gus can become patulous, resulting in an
times spontaneously improving over time. increased risk for aspiration, particularly
For symptomatic patients, a trial of cortico- at night when the patient sleeps prone.
steroids is indicated, although the response Common symptoms of aspiration include
rates from limited published data are uncer- nocturnal cough and wheezing. PFTs may
tain.36,39 Occasionally, progressive dyspnea show a decreased forced expiratory volume
and loss of lung volumes requires cyto- in 1 second (FEV1)/FVC ratio. A decreased
toxic treatments, such as azathioprine or DLCO in the setting of preserved lung
cyclophosphamide.40 Little is known about volumes also may suggest chronic aspira-
shrinking lung syndrome in pediatric SLE, tion. Esophageal dysmotility is often evident
with only a few cases reported.40 In our on barium swallow, although incidental
clinic, we care for a boy with shrinking detection of a patulous esophagus may occur
lung syndrome and concomitant valvulitis with chest CT scans ordered to exclude
requiring a valvular replacement. ILD. High-resolution CT may show patchy
The airways are infrequently affected in SLE ground-glass opacities in the right lower lobe.
(Table 10-3). Rare cases of bronchiolitis oblit- Treatment includes aggressive acid-reducing
erans with organizing pneumonia (BOOP) therapy, preferably with proton-pump inhib-
have been reported.2,3,41,42 BOOP lesions are itors. In addition, antiaspiration interven-
characterized histologically by inflammatory tions (Table 10-4) and prebedtime doses of
changes within the distal airways and alveoli metoclopramide to enhance lower esopha-
associated with nonspecific bronchiolar geal and gastric emptying may benefit some
inflammation. Patients present with dyspnea patients.
caused by a restrictive ventilatory deficit. Patients with SLE have immunocompro-
Fever, interstitial infiltrates, and cough may mise, placing them at risk for respiratory tract
be part of the initial presentation. In most infection, often with opportunistic organisms.
cases, open lung biopsy is needed to confirm Compromised immune responsiveness in
Table 10-3 Rare Airway Diseases in Systemic Lupus Erythematosus
PATHOLOGY ESTIMATED PREVALENCE

Upper Laryngeal inflammation Rare
airway Epiglottitis Rare
Subglottic stenosis Rare, may be risk in postextubation period
Lower Reactive airway disease Rare, may be associated with reflux and aspiration
airway in patients with esophageal dysmotility
Bronchiolits obliterans with Probably rare
organizing pneumonia
carinii) also have been cultured from the lungs

Managing Aspiration Associated
Table 10-4 with Esophageal Dysmotility of these patients. Patients with immune dys-
function and patients receiving immunosup-
PATHOLOGY INTERVENTION pressive therapy should receive routine
Acid reflux and Proton-pump inhibitor; may trimethoprim-sulfamethoxazole prophylaxis.
aspiration require dose titration to
eradicate symptoms of
heartburn
Aspiration Raise the head of the bed 2-4
Drug-Induced Lupus
inches
Avoid bed wedges, multiple The development of DIL syndromes has
pillows been most strongly associated with pro-
Nothing to eat or drink within cainamide, hydralazine, and phenytoin.
3-4 hr of going to bed Through various mechanisms, these agents
Avoid caffeinated beverages after induce autoreactive immune responses in
dinner
some patients, resulting in clinical lupus-like
Esophageal Prokinetic therapy, preferably
dysmotility metoclopramide, taken before disease. Other agents have been associated
bedtime; additional dose of with lupus-like conditions (Table 10-5) that
metoclopramide before dinner are more heterogeneous than classic DIL.
may be necessary
Pleuropulmonary manifestations, particu-
larly pleurisy and pleural effusions, are the
SLE is a result of abnormalities of complement most common clinical features of DIL; other
or cell-mediated immunity, reduced pulmo- features include arthralgia, fever, and, less
nary macrophage and phagocytic function, commonly, rash.43 Most affected patients
treatment with medications (corticosteroids also develop autoantibodies, including anti-
and immunosuppressive agents), and compro- nuclear antibodies (ANAs) and antihistone
mised airway clearance resulting from airway antibodies. After discontinuation of the
inflammation and weak cough (respiratory offending drug, the clinical manifestations
muscle weakness). The most common organ- are self-limited in most cases. Treatment
isms responsible for respiratory tract infection is typically conservative, using NSAIDs
in SLE patients include Klebsiella aerobacter, and occasionally corticosteroids to manage
Escherichia coli, and b-hemolytic streptococ- symptoms.
cus. Candida albicans, Aspergillus species, and Chronic SLE and internal organ involve-
Pneumocystis jiroveci (formerly Pneumocystis ment, particularly central nervous system
Table 10-5 Agents Associated with Drug-Induced Lupus Syndromes
STRENGTH OF ASSOCIATION WITH PLEUROPULMONARY

DRUG-INDUCED LUPUS AGENT MANIFESTATIONS (%)
Strong Procainamide 75
Hydralazine 25
Phenytoin Probably uncommon
Moderate Isoniazid Uncommon
Methyldopa Uncommon
Penicillamine Uncommon
Quinidine Uncommon
Minocycline Uncommon
Tumor necrosis factor-a Uncommon
inhibitors
Weak Statins Uncommon
Interferons Uncommon
Terbinafine Uncommon
Zafirlukast Uncommon
or renal disease, are very unusual complica-

Kasukawa Criteria for Diagnosis
tions of DIL. Antihistone antibody titers Table 10-6 of Mixed Connective Tissue
often decrease as DIL wanes, but ANA titers Disease*
may remain elevated indefinitely and are 1. Raynaud phenomenon or swollen fingers or
not worthy of serial assessment. In rare hands, or both
cases, usually with procainamide, pulmo- 2. Antiribonucleoprotein antibody positive
nary parenchymal disease may develop and 3. At least one feature from two of the following
even be associated with pulmonary fibro- three categories
sis. Aggressive immunomodulatory therapy SLE features
is not typically indicated, however, even Polyarthritis
in these settings. Because DIL may take Facial rash
weeks to months (rarely up to a year) to Serositis
resolve, patients with pulmonary manifes- Lymphadenopathy
tations, particularly dyspnea or abnormal Leukopenia
PFTs, should be monitored on a regular Thrombocytopenia
basis. Pulmonary manifestations with drugs Scleroderma features
less traditionally associated with DIL, such Sclerodactyly
as minocycline, are less common and should Esophageal dysmotility
be viewed as potential manifestations of Pulmonary fibrosis
another pulmonary process or evidence of Vital capacity <80% of normal
chronic SLE that has been unmasked by Diffusing capacity <70% of normal
the drug. Dermatomyositis features
Muscle weakness
Elevated serum muscle enzymes
Mixed Connective Tissue EMG abnormalities of myositis
Disease *Must meet all three criteria to be diagnosed with mixed
connective tissue disease.
Mixed connective tissue disease (MCTD) is EMG, electromyogram; SLE, systemic lupus erythematosus.
From Kasukawa R, Tojo T, Miyawaki S: Preliminary diagnostic
categorized as an overlap syndrome because criteria for classification of mixed connective tissue disease.
patients manifest features that are character- In Kasukawa R, Sharpe G, eds: Mixed Connective Tissue
Disease and Antinuclear Antibodies. Amsterdam, Elsevier,
istic of multiple defined autoimmune dis- 1987, pp 41-47.
orders (Table 10-6). They often develop
a mixture of features of SLE, rheumatoid
arthritis, and dermatomyositis. The defining
serologic feature of MCTD is the pres- and PAH are the most common and clini-
ence of antiribonucleoprotein autoanti- cally important forms (Table 10-8).51,53-59
bodies. Table 10-7 lists the most common Pleuritis occurs occasionally, a distinct dif-
clinical findings.44-50 In MCTD, serious ference from SLE, but rarely MCTD can be
complications of lupus, such as nephritis associated with large, symptomatic pleural
or central nervous system pathology, are effusions.60 Patients typically are managed
unusual. Consequently, MCTD is generally with NSAIDs for mild to moderate pleuritis
regarded as having a better prognosis, or corticosteroids for large symptomatic
provided that inflammatory muscle disease effusions. Rarely, venous thromboembolic
and deforming synovitis can be controlled disease associated with antiphospholipid
with immunomodulatory therapy.13 Pro- antibodies may occur. Progressive esopha-
spective cohort studies now suggest, how- geal dysmotility is far more common in
ever, that the insidious development of MCTD than in SLE, and increases the risk
ILD or PAH results in a substantial increase for aspiration pneumonia or chronic aspira-
in morbidity and mortality for a subset tion–associated bronchoconstriction or mild
(approximately 20% to 30%) of patients pulmonary fibrosis. The management of
with MCTD.51 antiphospholipid antibody syndrome and
There are many reported pleuropulmon- esophageal dysmotility in MCTD is identical
ary manifestations of MCTD. ILD, pleuritis, to that in SLE patients.
Table 10-7 Clinical Manifestations of Mixed Connective Tissue Disease
CLINICAL FEATURE FREQUENCY IN ADULTS (%) FREQUENCY IN CHILDREN (%)

Inflammatory arthritis 95 82-93
Myositis 63 47-61
Pulmonary disease 20-80 35-60
Raynaud phenomenon 85 85-94
Skin rash 38 33-38
Esophageal dysmotility 67 21-41
Hepatosplenomegaly 15-19 29
Serositis 43 23-28
Antiribonucleoprotein antibody 100 100
Rheumatoid factor 70 57-68
Inflammatory and fibrosing ILD affects symptomatic improvement and decreased

66% of patients with MCTD.61 Most patients lung volumes and DLCO on follow-up PFTs
with abnormally low lung volume or DLCO (within 3 months), the addition of cyclo-
on PFTs are asymptomatic, although an phosphamide should be considered. Mostly
unknown subset of these patients develop small, retrospective reports and case studies
progressive interstitial inflammation and seem to support the efficacy of cyclophos-
pulmonary fibrosis. The lower rate of pro- phamide.57,61,63 In patients presenting with
gressive pulmonary fibrosis differentiates significant pulmonary functional loss, sub-
lung disease in MCTD from ILD in sclero- stantial fibrosis, and intensely inflammatory
derma, which progresses to marked fibrosis BAL fluid, or a rapidly progressing course,
and severe pulmonary functional decline in the clinician should consider combination
a greater portion of patients.62 Patients with therapy with corticosteroids and cyclophos-
MCTD who develop ILD typically present phamide at the outset of treatment.
with progressive dyspnea on exertion. Dry Our center uses the same treatment regi-
cough also is reported. PFTs most commonly men in scleroderma-associated ILD and mod-
show a restrictive pattern with reduced lung erate to severe ILD associated with MCTD,
volumes and decreases in DLCO. PFTs are which incorporates intravenous pulses of
considered to be more sensitive technol- cyclophosphamide (0.5 to 1 mg/kg/mo) with
ogy for detecting ILD. Characteristic high- tapering doses of corticosteroids. The most
resolution CT scan findings include septal appropriate duration of cyclophosphamide
thickening and ground-glass opacities with therapy is unknown at this time for ILD asso-
peripheral and basilar lung zone predomi- ciated with MCTD. Our center administers
nance. Traction bronchiectasis and honey- 6 to 12 monthly doses depending on the
comb changes form later in the disease severity of the lung disease and the quality
process, typically with a basilar, subpleural of the initial clinical response. Corticosteroids
distribution. As in scleroderma-associated may induce scleroderma-renal crisis; their
ILD, rare cases of ILD associated with MCTD use in scleroderma lung disease should be
may manifest with dyspnea and abnormal minimized or used cautiously. Because of
PFTs, but normal-appearing chest x-ray. BAL the low risk of scleroderma renal crisis in
may be a useful diagnostic tool in this MCTD, initial corticosteroid doses are more
setting. Most patients with ILD show a neu- aggressive, beginning at 1 mg/kg/day and
trophilic or eosinophilic predominance in tapering over 3 to 6 months. Patients should
the cell count differential. be monitored closely with at least quarterly
Treatment of ILD in patients with MCTD PFTs and scans at least every 6 months. Serial
depends on the severity of the process at 6-minute walk tests provide a useful measure
the time of diagnosis. Most cases seem to be of changes in functional capacity. In addition,
mild, so corticosteroids are the initial immu- measuring pulse oximetry during the test can
nosuppressant of choice. In patients without assess the need for supplemental oxygen.
214
Table 10-8 Pulmonary Manifestations of Mixed Connective Tissue Disease

PLEUROPULMONARY FREQUENCY DIFFERENTIAL
DISEASE (%) CLINICAL FEATURES DIAGNOSTIC TESTING DIAGNOSIS TREATMENT
Pleuritis and pleural 20 Pleurisy, dyspnea CXR PE, angina, chest wall NSAIDs, corticosteroids
effusion disease, infection
ILD 20-50 Often asymptomatic; cough, PFTs, BAL, open-lung PAH, aspiration, infection Corticosteroids with
dyspnea biopsy or without CYC
PAH 20-30 Dyspnea, right heart failure Echocardiogram, PFTs, ILD, pulmonary venous Vasodilators and
BNP hypertension (left heart antiproliferative agents
disease, pulmonary (ETRAs, prostanoids,
fibrosis), CVTED phosphodiesterase type
5 inhibitors)
Immunosuppression—
corticosteroids with or
without CYC
Venous Rare Acute dyspnea, pleurisy, cough, Spiral CT, ventilation/ Infection, vasculitis, Anticoagulation
thromboembolic hemoptysis perfusion scan, pleuritis
disease D-dimer,
antiphospholipid
antibody testing
Aspiration Rare Acute dyspnea with cough, CXR, PFTs, BAL, barium Infection, ILD Aspiration/reflux therapy,
pneumonitis classically right lower lobe swallow antibiotics
infiltrate, fever; can progress to
ARDS
Alveolar hemorrhage Rare Acute dyspnea, patchy acinar CXR, BAL, serial Infection, PE, Corticosteroids, CYC
infiltrates with bibasilar hemoglobin Goodpasture syndrome,
predominance, fever, hemoptysis, SNV
rapid decline in hemoglobin
Pulmonary vasculitis Rare Dyspnea, hemoptysis, patchy PFTs, open-lung biopsy Alveolar hemorrhage, PE, Corticosteroids, CYC
interstitial or alveolar infiltrates infection, SNV; may be
cause of PAH
Obstructive airways Rare Wheezing, cough; nocturnal PFTs, barium swallow Likely associated with Aspiration/reflux therapy,
disease symptoms may predominate if reflux/aspiration from bronchodilators, consider
aspiration is the cause esophageal dysmotility corticosteroids
BAL, bronchoalveolar lavage; BNP, brain natriuretic peptide; CVTED, chronic venous thromboembolic disease; CXR, chest radiograph; CYC, cyclophosphamide; ETRAs, endothelin receptor
antagonists; ILD, interstitial lung disease; NSAIDs, nonsteroidal anti-inflammatory drugs; PAH, pulmonary arterial hypertension; PE, pulmonary embolism; PFTs, pulmonary function tests;
SNV, systemic necrotizing vasculitis.
In children, ILD has been reported in mild in MCTD management. PAH may develop
and severe forms. There is no evidence for 20 years after diagnosis.71
a difference in the prevalence or clinical PAH in patients with MCTD has rarely been
characteristics of ILD in children compared reported to improve with immunomodula-
with adults with ILD. Because ILD in this tory therapy.33,34,67,69 Because responsiveness
disease tends toward pulmonary fibrosis, it to immunosuppression is not characteristic of
is important to monitor all patients for ILD PAH in scleroderma, it is possible that some
with frequent PFTs, preferably every 3 to patients with MCTD may develop PAH as a
6 months in the first few years after diag- consequence of an immune-mediated inflam-
nosis, and then annually. Patients who matory process, such as a vasculitis. To date,
develop dyspnea and restrictive pattern there are no substantiating pathologic data
on PFTs should undergo or experience a to support this hypothesis. The rate of
decrease in DLCO. If the result is unremark- response to immunosuppressive therapy sug-
able, and no other explanation is available gests, however, that treatment of PAH in
for the pulmonary decline, BAL is indicated patients with MCTD should incorporate a
to confirm the presence of interstitial course of corticosteroids and intravenous
inflammation. In these cases, BAL also may pulse cyclophosphamide for 3 to 6 months.34
be a useful outcome measure, especially if In our center, all patients with MCTD are
the scan fails to show changes. concomitantly treated with standard vasoac-
The leading cause of death in MCTD is tive medications, such as endothelin receptor
PAH.51 PAH is now recognized to develop antagonists or phosphodiesterase type 5 inhi-
in nearly one third of MCTD patients bitors. We may initiate parenteral prostanoid
and has been reported in children and therapy (continuous subcutaneous treprosti-
adults.47,51,64-69 Postmortem studies have nil or continuous intravenous epoprostenol)
shown intimal proliferation and medial in patients with rapidly progressing PAH,
smooth muscle hypertrophy in the small fulminant or severe right heart failure, or
vessels of the lungs, occasionally associated extremely poor functional status. At present,
with superimposed thrombosis and plexi- there is no clear evidence of efficacy or safety
form lesions.70 The histologic features in favoring any single PAH treatment in MCTD.
MCTD are identical to the features observed
in PAH patients with scleroderma. Because
antiphospholipid antibody syndrome is far Sjögren Syndrome
less common in patients with MCTD, PAH
developing as a consequence of chronic Sjögren syndrome is a chronic autoimmune
venous thromboembolic disease is unlikely. disease that primarily affects the lacrimal and
In all patients who develop PAH, routine salivary glands. The cardinal clinical features
screening for underlying causes of second- are parotitis, keratoconjunctivitis sicca, and
ary PAH should be done, including screen- xerostomia; there is variable systemic involve-
ing for chronic venous thromboembolic ment. Clinical manifestations include dry
disease, HIV, sickle cell disease, and congen- eyes, dry mouth with oral ulcerations, dental
ital heart disease. The natural history of PAH caries, salivary gland swelling, difficulty swal-
in MCTD is unclear. Although there are rare lowing, vulvovaginitis, and gastrointestinal
reports of remission in patients treated with problems. The hallmark autoantibody find-
immunosuppressive and other drugs, pro- ings include a positive ANA, Ro (SS-A), La
gressive PAH followed by right heart failure (SS-B), and rheumatoid factor (RF). Addition-
is the leading cause of death in MCTD. ally, patients with Sjögren syndrome often
PAH progresses more rapidly in patients have an elevated erythrocyte sedimentation
with underlying connective tissue disorders rate and hypergammaglobulinemia. Similar
than in patients with idiopathic PAH. to other autoimmune diseases, it affects
Annual screening with echocardiogram, females significantly more often than males,
PFTs, serum brain natriuretic peptide, and with a ratio of approximately 9:1. Sjögren
6-minute walk test is a key component syndrome may occur alone (primary) or in
association with other connective tissue dis-

eases, such as rheumatoid arthritis, SLE, and
systemic sclerosis (secondary).
In the pediatric population, Sjögren syn-
drome is extraordinarily rare with a mean age
of onset of 10 years.72 A review of 145 pediatric
cases revealed parotid enlargement in 70%, eye
involvement in 66%, and xerostomia in 43%.
A positive ANA was detected in 78%. Antibod-
ies to Ro, La, and RF were positive in 74%, 65%,
and 66% of patients. Depending on which
modality is used, pulmonary involvement in
adult Sjögren syndrome has been estimated at
9% to 75%. In contrast to adults, pulmonary
involvement is rare in children.
Pulmonary involvement can manifest clini-
cally with progressive dyspnea and dry cough.
Physical examination may reveal bibasilar
crackles; digital clubbing is usually absent.
PFTs typically reveal a restrictive pattern with
diminished DLCO. Chest radiographs are less
sensitive than high-resolution CT, but may
show reticular or nodular opacities. Findings
include ground-glass opacities, honeycomb-
ing, lung cysts, consolidation, and bronchi-
ectasis. A CT scan from a patient with
Sjögren syndrome is shown in Figure 10-3.
Although BAL is not routinely warranted, it
may assist in excluding an infectious etiol-
Figure 10-3. CT scan of the chest shows diffuse ground-
ogy. BAL can show evidence of lymphocytic glass opacities with parenchymal cysts in a patient with
or neutrophilic alveolitis, the latter asso- Sjögren syndrome and interstitial lung disease.
ciated with more progressive disease. Various
histopathologic patterns are seen, including
lymphocytic interstitial pneumonia, nonspe-
cific interstitial pneumonia, usual interstitial
pneumonia, cryptogenic organizing pneu-
monia, primary pulmonary lymphoma, and
fibrosis. The hallmark finding on lung histo-
pathology is a CD4þ polyclonal lymphocytic
and plasma cell infiltrate. Figure 10-4 shows
pulmonary histopathology from a patient
with Sjögren syndrome who shows a lympho-
cytic interstitial pneumonia pattern.
Treatment of ILD in Sjögren syndrome cen-
ters on immunosuppression, usually with sys-
temic corticosteroids. No controlled trials have
examined the efficacy of alternative immuno-
suppressive agents, such as azathioprine, cyclo-
sporine, and cyclophosphamide. Treatment
needs to be adjusted depending on the severity Figure 10-4. Lung biopsy histopathology specimen
from a patient with Sjögren syndrome. The pattern is that
of disease and the presence or absence of other of a patchy and nodular diffuse lymphoid interstitial
systemic features. pneumonitis.
involvement in children with JRA are sparse.

Juvenile Rheumatoid A study of 191 patients with JRA at a single
Arthritis academic center identified evidence of lung
or pleural involvement in 4% of children.4
Juvenile rheumatoid arthritis (JRA) is a Most of the children (75%) had systemic-
chronic inflammatory disease of unclear onset JRA.76 A smaller study examined the
etiology, which can manifest with articu- prevalence of PFT abnormalities in patients
lar and extra-articular involvement. The with JRA and found asymptomatic abnormal
American College of Rheumatology (ACR) PFTs in 60%, half of whom had subnormal
has classified JRA into three subtypes73: DLCO.77 Only one patient had an abnormal
(1) polyarthritis characterized by involve- chest radiograph. In contrast, PFT measure-
ment of five or more inflamed joints, (2) oli- ments in a separate population of JRA patients
goarthritis with involvement of fewer than did not identify any differences between
five inflamed joints, and (3) systemic onset DLCO, total lung capacity (TLC), or FEV1
with features of arthritis and characteristic compared with controls.83 Children with JRA
fever.73 Systemic-onset JRA is most com- had lower FVC and peak expiratory flow rates,
monly associated with extra-articular mani- which were attributed to respiratory muscle
festations, but the other subtypes may be weakness rather than intrinsic lung disease.
complicated by nonarticular organ involve- Pleuropulmonary manifestations of JRA
ment. Lung involvement, although uncom- can manifest indolently and can precede the
mon, can have deleterious consequences onset of arthritis.78,84-90 Data, particularly
when not recognized and treated. those obtained from PFTs, suggest that there
The pleuropulmonary manifestations of may be a prodromal period of asymptomatic
JRA can be classified as involvement of the disease.77,83 No longitudinal studies have
parenchyma, airways, pleura, and pulmonary assessed the significance of abnormal PFT
vasculature.74,75 These manifestations include measurements in children with JRA. The
parenchymal or pleural infection, interstitial available data suggest that the prevalence of
pneumonia/pneumonitis (IP), interstitial fi- lung disease remains low in these patients.76
brosis, BOOP, rheumatoid nodules, bronchi- In circumstances where pleuropulmonary
ectasis, chronic obstruction, obstructive involvement precedes onset of arthritis,
bronchiolitis, pleuritis, pleurisy, pulmonary patients can present with cough, dyspnea,
vasculitis, and PAH.74,75 When referring and tachypnea.84,85,87,90 A prior history
to the involvement of lung parenchyma, the of recurrent pulmonary infiltrates, often
term “interstitial lung disease” has been treated as infections, has been reported.85,90
applied. The pulmonary toxicities of medica- Patients with a known diagnosis of JRA can
tions used to treat JRA (discussed subse- present with similar subjective symptoms
quently) can add a level of complexity when of cough, dyspnea, and tachypnea in addi-
assessing the impact of the disease. tion to chest pain.76,78,86,88,91,92 Physical
In contrast to adults with rheumatoid examination findings may reveal digital
arthritis, lung involvement in JRA histori- clubbing, cyanosis, bibasilar crackles on
cally has been seen with much less fre- chest auscultation, nasal flaring, tachycar-
quency.76-78 Pleuropulmonary involvement dia, tachypnea, and hypoxia.76,78,84-88,90-92
has been reported in 1% to 40% of adults The presence of clubbing is often an indica-
with rheumatoid arthritis.79 This range is tor of prolonged disease.
influenced by the method used to detect evi- Occasionally, the objective physical
dence of lung disease. Earlier studies relied examination findings can be difficult to
on data obtained from chest x-rays and interpret in the setting of active arthritis,
PFTs.79 The use of high-resolution CT of the especially in patients with systemic-onset
chest has improved our ability to identify lung JRA. These patients can have a febrile illness
disease.80-82 In a prospective assessment of associated with arthritis, rash, lymphade-
150 rheumatoid arthritis patients, 20% had nopathy, hepatosplenomegaly, elevated
findings on CT consistent with ILD.81 Data inflammatory markers erythrocyte sedi-
on the prevalence of pleuropulmonary mentation rate, and C-reactive protein,
leukocytosis, and serositis.73 Under these in an asymptomatic child may be of limited

circumstances, it is important to be vigilant clinical utility.
for other mimics of chronic inflammatory Findings include pleural effusions, patchy
arthritis, such as infection and malignancy. pulmonary infiltrates, reticulonodular infil-
If the physical examination suggests a pleur- trates, and alveolar infiltrates with air
opulmonary process, it is advisable to assess bronchograms.76,78,84,85,87,88,90,91,93 One pa-
the problem thoroughly. tient presented with a pneumomediastinum
The use of PFTs for diagnosing and screen- in the setting of organizing bronchiolitis.93
ing for pleuropulmonary disease in JRA Other findings include ground-glass opaci-
is of paramount importance. A diminished ties, reticular lesions, honeycombing, intra-
DLCO has been observed in 0% to 30% lobular septal thickening, bronchiectasis,
of children with JRA.77,83 In controlled consolidations, pleural effusions, pleural
studies, significant decreases of FVC and peak irregularities, and mediastinal lymphade-
expiratory flow have been observed, but were nopathy.80,91,93
attributed to respiratory muscle weakness.83 Studies using high-resolution CT scan of the
Most PFT abnormalities can be described as chest have shown the greater sensitivity of this
restrictive lung defects with impaired diagnostic study compared with conventional
DLCO.78,84,85,87-90 An isolated depression of chest radiographs in detecting ILD.80,81 High-
DLCO can be seen independently of restric- resolution CT provides the opportunity to
tive or obstructive lung physiology.86 The lack detect ILD at an earlier stage and potentially
of longitudinal PFT assessment studies in JRA to improve long-term prognosis.
has limited the ability to interpret these find- The pleuropulmonary manifestations of
ings. Several case reports have documented JRA can be categorized as manifestations
improvement or stabilization of PFTs in chil- involving the pleura, parenchyma, airways,
dren with JRA over time, many of whom were or vasculature. In contrast to adults with
treated with immunosuppressive ther- rheumatoid arthritis–related ILD, pulmo-
apy.76,86,87,90,92 Progressively worsening PFTs nary rheumatoid nodules are rare in chil-
portend greater morbidity and mortality.85,87 dren with JRA.73,78,94 Rheumatoid nodules,
An additional use of PFTs is to focus on which are usually present at the elbows
the assessment of PAH. Although uncom- and distally, are classically seen in patients
mon in patients with JRA, primary PAH who are RF-positive. Histologic examination
has been seen in a child with systemic- of a rheumatoid nodule is characterized by a
onset JRA.86 In this patient, all parameters central area of fibrinoid necrosis surrounded
of pulmonary function were normal except by palisading epithelioid histiocytes, which
for DLCO, which was 35% of normal. The is surrounded further by a matrix of lym-
authors have seen two patients whose phocytes, plasma cells, and fibroblasts.75,95
course of systemic-onset JRA was compli- Most children with JRA are RF-negative.73
cated by PAH. Both patients died as a result Population-based estimates have docu-
of their disease. Although PFTs may suggest mented positive RF in 3% to 42% of
PAH, the diagnosis is confirmed by direct children with JRA.96,97 The greater presence
measurement of pulmonary arterial pressure of positive RF was seen in an aboriginal
by a right heart catheterization. Canadian population with a known HLA
Chest radiographs have frequently failed association with rheumatoid arthritis.97 Of
to provide important qualitative descrip- children who have a positive RF, most are
tions or indications of disease severity in adolescents and have a polyarticular course
rheumatoid arthritis.74,81 Of 28 adults with that mimics adult rheumatoid arthritis.73
rheumatoid arthritis with evidence of ILD, When feasible, pleural fluid assessment
only 36% had abnormal chest radiographs. can help identify the underlying cause of
Multiple case reports of children with active pleuritis. Pleural fluid suggestive of an exu-
pleuropulmonary manifestations of JRA dative rheumatoid effusion is often charac-
showed objective abnormal findings on terized as follows: lymphocyte-predominant
chest radiographs, however.76,78,84,87,88,90-92 leukocytosis (100 to 7000 cells/L), low
Using a chest radiograph to screen for JRA glucose (<50 mg/dL), elevated lactate
dehydrogenase (>1000 IU/L), elevated pro- lymphoid bronchiolitis, isolated lymphoid

tein (>4 g/dL), and depressed comple- bronchiolitis, BOOP, IP with thickened
ments.75,95 It is necessary to exclude alveolar septa, and septal lymphocytic IP
infection because this is also one of the few with prominent lymphoid follicles and ger-
conditions associated with low pleural fluid minal centers.76,84,85,88,90,93 An adolescent
glucose levels. In patients with systemic- girl with seropositive JRA complicated by
onset JRA, pleuritis is the most common small vessel vasculitis developed ILD with
pleuropulmonary complication.73,76 evidence of severe pulmonary fibrosis and
BAL offers potential advantages in assess- arteritis of the pulmonary vessels on lung
ing ILD in JRA. It allows for analysis of biopsy specimen.87 The family history was
inflammatory cells, and can aid in excluding positive for seropositive JRA with ILD in the
infectious etiologies in acute and chronic patient’s mother. One child with systemic-
processes. Compared with open lung biopsy, onset JRA who was RF-negative developed
it is less invasive. Studies in adults with rheu- pulmonary interstitial and intra-alveolar
matoid arthritis–related ILD have shown cholesterol granulomas, also called “lipoid”
poor correlation between BAL findings and pneumonia.91 Whether this pneumonia was
PFTs.80,82 There was a trend toward increased related to the underlying disease or therapy
numbers of neutrophils in patients with was unclear because the patient had been
usual interstitial pneumonia compared with treated with chlorambucil, cyclophospha-
nonspecific interstitial pneumonia. Overlap mide, and methotrexate. A child with sero-
was noted on BAL findings, however, in negative systemic-onset JRA underwent
patients with usual interstitial pneumonia lung biopsy with objective evidence of
and patients with inflammatory airway PAH.86 Histology showed pulmonary vascu-
disease with organizing pneumonia. These lar obstruction with findings of intimal
findings highlight the difficulty in inter- fibrosis of the small and medium-sized
preting BAL specimens, but do not obviate pulmonary arteries. Postmortem pleuropul-
the utility of BAL to exclude infection. monary evaluation of 16 patients with a
Lung biopsy remains the gold standard known diagnosis of JRA found radiographi-
for assessing pleuropulmonary disease in cally and clinically detectable pulmonary
JRA. An appropriate sample can provide lesions in 70%.94 Gross assessment showed
information about parenchymal, pleural, lung edema in 13 patients, pleural effusions
airway, and vascular involvement. Although in 3 patients, and pulmonary amyloidosis in
a lung biopsy is not necessary in every JRA 3 patients, and no pulmonary nodules.
patient with an acute pulmonary process, it Most of the patients died of complications
should be considered in circumstances of amyloidosis, and many had multiorgan
in which therapy is predicated on discerning failure that may have contributed to the
between an aseptic inflammatory process, an pulmonary findings at autopsy.
infectious process, and a vascular process. The pathogenesis of pleuropulmonary
Most, but not all, children with JRA with disease in JRA is incompletely understood.
biopsy-proven pleuropulmonary disease Data collected from adults with rheumatoid
are RF-positive.76,84-88,90,91 Lung biopsy speci- arthritis suggest aberrant T cell and B cell
mens were obtained in patients who activation in patients with extra-articular
had radiographic evidence of parenchymal disease.98,99 Patients with rheumatoid ar-
disease.76,84,85,87,88,90,91 In one patient who thritis with interstitial pneumonitis (usual
was diagnosed with primary PAH, a lung bi- interstitial pneumonia or nonspecific inter-
opsy specimen was obtained to exclude vascu- stitial pneumonia) have significantly greater
litis in the setting of normal imaging studies.86 levels of CD4þ T cells and, to a lesser extent,
The predominance of lung biopsy specimens CD3þ cells on lung biopsy specimens
obtained from patients with parenchymal dis- compared with patients with idiopathic IP,
ease adds an element of selection bias, partic- suggesting a possible crucial role of CD4þ
ularly with regard to assessing pleural disease. T cells in the pathogenesis of rheumatoid
Findings on lung biopsy have shown arthritis–associated IP.98 Similarly, patients
lymphoid interstitial pneumonitis, IP with with rheumatoid arthritis with IP have
increased numbers of CD20þ B cells on lung found with JRA, it should be treated similarly
biopsy specimens.99 Aggregates of CD20þ B to PAH associated with scleroderma, with
cells were found predominantly in a peri- emphasis on the use of pulmonary vaso-
bronchiolar distribution. The central role dilators used in idiopathic PAH. Even with
of B lymphocytes in the pathogenesis of advances in therapeutics, however, it is
rheumatoid arthritis has been well described important for care providers and families to
and is supported by the effectiveness of recognize that the pleuropulmonary mani-
targeted B cell therapy in patients with festations of JRA can be fatal despite aggres-
rheumatoid arthritis.100-103 Whether these sive immunosuppressive therapy.87,91,94
findings suggest a direct role of B cells in
the pathogenesis of rheumatoid arthritis–
related IP remains to be determined. In addi- Scleroderma
tion, patients with rheumatoid arthritis
with IP have greater numbers of mast cells The cardinal clinical characteristic of sclero-
on lung biopsy specimens.104 It is unclear derma (also known as systemic sclerosis) is
whether the increased presence of mast cells fibrous involvement of skin. Scleroderma
is secondary to elevated CD4þ T cells or in children is divided into two distinct
underlying pulmonary fibrosis. It is possible clinical categories, juvenile localized sclero-
that mast cells or mast cell mediators induce derma (JLS) and juvenile systemic sclerosis
the release of transforming growth factor-b, (JSSc).105 Although the more common man-
which is associated with the development ifestation is JLS,106,107 it is estimated that
of pulmonary fibrosis. The elucidation of 10% of all cases of systemic sclerosis have
these pathways is key to the identification had onset in the pediatric age group.108,109
of novel therapeutic targets. The incidence of JLS has been estimated
To date, no randomized trials have shown to be 2.7 per 100,000.110 The incidence of
the efficacy or superiority of immuno- JSSc has not been reliably reported in the
suppressive agents in treating rheumatoid literature, and it is recognized as being rare.
arthritis–associated ILD. Limited experience It has been estimated that less than 1% of
in treating children with pleuropulmon- all children followed in pediatric rheumatol-
ary disease and JRA produced variable ogy clinics have JSSc.111 There is not a clear
results.76,84,85,87,88,90,91,93 Although some gender or racial predilection for JSSc, in con-
patients had complete resolution of their trast to adult scleroderma, in which women,
lung disease, others had chronic or pro- African Americans, and Native Americans
gressive ILD as evidenced objectively and are more likely to be affected.112
subjectively. Classification of JLS is generally divided into
Glucocorticoids have been the mainstay of five categories: plaque morphea, generalized
therapy for pleuropulmonary disease in JRA. morphea, bullous morphea, deep morphea,
Additional immunosuppressive agents that and linear scleroderma, including scleroderma
have been used with variable success include en coup de sabre and Parry-Romberg syndrome
cyclophosphamide, cyclosporine, intravenous (Table 10-9). Pulmonary manifestations usu-
immunoglobulin, salicylates, parenteral gold, ally do not occur in the JLS subtypes, but
methotrexate, etanercept, penicillamine, and are common in JSSc. Provisional criteria for
hydroxychloroquine.76,84,85,87,88,90,91,93 The the diagnosis of JSSc were determined by an
evidence does not indicate clearly whether international expert consensus conference
prognosis may correlate with initiation of comprising the Pediatric Rheumatology Euro-
therapy early in the course of lung disease. pean Society, the ACR, and the European
When monitored serially, patients with League Against Rheumatism and have been
baseline evidence of restrictive lung disease approved by the ACR (Table 10-10).113,149
often continue to have a component of The presence of proximal skin sclerosis/
restrictive lung function.76,85,90,93 Complete induration of the skin is the required major
resolution of radiographic abnormalities criterion needed for diagnosis of JSSc
might be predictive of a good pulmonary (see Table 10-10). At least 2 of 20 minor cri-
prognosis.76,84,88 When isolated PAH is teria also need to be present, of which the
Table 10-9 Classification of Juvenile Localized Scleroderma (JLS)
SUBTYPE CLINICAL CHARACTERISTICS % OF JLS

Plaque morphea Discrete patch, confined to dermis with occasional 26
involvement of subcutaneous tissue
Generalized morphea Multiple plaque morphea lesions in at least 3 anatomic 7
sites or multiple confluent patches
Bullous morphea Multiple bullae most common in lower extremities
associated with lymphatic dilatation
Linear scleroderma Involvement of subcutaneous tissue, muscle, bone 65
Limb Linear plaques that follow dermatome pattern,
hyperpigmented, depressed when healed, may involve
underlying muscle or bone, causing atrophy of limb,
limb-length discrepancy
Coup de sabre Linear lesions on face, commonly unilateral, may cause
alopecia of scalp or eyebrows with asymmetric facial
development
Parry-Romberg syndrome Progressive hemifacial atrophy
Deep morphea Least common but most disabling, primary site of 2
involvement in panniculus or subcutaneous tissue
three possible pulmonary manifestations are activation, and may be the first manifesta-
evidence of pulmonary fibrosis by chest tion of SSc.118 This vasculopathy is seen
radiograph or high-resolution CT scan, clinically as Raynaud phenomenon, periun-
decreased DLCO, or PAH.113 Skin involve- gual telangiectasias with capillary dropout,
ment is characterized by skin that is initially cutaneous telangiectasias, PAH, gastric
edematous, followed by thickening and antral vascular ectasia, and scleroderma
eventual fibrosis and thinning of skin. renal crisis with malignant hypertension.
Defining the extent of skin involvement is Microvascular injury leads to vascular remod-
important because it has become recognized eling with eventual progressive narrowing
that patients with diffuse scleroderma have and obliteration of the vascular lumen. The
a greater risk of cardiac and renal disease, vasculopathy is thought to induce autoim-
although a similar risk of pulmonary dis- munity and an inflammatory reaction.117
ease. It also is recognized that patients with The inflammatory reaction is initially
sclerodermatous induration of the torso seen as a perivascular monocyte and a mac-
have significantly increased risk of severe rophage infiltrate that progresses to involve
organ damage and death.114 Scleroderma multiple inflammatory cell types. An altered
primarily progresses within the first 5 years balance between T helper subtype 1 and T
of disease, at which time it may enter a helper subtype 2 cytokines may be the basis
period of relative quiescence.115 There are for the pathogenesis of the inflammatory
case reports, however, of pulmonary fibrosis response.119 Autoimmunity is evidenced by
occurring more than 10 years after onset of the findings of scleroderma-specific autoan-
scleroderma.116 Pulmonary manifestations tibodies (see Table 10-10). A role for B cells
of systemic sclerosis can be from intrinsic in the pathogenesis of scleroderma also
lung pathology, from effects of PAH, or from has been postulated. Depletion of B cells
fibrosis of the skin of the torso resulting in resulted in reduction of skin fibrosis, auto-
restriction of the chest wall and lungs. antibody production, and hypergammaglob-
The etiologies and pathogenesis of sclero- ulinemia when given to newborn mice in a
derma, JSSc, and JLS are unknown. The mouse model for scleroderma.120 Adult mice
basic pathology of scleroderma is threefold: with established disease undergoing B cell
There is a widespread vasculopathy, an auto- depletion did not have any improvement
immune and inflammatory reaction, and in these measures, suggesting that when
progressive fibrosis.117 The vasculopathy the inflammatory reaction is established, it
manifests as endothelial cell injury and triggers irreversible fibrosis.
production of extracellular matrix (especially

Classification Criteria for
Table 10-10 Juvenile Systemic Sclerosis collagen) that replaces normal tissue.117
After fibrosis has progressed, it tends to be
Major Criterion Proximal skin sclerosis/
(required) skin induration irreversible and refractory to treatment.
Minor Criteria (at least Pulmonary involvement is currently the
2 of 20 required) leading cause of death in scleroderma,
Cutaneous Sclerodactyly given the progress in managing the previ-
Peripheral vascular Raynaud phenomenon ously lethal scleroderma renal crisis with
Nail-fold capillary the introduction of angiotensin-converting
abnormalities enzyme inhibitors and reduced reliance on
Digital tip ulcers long-term therapy with high-dose cortico-
Gastrointestinal Dysphagia steroids. The period of most rapid decline in
Gastroesophageal reflux lung function in adults is in the first 4 years
Cardiac Arrhythmias of disease.122 Clinical manifestations occur
Heart failure late in the progression of lung disease, so it
Renal Renal crisis is imperative that children with scleroderma
New-onset arterial be screened for pulmonary involvement.
hypertension
Given the paucity of data in the pediatric
Respiratory Pulmonary fibrosis
(by BAL or HRCT) population, current knowledge is derived
Decreased DLCO from available adult studies. In addition to
Pulmonary arterial the more common manifestations of sclero-
hypertension derma, such as alveolitis and ILD (discussed
Neurologic Neuropathy subsequently), less common phenotypes
Carpal tunnel include shrinking lung syndrome123 and
syndrome pulmonary-renal syndrome with renal failure
Musculoskeletal Tendon friction rubs and diffuse AH.124
Arthritis The lung pathology of scleroderma is
Myositis that of an initial alveolitis that eventually
Serologic Antinuclear antibodies progresses to fibrosis and is seen clinically as
SSc-selective ILD. Early changes include interstitial edema
autoantibodies
and patchy inflammation of alveolar walls,
Anticentromere,
anti–topoisomerase I primarily with lymphocytes and monocytes,
(Scl70) leading to a combination of inflammatory
Antifibrillarin, anti- reaction and fibroblast proliferation.125-127
PMScl An increase in memory T cells also is seen,
Anti–RNA likely contributing in the long term to the
polymerase I or III
evolution of pulmonary injury and remodel-
DLCO, diffusing capacity for carbon monoxide. ing.128 With progressive thinning and rup-
Data from references 1, 52.
ture of alveolar walls, numerous tiny cysts
form in association with interstitial and peri-
bronchial fibrosis.129 Consequently, lung
volumes and DLCO progressively decrease.
The fibrosis in scleroderma accounts for Lung inflammation has been shown to be
most of the morbidity. The fibrosis tends to associated with the evolution of progressive
increase as the inflammatory cellular infil- restrictive lung disease.130-132
trates decrease, and then may ultimately The diagnosis of the initial lesion, the
regress.121 Various cells upregulate pro- alveolitis, remains a clinical challenge. In a
fibrotic soluble factors; these include trans- group of 13 children with scleroderma
forming growth factor-b, interleukin-4, examined for lung disease, only 2 had dys-
platelet-derived growth factor, monocyte pnea on exertion, even though 11 had ILD
chemoattractant protein-1, and CTGF. These by high resolution CT scan of the chest.132
soluble factors activate fibroblasts and The most common clinical manifestation
related mesenchymal cells to increase the of lung involvement in another study of
13 children was a chronic nonproductive normalization of BAL abnormalities after

cough.133 Chest radiographs are often nor- cyclophosphamide therapy did not differen-
mal until late in the disease, when irre- tiate clinical response in a group of 25
versible fibrosis has already occurred.132 patients who underwent BAL before and after
A combination of PFTs and BAL may be cyclophosphamide therapy.145
the best way to detect pulmonary involve- Although abnormal BAL fluid analysis
ment and follow treatment response.134 with increased polymorphonuclear leuko-
PFTs show decreased FVC and decreased cytes and eosinophils suggests alveolitis and
DLCO. A decreased FVC has been shown predicts changes on high-resolution CT scan,
to correlate with the presence of honey- at present there is no good rationale for
combing and ground-glass appearance.132 repeating the BAL after therapy for sclero-
A decreased DLCO has been found to reflect derma lung disease. The utility of early BAL
best the extent of fibrosing alveolitis, but is for early diagnosis of alveolitis (often
also can be reflective of pulmonary vascular before findings emerge on the chest radio-
disease.135,136 Other findings on examina- graph) and for excluding potential infection.
tion in children with scleroderma include The development of high-resolution CT
subpleural micronodules and linear opaci- as an imaging tool has improved the detection
ties.137 An autopsy in a child with sclero- of alveolitis in scleroderma. The prevalence of
derma correlated ground-glass attenuation pulmonary fibrosis in scleroderma, as
on high resolution CT scan of the chest detected by high-resolution CT, has been
with extensive interstitial fibrosis.132 described to be present in 90% of adults with
BAL has been proposed as an approach to scleroderma. Plain chest radiographs are not
tracking and predicting the evolution of sensitive for diagnoses of alveolitis or fibrosis.
pulmonary inflammation in patients with Common findings include ground-glass opa-
scleroderma. In adults with scleroderma, an cities, reticular linear opacities, honeycomb-
increased percentage of polymorphonuclear ing, nodules, cylindrical bronchiectasis, and
leukocytes and eosinophils or both on parenchymal bands. Ground-glass appear-
BAL have been correlated with a decline in ance is more indicative of cellular infiltration,
FVC over time and increased early mortal- whereas a reticular pattern is correlated with
ity.131,138,139 A polymorphonuclear count fibrosis.146 Serial studies in patients with
of 4% or greater and eosinophils 2% or fibrosing alveolitis have shown that ground-
greater of total white blood cells recovered glass appearance regresses with treatment
on BAL has been defined as evidence of when it is the predominant finding. If this
active alveolitis.140,141 Thus defined, active appearance is seen in a mixed pattern with
alveolitis on BAL has been found to corre- reticular opacities, however, treatment is
late with abnormalities and tracks with a often ineffective.147 Mediastinal adenopathy
future decrease in FVC. is present in more than 50% of patients with
Controversy persists because BAL abnor- scleroderma; a significant relationship has
malities have been found more recently not been described between mediastinal adenopa-
to be predictive of long-term disease pro- thy and the presence of interstitial disease.148
gression or treatment response, although The development of PAH in scleroderma
increased polymorphonuclear leukocytes remains an ominous sign because PAH is a
were linked to early mortality.142,143 The major cause of morbidity and mortality.
selection of the site of sampling of BAL fluid PAH is a pathologic state accompanied by a
(right middle lobe versus site of abnormality progressive increase in pulmonary vascular
on diagnostic imaging) may explain some of resistance leading to right-sided heart fail-
the differences in prognostic utility.144 Tech- ure and premature death. It is characterized
nique in BAL fluid acquisition and analysis by a mean arterial pressure greater than
also has been a potential explanation for the 25 mm Hg at rest or greater than 30 mm
disparity in studies. Despite the lack of con- Hg during exercise.149 PAH in patients with
sistent prediction of treatment response, scleroderma is encountered most commonly
alveolitis on BAL does correlate with abnorm- as part of the vasculopathy of the micro-
alities on high-resolution CT scan.143 Lack of circulation.150,151 Other causes of PAH in
scleroderma include thrombotic disease and ventricular systolic pressure is estimated by

underlying cardiopulmonary disease. The the echocardiogram and is used as a surrogate
prevalence of PAH in scleroderma is 50%, measure of systolic pulmonary arterial
whereas its clinical presence is apparent in pressure. Some authors have advocated for
only 20% to 30%.152,153 a combination of DLCO measurement with
The frequency of symptoms and signs of echocardiographic estimate of pulmonary
PAH have been determined by a national reg- arterial pressure, but these screening methods
istry. The most common initial symptom have been poorly validated.159,160
was dyspnea (60%) followed by fatigue Treatment of scleroderma lung disease
(19%), syncope or near-syncope (13%), chest should be initiated when an active alveolitis
pain (7%), palpitations (5%), and edema (compared with lung fibrosis) is the domi-
(3%).154 Signs of PAH can be subtle and nant histopathology. Cyclophosphamide
include accentuated second heart sound (S2) given daily at a dose up to 2 mg/kg orally
in 93%, right-sided S4 in 38%, right-sided S3 has been the only effective agent shown
in 23%, peripheral edema in 32%, and cyano- in a prospective multicenter trial to slow
sis in 20%. Other clinical signs of PAH include the loss of FVC over time, while improving
a left parasternal right ventricular heave and dyspnea, skin scores, and health-related
signs of elevated jugular venous pressure. quality of life.161,162 Whether to add low-
Clinical signs of PAH can be subtle, lead- dose prednisone to cyclophosphamide is
ing to delay in diagnosis and treatment. controversial and unproven. Smaller studies
A right-sided heart catheterization with and retrospective cohort studies have sug-
measurement of pulmonary arterial pressure gested that mycophenolate mofetil may be
is the gold standard for determination effective; however, prospective randomized
of PAH and should be done if clinical suspi- data are unavailable to date.163,164 Clinical
cion arises. A decreased DLCO is associated trials of drug therapy to date have not tar-
with PAH, although this also can be a sign geted the pediatric population.
of pulmonary alveolitis or fibrosis. A DLCO Aggressive and early treatment of PAH
less than 53% predicted, or a DLCO that has dramatically increased life expectancy
declines over time has been shown to be in PAH associated with systemic sclerosis.
a predictor of subsequent development of General supportive measures for management
PAH.155 Electrocardiogram may suggest the of PAH include correction of hypoxia with
diagnosis if signs of right ventricular hyper- oxygen therapy, regulation of intravascular
trophy or strain are seen. Generally, the volume status with fluid/sodium restriction
electrocardiogram is too insensitive and non- or diuretics, digitalis (although efficacy
specific as a tool to be used for screening for is unproven), anticoagulation, and prevention
PAH.156 Findings on chest radiograph that of pulmonary infections with vaccinations for
suggest PAH include prominence of the main influenza and pneumococcal pneumonia.165
pulmonary artery, enlarged hilar vessels, and Medical treatment of PAH in childhood
decreased peripheral vessels. Right atrial and is more often targeted to children with con-
ventricular enlargement also may be seen in genital heart defects; scleroderma-specific
more advanced cases.149,157 A normal chest treatments are lacking. Medical treatment
radiograph does not rule out PAH. of PAH includes calcium channel blockers,
The most commonly used screening test for prostacyclin analogues, endothelin receptor
PAH is transthoracic Doppler echocardiogra- antagonists, phosphodiesterase type 5 inhibi-
phy. Although echocardiograms have reason- tors, and combination therapies (Table 10-
able sensitivity and specificity for detecting 11).157,165 The dual endothelin receptor
moderate to severe PAH, their role as a screen- antagonist bosentan has been reported to be
ing tool for early or mild disease has not been efficacious in treating PAH in children.166
established.158 Indirect signs of PAH include Combination therapies with bosentan and
right ventricular hypertrophy and enlarge- iloprost or sildenafil and bosentan have been
ment, right atrial enlargement, paradoxical attempted.157 Lung transplantation is an
motion of the interventricular septum, and option for patients in whom medical therapy
diastolic left ventricular compression. Right ceases to be effective.
Table 10-11 Treatment of Pulmonary Arterial Hypertension in Scleroderma
DRUG CATEGORY MECHANISM OF ACTION EXAMPLES ADMINISTRATION SPECIAL NOTES

Prostacyclins Pulmonary and systemic Epoprostenol Continuous
vasodilator, platelet intravenous
aggregation inhibition Treprostinil Continuous
subcutaneous
Iloprost Inhaled q3-4h
Calcium channel Long-term vasodilator Nifedipine Oral Use only in patients
blockers Diltiazem proven to have
pulmonary
vasodilator
response on right
heart
catheterization
Endothelin Block receptors for Bosentan Oral Two receptors
receptor endothelin, a potent described, ETA,
antagonists endogenous ETB. Bosentan:
vasoconstrictor inhibits both
receptors; selective
blockers are in
development
Phosphodiesterase Inhibits phosphodiesterase Sildenafil Oral
type 5 inhibitor type 5, which inactivates
cGMP, which relaxes
pulmonary vascular
smooth muscle cells.
Phosphodiesterase
type 5 inhibitors
dilate pulmonary
arterial beds
cGMP, cyclic guanosine monophosphate.
Juvenile Dermatomyositis failure from thoracic muscle fatigue may

result. The onset of respiratory failure is
Juvenile dermatomyositis (JDMS) manifests often not heralded by classic signs of respi-
as a chronic autoimmune inflammatory dis- ratory distress, such as retractions or tachyp-
order of skin and muscle typically character- nea. Children with severe weakness should
ized by a rash, proximal muscle weakness, be monitored for respiratory muscle weak-
and elevation of muscle enzymes. The clini- ness (negative inspiratory force in younger
cal hallmarks are listed in Table 10-12. If the children), breathing capacity (vital capacity
rash is absent, the term “polymyositis” is in older children), or carbon dioxide reten-
applied. Polymyositis is rare in the pediatric tion (end-tidal capnography or blood gas
age group, however, and children with a measurements).
polymyositis syndrome without a rash Blood markers of JDMS are unhelpful. The
should be investigated for various meta- presence of ANAs is not required for the
bolic, neurologic, and endocrine disorders, diagnosis of JDMS, but they may be present
and for potential toxin exposure. Pulmo- in 50% of pediatric cases.
nary involvement with JDMS in children is The pulmonary pathology is largely extrap-
relatively rare. The characteristic histopa- olated from adults with dermatomyositis
thology of the disease is a generalized vascu- because 30% to 50% of adults have ILD,
litis, which produces the characteristic rash whereas the pulmonary expression of JDMS
and a typical pattern of proximal muscle is rare in children.167,168 The histopathology
weakness. When the expression of the is devoid of vasculitic contribution. The char-
proximal weakness is profound, respiratory acteristic lung fibrosis can manifest either as
interstitial/alveolar (usual interstitial pneu-

Characteristics of Juvenile
Table 10-12 Dermatomyositis monitis) or small airways obstruction
(BOOP). An alternative presentation is that
FINDINGS of acute respiratory distress syndrome with
Organ the pathophysiologic processes associated
Involvement with vascular leak, such as alveolar edema
Skin Heliotrope rash and the formation of hyaline membranes.
Purple, swollen eyelids Antibodies to the Jo-1 tissue antigen, unusual
Gottron papules (scaly lesions on in childhood, are associated with the evolu-
knuckles) tion of pulmonary complications, such as
Malar rash fibrosis. The histocompatibility antigens
Shawl rash (upper anterior/ HLA-DQA1*0501 and HLA-DQA1*0401 have
posterior thorax)
been reported to have increased expression in
Calcinosis may affect skin
white patients. A single case of lipoprotein-
Muscles Proximal myopathy
osis has been reported in a child with
Lymphocytic inflammation early
dermatomyositis.
Calcinosis late
Although much progress has been made
Electromyography has typical
changes in the therapy of JDMS, treatment strategies
Muscle biopsy are not grounded in prospective, controlled
Perivascular infiltrates data from pediatric clinical trials. Before
Small vessel occlusion the use of corticosteroids, the mortality
Fibrillar degeneration from JDMS was 30%, and another 30% had
Perifibrillar mononuclear cell chronic illness. After the implementation
cuffing of corticosteroid therapy in the 1960s, the
Sarcolemma nuclear mortality has diminished to less than 10%.
proliferation This therapy remains the mainstay for skin
Elevation of muscle enzymes and muscle disease and is administered
Lung Disease* Not a vasculitis either orally or intravenously. More severe
Histopathology Usual interstitial pneumonitis
Bronchiolitis obliterans with
disease, such as weakness of the thoracic
organizing pneumonia musculature, is often treated with pulse
Capillary leak syndrome methylprednisolone (30 mg/kg up to 1 g
Lung disease Antibody to Jo-1 associated with given intravenously over 1 hour). Hydroxy-
marker pulmonary complications such chloroquine is used to control skin manifes-
as fibrosis tations and may permit a more rapid taper
Radiographic Pulmonary fibrosis of therapy with corticosteroids. Methotrex-
changes Pneumothorax or
ate is increasingly used as a first-line agent;
pneumomediastinum (less
common) some centers still reserve its use for ther-
Patchy alveolar infiltrates (less apy of resistant disease. Alternative immu-
common) nomodulatory therapies for JDMS have
Therapy Corticosteroids standard (oral or included azathioprine, cyclophosphamide,
intravenous) and cyclosporine. A National Institutes of
Hydroxychloroquine for skin Health–sponsored trial of rituximab for the
disease, may be steroid-sparing
treatment of refractory JDMS is ongoing
Methotrexate (some use as
standard; some use only for (http://www.clinicaltrials.gov).
drug-resistant disease)
Alternative anti-inflammatory
agents Ankylosing Spondylitis
Azathioprine
Cyclophosphamide Juvenile ankylosing spondylitis (JAS) is one
Cyclosporine of the rarest spondyloarthropathies, a group
Rituximab (ongoing trial) of disorders that share the following fea-
*Rare in childhood; data are from adults.
tures: inflammation of the axial skeleton
(especially sacroiliitis) and inflammation of
the entheses (the insertion points on bone

Table 10-13 Enthesitis-Related Arthritis
of tendons and ligaments), RF-seronegative,
absence of rheumatoid nodules, infrequency Required Features
of other autoantibodies, genetic association Arthritis and enthesitis or
with the histocompatibility antigen HLA- Arthritis or enthesitis plus at least two of the
following
B27, and family clustering of the related
Sacroiliac joint tenderness and/or inflammatory
disorders (inflammatory bowel disease, pso- spinal pain
riatic arthritis, and reactive arthritis).169 Positive for HLA-B27
Extra-articular manifestations cross these Family history positive for one or more first-degree
disease lines and include iritis and psoriatic- or second-degree relatives with HLA-B27-
like rashes. confirmed disease
Although the criteria for the diagnosis of Anterior uveitis usually associated with erythema,
pain, or photophobia
ankylosing spondylitis in adults are well
Onset of arthritis in a boy >8 years old
worked out and require a confirmation of
Exclusions
sacroiliitis, a major challenge for pediatri-
Dermatologist-confirmed psoriasis in a first-degree
cians is that the expression of arthritis in or second-degree relative
the axial skeleton is often not the earliest Presence of systemic arthritis
manifestation, which can evolve slowly
over years. Progress in the classification From Petty RE, et al: Revision of the proposed classification
criteria for juvenile idiopathic arthritis. Durban, 1998.
of these disorders was achieved with the J Rheumatol 25:1991-1994, 1998.
recognition of the seronegative enthesitis
and arthritis syndrome.170 The seronegative
enthesitis and arthritis syndrome classifica- arthritis in a first-degree or second-degree rel-
tion system allowed the identification of ative or the presence of systemic arthritis.
children with enthesitis or peripheral arthri- Because of the tendency of JAS to evolve
tis or both who lacked the classic finding over time, most patients with this diagnosis
of arthritis of the axial skeleton. Follow-up are in late childhood or adolescence. Some
studies171 revealed that many of these chil- children with enthesitis-related arthritis
dren subsequently developed spine or sacro- are diagnosed with ankylosing spondylitis
iliac joint involvement that completed the or related arthropathy in adulthood. The
diagnostic criteria of JAS. Because the cri- male-to-female ratio is approximately 7:1.
teria for adult ankylosing spondyloar- The frequency of diagnoses of ankylosing
thropathy fail to discern children who are spondylitis is low in African Americans and
developing JAS or are at risk of develop- in native Japanese.
ing JAS, criteria172 for the related disorder, The precise etiology of the disorder is
enthesitis-related arthritis, have become unknown. The association of the disease
popular among pediatricians caring for with the HLA-B27 antigen suggests a molec-
these children (Table 10-13). In this scheme, ular genetic pathway. T helper subtype 1
a diagnosis of enthesitis-related arthritis lymphocytes, CD8þ and CD14þ inflamma-
is confirmed by the presence of arthritis and tory cells, and the cytokine tumor necrosis
enthesitis. Alternatively, a diagnosis of factor (TNF)-a all have been implicated in
enthesitis-related arthritis can be confirmed the etiology.
by the presence or either arthritis or enthesi- Respiratory complications of JAS are
tis, provided that two of the following five rare.173-188 Chest wall restriction results from
criteria are met: (1) sacroiliac joint tenderness arthritis or ankylosis of sternocostal or costo-
or inflammatory spinal pain or both, (2) vertebral joints, and manifests most frequently
HLA-B27 seropositive, (3) positivity of HLA- as a reduced TLC or a reduced FVC. It most
B27-associated disease in a first-degree or sec- often is not associated with dyspnea. In a series
ond-degree relative, (4) anterior uveitis, or (5) of more than 1000 adults with ankylosing
onset of arthritis in a boy older than 8 years. spondylitis, approximately 1% were shown to
The diagnosis of enthesitis-related arthritis have pleuropulmonary manifestations.173
is excluded by the presence of either a derma- Pleural thickening (but not pleural effusion)
tologist-confirmed diagnosis of psoriatic was relatively common, and fibrous and
bullous disease was seen. Pleural thickening, accompanied by a strong family history.195
when observed, would usually become bilat- Fifty percent to 90% of familial and non-
eral. Symptoms of inflammatory or fibrotic dis- familial versions196 of early-onset systemic
ease were uncommon. High-resolution CT granulomatous syndromes manifest one of
scans show a greater sensitivity in detecting several mutations in the caspase recruitment
pulmonary parenchymal abnormalities. Infre- domain-15 (CARD15)/nucleotide-binding
quent findings in adults include ILD, oligomerization domain-2 (NOD2) proteins,
bronchiectasis, paraseptal emphysema, and members of the NOD family of proteins,
apical fibrosis. located on chromosome 16.197 These muta-
The most common pulmonary function tions are associated with the activation of
changes in a group of asymptomatic adults nuclear factor kB, a nuclear transcription fac-
with a history of normal chest radiographs tor associated with the upregulated expres-
were a reduced TLC and FVC. Flow rates, sion of numerous inflammatory cytokines.
DLCO, elastic recoil, and exercise tolerance These patients frequently develop hyperten-
were normal except in the patients with sion, fever, hepatosplenomegaly, and parotid
the most severely restricted lung capaci- swelling with a risk of cardiac or cerebral
ties.174 Studies of pulmonary function in sequelae. Only infrequently do they develop
patients with JAS are few and show slightly lung disease,194,198 including when a muta-
different patterns.175,177 Of 18 older chil- tion occurs in the CARD15 gene family.199
dren and adolescents with JAS, none had These cases are often refractory to therapy,
respiratory symptoms. All had chest radio- including the use of systemic corticosteroids.
graphs that were initially normal. Six had The more common presentation of sarcoid-
abnormalities of pulmonary function, of osis (which is not associated with mutations
which a reduced vital capacity was most in the CARD15/NOD2 gene complex200-202)
common. A few showed an elevation of occurs most frequently in the third and
the FRC or a reduced DLCO. fourth decades of life, and includes combina-
tions of lung disease, lymphadenopathy,
fever, weight loss, and hypercalcemia.203
Sarcoidosis Variations of this phenotype occur through-
out the school-age years and are more com-
Sarcoidosis is a chronic multisystem inflam- mon in adolescents. School-age children are
matory disorder of unknown etiology more likely to have pulmonary parenchymal
characterized by the expression in a wide involvement in addition to hilar or para-
range of tissues of noncaseating granulomas tracheal adenopathy compared with adults
in lesions that lack infections that might with sarcoidosis.204-219 Although multiorgan
ordinarily cause them. Because of the broad disease expression in children is typical (com-
range of potential tissue sites, sarcoidosis, monly in unexpected combinations), isolated
similar to tuberculosis, can mimic an expan- involvement of a wide range of organs is
sive array of clinical disorders and can be described in numerous case reports that
asymptomatic or organ-threatening or life- include infants and younger children.
threatening. Commonly affected organs Sarcoidosis apparently affects boys and
include thoracic lymph nodes, lungs, liver, girls equally.204 The true incidence of the
spleen, eyes, bones, joints, salivary and disease is unknown because of the absence
lacrimal glands, central nervous system, and of screening programs and the frequency
skin. Less commonly affected organs include of asymptomatic disease, but is estimated
the heart, blood vessels, other lymph nodes, to be 5 per 100,000 in whites and 40 per
kidneys, gut, and peripheral nerves.189-191 100,000 in African Americans in the United
Sarcoidosis may occur in the preschool States.204,232 Most reported U.S. cases are
age group with a triad of a granulomatous located in the southeastern United States.
skin rash, uveitis, and arthritis,192,193 origi- In Europe, sarcoidosis is more apparent in
nally described as Blau syndrome,194 a northern countries, such as Sweden, where
syndrome of early-onset systemic granulo- autopsy-derived data suggest a prevalence
matosis, similar to early-onset sarcoidosis, of 641 per 100,000.220,221 The prevalence
also is greater throughout Scandinavia and natural course is hyalinization and genera-
Great Britain and in ethnic Japanese com- tion of collagen and other ground substances
pared with the United States.190 Although to form fibrous and otherwise remodeled
several HLA associations have been suggested, tissue.
no definitive genetic etiology has emerged. The exact mechanisms that drive these
Several familial clusters nonetheless have differential paths of inflammation resolu-
been reported. tion or progression are unknown. Although
The classic lesion suggesting a diagnosis this process lacks the full expression of
of sarcoidosis in a tissue biopsy specimen T helper subtype 2 orchestration that charac-
is a noncaseating granuloma.191 This lesion terizes an allergic inflammatory response,
is seen in various disorders other than sar- the critical participation of CD4þ T lym-
coidosis, such as certain toxic exposures phocytes in the generation of the granulo-
(beryllium) and certain viral and fungal mas helps explain the usually dependable
infections, and in lymph node–draining response of the lesions to treatment with sys-
sites of cancer, so a careful analysis of the temic corticosteroids, which is the mainstay
clinical context and an expert pathologic of therapy for more severe or risk-loaded
review of the entire specimen are crucial.190 cases of sarcoidosis.222,224 The granulomas
Noncaseating granulomas also can be seen are known to be capable of secreting and
in specimens from patients with disorders activating vitamin D,189,191 which helps to
such as tuberculosis that are characterized explain the frequently observed complica-
by caseating and necrotizing granulomas. tions of hypercalcemia and hypercalciuria
A typical lesion consists of an organized and their frequently positive response to
ring of epithelioid cells that are compact treatment with corticosteroid therapy.
and radially arranged, are populated with The clinical expression of sarcoidosis
Langerhans-type giant cells (also arranged depends on the intensity of the inflamma-
circularly around a central granular zone), tory response, its level of generalization,
and are surrounded by lymphocytes.191,205 and whether or not the granulomatous
There is no evidence of caseation in lesions process interferes critically with organ
of patients with sarcoidosis, and necrotizing function. In most children, multiple organs
features are unusual. are involved, regardless of symptoms.204
The immune inflammatory response Because there is widely disseminated inflam-
believed to be responsible for the evolution mation, many children present with non-
of the granulomas is thought to originate specific complaints, such as malaise, weight
with the presentation of antigens by a loss, lethargy, anorexia, headache, and, less
macrophage to T lymphocytes, which then commonly, fever, abdominal pain, or nau-
elaborate the activating cytokine interleu- sea. If the inflammation is focused, there
kin-1.191,222,223 This serves to recruit CD4þ may be organ-localizing symptoms or signs,
lymphocytes from peripheral blood to the such as pain or swelling, but it is common
site of activation (the lung), where they for such symptoms to be absent. Even cuta-
induce the differentiation of B lymphocytes neous lesions may be asymptomatic. Because
that secrete IgM, IgA, and IgG. Local T cells any organ or multiple organs might be
elaborate interleukin-2,a cytokine important involved, a thorough physical examina-
for lymphocyte proliferation. Additional tion directed to uncommon findings is
cytokines and chemokines activate macro- mandated.
phages and recruit blood monocytes to the Respiratory symptoms, if present, include
lung, where they differentiate into addi- cough, dyspnea, chest pain, or sputum
tional macrophages and amplify the production.222 Signs often are absent, but
response. Other inflammatory cells are acti- might include unequal, coarse, or muffled
vated, and various humoral factors are pro- breath sounds or wheezing or crackles. In
duced with a resulting robust and complex contrast, most chest radiographs of children
inflammatory response that may resolve with sarcoidosis are positive. In a series
spontaneously or may persist and intensify. published from Duke University225 of 19
If the granulomatous response persists, its children with sarcoidosis, all the radiographs
showed abnormalities. Nearly all cases show study. Syndromes of airway hyperresponsive-
parabronchial (“hilar”) adenopathy, and ness231 and airway obstruction are common
most show paratracheal adenopathy. Paren- in sarcoidosis. It is unknown whether these
chymal involvement is usually present with syndromes result from endobronchial granu-
or without evidence of adenopathy. Typical lomatous lesions,232 airway compression by
features include reticulonodular and inter- enlarged lymph nodes,189 altered airway
stitial patterns. Less typical features include growth, inflammation-directed airway hyper-
alveolar filling processes; distinct nodules; responsiveness, or an overlap syndrome
fibrotic phenotypes; or more dramatic with childhood asthma. For children with
changes, such as pneumothorax, pleural these syndromes, a trial of bronchodilators
effusion, calcification, pleural thickening, and asthmatic anti-inflammatory therapy
or atelectasis.225,226 may be helpful. For the few children with air-
The adult radiographic staging process way compression from enlarged paratracheal
has been adopted for use in evaluating or parabronchial lymph nodes, a trial of
children.190,191,222,227,239 Stage 0 is a normal systemic corticosteroids to reduce the mass
chest radiograph. Stage 1 indicates the of the nodes may be warranted.
presence of bilateral parabronchial adenopa- In rare cases, granulomas may involve
thy. Stage 2 criteria include the presence of any of the structures of the larynx and
parabronchial adenopathy and pulmonary upper airway, producing hoarseness, stridor,
parenchymal infiltrates. A stage 3 radiograph dyspnea, obstructive sleep apnea, cough,
shows parenchymal infiltrates without the or dysphagia.190 If the symptoms are sig-
perihilar adenopathy. The presence of nificant, treatment with oral or systemic
fibrotic lesions and bullous emphysema is corticosteroids may bring needed relief.
considered to indicate either late stage 3 or The diagnosis of sarcoidosis is based on
stage 4 sarcoidosis. The utility of this staging criteria published in a joint consensus state-
paradigm has been validated in multiple ment of the American Thoracic Society and
studies in adults, and the experience with European Respiratory Society in 1999.227
children seems consistent with these results. The diagnostic criteria for children do not
Generally, disease progression follows differ from those for adults. The diagnosis
the sequence of the radiographic staging, requires (1) a compatible clinical profile,
and the prognosis worsens with the more (2) histologic evidence of noncaseating
advanced stages. When the hilar or paratra- granulomas without pathologic evidence of
cheal adenopathy is not evident, it does another etiologic process, and (3) exclusion
not generally reappear at a later time. Most of other disease processes that might mani-
patients with either stage 1 or stage 2 disease fest with a similar clinical profile or histo-
undergo remissions, whereas the rate of pathology (notably infections and toxins).
remission declines with the progression of The crucial parts of the diagnosis are the
the stages. Despite the fact that patients requirement of tissue confirmation and the
with stage 1 disease may have granulomas elimination by careful history, physical
on lung biopsy or parenchymal disease on examination, and laboratory evaluation of
high-resolution CT scans,226 the better prog- confounding candidates.
nosis remains linked to the appearance of The performance of lung cultures via
the plain radiographic appearance, despite bronchoscopy is sometimes necessary to
its apparent lack of sensitivity in detecting complete the analysis. The tissue source
subtle parenchymal disease. can be a suspicious lesion anywhere on
The most consistently shown abnormal- the body, such that superficial targets, such
ity226,228-230 of pulmonary function (50% of as skin or conjunctival lesions, are often
children in one large series) is a restrictive pat- preferred to avoid the necessity of general
tern in which the TLC and FRC are reduced. anesthesia.190 One series from Turkey deter-
DLCO abnormalities also are seen. Less com- mined that biopsy of the minor salivary
mon are obstructive patterns, in which the glands yielded a 48% positive yield for non-
FEV1-to-FVC ratio is reduced; this accounted caseating granulomatous lesions in patients
for 15% of the abnormalities in the same with confirmed sarcoidosis with no positive
lesions in children with tuberculosis.233 The recover without intervention, raising ques-
feasibility of fine needle aspiration of lung tions about the need for therapy for many
or mediastinal lymph nodes has been patients. Nonetheless, many shorter term
shown in adolescent patients. Other sites studies in adults have shown the effective-
of biopsy that frequently yield a diagnosis ness in improving symptoms, pulmonary
include peripheral muscles and liver. function, and radiographic appearance. Typ-
Supportive diagnostic studies that are not ical treatment strategies include an initial
entirely specific are often useful and neces- oral dose of prednisone or prednisolone
sary because of potentially confounding of 1 mg/kg/day to a usual maximum of
clinical presentations. The erythrocyte sedi- 60 mg/day.222 When the desired treat-
mentation rate is usually elevated in active ment effect is achieved (improvement in
sarcoidosis. Levels of serum angiotensin- symptoms, pulmonary function, or radio-
converting enzyme are elevated in 80% of graph), usually in several weeks, the daily
children with sarcoidosis; the angiotensin- dose is tapered over several weeks to a few
converting enzyme is synthesized in the months. Therapy typically lasts approxi-
epithelioid cells of the granulomas.191,234 mately 6 months, but longer treatment
The level of the angiotensin-converting intervals are sometimes required. As doses
enzyme also can be used as a marker of decline, alternate-day therapy usually sus-
disease activity in patients who have eleva- tains the positive effects until the patient
tions with disease activity that decline with can be weaned off the medication. A less
remission. For many patients, this is a very studied but often effective alternative ther-
helpful marker. Many diseases, including apy is chloroquine, given as 250 mg by
diabetes, liver disease, and several neoplasms, mouth twice daily for 2 weeks and then
also are associated with elevated angiotensin- once daily for long-term suppression of
converting enzyme levels, however.235 Angio- inflammation. To minimize the risk of
tensin-converting enzyme levels in children chloroquine-associated retinopathy, the max-
younger than 15 years can be 50% greater imal maintenance dosage should not be
than their adult counterparts, so pediatric- greater than 3.5 to 4 mg/kg of ideal body
specific normal values should be applied. weight each day.222 Sarcoidosis that is refrac-
Serum chitotriosidase has been proposed tory to usual therapy may respond to metho-
as a disease marker for sarcoidosis activity, trexate or to pharmacologic blockade of
but its sensitivity, specificity, and utility have TNF-a, such as etanercept or infliximab. The
not yet been confirmed.236 For children response to therapy for early-onset sarcoidosis
whose diagnosis or management includes (Blau syndrome) is often disappointing
bronchoscopy, the determination of a BAL and challenging.
fluid ratio of CD4þ-to-CD8þ lymphocytes of A more recently published approach238
greater than 3.5, although insensitive (53% suggests an alternative treatment decision
detection), has been determined to be highly paradigm designed to limit the use of sys-
specific (94%) for the diagnosis of sarcoido- temic corticosteroids to those satisfying
sis.237 In addition, criteria have been deter- preset standards in the following categories:
mined that are characteristic for pulmonary (1) severity of disease expression, (2) pro-
parenchymal sarcoidosis and help to confirm gression of the disease, (3) risk to vulnerable
the diagnosis. organs, or (4) unacceptability of the quality
The hallmark of therapy for sarcoidosis is of life with untreated disease. The specific
oral or parenteral corticosteroids.189,222,238 criteria for respiratory-related issues are
Several trials have shown improvement in listed in Table 10-14. The paradigm also
clinical symptoms and pulmonary function specifies that corticosteroid therapy should
with the daily administration of oral corti- be administered to patients with disease
costeroids, but despite more than 50 years localization to heart or central nervous sys-
of use, data are still lacking for evidence of tem; to patients with sight-threatening
their impact in modifying the trajectory ocular disease uncontrolled by local mea-
of the underlying disease or preventing sures; to patients with severe hypercalcemia
death. Many patients with mild disease (3 mML1 ionic calcium); to patients
variability of expression, these multiple phe-

Criteria for Corticosteroid
Table 10-14 Therapy of Pulmonary notypes need characterization by large, mul-
Sarcoidosis ticenter trials. Only with these data can the
Absolute Criteria
treatment guidelines be rationalized.
Severe restriction or diffusion impairment on
presentation (FVC <50% or DLCO <50%
predicted) Pneumonitis Resulting from
Severe airway obstruction on presentation (FEV1 Antirheumatic Therapy
<50% predicted)
Progressive pulmonary disease (decrease of FVC
>10% or DLCO >15% from baseline) Methotrexate Pneumonitis
Evidence for severe or progressive lung fibrosis with
active disease Methotrexate has emerged as an important
Relative Criteria therapy for JRA and other rheumatic dis-
Symptomatic pulmonary disease with mild-to- eases.240,241 At doses commonly used in chil-
moderate lung function impairment dren and adolescents, 0.5 to 1 mg/kg or 10
Symptoms cause unacceptable quality of life (e.g., to 15 mg/m2/wk, methotrexate is efficacious
dyspnea, fatigue, or weight loss)
and well tolerated. An uncommon but
DLCO, diffusing capacity for carbon monoxide; FEV1, forced concerning pulmonary complication of meth-
expiratory volume in 1 second; FVC, forced vital capacity. otrexate therapy is hypersensitivity pneumo-
Adapted from Grutters JC, van den Bosch JMM: Corticoste-
nitis. Methotrexate pneumonitis is more
roid treatment in sarcoidosis. Eur Resp J 28:627-636, 2006.
prevalent in adult patients than in children.
Estimates of pneumonitis in adults using low
with hypercalciuria with nephrocalcinosis doses of methotrexate (25 mg/wk) range
and renal dysfunction; to patients with from 0.5% to 14%.242-246 Risk factors include
granulomatous interstitial nephritis; to older age, preexisting lung disease, previous
patients with liver involvement with intra- use of disease-modifying antirheumatic drugs,
hepatic cholestasis, portal hypertension, and hypoalbuminemia.247
or hepatic failure; or to patients with bone Symptoms of methotrexate pneumo-
marrow involvement with pancytopenia. nitis include dyspnea, dry cough, and
The relative criteria also would apply to fever.244,246,248,249 Peripheral eosinophilia
patients with disfiguring skin involvement. can be found, but is neither sensitive nor
With or without therapy, the outcome specific.245,246 The physical examination
for most school-age children seems to be may reveal bibasilar crackles and tachyp-
favorable. The prognoses for school-age chil- nea.246,249 Chest radiographs rarely appear
dren with more advanced pulmonary disease normal, and frequently reveal interstitial
and for preschool-age children with the more or alveolar infiltrates or both.246,249 High-
difficult-to-control triad of skin lesions, ocu- resolution CT scans of the chest often
lar disease, and arthropathy are more identify ground-glass opacities, interstitial
guarded.210 Because several features of dis- infiltrates, or alveolar infiltrates.246 BAL fluid
ease expression in this younger group differ, with a predominance of CD4þ lymphocytes
including the general absence of respiratory supports a diagnosis of methotrexate pneu-
system involvement, this seems to be a dif- monitis.243,246,250,251 Lung pathology is
ferent disease whose criteria for therapy and nonspecific, but findings include interstitial
follow-up need sharper definition. infiltrates, fibrosis, granulomas, and diffuse
For patients with pulmonary disease, there alveolar damage.
is a need for adequately controlled trials of Serial PFTs in children with JRA have
therapy with corticosteroids,238 and alterna- shown that there is no relationship between
tive candidate therapies in children whose the development of pulmonary disease and
disease is well characterized and for whom methotrexate exposure.252-255 Cron and col-
the treatment protocols allow for stage- leagues248 reported a girl with polyarticular
specific evaluations of outcomes. There is JRA who presumably developed methotrex-
a special need for better defined therapy ate pneumonitis. The patient had a dimin-
for early-onset sarcoidosis. Because of the ished FVC, but DLCO was not assessed,
and a chest radiograph was normal. These damage.271 There have been reports of
abnormalities resolved with discontinuation interstitial pneumonitis in patients with
of methotrexate and initiation of systemic lymphoproliferative disease who were
corticosteroids. treated with the B cell–depleting agent ritux-
The signs and symptoms of methotrexate imab.272 Bronchiolitis has been described
pneumonitis are frequently indistinguishable in patients exposed to penicillamine, a med-
from an infectious process. Searles and ication that is less commonly used today
McKendry256 proposed diagnostic criteria for because of the availability of safer and
methotrexate pneumonitis that are based on more effective medications.273,274 Gold salts,
the absence of an infectious etiology as deter- which are rarely prescribed in today’s bio-
mined by blood or sputum cultures or histologic era, have been associated with a pulmo-
pathologic examination of a lung biopsy nary hypersensitivity reaction characterized
specimen. If methotrexate pneumonitis is by pulmonary infiltrates and peripheral
suspected, methotrexate should be discontin- eosinophilia.274,275 Such complications are
ued. Systemic corticosteroids are often rare, and infectious processes are more fre-
required, and can be tapered over weeks to quently implicated as causing acute pul-
months.246,248,249 Resumption of methotrex- monary exacerbations with accompanying
ate is generally not recommended. radiographic changes.
Tumor Necrosis Factor-a Blockade Summary

and Tuberculosis
The array of pediatric pulmonary complica-
Therapies aimed at inhibiting the proin-
tions of the various rheumatologic disorders
flammatory effects of TNF-a have emerged
illustrates the complexities and challenges of
as promising treatment options for children
the underlying disorders and the continuing
with JRA.257,258 TNF-a inhibitors, such as
lack of detailed knowledge of the pathophysi-
etanercept, adalimumab, and infliximab,
ology and optimal treatment paradigms in
increase the risk of reactivation of latent
children. Although the vertical transfer of
tuberculosis.259-262 This potential complica-
information of disease pathogenesis and man-
tion can be minimized with appropriate
agement has made much progress from adult
screening for tuberculosis. The clinical use
studies, such as with the diagnosis and man-
of infliximab has been associated with rare
agement of PAH, there also is abundant evi-
reports of interstitial pneumonitis.263,264
dence that in many instances the underlying
disorders may differ in important and funda-
Other Rheumatology Medications mental respects between children and adults.
Associated with Pulmonary Disease Recognition of pulmonary complications of
rheumatic disorders in children is often more
Cyclophosphamide, a cytotoxic agent that difficult and requires enlightened anticipa-
has been used in the treatment of organ- tion and a high index of suspicion. Further
threatening rheumatic disease, can rarely progress in understanding and treating the
cause interstitial pneumonitis.265 Cases various pediatric disorders is hampered by
of cyclophosphamide-induced pulmonary the lack of pediatric-specific information.
fibrosis are confounded by the presence Crucial to further progress are the expan-
of an underlying disease with known pul- sion of orphan childhood disease databases
monary manifestations independent of and the expansion of the current pediatric
medication exposure.266 Leflunomide and rheumatology research groups to include a
sulfasalazine, drugs historically used in the national clinical trials and outcomes effort.
treatment of inflammatory arthritis, are In this way, a comprehensive approach to
linked with the development of interstitial determining basic natural history, risks,
pneumonitis.267-270 Similarly, azathioprine and outcomes and to defining the next gen-
has been associated with interstitial pneu- eration of therapies in a disease-specific and
monitis, bronchiolitis, and diffuse alveolar age-specific manner can be achieved.
Acknowledgments Presentation and management. Chest 118:

1083-1090, 2000.
18. Eagen J, et al: Pulmonary hemorrhage in systemic
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assistance of Donald Frush, MD, in the prep- 19. Boumpas DT, et al: Systemic lupus erythematosus:
Emerging concepts, part 1: Renal, neuropsychia-
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and Alexander Spock, MD, in the prepara- disease. Ann Intern Med 122:940-950, 1995.
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systemic lupus erythematosus. N Y State J Med
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21. Eisenberg H, et al: Diffuse interstitial lung disease
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225. Marcille R, et al: Long-term outcome of pediatric 246. Zisman DA, et al: Drug-induced pneumonitis:
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CHAPTER 11
of Systemic Vasculitis
BRIAN P. O’SULLIVAN AND TED KREMER
Definition of Vasculitis 241 Churg-Strauss Syndrome 250

Specific Vasculitis Syndromes 244 Behçet Disease 251
Pulmonary-Renal Syndromes 244 Takayasu Arteritis 252
Henoch-Schönlein Purpura 246 Idiopathic Pulmonary-Renal Syndrome 253
Wegener Granulomatosis 247 Summary 254
Microscopic Polyangiitis 249 References 254
The pulmonary vasculitides are a heteroge- medium-sized, or small arteries may be

neous group of primary or secondary diseases, involved; the infiltrate may be neutrophils,
in which there is inflammation that may lead lymphocytes, eosinophils, or plasma cells;
to progressive destruction of the pulmonary the inflammation may be necrotizing or
microvasculature. Pulmonary involvement granulomatous; there may or may not be
may develop because the lung has an exten- immune complex deposition or antineutro-
sive vascular and microvascular network, sen- phil antibodies. All of these characteristics
sitizing antigens can easily reach the lung, and determine the specific type of vasculitis.
there are large numbers of vasoactive and acti- A definite diagnosis cannot be made with-
vated immune cells in the lung. Primary or out tissue biopsy, although several clinical
isolated pulmonary vasculitis is extremely rare syndromes are fairly typical and should sug-
in children. Pulmonary vasculitis is an gest what type of pathology one is likely to
unusual condition in children and is almost see. The clinical and pathologic features vary,
always seen in conjunction with a systemic and depend on the site and type of blood ves-
vasculitis syndrome. This chapter reviews sel involved. Although many vasculitides
common systemic vasculitides associated affect adults and children, some, such as
with pulmonary disease and discusses presen- Kawasaki disease, occur almost exclusively
tation, diagnosis, and therapy. in children. Other vasculitides, such as tem-
poral arteritis, rarely, if ever, occur in child-
hood, and others, such as polyarteritis and
Definition of Vasculitis Wegener granulomatosis, have different etio-
logic, clinical, and prognostic characteristics
Before embarking on a discussion of specific in children.1 It was thought inappropriate
illnesses associated with inflammation of to continue applying the adult classification
blood vessels and pulmonary involvement, criteria to vasculitis occurring in childhood.
clarifying what is meant by “vasculitis,” The newly adopted classification for child-
how vasculitides may manifest systemically, hood vasculitides comes from the consensus
and some of the serologic markers asso- criteria endorsed by the European League
ciated with these diseases is in order. Simply Against Rheumatism and the Pediatric Rheu-
defined, vasculitis is inflammation of the matology European Society (Table 11-1).1
walls of blood vessels. Perivascular cuffing Despite extensive investigation, the patho-
is not a vasculitis. The involved vessels genesis of vascular inflammation is unknown
may be arteries, veins, or capillaries; large, in most cases. Vasculitis probably results from
241
Table 11-1 New Classification of Childhood Vasculitis

I. Predominantly large vessel vasculitis
A. Takayasu arteritis
II. Predominantly medium-sized vessel vasculitis
A. Kawasaki disease
B. Childhood polyarteritis nodosa
C. Cutaneous polyarteritis
III. Predominantly small vessel vasculitis
A. Granulomatous
1. Wegener granulomatosis
2. Churg-Strauss syndrome
B. Nongranulomatous
1. Henoch-Schönlein purpura
2. Microscopic polyangiitis
3. Isolated cutaneous leukocytoclastic vasculitis
4. Hypocomplementemic urticarial vasculitis
IV. Other vasculitides
A. Behçet disease
B. Vasculitis secondary to infection (including hepatitis B–associated polyarteritis nodosa), malignancies,
and drugs (including hypersensitivity vasculitis)
C. Vasculitis associated with connective tissue diseases
D. Isolated vasculitis of the central nervous system
E. Cogan syndrome
F. Unclassified
the combination of multiple risk factors, vessel vasculitides, such as giant cell arteritis
including genetic predisposition, environmen- and Takayasu arteritis, do not cause much pul-
tal factors (infection and inhalation of particu- monary disease because the intrapulmonary
late matter), and chance. Figure 11-1 shows vessels are medium-sized arteries or smaller.
the distribution of vasculitis type in vessels of Medium-sized vessel arteritides include polyar-
various sizes. There is a great deal of overlap teritis nodosa. Classic polyarteritis nodosa is
regarding which vessels are involved in some uncommon in children and generally not asso-
common vasculitides, notably Wegener granu- ciated with lung disease,3 although case reports
lomatosis and microscopic polyangiitis.2 Large of lung disease in association with polyarteritis
Aorta (large artery)

Renal artery (medium sized artery)
Lobar artery (medium sized artery)
Arcuate artery (small artery)
Giant cell (temporal) arteritis

Interlobular artery (small artery)
and Takayasu
arteritis Arteriole
Polyarteritis nodosa and
Kawasaki disease
Glomerulus
Microscopic polyangiitis, Wegener granulomatosis and

Churg-Strauss syndrome
Henoch-Schönlein purpura,
essential cryoglobulinemic vasculitis and
antiglomerular basement membrane
antibody mediated disease
Figure 11-1. Spectrum of systemic vasculitides organized according to predominant size of vessels affected. (From
Savage COS, et al: ABC of arterial and vascular disease: Vasculitis. BMJ 320:1325-1328, 2000.)
Chapter 11—Pulmonary Manifestations of Systemic Vasculitis 243
nodosa and Kawasaki disease have been pub- presence of antineutrophil cytoplasmic anti-
lished.4-6 The small vessel variant of polyar- bodies (ANCA).
teritis nodosa, microscopic polyangiitis, is There is mounting evidence that ANCA play
associated with lung disease and is discussed a causative role in Wegener granulomatosis
in detail subsequently. and microscopic polyangiitis (Fig. 11-2).7
Typically, patients with small vessel vasculi- A strong case can be made that the presence
tides present with pulmonary manifestations. of ANCA directly leads to disease based on sev-
These include Wegener granulomatosis, eral lines of evidence. First, an infant who was
microscopic polyangiitis, Henoch-Schönlein born to a mother with high circulating levels
purpura, Churg-Strauss syndrome, and Good- of ANCA developed pulmonary hemorrhage
pasture syndrome. and glomerulonephritis within days of birth.8
Systemic manifestations of vasculitides The infant’s serum was ANCA-positive. Treat-
include malaise, fever, weight loss, joint pain, ment with corticosteroids and exchange trans-
kidney disease, and skin rash.2 Diagnosis of a fusion brought the disease into remission.
specific vasculitis syndrome depends on clin- Second, neutrophils that have been activated
ical and serologic characteristics. by ANCA-IgG kill cultured endothelial cells.9
Typical vasculitis syndromes are associated Third, monocytes and neutrophils interact
with deposition of immune complexes in with ANCA, and monocyte-derived mediators
blood vessel walls.7 Goodpasture syndrome is of inflammation can damage vessel walls fur-
the classic example of IgA-related complex ther.10 Finally, glomerulonephritis has been
deposition. A subset of small vessel vasculitides precipitated in several murine models with
has minimal immune-complex deposition in transfer of ANCA-IgG.7 Taken together, these
vessel walls. These so-called pauci-immune findings indicate that the presence of ANCA
vasculitides include Wegener granulomatosis, may be toxic to blood vessels and precipitate
microscopic polyangiitis, Churg-Strauss syn- disease.
drome, and renal-limited vasculitis. Small ANCA come in two forms, and the nomen-
amounts of immune complexes form on the clature has become confused as more has
surfaces of blood vessels in these diseases, but been learned about these antibodies. Ini-
differ from larger vessel vasculitides in that tially, the designations used for ANCA-IgG
there is not the gross accumulation of immune were P-ANCA (for perinuclear staining) and
complexes seen in the large vessel diseases; C-ANCA (for cytoplasmic staining) when
also, the small vessel vasculitides are asso- anti-ANCA antibodies were used to detect
ciated with a greater degree of necrotizing the presence and location of intracellular
injury. The precise cause of tissue injury in ANCA (Fig. 11-3). These older terms have
Wegener granulomatosis and microscopic been replaced by more precise terms based
polyangiitis is uncertain, but there is a strong on the specific antigens against which
association between disease activity and the ANCA is directed. The target for P-ANCA is
ANCA Figure 11-2. Events in the patho-

ANCA antigen genesis of antineutrophil cytoplas-
Cytokine mic antibody (ANCA) small vessel
Cytokine receptor vasculitis that have been observed
Fc receptor in vitro. Beginning in the top left
Adhesion molecule and moving to the right, cytokines
Adhesion molecule receptor or other priming factors induce neu-
trophils to express more ANCA anti-
gens at the cell surface, where they
are available for binding to ANCA,
which activates neutrophils. Neutro-
phils that have been activated by
ANCA interact with endothelial cells
via adhesion molecules and release
toxic factors that cause apoptosis
and necrosis. (From Jennette JC, Xiao
H, Falk RJ: Pathogenesis of vascular
inflammation by anti-neutrophil cyto-
plasmic antibodies. J Am Soc Nephrol
17:1235-1242, 2006.)
A B
Figure 11-3. A and B, Indirect immunofluorescence staining showing perinuclear antineutrophilic cytoplasmic anti-
body (A) and cytoplasmic antineutrophilic cytoplasmic antibody (B) distribution.
most frequently myeloperoxidase (MPO) Positive ANCA by indirect immunofluores-

(although some other antigens have been cence alone is not specific for systemic vasculi-
reported), and the target for C-ANCA is pro- tis; a positive indirect immunofluorescence
teinase-3 (PR3).7,11 On activation, neutrophil test can be seen in patients with systemic
cytoplasmic granules move to the cell surface lupus erythematosus, rheumatoid arthritis,
where expression of MPO and PR3 antigens Felty syndrome, ulcerative colitis, and other
allows association with circulating ANCA. multisystem conditions.13 It is imperative also
ANCA activation of neutrophils requires to employ the enzyme-linked immunosor-
antigen binding and Fc-receptor engage- bent assay test, which differentiates PR3-
ment. Levels of PR3 antigen expression may ANCA from MPO-ANCA. This distinction is
be genetically determined, making some important because, as noted before, different
individuals more prone to ANCA-associated ANCA may be associated with various disease
diseases than others.12 processes. ANCA-associated diseases are the
Consistent with the association of these same in children as in adults.14
two ANCA with different disease processes,
internalization of MPO-ANCA and PR3-ANCA
causes different cellular responses. MPO- Specific Vasculitis Syndromes
ANCA causes generation of intracellular oxi-
dants, whereas PR3-ANCA causes endothelial Pulmonary-Renal Syndromes
cell apoptosis.7 MPO-ANCA and PR3-ANCA
activate neutrophils to release mediators of Numerous disorders affect the small vessels of
acute inflammation. the lungs and the kidneys. These conditions
Indirect immunofluorescence and enzyme- are associated most often with a combination
linked immunosorbent assay tests for ANCA of pulmonary hemorrhage and nephritis. Pul-
are available. It is recommended that a combi- monary hemorrhage may not be obvious, and
nation of these tests be used if the diagnosis of can manifest simply as diffuse, patchy pulmo-
an ANCA-associated vasculitis is suspected. nary infiltrates on a chest radiograph in a
child who has unexplained anemia. Although manifests as anemia in association with
easy to diagnose when the lungs and kidneys pulmonary infiltrates on chest radiographs
are affected simultaneously, in all of these syn- (Fig. 11-4). Glomerulonephritis can be sudden
dromes there may be temporal separation of and severe with little prodrome. Early treat-
specific organ involvement. ment with anti-inflammatory agents is lifesav-
The pulmonary-renal syndromes consist of ing, so a high degree of suspicion for and rapid
Henoch-Schönlein purpura, Wegener granulo- recognition of this syndrome are key.16
matosis, microscopic polyangiitis, Churg-
Strauss syndrome, Goodpasture syndrome, and
systemic lupus erythematosus.15 All of these B
entities are associated with an inflammatory LM
M
component, and children affected by them
generally have an elevated erythrocyte sedi-
mentation rate and other serum markers of
inflammation. Table 11-2 highlights the clini-
cal and laboratory features of these syndromes.
The pulmonary manifestations of systemic
lupus erythematosus are discussed in detail
in Chapter 10 and are not reiterated here.
All of the pulmonary-renal syndromes occur
with a low frequency in childhood. The most
common small vessel vasculitis in childhood,
Henoch-Schönlein purpura, has the lowest
incidence of associated pulmonary disease,
and all the other forms of vasculitis in child-
hood are quite rare in general, so despite the Portable
fact that they are commonly associated with Upright RM 7/11/90
lung disease, they are still unusual causes of Figure 11-4. Chest x-ray shows patchy infiltrates caused
pulmonary hemorrhage. When a pulmonary- by pulmonary hemorrhage in a 16-year-old boy with peri-
renal syndrome does occur, however, it can nuclear antineutrophilic cytoplasmic antibody-positive
pulmonary-renal syndrome. The patient had a hemoglo-
be devastating. Pulmonary hemorrhage can bin of 4.1 g/dL with a hematocrit of 11.5% at the time
be massive and life-threatening, and usually of presentation.
Table 11-2 Clinical and Serologic Findings in Patients with Pulmonary-Renal Syndromes*
HSP GPS WG MPA SLE

Pulmonary 0 to þ þþþþ þþþ þþþ þ to þþ
hemorrhage
Glomerulonephritis þþþþ þþþþ þþþþ þþþþ þþþ to þþþþ
Upper airway 0 0 þþþþ þþ þ to þþ
involvement
Skin rash þþþþ 0 to þ þþþ þþþ þþþþ
Arthralgia þþþþ 0 þþþ þþþ þþþþ
Elevated ESR þ 0 þþþþ þþþþ þþþþ
Abdominal þþþþ 0 0 0 0
involvement
Serology IgA positive, Anti-GBM C-ANCA P-ANCA, ANA, anti–double-
IgM (rarely (rarely C- stranded DNA (rarely
positive P-ANCA) P-ANCA) ANCA P-ANCA)
*0 ¼ not present; increasing association with increasing number of þ signs.

ANA, antinuclear antibody; C-ANCA, cytoplasmic antineutrophilic cytoplasmic antibody; ESR, erythrocyte sedimentation rate;
GBM, glomerular basement membrane; GPS, Goodpasture syndrome; HSP, Henoch-Schönlein purpura; MPA, microscopic
polyangiitis; P-ANCA, perinuclear antineutrophilic cytoplasmic antibody; SLE, systemic lupus erythematosus; WG, Wegener
granulomatosis.
Any child with anemia and pulmonary The classic presentation includes ery-
infiltrates must be suspected of having pul- thematous papules followed by nonthrom-
monary hemorrhage, be it idiopathic, trau- bocytopenic palpable purpura in the lower
matic, or due to small vessel vasculitis.17 extremities, trunk, and face; arthralgia or
The skin also should be examined for signs arthritis; abdominal pain; gastrointestinal
of cutaneous vasculitis (palpable purpura, bleeding; and nephritis. Renal involvement
erythema nodosum, ulceration, splinter occurs in approximately 60% of cases and
hemorrhages),18 and the nose, ears, and leads to a significant degree of morbidity
nasopharynx and oropharynx should be (Table 11-3).
examined for the presence of bleeding or Although renal abnormalities in Henoch-
granuloma. When the diagnosis of small Schönlein purpura are common, the classic
vessel vasculitis is being considered, urine pulmonary manifestations, such as diffuse
sediment must be evaluated for the presence alveolar hemorrhage and interstitial pneumo-
of cellular casts and protein. Serum creati- nitis, are thought to be infrequent. Subclinical
nine levels can be maintained in the normal pulmonary manifestations, including diffu-
range even in the face of glomerular injury, sion defects and radiographic anomalies,
so waiting for an increase in serum urea seem to be quite frequent in patients with
and creatinine unduly delays the diagnosis. Henoch-Schönlein purpura, but are not
commonly reported. Other respiratory mani-
Henoch-Schönlein Purpura festations include pleural effusion and chy-
lothorax. Diffuse alveolar hemorrhage is the
Henoch-Schönlein purpura is the most com- most frequent pulmonary complication asso-
mon form of small vessel vasculitis in child- ciated with Henoch-Schönlein purpura, but,
hood. Its incidence is estimated to be 10 to as previously noted, pulmonary hemorrhage
14 per 100,000, with boys affected twice as is rare in these patients, although it has been
frequently as girls. In the United States, the reported.19,20
prevalence peaks in children 5 years old. Pulmonary hemorrhage is secondary to
Approximately 75% of cases occur in chil- disruption of the alveolar-capillary mem-
dren 2 to 11 years old. Henoch-Schönlein branes by circulating immune complexes.
purpura is rare in infants and young children. In a series reported from the Mayo Clinic
The etiology of Henoch-Schönlein purpura of 28 patients with pulmonary involvement
is largely unknown, although it commonly in Henoch-Schönlein purpura, 18 patients
follows an upper respiratory tract infection. were 20 years old or younger. Of these
Group A streptococcus has been implicated patients, 26 had diffuse alveolar hemor-
as a trigger for Henoch-Schönlein purpura rhage, 5 of whom had associated pleural effu-
because many patients with Henoch-Schön- sions; 9 patients died (3 children).21 The
lein purpura have elevated antistreptolysin O youngest reported patient with pulmonary
antibodies. The pathophysiology of Henoch- disease associated with Henoch-Schönlein
Schönlein purpura is not fully understood, purpura was a 5-month-old infant who died
but IgA plays a crucial role in the immu-
nopathogenesis, as evidenced by increased
serum IgA concentrations, IgA-containing cir-
culating immune complexes, and IgA im- Table 11-3 Henoch-Schönlein Purpura
mune complex deposition in vessel walls and
At least one of the following four conditions should
renal mesangium. Henoch-Schönlein purpura be present
is almost exclusively associated with abnor- Diffuse abdominal pain
malities involving IgA1, rather than IgA2. Any biopsy specimen showing predominant IgA
IgA-negative biopsies occur in 10% to 25% of deposition
cases of Henoch-Schönlein purpura, although Arthritis or arthralgia
it is possible that these IgA-negative cases Renal involvement (any hematuria or proteinuria
represent other, unidentified vasculitic syn- or both)
dromes misdiagnosed as Henoch-Schönlein In the presence of palpable purpura (mandatory
criterion)
purpura because of overlapping features.
of complications associated with diffuse alve- Wegener Granulomatosis

olar hemorrhage and interstitial fibrosis.22
The clinical presentation of patients with Wegener granulomatosis is a necrotizing
Henoch-Schönlein purpura complicated by granulomatous vasculitis with a broad spec-
diffuse alveolar hemorrhage may vary. Typi- trum of findings and progression. Wegener
cally, these patients are diagnosed with granulomatosis and microscopic polyangii-
Henoch-Schönlein purpura before the onset tis are extremely similar diseases with great
of pulmonary symptoms. Some patients overlap in clinical and pathologic presenta-
may develop milder pulmonary symptoms, tions. As such, it has been suggested now
such as cough, which may be associated to combine these diseases under the rubric,
with blood-tinged sputum and crackles on “ANCA-associated small vessel vasculitis.”
lung auscultation. Other patients progress These two entities are discussed separately
to dyspnea at rest, hemoptysis, and occa- here partly for historical reasons and partly
sionally respiratory failure requiring intuba- because there remain many clinical studies
tion and ventilatory support. Blood loss that focus on either one or the other of
into the lungs may be severe enough to these entities. Practically, it might be impos-
require transfusion therapy. Chest radio- sible to distinguish Wegener granulomatosis
graphs show diffuse pulmonary infiltrates from microscopic polyangiitis, however,
secondary to alveolar hemorrhage. Bron- even with tissue biopsy. What looks to be
choscopy is useful only if uncertainty exists microscopic polyangiitis initially may prove
regarding pulmonary hemorrhage versus to be Wegener granulomatosis later, when
infection as the cause of the physical exam- manifestations in other organs become
ination and radiologic abnormalities. Lung apparent, and granulomas are present. The
biopsy is rarely needed because affected tis- overlap in serology between these two enti-
sue generally can be obtained from less dan- ties is highlighted in Table 11-3.
gerous biopsy sites (skin or kidney). Wegener granulomatosis is uncommon in
Treatment of Henoch-Schönlein purpura children; its peak incidence is in adults in
almost always includes the use of corti- their 60s and 70s. The etiology of Wegener
costeroids. Prednisone, 1 to 2 mg/kg/day, is granulomatosis is unknown, and it does
the initial choice. Cyclophosphamide, 2 to not have specific genetic markers. In adults,
3 mg/kg/day, commonly is added in cases systemic Wegener granulomatosis is noted
involving severe pulmonary hemorrhage. for its severity and high mortality.25 Still,
Length of therapy depends on the time to Wegener granulomatosis has been reported
resolution of symptoms and radiographic in children; as in adults, it generally mani-
clearance of pulmonary infiltrates. Support- fests with the triad of upper airway, lower
ive care, including mechanical ventilation, airway, and renal involvement. Children
is often necessary in cases with severe alveo- frequently present with cough, sinus pain,
lar damage. fever, arthralgias or arthritis, hemoptysis,
Although clinically important pulmonary and skin rashes or ulceration. Cutaneous
disease is rare in Henoch-Schönlein pur- manifestations may precede other systemic
pura, even patients without respiratory symptoms by months and occur most com-
symptoms have objective signs of mild lung monly on the legs. The predominant skin
abnormalities. In a cohort of children with finding is palpable purpura, but lesions
Henoch-Schönlein purpura free of clinical may be vesicular, papular, or nodular, and
pulmonary symptoms, patients were noted even urticaria has been reported.18 Upper
to have an impaired diffusing capacity for airway manifestations of Wegener granulo-
carbon monoxide. In this study, 70% of matosis include rhinorrhea, purulent or
the patients had radiographic evidence for bloody discharge, persistent otitis media,
mild interstitial lung changes.23 In another sinusitis, saddle-nose deformity, subglottic
group of children with Henoch-Schönlein stenosis, and tracheal stenosis.26 Renal
purpura who had no evidence for lung disease involvement may occur early or late in the
clinically or radiographically, the finding of course, and when present, it requires aggres-
an abnormal diffusing capacity for carbon sive management to avoid rapid progression
monoxide was again seen.24 to end-stage renal disease.
The American College of Rheumatology hemorrhage as the most consistent finding

criteria require the presence of two of the in a group of 11 children with Wegener
following four criteria for the diagnosis of granulomatosis (7 of 11). Of the other four,
Wegener granulomatosis: nasal-oral inflamma- one child had a thick-walled cavitary lesion,
tion, abnormal findings on chest radiograph, and another child had bilateral nodules.
abnormal urinalysis, and granulomatous in- Computed tomography (CT) scans of the
flammation on biopsy specimen.1 The pres- sinuses and of the chest are helpful for diag-
ence of subglottic, tracheal, or endobronchial nosis. CT virtual bronchoscopy (high-reso-
stenosis, and the presence of a high titer of lution helical CT with three-dimensional
PR3 or positive C-ANCA staining have been reconstruction) allows visualization of cen-
included more recently in the diagnostic tral airway stenosis with high specificity,
criteria.1 The new classification of a child as but low sensitivity; it does not eliminate
having Wegener granulomatosis requires the the need for bronchoscopy.
presence of three of the newly established The diagnosis of Wegener granulomatosis
criteria of six (Table 11-4). may be made histologically or serologically
Pulmonary disease develops in nearly 75% in the right clinical setting. Histologic
of children with Wegener granulomatosis.27 changes are patchy, making false-negative
The clinical spectrum of pulmonary involve- biopsy results owing to sampling error possi-
ment in Wegener granulomatosis includes ble. The accuracy of the biopsy depends on
cough, sinusitis, chest pain, pleuritis, or the site, disease activity, and amount of tis-
hemoptysis. In children, densities on the sue obtained. Given the presence of skin,
chest radiograph of an asymptomatic patient kidney, or upper airway lesions in many
may be the first sign of disease. One third of patients with Wegener granulomatosis,
all abnormal chest radiographs in children biopsy of these areas, where diagnostic find-
with Wegener granulomatosis are not asso- ings may occur and where the risk of the
ciated with pulmonary symptoms. Radio- procedure is low, is preferred. In some cases,
graphic findings frequently include transient lung biopsy may be necessary, however.
or persistent infiltrates and nodules, whereas Bronchoscopic transbronchial biopsy is not
focal atelectasis, pleural effusion, pulmonary recommended because the likelihood of
hemorrhage, and mediastinal or hilar lymph obtaining a diagnostic specimen is low.
node enlargement are less common.28 Open lung biopsy always is risky, and this
The precise radiographic findings in chil- may be especially true in the pulmonary
dren are difficult to state because there are vasculitides. Surgical pathology of the lung
no large case series in children younger than in Wegener granulomatosis shows three
18 years old. Wadsworth and colleagues29 characteristic changes: (1) parenchymal
reported diffuse interstitial and alveolar necrosis, (2) vasculitis, and (3) granuloma-
infiltrates secondary to diffuse alveolar tous inflammation.31 Figure 11-5 shows the
pathogenesis of the vasculitis and granu-
loma formation in Wegener granulomatosis.
Classification Criteria for Serologic diagnosis of Wegener granulo-
Table 11-4 Wegener Granulomatosis matosis depends on testing for ANCA.
Three of the following six conditions should be ANCA directed at PR3 are found in 70% to
present
90% of patients with active Wegener granu-
Abnormal urinalysis*
lomatosis.32 In the appropriate clinical
Granulomatous inflammation on biopsy
specimen
setting, the positive predictive value of posi-
Nasal-sinus inflammation
tive PR3 ANCA approaches 99%. In the
Subglottic, tracheal, or endobronchial stenosis
appropriate circumstance, patients can be
Abnormal chest x-ray or CT scan of the chest
treated for Wegener granulomatosis on the
High titer of proteinase-3 or positive C-ANCA
basis of positive ANCA without obtaining tis-
staining sue for diagnosis.33 MPO-ANCA may be posi-
tive in Wegener granulomatosis, although
*If kidney biopsy is performed, it characteristically shows
necrotizing pauci-immune glomerulonephritis.
this is much less common. The accuracy of
C-ANCA, cytoplasmic antineutrophilic cytoplasmic antibody. any diagnostic test is based on pretest
prednisone (2 mg/kg/day) and oral daily

cyclophosphamide (2 mg/kg/day). High-
dose prednisone is maintained until active
disease manifestations have decreased, and
then it is tapered, depending on disease
activity. Therapy with cyclophosphamide is
continued for at least 1 year after achieving
complete remission, and is then tapered.
Intravenous gamma globulin has been used
successfully in some cases refractory to
above-mentioned therapy.34 If the disease
A
is in remission, further switching of therapy
to azathioprine has proved efficacious in
adults and is worth trying in children.34
Prophylaxis with trimethoprim-sulfameth-
oxazole is now commonly prescribed for chil-
dren with Wegener granulomatosis. Use of
such an aggressive regimen has improved the
prognosis for adults and children with Wege-
ner granulomatosis. It seems that Wegener
granulomatosis associated with the presence
of PR3-ANCA has an earlier response to ther-
apy than MPO-ANCA-associated disease.35 A
B
significant portion of pediatric patients are
Figure 11-5. Photomicrographs of lung biopsy speci- still subject to chronic morbidity and mortal-
men from a patient with Wegener granulomatosis. A,
Necrotizing granulomatous vasculitis with destruction of
ity.27 Persistence of granuloma may be the
vessel wall and obliteration of lumen. B, Granulomatous root of relapses in Wegener granulomatosis,
inflammation with multinucleated giant cells. (From Curg A, and much work is ongoing to uncover the
Brallas, Metal. Am Rev Respir Dis 134:149-166, 1986.)
driving force behind this persistence and
means of eradicating the granuloma.25
probability. Positive ANCA in a patient with
few or no clinical signs or symptoms of Wege-
ner granulomatosis or microscopic polyan- Microscopic Polyangiitis
giitis should be interpreted with caution.
Wegener granulomatosis shows signifi- Microscopic polyangiitis is a necrotizing
cant pulmonary morbidity. Pulmonary pauci-immune vasculitis affecting predomi-
function tests may show obstructive defects nantly small vessels and is often associated
in 55% of cases; such defects are often with a high titer of MPO-ANCA or positive
caused by endobronchial lesions and scar- P-ANCA staining.1 Microscopic polyangiitis,
ring, whereas restrictive defects and reduced similar to Wegener granulomatosis, can be
lung volumes or diffusing capacity for car- associated with crescentic glomerulonephri-
bon monoxide may be found in 30% to tis and hemorrhagic pulmonary capillaritis.
40% of cases. Sinus or pulmonary infections Microscopic polyangiitis has an incidence
may mask the diagnosis or be found at the of approximately 1:100,000 in the general
time of the initial evaluation. Similar find- population with mean age of onset of about
ings often occur during treatment. Pneumo- 50 years.36 Microscopic polyangiitis is more
nia accounts for 40% of serious infections prevalent than Wegener granulomatosis,37
and is associated with significant mortality. although both are quite rare in adults and
The effective management of Wegener rarer yet in children.
granulomatosis requires early diagnosis, Pulmonary involvement occurs in one quar-
close patient follow-up, and careful atten- ter to one third of patients with microscopic
tion to potential treatment complications. polyangiitis.38 There may be a long delay
Therapy is usually initiated with high-dose between onset of symptoms and diagnosis
because of the nonspecific characteristic of Treatment of microscopic polyangiitis is

many of the symptoms.39 In one case series of the same as for Wegener granulomatosis—a
adults with microscopic polyangiitis selected combination of corticosteroids, cyclophos-
for the presence of alveolar hemorrhage, renal phamide, and azathioprine. Disease relapses
signs were present in 97% of patients, showing are common within the first 2 years of diag-
a strong concordance between renal and lung nosis. The risk of death from microscopic
disease when the latter is present.39 polyangiitis is greater in patients who are
Microscopic polyangiitis can present very PR3-ANCA-positive and is increased if pul-
similarly to Wegener granulomatosis, but monary hemorrhage is present.39
without granuloma formation or nasopha-
ryngeal/large airway involvement. As with
any patient with vasculitis, systemic manifes- Churg-Strauss Syndrome
tations, such as fever, weight loss, asthenia,
myalgias, and arthralgias, are common. Churg-Strauss syndrome is another pauci-
Isolated pulmonary hemorrhage may occur, immune pulmonary-renal syndrome. Churg-
but most patients with alveolar-capillary Strauss syndrome is defined as an ANCA-
hemorrhage have extrathoracic manifesta- associated, eosinophil-rich granulomatous
tions.38 Interstitial fibrosis may predate the disease involving the respiratory tract, nota-
onset of pulmonary vasculitis by years and bly the lungs and sinuses. The hallmark of
can be the initial manifestation of micro- Churg-Strauss syndrome is its association
scopic polyangiitis.40 In classic microscopic with peripheral blood eosinophilia and
polyangiitis, chest radiographic abnormal- asthma; this is accompanied by extravas-
ities reflect pulmonary hemorrhage with the cular granulomas and a necrotizing vasculitis
major finding being patchy, bilateral airspace affecting small to medium-sized vessels.1,42
opacities. The nodules seen in Wegener gran- The triad of tissue infiltration by eosinophils,
ulomatosis are not present in microscopic necrotizing vasculitis, and extravascular gran-
polyangiitis because of the lack of granuloma ulomas is rarely seen simultaneously, and the
formation. A study looking at CT findings in three are found together in only a few
51 patients who had MPO-ANCA-positive patients.42 Because of its rarity, the preva-
microscopic polyangiitis showed ground- lence and incidence of Churg-Strauss syn-
glass attenuation in greater than 90% with drome in children are unknown.
areas of consolidation and bronchovascular Diagnosis of Churg-Strauss syndrome is
thickening in many of these patients. Patho- based on criteria developed by the American
logic correlation showed that these findings College of Rheumatology (Table 11-6). For
were due to pulmonary hemorrhage, intersti- classification purposes, a patient is said to
tial inflammation, and fibrosis.41 have Churg-Strauss syndrome if at least four
Serologic diagnosis is less certain with of these six criteria are positive. The pres-
microscopic polyangiitis than with Wegener ence of any four or more of the six criteria
granulomatosis. Although most patients with yields a diagnostic sensitivity of 85% and a
microscopic polyangiitis are MPO-ANCA- specificity of greater than 99%.43
positive, PR3-ANCA may be present in 40%, Churg-Strauss syndrome occurs in phases,
and 10% of patients with microscopic polyan- with the prodromal phase including rhinitis
giitis may be ANCA-negative (Table 11-5).38 and asthma, the second phase including
Table 11-5 Distribution of ANCA Serology in Wegener Granulomatosis and Microscopic Polyangiitis
ANCA RESULT WEGENER GRANULOMATOSIS MICROSCOPIC POLYANGIITIS

Positive PR3 ANCA/C-ANCA 65–70% 35–45%
Positive MPO ANCA/P-ANCA 15–25% 45–55%
Negative ANCA 10–20% 10–20 %
ANCA, antineutrophilic cytoplasmic antibody; C-ANCA, cytoplasmic antineutrophilic cytoplasmic antibody; MPO,
myeloperoxidase; P-ANCA, perinuclear antineutrophilic cytoplasmic antibody; PR3, proteinase-3.
represent the small vessel involvement, with

Criteria for the Classification
Table 11-6 of Churg-Strauss Syndrome purpura and subcutaneous nodules being
most common. Such lesions are a common
Asthma
early presenting symptom of the vasculitis
Eosinophilia >10%
phase in children.45 Mononeuritis multiplex
Neuropathy—mononeuropathy or polyneuropathy
is seen in many adults with Churg-Strauss
Pulmonary infiltrates, nonfixed
syndrome; optic neuritis also is reported.
Paranasal sinus abnormality
Pulmonary findings beyond the presence
Extravascular eosinophils
of asthma include abnormal chest radio-
graphs with patchy infiltrates. During the
second phase of the illness, when tissue
peripheral blood and tissue eosinophilia, eosinophilia is present, radiographs may
and the third phase consisting of systemic have the appearance of chronic eosinophilic
vasculitis. Asthma and sinusitis may precede pneumonia. Pleural effusion has been
the onset of vasculitis by many years. Peri- reported in 25% to 50% of adults.42 Renal
carditis, myocarditis, and tamponade may involvement in Churg-Strauss syndrome is
be seen in the vasculitis phase of the dis- less severe and prominent than in Wegener
ease, and occur in approximately half of all granulomatosis. Although pulmonary vas-
patients with Churg-Strauss syndrome. In culitis is present, diffuse alveolar hemor-
one series, congestive heart failure and myo- rhage is not as prominent in Churg-Strauss
cardial infarction were responsible for syndrome as in the other pulmonary-renal
nearly half of deaths from Churg-Strauss syndromes.46
syndrome.44 Asthma and eosinophilia are common
Boyer and colleagues45 reported two pedi- findings in children. The diagnosis of
atric patients with Churg-Strauss syndrome Churg-Strauss syndrome is considered when
presenting with prominent pulmonary more involved pulmonary disease (includ-
involvement. One, a 16-year-old with a pre- ing pleuritis) occurs, or when other signs of
vious history of asthma, presented with systemic vasculitis, such as cutaneous
pleuritic chest pain and a peripheral pulmo- lesions, cardiomyopathy, nephritis, or neu-
nary nodule complicated by an eosinophilic ropathy, become manifest. Laboratory stud-
pleural effusion. The other patient pre- ies suggestive of Churg-Strauss syndrome
sented at age 6 with cough, weight loss, include eosinophilia, elevated erythrocyte
and radiographic infiltrates. Lung biopsy sedimentation rate, and, in some patients,
specimens revealed elements characteristic positive MPO-ANCA. Because of the lack of
of Churg-Strauss syndrome, including specificity of these findings, tissue diagnosis
eosinophilic microabscesses and vasculitis. is often necessary. Biopsy of low-risk, easily
There has been an increase in reported cases accessible lesions such as skin lesions is
of pediatric Churg-Strauss syndrome in preferable. If the only organ involved with
more recent years, but whether this reflects systemic vasculitis is the lung, a transbron-
a true increased incidence or rather height- chial biopsy can be performed, but the small
ened diagnostic suspicion is unclear. The sample of tissue obtained from a child
youngest children reported to have Churg- should not be considered sufficient to rule
Strauss syndrome were 2 years old.45 In con- out the diagnosis if it is negative for eosino-
trast to adult patients with Churg-Strauss philic vasculitis or granuloma. In these rare
syndrome, in whom MPO-ANCA positivity cases, a video-assisted thoracoscopic biopsy
is common, children with Churg-Strauss syn- may be necessary.
drome are generally ANCA-negative. ANCA
testing should be done in any child for whom
the diagnosis is considered, but a negative Behçet Disease
test does not exclude the diagnosis.
Cutaneous findings are common in Churg- Behçet disease is a chronic, multisystem,
Strauss syndrome, occurring in one half to inflammatory disease that classically mani-
three quarters of patients.42 These lesions fests with a clinical triad of relapsing ulcers
of the mouth, genital ulcers, and uveitis/iri- Thrombosis of aneurysms in the pulmonary
tis.34 It also may manifest with systemic fea- artery may occur, leading to infarction
tures, including arthritis, thrombophlebitis of downstream pulmonary parenchyma.
migrans, erythema nodosum, meningoen- Thrombus formation may occur in other
cephalitis, and arterial aneurysms. The inci- major vessels, including the superior and infe-
dence in the United States is estimated at rior vena cavae.
7.5 per 100,000 with approximately 1% to Chest radiographs are abnormal in 90% of
2% of patients being children. Behçet dis- cases, with pleural effusion in 70%, diffuse
ease may be diagnosed at any age, but the bilateral infiltrates in 37%, right lower lobe
peak age of onset is between the second infiltrate in 28%, hilar vascular prominence
and fourth decades of life. Male-to-female in 14%, and round densities in 10% of
ratio is equal. An important feature for cases.48 Pulmonary artery aneurysms appear
making the diagnosis in children is a posi- as hilar enlargement on radiographic stud-
tive family history.34 Multiple organs are ies. Helical CT of the chest is the preferred
usually involved, including the skin, central method for diagnosis of aneurysms because
nervous system, gastrointestinal tract, geni- angiography may cause trauma to arteries
tourinary system, joints, heart, and lungs. and lead to additional aneurysm formation.
Histologically, an extensive vasculitis Pulmonary parenchyma and pleural
occurs, affecting arteries and veins of all involvement in Behçet disease are usually
sizes. Immune complex disease in large ves- attributed to pulmonary hemorrhage or
sels leads to aneurysm formation or throm- infarction or both. Findings include focal
bosis. Pulmonary artery involvement is the or diffuse alveolar infiltrates, wedge-shaped
most severe complication of the disease. or linear shadows, volume loss, and ill-
The etiology of Behçet disease is unknown, defined reticular or nodular opacities of the
although a genetic predisposition associated parenchyma or pleura. Pleural effusions sec-
with a trigger such as an infectious agent or ondary to pulmonary infarction, pleural
environmental exposure likely results in the vasculitis, or superior vena cava thrombosis
onset of the disease. The finding of HLA-B51 may occur. The literature includes one case
immunogenetics supports the diagnosis.47 report of organizing pneumonia associated
More severe cases are noted in young men with pulmonary artery aneurysm.
diagnosed before age 25 years. Typically, the Treatment for patients with Behçet disease
course is relapsing and remitting. and pulmonary complications often involves
Lung disease occurs in 1% to 5% of cases.48 a combination of corticosteroids and cyclo-
Pulmonary involvement in Behçet disease phosphamide. Anticoagulant and thrombo-
varies greatly and includes findings such as lytic therapy should be used with caution
pulmonary artery aneurysm, pulmonary because hemorrhage from an existing pulmo-
artery thrombosis, and pleural and parenchy- nary artery aneurysm is a risk. Autologous
mal abnormalities. Pulmonary artery aneu- stem cell transplantation has been used suc-
rysm is a rare complication of Behçet disease, cessfully for therapy of Behçet disease in two
but the lung is the second most common site patients (32 years old and 49 years old) with
for aneurysms after the aorta. The most com- pulmonary involvement presenting with
mon clinical presentation is hemoptysis hemoptysis and pulmonary artery aneurysms
resulting from rupture of the aneurysm and resistant to conventional therapy.49 The dura-
erosion into a bronchus. Other clinical find- tion of remission at the time of this report was
ings include cough, chest pain, and dyspnea. greater than 5 years.
Hemoptysis can be misdiagnosed as a pulmo-
nary embolism because deep venous throm-
bosis and abnormal ventilation/perfusion Takayasu Arteritis
scans are often seen in patients with Behçet
disease. Embolism of thrombi to the lung is Takayasu arteritis is a chronic inflammatory
actually quite rare in Behçet disease because and obliterative disease of large vessels, with
thrombi in inflamed veins are highly adher- preference for the aorta and its major
ent to the vessel wall and rarely migrate. branches. Table 11-7 lists more recently
stenosis of various large vessels—carotid,

Table 11-7 Takayasu Arteritis subclavian, or abdominal aorta. Magnetic
resonance angiography may be helpful as a
At least one of the following four conditions should
be present noninvasive test for subsequent monitoring
Decreased peripheral artery pulses or claudication of affected vessels.
of extremities or both Early identification and surgical resection
Blood pressure difference >10 mm Hg of the predominant lesions are essential, in
Bruits over aorta or its major branches or both conjunction with appropriate immunosup-
Hypertension (related to childhood normative pressive therapy. Prevention of chronic hyper-
data) tension and decreased perfusion sometimes
In the presence of angiographic abnormalities (on can be accomplished by excision of a stenotic
radiography, CT, or MRI) of aorta or its main
branches (mandatory criterion) area with graft replacement or stent insertion
to prevent restenosis.
published diagnostic criteria.1 This vasculitis Idiopathic Pulmonary-Renal

is more commonly found in Asian and Syndrome
Indian populations, with a female-to-male
ratio of 2.5:1, and is rarely found in other The term “idiopathic pulmonary-renal syn-
populations. One third of cases occur before drome” has been applied to a group of poorly
age 20 years, and symptoms usually appear defined disorders characterized by unex-
after age 10 years. plained pulmonary hemorrhage and rapidly
Early disease manifestations (pre-pulseless progressive glomerulonephritis without other
phase) include night sweats, weight loss, organ involvement.52 Pulmonary capillaritis
myalgias, and arthritis, often followed by with diffuse alveolar hemorrhage is almost
unexplained hypertension. During the pulse- always present in these patients. Many of
less phase, systemic symptoms are very these cases are associated with P-ANCA and
common. Skin manifestations include ery- no other identifying markers. Idiopathic pul-
thema nodosum, malar rash, and erythema monary renal syndrome likely represents
induratum. Cardiac involvement includes many different disease processes not clearly
dilated cardiomyopathy, myocarditis, and defined. Although an uncommon associa-
pericarditis. Other associated conditions tion, pulmonary fibrosis and hemorrhage
include interstitial lung disease and pneu- can occur with juvenile rheumatoid arthritis
monic consolidation. Pulmonary artery and is presumably secondary to rheumatoid-
involvement may occur, but is an infre- associated small vessel vasculitis.53,54
quent presenting sign. Cases of diffuse alveolar hemorrhage with
The presence of intermittent unexplained isolated pulmonary vasculitis without evi-
systemic symptoms of variable duration with dence of systemic disease and without posi-
a significantly elevated erythrocyte sedimenta- tive ANCA serology have been reported.55
tion rate (60 mm/hr) and a hypochromic In this one case series, eight patients had
microcytic anemia with leukocytosis should pulmonary capillaritis, but none of the
prompt periodic auscultation of large arteries eight had glomerulonephritis or other sys-
and blood pressure measurements in all four temic disease, and none had remarkable
limbs. A polyclonal hypergammaglobulinemia serologic studies (i.e., all relevant serologies
is present in one third of the cases. Comple- were negative). We provide care for one child
ment activation results in elevated levels of with a similar presentation. She had isolated
C3a and C5a, which may be used to guide pulmonary hemorrhage with profound ane-
therapy. mia and respiratory failure at age 3. Open lung
The diagnosis is confirmed by angiogra- biopsy showed the presence of small vessel
phy, which often outlines a massively dilated vasculitis. She has had mildly elevated eryth-
aortic arch, with aneurysmal dilation and rocyte sedimentation rate (26 to 34 mm/hr)
and multiple negative ANCA studies without

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a variable frequency. Lung disease is an patients with systemic vasculitis and idiopathic nec-
important feature of the ANCA-associated rotizing and crescentic glomerulonephritis. N Engl J
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22. Paller AS, Kelly K, et al: Pulmonary hemorrhage: An microscopic polyangiitis. Chest 123:297-301,
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CHAPTER 12
of Dermatologic Diseases
ROBERT SIDBURY AND NELSON L. TURCIOS
Yellow Nail Syndrome 256 Ehlers-Danlos Syndrome 264

Neurofibromatosis Type 1 258 Pseudoxanthoma Elasticum 265
Tuberous Sclerosis Complex 259 Xanthoma Disseminatum and
Hereditary Hemorrhagic Erdheim-Chester Disease 266
Telangiectasia 261 Hermansky-Pudlak Syndrome 267
Klippel-Trénaunay-Weber Erythema Multiforme 267
Syndrome 263 Mastocytosis 269
Cutis Laxa (Generalized Dyskeratosis Congenita 271
Elastolysis) 264 References 272
Systemic diseases often manifest with cuta- pericardial effusion at 6 months of age.4
neous findings. Many pediatric conditions The classic clinical presentation includes
with prominent skin findings also have sig- yellowish nail discoloration and dystrophy
nificant pulmonary morbidity. These condi- (89%), lymphedema (80%), and pleuropul-
tions include inherited multisystem genetic monary disease (63%).2 Two of the three
disorders, such as yellow nail syndrome, neu- clinical manifestations are required for the
rofibromatosis type 1 (NF1), tuberous sclero- diagnosis of yellow nail syndrome. The
sis complex (TSC), hereditary hemorrhagic cause of this syndrome remains unknown,
telangiectasia (HHT), Klippel-Trénaunay- although a few cases apparently followed
Weber syndrome, and Ehlers-Danlos syn- episodes of pneumonia. Many cases have
drome (EDS), and reactive processes, such as been attributed to congenital lymphatic
xanthoma disseminatum and mastocytosis. hypoplasia, similar to that occurring in pri-
This chapter discusses the common presenta- mary lymphedema.3 Yellow nail syndrome
tions and pulmonary manifestations of these has been associated with numerous malig-
disorders. nancies and immunodeficiencies.5
Yellow nail syndrome is characterized by
thickened, yellowish gray, slow-growing nails
Yellow Nail Syndrome that are excessively curved along both axes.
Nail changes are insidious in onset, are bilat-
Yellow nail syndrome was described first in eral, and affect hands and feet (Fig. 12-1). Nail
1964 in a group of 13 patients with lymph- changes may occur before or after other phys-
edema and distinctive nail findings.1 Yellow ical findings. Cuticles and lunula may be
nail syndrome is mostly a disease of early absent, and fragility and separation from the
middle age, affecting women more com- nail plate (onycholysis) may be seen. These
monly than men by 1.6:12; however, neona- findings may easily be confused with onycho-
tal chylothorax has been described in mycosis. Nail cultures are negative, and
association with yellow nail syndrome.3 It systemic antifungal therapy is unhelpful. His-
also has been reported in a male infant born topathologic changes in the nail matrix and
with congenital lymphedema, who devel- bed show dense fibrous tissue, which replaces
oped bilateral pleural effusions and a subungual stroma with numerous ectatic,
256
Chapter 12—Pulmonary Manifestations of Dermatologic Diseases 257
production of pleural fluid. Electron micros-

copy has revealed the presence of dilated
lymphatic capillaries in the visceral pleura,
suggesting an obstruction to the lymph drain-
age.8 Yellow nail syndrome associated with
bilateral cystic lung disease was reported in a
4-year-old girl, which suggests that normal
lymphatic drainage is essential for normal
lung development.9
There also is an increased incidence of
sinusitis, bronchiectasis, and lower respira-
tory tract infections in patients with yellow
Figure 12-1. Yellowish discoloration and thickening of
the nail plate.
nail syndrome, possibly related to an inher-
ent immunodeficiency.10 Bronchiectasis
affects mostly the upper lobes, and the cause
endothelium-lined vessels that are similar to is unknown.11 High-resolution computed
the pleural abnormalities found in yellow nail tomography (CT) of the chest is diagnostic.
syndrome.6 Other features that have been described in
Primary lymphedema typically involves yellow nail syndrome include Raynaud phe-
the upper and lower extremities. The nomenon, keratosis obturans involving the
lymphedema is believed to be secondary to external ear, excess cerumen, nephrotic syn-
congenital atresia or hypoplasia of the lym- drome, pericardial effusions, chylous ascites,
phatics.7 Lymphoscintigraphy is diagnostic. intestinal lymphangiectasia, and selective
The pleuropulmonary manifestations antibody deficiency. Several cases of yellow
include pleural effusions and bronchiecta- nail syndrome in association with cancer
sis. Pleural effusion may precede the onset of the breast, lung, and larynx have been
of nail changes by several years. Pleural effu- reported. The nail changes are related to
sions range from small, unilateral, and asymp- lymphatic obstruction, which is caused by
tomatic to large, bilateral, and recurrent the underlying malignancy.
(Fig. 12-2). The fluid can be an exudate or Large, recurrent pleural effusions may
transudate.7 Empyema has been reported require repeated thoracentesis, pleuroperito-
as a complication of yellow nail syndrome. neal shunting, chemical or surgical pleur-
The pleural effusion may be due to defec- odesis, or pleurectomy.12 Chylous effusions
tive lymphatic drainage, rather than excess are more difficult to treat and may require
A B
Figure 12-2. A, Chest x-ray of a patient with yellow nail syndrome reveals right-sided pleural effusion. B, CT scan
reveals bronchiectasis and fibrotic changes in anterior segment of right upper lobe and right-sided pleural effusion in a
patient with yellow nail syndrome.
dietary restriction of fat and supplements of

medium-chain triglycerides.13 Treatment of
the pulmonary disease or malignancy has
resulted in resolution of nail changes.
Neurofibromatosis Type 1
NF1, also called von Recklinghausen disease
or peripheral NF, is a common autosomal
dominant neurocutaneous disorder. Virtu-
ally every organ system may be affected.
These protean features may be present at
birth or in early childhood, but complica-
tions are generally delayed for years.14
NF1 occurs in 1 in 3000 individuals; there
is no ethnic or gender predilection. NF1 has
a high spontaneous mutation rate (50%)
and variable expression.15 The gene respon-
sible for NF1 is located on chromosome 17.
The gene product, neurofibromin, subserves
a tumor suppressor function, and loss of
heterozygosity results in the hamartoma-
tous multiorgan growth that accounts for Figure 12-3. Multiple café au lait macules in a child
the clinical heterogeneity seen in NF1. with neurofibromatosis type 1.
Café au lait macules are the hallmark cuta-
neous finding in NF1 and are present in
almost 100% of patients (Fig. 12-3). Other
cutaneous features may manifest slightly
later in infancy or childhood, including axil-
lary (Crowe sign) or inguinal freckling, or
both, and neurofibromas. Rubbery discrete
neurofibromas do not tend to occur until
adolescence or later, although plexiform neu-
rofibromas are generally present at birth
(Fig. 12-4). Plexiform neurofibromas grow
indolently and have a distinctive “bag of
worms” texture, and often have overlying
hyperpigmentation and hypertrichosis. Figure 12-4. Cutaneous neurofibromas.
Deeper plexiform neurofibromas may cause
asymmetry or localized gigantism. Neuropsychiatric disability is common,
Noncutaneous features include asymp- with 50% of NF1 patients having attention-
tomatic iris hamartomas (Lisch nodules). deficit/hyperactivity disorder, learning dis-
These nodules are present in 95% of NF1 ability, and verbal or nonverbal disability.
patients by 10 years of age.14 Optic gliomas Other features described in NF1 include
occur in 15%, but most are asymptomatic hypertension secondary to renal artery steno-
and nonprogressive. Skeletal features of NF1 sis or, less commonly, pheochromocytoma,
include scoliosis, long bone dysplasia, non- macrocephaly, and increased malignancy risk
ossifying cyst formation, and short stature. for pilocytic astrocytomas, peripheral nerve
A distinctive tibial anteromedial bowing sheath tumors, and leukemia.15
manifests often in the first year of life, with Diagnosis is based on established clinical
medullary sclerosis and cortical thinning criteria (Table 12-1). Gene testing also is avail-
seen radiographically. able, and newer techniques have improved
undergo malignant degeneration and com-

Diagnostic Criteria for
Table 12-1 Neurofibromatosis monly metastasize to the lungs.17 “Scar” can-
cer of the lung can complicate long-standing
Six or more café au lait macules >5 mm in greatest
diameter in prepubertal individuals and >15 mm NF1 pulmonary involvement.
in greatest diameter in postpubertal individuals
Axillary or inguinal freckling
Two or more iris Lisch nodules
Two or more neurofibromas or one plexiform Tuberous Sclerosis Complex
neurofibroma
Distinctive osseous lesion such as sphenoid wing TSC is a neurocutaneous disorder character-
dysplasia or cortical thinning of long bones
ized by intracranial abnormalities and dis-
Optic pathway gliomas
tinctive skin markings. Historically, this
First-degree relative with neurofibromatosis type 1
whose diagnosis was based on aforementioned disease was thought to consist of facial angio-
criteria fibromas and disabling neurologic disorders,
including epilepsy, mental retardation, and
autism, but it is now acknowledged to affect
mutation detection rates to around 90%. many organ systems, including the eye,
Brain magnetic resonance imaging (MRI) kidneys, heart, and lungs. Its incidence is
may reveal unidentified bright objects, but approximately 1 in 6000.19
these have unclear diagnostic and prognostic TSC is a disorder of cellular differentiation
significance, and no established recommen- and proliferation that is inherited as an
dation exists for routine brain imaging. autosomal dominant trait with variable
Genetic evaluation of suspected patients expression and a high spontaneous muta-
and family members, ophthalmologic evalu- tion rate.20 Molecular genetic analysis has
ation annually until 10 years of age for diag- implicated two causal mutations in the gen-
nostic screening in suspected patients, and esis of TSC: TSC1, on chromosome 9q34,
annual dermatologic examinations with a encodes hamartin, and TSC2, on chromo-
Wood light are helpful. some 16p13, encodes tuberin.21
Pulmonary involvement resulting from The diagnostic criteria for TSC consist of
NF1 is uncommon and manifests later in major and minor features (Table 12-2).21
childhood or early adulthood. Pulmonary Younger patients generally present with neu-
manifestations include diffuse pulmonary rologic manifestations, whereas pulmonary
fibrosis, bullous lung disease, endobronchial manifestations are more common in later life.
neurofibromas, and mediastinal masses.16 Cutaneous findings are age-related with 90%
Pulmonary fibrosis is usually seen in the of affected patients having hypopigmented
basal areas of the lungs, whereas bullous macules at birth or very early in infancy and
lesions occur predominantly in the apical childhood. The signature “ash-leaf macule”
areas.17 When mediastinal lesions are is most characteristic, but TSC-related hypo-
located in the posterior mediastinum, they pigmentation may be polygonal, confetti-like,
may manifest as “dumbbell” tumors with or segmental (Fig. 12-5). Three or more hypo-
intraspinal extension. MRI of the involved pigmented macules suggest TSC and should
spinal area is helpful in assessing the ana- initiate a thorough family history and diag-
tomic relationships of such tumors. Primary nostic work-up. Connective tissue nevi (Sha-
pulmonary neurofibromas are rare. Affected green patch) typically occur on the trunk or
patients typically present with dyspnea on face (fibrous forehead plaque) and may be
exertion.16 seen at birth or early in life. Ungual fibromas
Chest radiographs and chest CT scans reveal (Koenen tumors) (Fig. 12-6) and facial angiofi-
reticulonodular infiltrates in the bases and bromas manifest later in childhood or early
bullous lesions in the apices.18 Histologically, adolescence. Other organ systems involved
alveolar septal fibrosis and alveolitis lead to a include the eyes (“mulberry tumors” and reti-
mixed obstructive and restrictive lung dys- nal hamartomas), heart (rhabdomyomas),
function. In 5% of patients with NF, the neu- kidneys (cysts, angiomyolipomas), and lungs
rofibromas, regardless of their location, may (lymphangiomyomas).
Table 12.2 Diagnostic Criteria for Tuberous Sclerosis Complex
MAJOR FEATURES MINOR FEATURES

• Facial angiofibromas or forehead plaque • Multiple randomly distributed pits in dental enamel
• Nontraumatic ungual or periungual fibroma • Hamartomatous rectal polyps
• Hypomelanotic macules—more than three • Bone cysts
• Shagreen patch (connective tissue nevus) • Cerebral white-matter “migration tracts”
• Cortical tuber • Gingival fibromas
• Subependymal nodule • Nonrenal hamartoma
• Subependymal giant cell astrocytoma • Retinal achromic patch
• Multiple retinal nodular hamartomas • “Confetti” skin lesions
• Cardiac rhabdomyoma, single or multiple • Multiple renal cysts
• Lymphangiomyomatosis
• Renal angiomyolipoma
Adapted and reprinted with permission from Roach et al., 1998.

Source: J. Pediatr Health Care # 2007. Mosby, Inc.
Figure 12-6. Periungual fibromas (Koenen tumors) in

tuberous sclerosis.
respiratory distress syndrome secondary to

TSC was reported in a 4-year-old boy.23
Histopathologically, two patterns of lung
involvement have been described: lymphan-
giomyomatosis, also called lymphangioleio-
myomatosis, and micronodular pneumocyte
hyperplasia/multifocal alveolar hyperplasia.
Lymphangiomyomatosis occurs exclusively
Figure 12-5. Ash-leaf macule in a child with tuberous in women of childbearing age and is char-
sclerosis. acterized by widespread proliferation of abnor-
mal smooth muscle cells surrounding
lymphatic and blood vessels and small
Pulmonary involvement in TSC is uncom- airways.24
mon, typically occurring in adolescent girls Angiomyolipomas may produce gener-
or women. Respiratory symptoms include alized cystic or fibrotic changes in the lung
chronic cough, progressive dyspnea, hemop- and lead to spontaneous pneumothorax.
tysis, and recurrent pneumothoraces.21 Pul- Lymphatic obstruction may cause chylous
monary involvement is extremely rare in effusion, and venous obstruction may lead to
men or children. Unilateral lung cysts and alveolar hemorrhage and hemoptysis. Bron-
a large pneumothorax were described in a chiolar obstruction results in air trapping
7-year-old boy with TSC.22 Recurrent acute and later lung cyst formation.
Radiographic evidence indicates that the include chemotherapeutic agents, such as

incidence of lymphangiomyomatosis among cyclophosphamide. Tamoxifen has yielded
women with TSC is 26% to 39%.25 Chest mixed results to date, and corticosteroids
radiography may be normal or reveal diffuse are ineffective. Surgery has a role in pulmo-
interstitial lung disease or multifocal cysts. nary tuberous sclerosis to obtain a lung
Thoracic CT may show variable thin-walled biopsy specimen for diagnosis, and to treat
cysts scattered in all parts of the lungs, with complications such as pneumothorax, to
normal-appearing lung tissue between cysts. excise bullae, and to perform pleurodesis.
A thorough diagnostic evaluation should Because tumor cells from patients with
include a dermatologic examination with TSC activate mammalian target of rapamy-
Wood light to assess subclinical pigmentary cin (mTOR), mTOR inhibitor (sirolimus)
change and renal and cardiac ultrasound. has been identified as a potential thera-
Cardiac rhabdomyomas are congenital and peutic agent. The drug sirolimus suppresses
may regress spontaneously by several years mTOR signaling. The results of a clinical
of age. Consequently, two-dimensional trial of sirolimus in patients with TSC
echocardiography in the newborn period is and in patients with lymphangiomyomato-
indicated if TSC is suspected. Renal angio- sis revealed that lymphangiomyomatosis
myolipomas and cysts are present in 15% regressed during sirolimus therapy, but
of patients, and ultrasound or abdominal tended to increase in volume after therapy
CT can detect even asymptomatic lesions. was stopped. Suppression of mTOR signal-
Although benign, renal lesions are the sec- ing might constitute an ameliorative treat-
ond most common cause of morbidity ment in patients with TSC or sporadic
because of growth and parenchymal destruc- lymphangioleiomyomatosis.21
tion resulting in hematuria, hypertension, The prognosis for patients with pulmo-
and renal failure. An ophthalmologic exami- nary TSC is generally one of progressive
nation may detect the pathognomonic reti- decline as a result of lymphatic obstruction,
nal hamartomas, which occur in 76% of alveolar hyperplasia, pleural thickening,
patients. A dental examination can identify and cyst formation. In severe cases, progres-
enamel pits and craters in permanent teeth sive respiratory insufficiency and death may
and gingival fibromas. Evaluation of the cen- occur. These patients may be considered for
tral nervous system is essential, including a lung transplantation, but they are not can-
thorough neurologic examination and con- didates, given the coexisting conditions
trast-enhanced CT or MRI. from TSC.
Treatment for TSC is symptomatic. Many
physical findings are generally stable and
nonprogressive, such as the pigmentary
and connective tissue changes in the skin. Hereditary Hemorrhagic
Other findings, such as cardiac rhabdomyo- Telangiectasia
mas, recede spontaneously.
Therapy for pulmonary TSC is similar to HHT, also known as Osler-Weber-Rendu
that for lymphangiomyomatosis, which syndrome, is an autosomal dominantly
some consider a forme fruste of TSC.24 inherited condition characterized by telan-
Hormonal factors may play a role in the giectasias of the skin and mucous mem-
pathogenesis of lymphangiomyomatosis/ branes, and intermittent bleeding from
TSC, which is consistent with typical pre- vascular abnormalities. Angiomas of the
sentation in premenopausal women, and skin and oral, nasal, and conjunctival
are a potential therapeutic target. Medroxy- mucosa become evident in the second or
progesterone has been recommended when third decade of life.26 They appear bright
the disease becomes symptomatic or shows red, punctate or linear, and blanch on pres-
deterioration on pulmonary function tests. sure (Fig. 12-7).
Oophorectomy, radiotherapy, or a combina- HHT occurs in 1 in 10,000 individuals and
tion of these has been beneficial. Other has wide ethnic and geographic distribu-
therapies that have shown some benefit tion.26 Phenotypic heterogeneity exists with
systolic or continuous bruit over the site of

the fistula, and digital clubbing. Features of
HHT occur in about 50% of patients or other
family members and include recurrent epi-
staxis and gastrointestinal tract bleeding.28
Recurrent epistaxis secondary to telangiecta-
sia of the nasal septa and turbinates is the pre-
senting sign in more than 50% of patients,
and occurs in 95% at some point during the
course of illness. Nosebleeds in patients with
HHT, typically spontaneous and often noc-
turnal, have a mean age of onset of 12 years
Figure 12-7. Facial angiomas in tuberous sclerosis (i.e., and a mean frequency of 18 episodes per
adenoma sebaceum).
month.29
Chest radiographs may show oval or round,
variable age of onset, organ involvement, and homogeneous, nodular opacities from a few
severity even within families. Two separate millimeters to several centimeters in diameter
loci have been identified—endoglin (HHT-1), owing to large fistulas. Pulmonary angiogra-
on chromosome 9, and ALK-1 (HHT-2), on phy with contrast enhancement usually
chromosome 12—and this correlates with reveals an artery entering the fistula and a
phenotypic variability.27 Both genes are mem- vein leaving it (Fig. 12-8).28 Multiple fistu-
bers of the transforming growth factor-b las may be visualized on fluoroscopy as
receptor family. abnormal pulsations or on MRI. Selective pul-
HHT is the most common cause of pulmo- monary arteriography may be required to
nary arteriovenous malformations (AVMs). confirm site, extent, and distribution of fistu-
Pulmonary AVMs occur in approximately las and can confirm the diagnosis in virtually
30% of affected individuals and may remain all cases.
asymptomatic for many years.28 Fistulous In addition to pulmonary complications,
vascular communications in the lungs may patients with HHT may have AVMs of the
be large and localized, or smaller, multi- brain. Brain and systemic abscesses are poten-
ple, and diffuse. They are frequently bilat- tially serious complications in patients with
eral and have a predilection for the lower
lobes.28 The usual communication is between
the pulmonary artery and pulmonary vein;
direct communication between pulmonary
artery and left atrium is extremely rare.
Desaturated blood in the pulmonary artery
is shunted through the fistula into the
pulmonary veins, bypassing the lungs, and
entering the left side of the heart. This shunt
may result in systemic arterial desaturation
and cyanosis. The shunt across the fistula is
of low pressure and resistance so that pulmo-
nary arterial pressure is normal; cardiomegaly
is not present. The electrocardiogram is
normal.
The severity of pulmonary manifestations
depends on the magnitude of the right-to-left
shunting. Patients may present with dys-
pnea, exercise intolerance, and polycythe-
mia. Hemoptysis is rare in children, but is
Figure 12-8. Pulmonary angiography shows two pul-
the most common presenting symptom in monary arteriovenous malformations with a common
adults. Physical findings include cyanosis, a feeding artery (arrow).
HHT. Brain abscess can be the initial presenta- because new fistulas may develop after suc-
tion in a patient with previously asymptom- cessful treatment of earlier ones. Although
atic pulmonary AVM. Forty percent of embolization is the initial treatment of choice,
patients with pulmonary AVMs may present large, solitary, or localized pulmonary AVMs
with central nervous system manifestations, may require lobectomy or wedge resection,
such as transient dizziness, diplopia, aphasia, which usually results in complete resolution
motor weakness, or seizures. These findings of the symptoms.30 In most instances, fistulas
may result from cerebral thrombosis, abscess, are widespread such that surgery is impossi-
or paradoxical embolic events.28 Gastrointes- ble. If there is a communication between the
tinal bleeding secondary to telangiectasia pulmonary artery and the left atrium, it can
occurs in 40% of patients, although rarely in be obliterated by division and suture.
children. AVMs also may manifest in the gas-
trointestinal tract, but are more typically seen
in the liver. Hepatic AVMs, possibly more Klippel-Trénaunay-Weber
common in female patients, can lead to com- Syndrome
plications such as hemorrhage, portal hyper-
tension, and cirrhosis (Table 12-3). Klippel-Trénaunay-Weber syndrome, or angio-
Pulmonary hypertension in association osteodystrophy, is a noninheritable disorder
with HHT may involve the ALK-1 mutation that consists of the triad of cutaneous vas-
resulting in vascular dilation and occlusion cular malformation, venous varicosities, and
of small pulmonary arteries more typical of bony or soft tissue overgrowth.19 The cause
primary pulmonary hypertension. External of Klippel-Trénaunay-Weber syndrome is
manifestations, including perioral and unknown, and diagnosis is based on clinical
intraoral telangiectasia and facial and hand features. Affected patients typically present
involvement, generally occur during the with a unilateral, lower extremity, exten-
third or fourth decade. Abnormal nail-fold sive “geographic” capillary malformation
capillaries also may be seen. (port wine stain) at birth that may or may
Other complications include high-output not be associated with congenital ipsilat-
congestive heart failure and portosystemic eral extremity overgrowth (Fig. 12-9). Thick-
encephalopathy from hepatic AVMs. Dis- walled venous varicosities typically become
seminated intravascular coagulopathy has apparent ipsilateral to the vascular malforma-
been reported in 50% of patients with docu- tion after the child begins to ambulate. The
mented HHT. deep venous system may be absent, hypo-
Current treatment includes pulmonary plastic, or obstructed, resulting in lymph-
artery embolization using coils and other edema. Lymphedema and osteohypertrophy
intravascular devices.30 Multiple emboliza- tend to occur later, resulting in limb length
tions may be necessary in some patients or girth asymmetry. Pain can result from asso-
ciated chronic venous insufficiency, cellulitis,
Diagnostic Criteria of Hereditary
superficial thrombophlebitis, and deep vein
Table 12-3 Hemorrhagic Telangiectasia thrombosis.31
(HHT) The diagnostic work-up should include der-
HHT is diagnosed in an individual who meets three matologic and orthopedic evaluations and
or more of the following criteria* clinical and radiographic limb length mea-
Spontaneous, recurrent epistaxis; nocturnal surement, Doppler ultrasonography, arteri-
nosebleeds heighten concern ography, venography, and possibly CT or
Mucocutaneous telangiectasias (tongue, lips, oral MRI and lymphography to assess the extent
cavity, fingers, and nose)
and distribution of anomalous vasculature.
Internal arteriovenous malformations
(pulmonary, cerebral, hepatic, gastrointestinal, Uncommonly, urogenital and intestinal com-
spinal) plications can develop and should be investi-
First-degree relative with HHT according to these gated symptomatically.
criteria Pulmonary involvement is rare; however,
*Diagnosis is possible or suspected when two are present and
recurrent pulmonary thromboembolic events
unlikely when less than two. are well described and may occur in 22% of
Cutis Laxa (Generalized

Elastolysis)
Congenital cutis laxa is a rare disorder of
generalized elastolysis. The clinical picture
is characterized by inelastic, loose, hanging
skin more marked in flexural areas, giving
the appearance of premature aging.36 The
disease is inherited most commonly in a
severe autosomal recessive form, or as a
benign autosomal dominant form. There is
often systemic organ involvement in patients
with the autosomal recessive form. Cardio-
pulmonary abnormalities are common and
are the main determinants of the prognosis
and life expectancy.
Pulmonary emphysema resulting from a
loss of elastic tissue in the lungs is very com-
mon.37 Cor pulmonale and right-sided heart
failure generally caused by pulmonary
involvement are often seen in infancy.
Figure 12-9. Port-wine stains clearly visible on right Other reported pulmonary complications
hand of a child affected with Klippel-Trénaunay-Weber include pneumothorax, pulmonary fibrosis,
syndrome. recurrent pulmonary infections, bronchiec-
tasis, and tracheobronchomegaly. Various
affected patients. Pulmonary embolism in cardiovascular abnormalities, including aor-
Klippel-Trénaunay-Weber syndrome has been tic aneurysm, hypoplasia and stenosis of
described in children, but its mechanism is the pulmonary arteries, and pulmonary valve
unclear.32 Recurrent disease may be compli- stenosis, have been reported in patients with
cated by chronic thromboembolic pulmonary this form of congenital cutis laxa. Several
hypertension and small vessel pulmonary studies suggest a biochemical defect in elastin
arterial hypertension.33 in cutis laxa.
Consideration should be given to estro-
gen avoidance, aggressive deep vein throm-
bosis prophylaxis in patients undergoing Ehlers-Danlos Syndrome
surgical procedures, and anticoagulation
where appropriate. In high-risk patients, EDS is a heterogeneous group of inherited
venographic evaluation of the pelvic and disorders characterized by abnormalities in
abdominal venous anatomy may be war- connective tissue. Affected children appear
ranted, and suprarenal filter placement normal at birth, but skin hyperelasticity, fra-
should be considered.34 gility of the skin and blood vessels, and joint
Surgical correction or palliation is often dif- hypermobility develop. The basic defect is a
ficult. Leg length differences should be treated quantitative deficiency of collagen.38 EDS
with orthotic devices to prevent the develop- historically has been classified into 10 clini-
ment of spinal deformities. One avenue of cal forms, although more recent efforts have
research into Klippel-Trénaunay-Weber syn- tried to simplify the taxonomy.
drome has focused on the role of vasoactive Type IV EDS, the most severe form, mani-
factors. The angiogenic factor VG5Q has fests with thin, translucent, fragile skin;
been described more recently in patients with prominent underlying venous network;
Klippel-Trénaunay-Weber syndrome and may and easy bruising. Joint hypermobility is
relate to the pulmonary-vascular complica- less marked compared with the more com-
tions associated with Klippel-Trénaunay- mon EDS subtypes, and is usually confined
Weber syndrome.35 to the digits (Fig. 12-10). Distinctive gaunt
and fibro-osseous nodules also has been

described.41 These manifestations may be
related to an abnormal attempt at repair of
parenchymal or vascular tears. Recurrent
congenital diaphragmatic hernia in young
children also has been reported.42
Treatment of EDS-related pulmonary dis-
ease includes standard management of
pneumothoraces with thoracotomy tubes,
pleurodesis, and bullectomy where indi-
cated.43 Although no good data exist on
the lung mechanics of this patient popula-
Figure 12-10. Joint hypermobility in Ehlers-Danlos syn- tion, if mechanical ventilatory support is
drome type I.
required, excessive tidal volumes or ventila-
tory rates may predispose to pneumothorax
facial and limb features reflect diminished and should be avoided. Patients with type
subcutaneous fat. The diagnosis is based IV EDS tend to die prematurely of complica-
on the cutaneous features; physiognomy; tions associated with arterial rupture.
and history of arterial, intestinal, or uterine
rupture, which can manifest as an acute
abdomen. Pseudoxanthoma Elasticum
Type IV EDS (ecchymotic or arterial) may
have autosomal dominant or autosomal Pseudoxanthoma elasticum is a rare, autoso-
recessive inheritance. Its precise incidence mal recessive or autosomal dominant inher-
is unknown. Point mutations in the Col3A1 ited disorder characterized by progressive
gene that result in the production of a defec- calcification of elastic tissue.44 The skin, eyes,
tive collagen have been identified. and cardiovascular system are most com-
Type IV EDS may have pulmonary monly affected, but secondary complications
involvement. Histochemical studies of lung can develop in the lungs. Pseudoxanthoma
tissue in EDS have revealed markedly elasticum has varied clinical presentations
decreased type III collagen; fibroblasts even within the same family. Skin lesions
cultured from the abnormal lung produce begin indolently during the second or third
less than normal type III procollagen rela- decade and are often described as “plucked
tive to type I procollagen. Electron micros- chicken skin” (Fig. 12-11). Rubbery, yellow
copy analysis of lung specimens has shown coalescing papules are most often seen on
dilated endoplasmic reticulum of the fibro- the sides of the neck, axilla, inguinal folds,
blasts with normal collagen. Pulmonary and perineum. Affected skin may develop
complications have been described in comedones or calcify or both. Involvement
patients with type I EDS, including sponta- of the connective tissue of the media and
neous pneumothorax from bullous lung dis- intima of the arterial walls has been impli-
ease and severe panacinar emphysema, but cated in premature atherosclerosis. Ocular
most cases reported in the literature are findings include a reddish brown extension
associated with type IV EDS.39 Recurrent from the optic disk called an “angioid
pneumothoraces may result in bullous dis- streak,” which is due to rupture of Bruch
ease and ultimately cavitary lesions. EDS- membrane, and a degenerative chorioretini-
related weakness of the pulmonary arterial tis. Angioid streaks have been reported in
wall has resulted in rupture and hemoptysis, 13-year-old patients, although they typically
and spontaneous dissection of the aorta do not occur until the third decade of life.39
may occur. Tracheobronchomegaly similar This change is generally asymptomatic, but
to that in Mounier-Kuhn syndrome has visual loss can occur later in life.
been reported in a child with EDS.40 An Although rare, pulmonary complications
unusual pulmonary manifestation of EDS tend to be secondary to aberrant deposition
consisting of parenchymal cysts and fibrous of calcium in the elastic fibers of the
Upper respiratory involvement has been

reported most commonly in the buccal
mucosa, larynx, and pharynx, but few reports
describe in detail involvement of the lower
respiratory tract.46 One young patient with
xanthoma disseminatum has been reported
with progressive dyspnea and distinctive skin
lesions on the eyelids, neck, and axilla, and
digital clubbing. Chest radiographs revealed
hyperaeration and segmental atelectasis.
High-resolution CT scan of the chest showed
diffuse thickening of the tracheobronchial
wall with bilateral lower lobe bronchiecta-
sis. Bronchoscopy confirmed xanthomatous
infiltration.47
Xanthoma disseminatum runs a chronic
course, and the lesions may regress sponta-
neously. Obstructing lesions of the upper
airway can be managed with surgical or
Figure 12-11. Pseudoxanthoma elasticum, showing laser excision or tracheostomy, but small
typical “plucked chicken” grouped yellowish papules
and prominent skin folds on the neck. Lesions are usually lower airway involvement denotes a poor
most apparent on the neck or in the axillary region; the prognosis.
latter may be confused with Fox-Fordyce disease, but this Erdheim-Chester disease is a rare nonfa-
is confined to the axilla and does not have the soft slack-
ness of the skin that is a feature of pseudoxanthoma milial, proliferative non-Langerhans cell his-
elasticum. tiocytosis with multisystem involvement.
Erdheim-Chester disease is very rare in chil-
internal elastic lamina of some arteries, dren. The long bones are the classic locus of
arterioles, and venules, which leads to nar- involvement; however, other systems can be
rowing of vessel lumens.44 Arterial calcifica- involved, including the lungs, kidneys,
tion involving the coronary arteries or liver, spleen, central nervous system, and
cerebral vasculature generally manifests in pericardium.48 The cause is unknown.
adulthood, but intermittent claudication Approximately 20% of patients with
and angina have occurred in adolescence.41 Erdheim-Chester disease have lung involve-
Hypertension secondary to renal artery ste- ment. These patients present with dyspnea,
nosis also can be seen. There is no effective and chest radiographs reveal interstitial dis-
treatment, although laser therapy may help ease with interlobar septal thickening and
prevent retinal hemorrhage. centrilobar nodular opacity.49 Pulmonary
function tests show a restrictive pattern with
decreased diffusion capacity. Characteristic
Xanthoma Disseminatum lung histopathology includes the accumula-
and Erdheim-Chester Disease tion of histiocytes with variable amounts
of fibrosis and a variable lymphoplasma-
Xanthoma disseminatum is a rare prolifera- cytic infiltrate in a lymphangitic distribu-
tive disorder characterized by multiorgan tion.50 Immunostains are diagnostically
infiltration of non-Langerhans cell histio- useful, showing immunopositivity for CD68
cytes. The classic clinical triad is cutaneous and factor XIIIa and immunonegativity for
xanthomas, xanthomas of mucous mem- CD1a. Birbeck granules are uniformly absent
branes, and diabetes insipidus.45 Skin lesions ultrastructurally.51
manifest as coalescent, yellow-red papules Therapy is anecdotal, and the response is
and plaques with accentuation in the flex- unpredictable. Nonsteroidal immunosup-
ures, such as the neck and axilla. The cause pressants such as cyclosporine, interferon,
of xanthoma disseminatum is unknown, and chemotherapy and radiotherapy also
and treatment generally is unsatisfactory. have been attempted with limited results.
Hermansky-Pudlak Syndrome women as in men. Histologically, diffuse

septal and peribronchial stromal fibrosis is
Hermansky-Pudlak syndrome (HPS) is an seen. Accumulation of the telltale ceroid-
autosomal recessive inherited disorder char- like lipofuscin in alveolar macrophages is
acterized by oculocutaneous albinism, plate- the putative cause of this fibrosis.
let dysfunction with prolonged bleeding Findings on chest radiograph include reticu-
times, and lysosomal accumulation of cer- lonodular interstitial pattern, perihilar fibro-
oid-like lipofuscin in the reticuloendothelial sis, and pleural thickening. High-resolution
system, resulting in granulomatous colitis CT reveals septal thickening, ground-glass
and pulmonary fibrosis in some cases. opacities, and peribronchovascular thickening
Affected patients can exhibit a range of (Fig. 12-12).53 Age older than 30 and presence
cutaneous pigmentary dilution from frank of HPS-1 mutations portend more severe pul-
albinism resembling oculocutaneous albi- monary involvement, and high-resolution CT
nism type I to a pale tan hue with lenti- findings correlate well with decreasing pulmo-
genes and freckling.52 The severity of ocular nary function as measured by the percentage
involvement is directly correlated with the of forced vital capacity.
degree of cutaneous albinism and can Because the pulmonary fibrosis in HPS is
include nystagmus, decreased visual acuity, an irreversible, progressive process, symp-
and photophobia. Epistaxis is the most tomatic treatment is the only option. Pirfeni-
common manifestation of bleeding diathe- done, an antifibrotic agent, seems to slow the
sis, although patients may first note difficul- progression of pulmonary fibrosis in HPS
ties after dental or surgical procedures. Renal patients who have significant residual lung
failure, cardiomyopathy, and bacterial infec- function.54 Intravenous or intramuscular
tions also have been described. desmopressin injections have improved
Hermansky and Pudlak described this dis- platelet aggregation in some patients with
order in 1959. Mutations in one of four HPS. The patient’s response to desmopressin
human genes (HPS-1, HPS-2, HPS-3, HPS-4) should be evaluated before elective surgical
are now known to cause HPS. HPS-1 is the procedures. The report of a child with the
most common mutation, and there is a car- characteristic findings of HPS, which often
rier frequency of 1 in 18 in northwest goes unrecognized because of the discrete
Puerto Rico. HPS-1 encodes a lysosomal traf- nature of the cutaneous and hemorrhagic
ficking protein. manifestations, highlights the importance
HPS is diagnosed based on a combination of establishing this diagnosis because of the
of the above-described clinical features and risk not only of hemorrhage, but also of gran-
laboratory abnormalities including a pro- ulomatous colitis and long-term pulmonary
longed bleeding time with normal platelet fibrosis.55
count, prothrombin time/partial thrombo-
plastin time, and fibrinogen levels. Platelet
function is abnormal owing to storage pool Erythema Multiforme
deficiencies of adenosine diphosphate and
serotonin. Accumulation of ceroid-like “Erythema multiforme” is a confusing term
material in macrophages can be identified that has come to encompass a spectrum of
on peripheral smear. Patients with oculocu- disorders ranging from the typically benign,
taneous albinism and bleeding tendencies localized erythema multiforme minor, gen-
may be referred for genetic linkage analysis. erally confined to the skin, to the more
Pulmonary disease, which is common in severe Stevens-Johnson syndrome (SJS) and
HPS patients, usually begins in the third or toxic epidermal necrolysis (TEN). Some liter-
fourth decade of life and manifests with ature includes erythema multiforme major
chronic nonproductive cough and progres- within this group of mucocutaneous multi-
sive dyspnea.53 It follows a functional system reaction disorders.
restrictive lung disease process similar to idi- SJS/TEN is a multisystem inflammatory
opathic pulmonary fibrosis. The incidence dermatosis that most commonly results from
of pulmonary disease is twice as high in a hypersensitivity response to a medication.
A B
C
Figure 12-12. A and B, Chest radiograph in patient with Hermansky-Pudlak syndrome shows a diffuse bilateral emphy-
sema and a streaking suggestive of interstitial lung disease. (B). C, This is confirmed by the appearance of ground-glass
opacities with high-resolution CT examination, compatible with imaging pulmonary features described in albino patients
with Hermansky-Pudlak syndrome.
Medications associated with SJS/TEN include prodrome, abrupt mucocutaneous symptoms

sulfonamides; penicillin antibiotics; antisei- appear. The skin may be tender and has dis-
zure medications (phenytoin); and nonsteroi- crete erythematous symmetric macules that
dal anti-inflammatory agents such as evolve into blisters. These blisters may remain
ibuprofen, pyrazolones, piroxicam, and sali- localized or progress into more extensive epi-
cylates. Less commonly, SJS/TEN can be asso- dermal necrosis and loss (Fig. 12-13). SJS by
ciated with infections caused by herpes definition has two or more mucous mem-
simplex virus and Mycoplasma pneumoniae. branes affected, with hemorrhagic crusting
SJS/TEN has a prodrome of an upper respira- of the lips being the most characteristic
tory illness with associated fever, cough, and finding. Purulent conjunctivitis is typical
malaise, for which children often receive ther- and may help distinguish SJS/TEN from the
apy with antibiotics, antipyretics, or both. nonexudative ocular changes seen in Kawa-
During or up to 2 weeks beyond the saki syndrome, which can be in the clinical
treatment of potential infectious triggers, and

supportive therapy are the mainstays. The role
of systemic corticosteroids and intravenous
immunoglobulin is unclear. Numerous more
recent reports have supported the use of intra-
venous immunoglobulin in adults and chil-
dren with evolving SJS/TEN if started early in
the course in the absence of renal risk factors.59
Mastocytosis
Figure 12-13. Extensive skin necrosis in Stevens-Johnson Mastocytosis is a disorder of mast cells and
syndrome and toxic epidermal necrolysis.
can develop at any age. It usually appears
in the first weeks to months of life. The
cause is unknown. In young children, the
differential diagnosis. Anogenital involve- disease involves increased mast cells in the
ment with blisters and erosions is common. skin, but rarely other organs. In older chil-
Lymphadenopathy, occasional arthralgias, dren (>10 years old at diagnosis) and adults,
hepatitis, nephritis, and myocarditis are rarely it is more likely to be a systemic disease.
seen. Mast cells contain histamine and other
SJS/TEN has no ethnic or gender predilec- inflammatory mediators, which when trig-
tion. Although the exact mechanism has not gered are released into the skin, blood, and
been elucidated, cytokines released by acti- other organs. Cutaneous mastocytosis is
vated mononuclear cells and keratinocytes characterized by the degree of skin involve-
by the offending medication or infection ment. Involvement can be confined to the
may contribute to apoptosis of epidermal cells skin or may involve other organ systems,
and constitutional symptoms in a genetically including the lungs. The most common
predisposed individual. types in children are solitary mastocytomas,
Pulmonary complications are atypical in urticaria pigmentosa, and diffuse cutaneous
SJS/TEN.56 One prospective evaluation found mastocytosis.
that early pulmonary complications occurred Solitary mastocytomas are collections of
in 27% of cases and usually involved bron- mast cells with a single or multiple (usually
chial mucosal sloughing. Other respiratory five or fewer individual) orange-brown to
complications that have been described red-brown plaques or nodules ranging from
include hemoptysis and expectoration of 0.5 to 3.5 cm in diameter. They typically
bronchial mucosal casts, pulmonary edema, appear within 3 months after birth. They
patchy bronchopneumonic infiltrates, and may develop a peau d’orange, or an orange
chronic bronchiolitis obliterans.57 peel-like, texture. The clue to diagnosis is
Clinical respiratory manifestations consist Darier sign, which is the development of a
of cough, hoarseness, hemoptysis, and dys- wheal and flare after firm stroking of a lesion
pnea. Interstitial infiltrates and diffuse loss of with the dull edge of a pen or fingernail. The
bronchial epithelium in the proximal airways stroking leads to mast cell degranulation and
may be seen on bronchoscopy. Bronchial histamine release. The lesion typically devel-
biopsies confirmed epidermal necrosis with a ops a raised, white wheal in the center and
mixed mononuclear inflammatory infiltrate. then a surrounding bright red flare within
In one more recent study, 90% of patients several minutes (Fig. 12-14). Mastocytoma
with early pulmonary complications ulti- in children typically is self-limited and
mately required ventilatory support, and involves only the skin.60
40% died of complications associated with If there is enough histamine release,
respiratory failure.58 some patients may develop systemic symp-
Treatment of SJS/TEN is controversial. Imme- toms, including nausea, diarrhea, abdomi-
diate cessation of suspected medications, nal pain, flushing, pruritus, hypotension,
symptoms are more common with this sub-

type, including pruritus, wheezing, dyspnea,
hypotension, tachycardia, bronchospasm,
and syncope, and even death.
The diagnosis can be made with a careful
history, physical examination, and the
pathognomonic Darier sign on examination.
Skin biopsy is confirmatory and shows col-
lections of mast cells in the dermis. Diagnosis
can be confirmed further by measuring
serum tryptase, another mast cell mediator,
or urine histamine and its metabolites. Bone
Figure 12-14. Urtication secondary to stroking of a involvement may appear on radiographs,
mastocytoma (i.e., positive Darier sign).
but does not correlate with systemic involve-
ment and may be self-limited.61 Affected
and bronchospasm. Rarely, enough hista- patients may show abnormalities in periph-
mine is released to cause anaphylaxis and eral blood, such as anemia, leukocytosis,
death. The treatment of choice is admin- and hypereosinophilia.
istration of oral antihistamines, such as With the exception of diffuse cutaneous
diphenhydramine. Epinephrine can be mastocytosis, pulmonary involvement in
given in acute situations. Lesions typically any of these forms of mastocytosis generally
involute over 8 to 10 years. is not seen. Pulmonary complications have
Urticaria pigmentosa also occurs in infancy been rarely reported in patients with urti-
and is present in some patients at birth. caria pigmentosa and systemic mastocyto-
Brown spots are typically present by age 6 sis.62 Radiographic evidence of lung
months in most patients and may involve involvement in diffuse cutaneous mastocy-
mucous membranes. They appear as hyper- tosis occurs in 16% to 43%, and may
pigmented to red-brown, minimally elevated include reticulonodular opacities, nodules,
macules, papules, and plaques ranging in size and cysts (Fig. 12-15).63
from 0.5 to 1.5 cm in a random distribution. Treatment includes avoiding triggers of
Typically, the scalp, palms, soles, and sun- histamine release when possible. These trig-
exposed areas are spared. Lesions may gers include sudden weather changes, hot
become bullous in patients younger than beverages, hot baths, insect stings, mechan-
2 years old. Darier sign is positive, and ical irritation, and certain infections. Drugs
patients may complain of flushing, pruritus, known to induce symptoms include, but
or dermatographism. Symptoms typically are not limited to, alcohol, nonsteroidal
improve over time, and 50% of patients anti-inflammatory agents, aspirin, poly-
have resolution of lesions by adolescence. myxin B, vancomycin, morphine, codeine,
Extracutaneous involvement is uncommon. and some local and general anesthetics.
Diffuse cutaneous mastocytosis is rare and Anesthesiologists should be informed of
more commonly associated with systemic the condition before any surgical procedures
symptoms of histamine release. This form to avoid histamine-releasing agents. In addi-
involves diffuse infiltration of mast cells in tion, a nonsedating H1 blocker can be used
the skin, and patients may be at risk for for systemic symptoms. More severe symp-
systemic disease. Skin may appear normal or toms may require a classic (sedating) H1
have a thickened, red-brown appearance. blocker or H2 blockers (good for gastrointes-
Extensive blistering is common in infancy. tinal symptoms), or both. In rare cases of
Darier sign is difficult to elucidate in this type gastrointestinal symptoms, oral sodium cro-
because of the extensive skin involvement. molyn can be used. There is some evidence
The disease is usually present by age 3 that treatment with high-potency topical
years and spontaneously resolves in most steroids can reduce the reactivity of masto-
patients during early childhood, although cytomas. If they are causing significant sys-
dermatographism often persists. Systemic temic symptoms, solitary mastocytomas
dominant and recessive patterns have been

reported. The autosomal dominant form of
DKC usually lacks the classic skin findings.
It also is associated with idiopathic pulmo-
nary fibrosis. The mutant gene is DKC1
(located at Xq28) in the families studied.
The mucocutaneous features of DKC typi-
cally develop between age 5 and 15 years
A with abnormal skin pigmentation with tan-
to-gray hyperpigmented or hypopigmented
macules and patches. The typical distribu-
tion is on the upper trunk, neck, and face
(involvement of sun-exposed areas). Muco-
sal leukoplakia typically occurs on the buc-
cal mucosa and can affect the tongue and
oropharynx. The leukoplakia may become
verrucous, and ulceration may occur. Other
B mucosal sites may be involved (e.g., esopha-
gus, urethral meatus, glans penis, lacrimal
duct, conjunctiva, vagina, anus). There is
an increased incidence of malignant neo-
plasms, squamous cell carcinoma of the
skin, mouth, nasopharynx, esophagus, rec-
tum, vagina, and cervix.
Pulmonary disease is present in 20% of
patients with DKC. Affected patients had
C reduced diffusing capacity for carbon mon-
oxide or a restrictive defect on pulmonary
Figure 12-15. A, Chest radiograph shows diffuse fine
reticular interstitial infiltration pattern of both lungs. B, function testing. Pulmonary complications
CT scan of thorax shows faint cystic and nodular lesions are the second most common cause of death
of lung interstitium and mediastinal adenopathy at the in patients with DKC, about half occurring
time before interferon-a. C, After 6 months of treatment
with interferon-a, interstitial lesions of the lung markedly in patients who undergo bone marrow
improved on CT. transplant. Yabe and colleagues64 reported
a 9-year-old boy who was diagnosed at age
2 years. Autopsy results showed a mixed
can be surgically excised. Automatic injec- inflammatory cell infiltrate of bronchioles
tion devices containing epinephrine (Epi- and alveoli with interstitial fibrosis. Utz
Pens) are recommended for patients with and associates65 also reported two male
extensive disease, although all patients and patients, 28 years old and 48 years old,
their parents should be counseled about this who were diagnosed at age 10 years. Lung
possible complication. biopsy specimens from both patients
showed usual interstitial pneumonitis. The
first patient had a bone marrow transplant
12 years before biopsy and died 4 months
Dyskeratosis Congenita after the transplant. The second patient did
not undergo bone marrow transplant or cor-
Dyskeratosis congenita (DKC) is a rare ticosteroids and died 6 months after biopsy.
inherited condition characterized by cuta- The pathologic pattern for patients with a
neous reticulated hyperpigmentation, nail clinical diagnosis of idiopathic pulmonary
dystrophy, premalignant leukoplakia of the fibrosis or cryptogenic fibrosing alveolitis
oral mucosa, and progressive pancytopenia. reveals architectural destruction, fibrosis
The inheritance pattern of most cases of often with honeycombing, scattered fibro-
DKC is X-linked recessive, but autosomal blastic foci, patchy distribution, and
involvement of the periphery of the acinus or 18. Aughenbaugh GL: Thoracic manifestations of neu-
rocutaneous disease. Radiol Clin North Am
lobule. The prognosis of adults with usual 22:741-756, 1984.
interstitial pneumonitis is poor, with most 19. Behrman RE, et al, eds: Nelson’s Textbook of Pediat-
patients dying within 5 years of diagnosis. rics, 16th ed. Philadelphia, WB Saunders, 2005.
20. Roach ES, Delgado MR: Tuberous sclerosis. Derma-
Children given a diagnosis of idiopathic pul- tol Clin 13:151-161, 1995.
monary fibrosis or cryptogenic fibrosing 21. Bissler JJ, et al: Sirolimus for angiomyolipoma in
alveolitis often live much longer and have a tuberous sclerosis complex or lymphangioleiomyo-
matosis. N Engl J Med 358:140-151, 2008.
nonprogressive course, suggesting that they 22. Bowen J, Beasley SW: Rare pulmonary manifesta-
do not have usual interstitial pneumonitis. tions of tuberous sclerosis in children. Pediatr Pul-
monol 23:114-116, 1997.
23. Vicente MP, Pons M, Medina M: Pulmonary
involvement in tuberous sclerosis. Pediatr Pulmo-
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2. Nordkild P, Kromann-Andersen H, Struve-Christensen gioleiomyomatosis and micronodular pneumocyte
E: Yellow-nail syndrome—the triad of yellow nails, hyperplasia in women with tuberous sclerosis. Am
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11. McNicholas WT, Quigley C, FitzGerald MX: Upper small vessel pulmonary arterial hypertension. Tho-
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16. Unger PD, Geller SA, Anderson PJ: Pulmonary 39. Dowton SB, et al: Respiratory complications of
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CHAPTER 13
of Parasitic Diseases
SHERMAN J. ALTER AND NELSON L. TURCIOS
Protozoa 274 Trematodes 287

Malaria 274 Paragonimiasis 287
Amebiasis 276 Cestodes 290
Nematodes 280 Echinococcosis 290
Ascariasis 280 Other Parasites Causing Pulmonary
Hookworm 281 Disease 292
Strongyloidiasis 282 Summary 292
Toxocariasis 285 References 293
Respiratory diseases are important causes of gondii. In patients from appropriate geo-
morbidity and mortality among children graphic locations with respiratory symptoms
throughout the world. Although diseases and elevated peripheral eosinophil counts,
attributed to parasitic infection are uncommon infection with Ascaris lumbricoides, hook-
for many physicians in temperate climates, worm, S. stercoralis, or Toxocara species
these infections remain important conditions should be considered. This chapter reviews
that must be addressed. Because of the influx parasitic diseases that have pulmonary
of immigrants from developing countries and manifestations.
the volume of global travel, including children,
physicians should have a basic understanding
of respiratory illnesses attributed to parasitic Protozoa
infections.
The spectrum of syndromes related to par- Malaria
asitic respiratory infection is quite large.
Diagnosis of a parasitic infection should Epidemiology
be classified through the recognition of Malaria is endemic throughout the tropical
identifiable host characteristics, underlying areas of the world; one half of the world’s pop-
medical conditions, and specific clinical ulation lives in areas where malaria occurs.
manifestations. The etiology of acute respira- From a global perspective, there are approxi-
tory infections caused by parasitic agents can mately 300 to 500 million infections per year,
be suggested, however, through knowledge resulting in approximately 1 million deaths
of the specific geographic locale of the ill (Fig. 13-1). Most of these deaths occur in
child or the location from which the children.3
child has arrived (Table 13-1).1,2 Clinical pre-
sentations, findings on imaging studies, or Etiology
individual laboratory results can differentiate The Anopheles mosquito transmits the parasite
infection among particular parasitic organ- (Fig. 13-2). Various Plasmodium species—Plas-
isms. Underlying immunodeficiency should modium falciparum, Plasmodium vivax, Plasmo-
suggest infection with certain organisms, dium ovale, and Plasmodium malariae—are
such as Strongyloides stercoralis or Toxoplasma responsible for human malaria. Of these four,
274
Chapter 13—Pulmonary Manifestations of Parasitic Diseases 275
Table 13-1 Etiologies of Pulmonary Infiltrates Based on Geographic Distribution of Infecting Parasite
GEOGRAPHIC DISTRIBUTION
ORGANISM AF AM AS E OC WS
Helminthic
Ascariasis X
Capillariasis hepatica X X X X
Dirofilariasis X
Echinococcosis X X X X X
Filariasis X X X
Gnathostomiasis X*
Hookworm X
Paragonimiasis X X X X X
Schistosomiasis{ X X X
Strongyloidiasis X
Toxocariasis X
Trichinellosis (Trichinella spiralis) X
Protozoan
Amebiasis X
Cryptosporidiosis X
Malaria (Plasmodium falciparum) X X X X X
Toxoplasmosis X
*Rare in other geographic locales.

{
Infiltrate early in disease, Katayama disease.
AF, Africa; AM, Americas; AS, Asia; E, Europe; OC, Oceania; WS, widespread.
Modified from Martin G: Approach to the patient in the tropics with pulmonary disease. In Guerrant RL, ed: Tropical Infectious
Diseases, vol 2, 2nd ed. Philadelphia, WB Saunders, 2006, pp 1544-1553.
Figure 13-1. Geographic distri-

bution of malaria (dots). The infec-
tion is distributed widely in many
tropical and subtropical climates.
Plasmodium vivax is the most prev-
alent WORLDWIDE type of mal-
aria. Plasmodium ovale is especially
prevalent in tropical West Africa.
Infection with Plasmodium falci-
parum has the highest mortality
rate. (Adapted from Martinez S,
et al. Thoracic manifestations of tropi-
cal parasitic infections: a pictorial
review. Radiographics 25: 135-155,
2005.)
only P. falciparum causes pulmonary disease. Pathogenesis

The disease onset is almost always within 1 The pathogenesis of malarial lung disease is
year of exposure. attributed to a diffuse alveolar injury result-
ing in a capillary leak syndrome and acute
Clinical Manifestations pulmonary edema. This noncardiogenic pul-
Shortness of breath and cough are the main monary edema is associated with normal
respiratory symptoms in conscious patients; or low capillary wedge pressures without
some also report chest tightness. Dyspnea evidence of left ventricular dysfunction.5
often starts abruptly and progresses rapidly Hypoalbuminemia and high-level parasite-
over a few hours, causing life-threatening mia are risk factors associated with the deve-
hypoxia in patients with falciparum malaria.4 lopment of pulmonary disease. Pathologic
EXTERNAL ENVIRONMENT IN HUMANS
Sporozoites infect humans

through the skin from the Sporozoites invade
mosquito bite hepatocytes
Merozoites, released
from liver, invade the
Anopheles mosquito erythrocytes
Trophozoites of P. vivax
and P. falciparum
ARDS
Gametocytes are ingested by the
Anopheles by biting humans
Merozoites released
from erythrocytes
Figure 13-2. Life cycle of Plasmodium species (P. falciparum, P. vivax, P. ovale, and P. malariae). ARDS, acute respiratory
distress syndrome. (Adapted from Martinez S, et al. Thoracic manifestations of tropical parasitic diseases: a pictorial review.
Radiographics 25:135-155, 2005.)
findings may include features of acute respira- should be reviewed to identify areas of chlo-
tory distress syndrome in some individuals; roquine resistance. Severe malaria, such as
this is thought to be secondary to sequestered that complicated by pulmonary disease, war-
malaria parasites in the lung, inducing an rants therapy with parenteral medications. In
inflammatory cascade. This mechanism ma- addition to patient management in a critical
inly involves cytokines, neutrophils, and en- care unit, the mortality rate is high. For physi-
dothelial adhesion molecules. Substantial cians in nonmalarial areas, malaria always
evidence implicates the neutrophil as central should be considered in the differential diag-
to the pathogenesis of microvascular lung nosis of a sick patient who has traveled to a
injury, which results in increased capillary per- malaria-endemic area.
meability and subsequent pulmonary edema.
Amebiasis
Diagnosis
Radiographic and computed tomography (CT) Etiology and Epidemiology
findings may suggest noncardiogenic pulmo- Approximately 1% of the world’s population
nary edema. Pleural effusion, diffuse intersti- is infected with Entamoeba histolytica. After
tial edema, and lobar consolidation may be malaria and schistosomiasis, amebiasis is the
seen.6,7 Laboratory assessments may show third most common cause of mortality from
anemia and leukocytosis. A peripheral thick parasitic diseases. Although pleuropulmonary
blood smear has high sensitivity for detecting disease in E. histolytica infection is uncom-
parasitemia. A peripheral thin blood smear is mon, it can occur in 15% of individuals with
better for species differentiation and staging an amebic liver abscess.10
of parasite development in P. falciparum.
Pathogenesis
Treatment After a host ingests cysts in contaminated
Effective treatment strategies for falciparum food or drink, pathogenic amebic tropho-
malaria depend on the pattern of parasite drug zoites invade the colonic wall and disseminate
resistance in the geographic area where the hematogenously to the liver (Fig. 13-3). Less
infection is acquired and the severity of dis- commonly, infection may occur after aspira-
ease (Table 13-2).8,9 The website for the Cen- tion.11 Disease onset may be either acute or
ters for Disease Control and Prevention chronic. Diarrhea is frequently absent. As an
Table 13-2 Drugs to Treat Parasitic Lung Infections
INFECTION DRUG PEDIATRIC DOSE ADULT DOSE

Malaria (Plasmodium
falciparum—in areas of
chloroquine resistance)
Oral (only in uncomplicated
or mild disease)
Drugs of choice Atovaquone/proguanil <5 kg: not indicated 2 adult tabs bid or
5-8 kg: 2 pediatric tabs 4 adult tabs once daily
once daily 3 days 3 days
9-10 kg: 3 pediatric tabs
once daily 3 days
11-20 kg: 1 adult tab
once daily 3 days
21-30 kg: 2 adult tabs
once daily 3 days
31-40 kg: 3 adult tabs
once daily 3 days
>40 kg: 4 adult tabs
once daily 3 days
or
Quinine sulfate 30 mg/kg/day in 3 doses 650 mg q8h
3-7 days 3-7 days
plus
Doxycycline 4 mg/kg/day in 2 doses 100 mg bid 7 days
7 days
or plus
Tetracycline 6.25 mg/kg qid 7 days 250 mg qid 7 days
or plus
Clindamycin 20 mg/kg/day in 3 doses 20 mg/kg/day in 3
7 days doses 7 days
Alternatives Mefloquine 15 mg/kg followed 12 hr 750 mg followed 12 hr
later by 10 mg/kg later by 500 mg
Artesunate 4 mg/kg/day 3 days 4 mg/kg/day 3 days
plus
Mefloquine 15 mg/kg followed 12 hr 750 mg followed 12 hr
later by 10 mg/kg later by 500 mg
Malaria (P. falciparum—
chloroquine-susceptible)
Oral
Drug of choice Chloroquine phosphate 10 mg base/kg 1 g (600 mg base),
(maximum 600 mg then 500 mg
base), then 5 mg base/ (300 mg base) 6 hr
kg at 24 hr and 48 hr later, then 500 mg
(300 mg base) at
24 hr and 48 hr
Parenteral (all Plasmodium)
Drugs of choice Quinidine gluconate 10 mg/kg loading dose 10 mg/kg loading dose
(maximum 600 mg) in (maximum 600 mg)
normal saline over in normal saline
1-2 hr, followed by over 1-2 hr, followed
continuous infusion by continuous
of 0.02 mg/kg/min infusion of 0.02 mg/
until PO therapy can kg/min until PO
be started therapy can be
started
or
Quinine dihydrochloride 20 mg/kg loading dose 20 mg/kg loading dose
in 5% dextrose over in 5% dextrose over
4 hr, followed by 4 hr, followed by
10 mg/kg over 2-4 hr 10 mg/kg over 2-4 hr
q8h (maximum q8h (maximum
(Continued)
Table 13-2 Drugs to Treat Parasitic Lung Infections—Cont’d

1800 mg/day) until 1800 mg/day) until
PO therapy can be PO therapy can be
started started
Alternative Artemether 3.2 mg/kg IM, then 3.2 mg/kg IM, then
1.6 mg/kg daily 1.6 mg/kg daily
5-7 days 5-7 days
Ascariasis (Ascaris
lumbricoides—
roundworm)
Drug of choice Albendazole 400 mg once 400 mg once
or
Mebendazole 100 mg bid 3 days or 100 mg bid 3 days or
500 mg once 500 mg once
or
Ivermectin 150-200 mg/kg once 150-200 mg/kg once
Hookworm (Ancylostoma
duodenale, Necator
americanus)
Drug of choice Albendazole 400 mg once 400 mg once
or
Mebendazole 100 mg bid 3 days or 100 mg bid 3 days or
500 mg once 500 mg once
or
Pyrantel pamoate 11 mg/kg/day 11 mg/kg/day
(maximum 1 g) 3 (maximum 1 g) 3
days days
Strongyloidiasis
(Strongyloides stercoralis)
Drug of choice Ivermectin 200 mg/kg/day 2 days 200 mg/kg/day
2 days
Alternatives Albendazole 400 mg bid 7 days 400 mg bid 7 days
or
Thiabendazole 50 mg/kg/day in 2 doses 50 mg/kg/day in
2 days (maximum 2 doses 2 days
3 g/day) (maximum 3 g/day)
Amebiasis (Entamoeba
histolytica)
Severe intestinal or Metronidazole 30-50 mg/kg/day in 3 750 mg tid
extraintestinal disease doses 7-10 days 7-10 days
or
Tinidazole 50 mg/kg/day 2 g once daily 5 days
(maximum 2 g)
5 days
In treating extraintestinal Iodoquinol 30-40 mg/kg/day 650 mg tid 20 days
disease follow with (maximum 2 g) in 3
doses 20 days
or
Paromomycin 25-35 mg/kg/day in 25-35 mg/kg/day in
3 doses 7 days 3 doses 7 days
Alternative Diloxanide furoate 20 mg/kg/day in 3 doses 500 mg tid 10 days
10 days
Toxocariasis (visceral larva
migrans)
Drug of choice Albendazole 400 mg bid 5 days 400 mg bid 5 days
or
Mebendazole 100-200 mg bid 100-200 mg bid
5 days 5 days
Table 13-2 Drugs to Treat Parasitic Lung Infections—Cont’d

Echinococcosis
(Echinococcus
granulosus—hydatid
cyst)
Drug of choice Albendazole 15 mg/kg/day 400 mg bid 1-6 mo
Patients may benefit from (maximum 800 mg)
surgical resection or 1-6 mo
percutaneous drainage
of cysts
Echinococcosis Surgical excision is only
(Echinococcus available means of cure
multilocularis) for this infection. In
nonresectable cases,
treatment with
albendazole or
mebendazole is
recommended
Paragonomiasis
(Paragonimus
westermani—lung fluke)
Drug of choice Praziquantel 75 mg/kg/day in 3 doses 75 mg/kg/day in
2 days 3 doses 2 days
Alternative Bithionol 30-50 mg/kg on 30-50 mg/kg on
alternate days alternate days
10-15 doses 10-15 doses
Modified from Drugs for parasitic infections. Med Lett Drugs Ther 1-12, August 2004.
Cysts become pathogenic

trophozoites that invade
Cysts E. histolytica enter the human body the wall of colon and
by ingestion of contaminated food multiply
or drink
Cysts are eliminated Trophozoites encyst and become

in feces non-pathogenic but infective
Trophozoite
Extraintestinal compromise
of liver, lungs, brain, etc.
Figure 13-3. Life cycle of Entamoeba histolytica. (Adapted from Martinez S, et al. Thoracic manifestations of tropical parasitic
diseases: a pictorial review. Radiographics 25:135-155, 2005.)
amebic liver abscess enlarges, adhesions may infection may spread through lymphatics or
develop between the liver surface and the dia- via the bloodstream and extend through the
phragm. A sterile sympathetic pleural effusion diaphragm after abscess rupture with empy-
may develop above the abscess. Alternatively, ema formation. The rupture frequently evokes
severe pain in the right chest, back, or shoul- Nematodes

der. Fever, hypoxemia, and circulatory col-
lapse may follow. Classic “anchovy paste” Ascariasis
can be obtained from an amebic hepatic
abscess or from expectorate that has traveled Etiology and Epidemiology
through a hepatobronchial fistula.12 Infection with the roundworm Ascaris lumbri-
coides is highly prevalent throughout the
Clinical Manifestations world. It is estimated that at any one point in
Physical findings in children with pulmo- time more than 1 billion individuals have dis-
nary amebiasis include toxic appearance ease caused by Ascaris. The highest prevalence
and tachypnea with crackles and frequent is in developing countries, especially in regions
findings of consolidation in the right lung of Africa, Asia, and Central and South Amer-
base. Tender hepatomegaly and evidence of ica.15 The organism reproduces prodigiously.
pericardial involvement may be noted. An adult worm can produce 20 to 25 million
eggs.16Ascaris eggs are quite hardy because of
Diagnosis a thick proteinaceous coat, rendering them
In any individual from an area endemic resistant to many environmental threats.
for E. histolytica, a right-sided pulmonary The frequency and intensity of Ascaris
infiltrate or pleural effusion of obscure infections are greatest among children.17
origin should suggest underlying amebic Children unintentionally ingest Ascaris eggs,
liver abscess in the differential diagnosis.13 which can be found in materials that are con-
Chest radiography and CT may show right- taminated with human feces. Fully embryo-
sided basal consolidation, frequently with nated eggs that have matured under suitable
cavitations, and elevation of the right environmental conditions become infective.
hemidiaphragm. An amebic empyema and Under the influence of gastric acid and bile
pleural thickening are commonly noted. salts, eggs hatch in the intestine, and larvae
Abdominal CT and ultrasound are likely are liberated. They molt within the intes-
to show the associated liver abnormalities. tine into second-stage larvae and then travel
Stool examination is of limited diagnostic to the liver. Larvae may traverse to the pulmo-
utility, with cysts being noted in only 15% nary vasculature, penetrate the alveoli, and
to 33% of patients with extraintestinal ame- develop into third-stage larvae (Fig. 13-4).
biasis. It is possible that a patient with amebic After a period of 3 weeks, the organisms
forms identified in the stool may have pleur- ascend the tracheobronchial tree, are swal-
opulmonary disease of another etiology. Spu- lowed, and return to the intestinal lumen.
tum stain or analysis of fluid obtained via These develop into adult worms. After 2 to 3
bronchoalveolar lavage may identify tropho- months within the intestine, a worm is capa-
zoites after rupture into a bronchus. Serologic ble of producing thousands of eggs a day.
analysis can be helpful in making the diagno- Rarely, extremely heavy hematogenous dis-
sis in suspect cases in individuals from semination (versus transpulmonary migra-
nonendemic areas of the world. Antibodies tion) of Ascaris eggs and larvae can manifest
are detected in almost all cases. Although with cough, wheezing, and dyspnea asso-
liver function tests can be normal, mild ane- ciated with eosinophilia.
mia and leukocytosis are noted in most
infected patients.14 Clinical Manifestations
During lung migration by larvae, a nonproduc-
Treatment tive cough and fever commonly occur. Patients
Most patients with pulmonary amebiasis may complain of chest discomfort during
respond favorably over days following ther- coughing episodes or with deep breathing.
apy with a tissue-active amebicide. Metroni- Tachypnea is infrequent. Crackles or wheezing
dazole or tinidazole is recommended (see is noted in about half of patients, but evidence
Table 13-2). This therapy should be followed of consolidation is generally absent. An asso-
by a course of iodoquinol or paromomycin ciated rash, frequently urticarial, can occur dur-
in dosages effective to treat concurrent ing this period. Pulmonary symptoms typically
asymptomatic intestinal amebiasis as well. abate within 5 to 10 days.17
Eggs, developed in Released larvae penetrate the

external environment, duodenal wall, enter the
are ingested bloodstream, and migrate to the
lungs for 10–14 days. After that,
Eggs they are coughed up and
become swallowed.
infective
after 2
weeks in
soil
Female and male adults develop in the
small intestine after 60–75 days
Unfertilized and fertilized eggs
are released
Unfertilized egg
Figure 13-4. Life cycle of Ascaris lumbricoides. (Adapted from Martinez S, et al. Thoracic manifestations of tropical parasitic
The period of pulmonary migration of the days after transpulmonary migration, how-
parasite is associated with striking peripheral ever, for worms to deposit eggs within the
eosinophilia. It increases in magnitude several intestine. The absence of Ascaris eggs in stool
days and subsequently diminishes over sev- during an acute pulmonary disease followed
eral weeks. Individuals exposed to a large by detection of eggs 2 to 3 months later
burden of the parasite can present with Löffler would support the diagnosis of ascariasis.
syndrome consisting of transient pulmonary Ascariasis should be differentiated from infec-
infiltrates and eosinophilia. Ascariasis is the tions caused by either hookworm or Strongy-
most commonly identified etiology of Löffler loides, which can manifest with similar
pneumonitis.15 findings of pneumonitis and peripheral
eosinophilia.20 Antibody titers to Ascaris and
Diagnosis elevated IgE levels are found in infected
Chest radiography frequently shows either patients.
round or oval migratory infiltrates in both
Treatment
lung fields. The infiltrates can range from a
Benzimidazole drugs, such as albendazole and
few millimeters to several centimeters in size,
mebendazole, are effective first-line therapy
and may become confluent in perihilar areas.
against many helminths, including A. lumbri-
Findings on chest films are more likely to be
coides (see Table 13-2). Ivermectin is appar-
present in subjects with elevated blood eosi-
ently equal in efficacy, but it has not been
nophils (>10%). The infiltrates usually clear
extensively studied in children weighing less
completely after several weeks.18,19
than 15kg (see Table 13-2).8
Pulmonary ascariasis should be considered
in individuals presenting with Löffler syn-
drome. Occasionally, eosinophils and eosino- Hookworm
philia-derived Charcot-Leyden crystals can be
identified in sputum or bronchoalveolar Etiology
fluid. Larvae also can be found in gastric aspi- Human hookworms include two nematode
rates. Stool evaluation for Ascaris eggs can (roundworm) species, Ancylostoma duodenale
confirm intestinal ascariasis. It may take 40 and Necator americanus. A smaller group of
hookworms infecting animals can invade symptoms. Respiratory symptoms consisting

and parasitize humans (Ancylostoma ceylani- of chest discomfort, cough, and occasional
cum) or can penetrate the human skin (caus- wheezing can be seen during pulmonary
ing cutaneous larva migrans) but do not migration of the larvae. Gastrointestinal and
develop any further (Ancylostoma braziliense, nutritional/metabolic symptoms also may
Ancylostoma caninum, Uncinaria stenoce- occur. A history of a local pruritic, erythema-
phala). Occasionally, A. caninum larvae may tous, papular rash (“ground itch”) occurring
migrate to the human intestine causing during initial penetration by the filariform lar-
eosinophilic enteritis; this may happen vae can be elicited from some individuals with
when larvae are ingested, rather than respiratory disease.
through skin invasion.15
Diagnosis
Epidemiology Findings on chest radiography in patients
The burden of hookworm infection is consid- with the pneumonitis of hookworm infec-
erable in children. There is a steady increase tion are less evident than the findings noted
in the numbers of individuals infected as in patients with pulmonary ascariasis. Tran-
they get older, with a peak or plateau in ado- sient round or irregularly shaped infiltrates
lescence or early adulthood.21 High rates of may be seen in both lung fields. Sometimes
hookworm transmission occur in the world’s a nodular infiltrate may become confluent.22
coastal regions, where sandy, moist soils, and Microscopic identification of eggs in a con-
temperature are optimal for viability of lar- centrated stool specimen is the most com-
vae. Eggs passed in the stool hatch into lar- mon method for diagnosing hookworm
vae. The released rhabditiform larvae grow infection. In areas where concentration pro-
in feces or soil, and become infective. These cedures are unavailable, a direct wet mount
can survive 3 to 4 weeks in favorable environ- examination of the specimen is adequate for
mental conditions. On contact with the detecting moderate to heavy infections.17
human host, the larvae penetrate the skin
and are carried through the venous circula- Treatment
tion to the heart and lungs. Within 10 days A single dose of a benzimidazole agent, either
of skin penetration, larvae invade the pulmo- albendazole or mebendazole, is effective in
nary alveoli, and ascend the bronchial tree to removing hookworms from the intestine (see
the pharynx, where they are swallowed. After Table 13-2). Antihelminthic treatment com-
reaching the small intestine, the larvae bined with respiratory support in cases with
mature into adults, attach to the intestinal pulmonary disease result in rapid improve-
wall and are eliminated within 1 to 2 years. ment. Within a community, proper sanitation
N. americanus always requires a transpulmon- and the wearing of footwear are important in
ary migration phase. However, after pene- the control of hookworm infections.21
tration of the host skin, some A. duodenale Antihelminthic deworming of children may
larvae can become dormant (in the intestine offer important health-related benefits to the
or muscle).15A. duodenale also can infect by population.
mouth when larvae are swallowed and
develop into adult forms, without under- Strongyloidiasis
going the lung migration.
Infection with the nematode S. stercoralis,
Clinical Manifestations unlike that with other helminths, may occur
The major clinical manifestations in humans as autoinfection with massive parasite inva-
infected with hookworms are related to sion of the host (hyperinfection syndrome
chronic blood loss at the site of intestinal or disseminated strongyloidiasis) that may
attachment of the adult worms. Because be fatal. This complication is more frequent
women and children have lower iron stores, in malnourished or immunosuppressed indi-
they are most vulnerable to effects of hook- viduals. Although the parasite exists world-
worm-related intestinal blood loss. Severe ane- wide, infection is primarily encountered in
mia can be accompanied by cardiopulmonary individuals living in endemic tropical and
subtropical areas of the world. Infection is with S. stercoralis, worm burden increases
sporadic in the United States, with the high- markedly because of the completion of this
est rates of infection in individuals residing autoinfection cycle within the host.
in Appalachia or in southeastern states. The
infection occurs more frequently in rural Epidemiology
areas and in lower socioeconomic groups. Humans are the primary hosts of S. stercoralis.
The infection can persist for years to decades, Transmission of infection and its endemicity
and is often seen in immigrants one or more depend on suitable soil, climatic conditions,
years after entry in the United States. and poor sanitary habits. Close contact and
poor personal hygiene are important because
Etiology the prevalence of infection is much higher in
S. stercoralis has its entire life cycle within the
institutions for the mentally handicapped.
human (Fig. 13-5).23 Infected individuals
Host factors such as nutrition and immune
pass S. stercoralis larvae in their stools; these
status may have a crucial role in the develop-
parasites may develop into free-living adults
ment of the hyperinfection syndrome.
in the soil or may change into infective filari-
form larvae, which must penetrate the skin of
a host in order to continue their life cycle. Pathogenesis
After penetration, they spread hematogen- Acute infection with Strongyloides larvae can
ously to the lungs. Organisms ascend the tra- elicit a cutaneous eruption at the site of skin
chea, are swallowed, and are transported to penetration. A Löffler-like syndrome with
the intestine, where they complete their life eosinophilia may be noted during migration
cycle. Only adult female worms inhabit the of the larvae through the lungs. Eosinophilia
intestine, depositing their eggs, which hatch also may occur when adult worms burrow into
into noninfectious first-stage (L1) larvae. In the intestinal mucosa. Disseminated strongy-
some individuals, larvae undergo morpho- loidiasis is a complex pathologic entity owing
logic changes into filariform (infective) lar- to larval invasion and injury of internal organs
vae; these larvae are capable of infecting the such as the liver, heart, pancreas, kidneys,
same individual, resulting in autoinfection. and central nervous system. It may be accom-
In children and adults chronically infected panied by gram-negative bacteremia.
Filariform larva penetrates

through the skin to Larvae are caught up
the lungs and swallowed
Infective filariform larva

Autoinfection from Adult worms develop in mucosa of the
the intestine to the small intestine
lung
Free-living adults in
external environment Rhabditiform larvae
(soil) and eggs in feces
Figure 13-5. Life cycle of Strongyloides stercoralis. (Adaptped from Martinez S, et al. Thoracic manifestations of tropical parasitic
Clinical Manifestations immunodeficiency syndrome.24 Malnour-

Signs and symptoms of strongyloidiasis occur ished and debilitated individuals are at
in only a small proportion of infected individ- increased risk, especially if they are receiving
uals or in individuals with the hyperinfection systemic steroids. Overwhelming infection
syndrome. Because of the autoinfection phe- also can occur after treatment with cytotoxic
nomenon, many patients have a chronic medications or corticosteroids. Pulmonary
infection, and symptoms may continue for manifestations are increasing cough and dys-
years. Hyperinfection is the most serious and pnea along with odorless mucopurulent or
potentially fatal manifestation. Symptoms fall blood-tinged sputum. These manifestations
into three broad categories: cutaneous, pulmo- may be accompanied by shock owing to
nary, and intestinal. These can be present dur- gram-negative septicemia. Hypoxemia, respi-
ing acute and chronic disease, and during ratory failure, and acute respiratory distress
hyperinfection syndrome. syndrome may be seen. Frequently, even with
The acute disease is often recognized by its effective therapy, the prognosis in patients
cutaneous manifestations followed by pul- with pulmonary strongyloidiasis and acute
monary and intestinal symptoms. The hall- respiratory distress syndrome is poor. Indivi-
mark of cutaneous symptoms is pruritus at duals presenting with an overwhelming pul-
the site of larval entry, usually at the foot or monary infection may have findings of
ankle. Within a week or so, the migration of secondary bacterial or fungal infection.23
larvae into the tracheobronchial tree causes
itching of the throat, dry cough, and Löffler- Diagnosis
like pneumonia with eosinophilia. This is fol- The chest radiograph is normal in most
lowed by intestinal manifestations that infected patients. Alveolar infiltrates in either
include epigastric abdominal pain and dis- a lobar or a segmental distribution are seen
tention and diarrhea. Acute infection is fol- in most patients with symptomatic pulmo-
lowed by the stage when the symptoms may nary strongyloidiasis.25 Less often, diffuse
be recurrent or continuous as the patient infiltrates are noted. In patients with hyperin-
enters the chronic stage of the disease. fection, changes on chest radiograph that
Although occurring less commonly in range from focal to diffuse alveolar infiltrates,
children than in adults, the hyperinfection abscesses, and cavitations to pleural effusions
syndrome is disseminated strongyloidiasis may be noted.25 Eosinophilia is often absent
from massive autoinfection, resulting in an in hyperinfection syndrome; as a result, this
overwhelming larval burden and wide- is considered a poor prognostic indicator.
spread dissemination to the lungs and other Definitive diagnosis of Strongyloides infec-
organ systems (Fig. 13-6).24 Severe pulmonary tion relies on identification of first-stage
and extrapulmonary systemic symptoms rhabditiform larvae in the feces of an infected
result. Although this syndrome can occur individual. However, because the female S.
without a predisposing cause, it is usually stercoralis releases few eggs, multiple stool
associated with conditions of defective cellu- specimens may be required, each concen-
lar immunity, such as lymphoma, Hodgkin trated by the use of various techniques may
disease, organ transplantation, and acquired be required. A sensitive blood-agar plate
Figure 13-6. Strongyloidiasis in

an 18-year-old man with hemop-
tysis. A, Chest radiograph shows
extensive bilateral patchy areas
of consolidation. B, High-resolu-
tion CT scan more clearly deline-
ates the areas of consolidation.
Bronchoalveolar lavage revealed A B
larvae of Strongyloides stercoralis.
method useful for detecting larvae in various Etiology

clinical specimens also has been described. Two species of Toxocara are primarily respon-
Alternatively, the number of larvae recovered sible for most cases of VLM: Toxocara canis
from feces can be amplified by allowing and Toxocara cati, which are transmitted from
them to undergo the heterogonic cycle in dogs and cats, respectively. Other Toxocara
Baermann cultures. Serologic analysis also species have been implicated in human
may be helpful in the diagnosis of strongyloi- infection, including Toxocara leonine, from
diasis. Sputum or bronchoalveolar lavage dogs and foxes, and Baylisascaris procyonis,
may show larvae or, rarely, eggs.26 Sputum from raccoons.
analysis and culture may note evidence of
secondary bacterial or fungal infection. Duo-
Epidemiology
denal aspirates looking for parasites may be
Toxocara are found worldwide in domesti-
helpful in some cases. Lung biopsy may
cated and wild dogs and cats. Infection with
reveal larvae or findings documenting sec-
Toxocara is more prevalent than realized
ondary infection.
because many individuals do not express
the complete VLM syndrome. Domestic ani-
Treatment
mals, especially young ones, in urban and
Because of the risk of hyperinfection, all indi-
rural environments may harbor the parasite.
viduals found to harbor Strongyloides should
T. canis is a common parasite of dogs found
be treated, even in the absence of symptoms.
throughout the world. In fact, an estimated
The treatment goal is to eliminate all the
20% of dogs in the United States excrete
worms; repeated treatment is sometimes
T. canis, and almost all juvenile raccoons
needed. The two agents of choice for the treat-
excrete B. procyonis. Puppies are particularly
ment of strongyloidiasis are thiabendazole
dangerous because transplacental transmis-
and ivermectin. Thiabendazole is adminis-
sion results in 77% to 100% of puppies
tered at a dose of 25mg/kg twice a day (maxi-
becoming infected. By the time the animals
mum 3g/day) for 2 days, or for 2 to 3 weeks
are 3 weeks old, mature egg-laying worms
for hyperinfection syndrome (if started early).
can be present. Adult female worms pass
Ivermectin (200mg/kg/day for 1 to 2 days) is
200,000 unembryonated eggs per day onto
also effective in the treatment of gastrointesti-
the soil in the feces of the infected animal.
nal tract disease. However, ivermectin has not
Under suitable soil conditions, the eggs
been extensively studied in children. Safety
become embryonated and infectious in
profiles have not been established for children
2 to 3 weeks. Dogs and cats often defecate
weighing less that 15kg (see Table 13-2).8
in areas where children play. Under optimal
Nonetheless, because of its greater efficacy,
soil conditions, the deposited thick-shell
some clinicians still prefer it as first-line treat-
embryonated eggs of T. canis and T. cati
ment for strongyloidiasis.
can survive for months to years.28 Most
infections occur in children with a history
of pica and close contact with dogs and cats
Toxocariasis or in individuals who have accidentally
ingested contaminated soil. Animals are
Toxocariasis is a worldwide soil-transmitted
not directly infectious because of the time
zoonotic infection that causes two main dis-
lag before the eggs become infectious. Ocu-
eases in humans: visceral larva migrans
lar larva migrans commonly occurs in older
(VLM), which can involve many organs and
children or young adults, rarely with sys-
characteristically causes peripheral eosino-
temic manifestations.
philia, hepatosplenomegaly, and pneumoni-
tis, and ocular larva migrans. Humans are
incidental hosts and not necessary for the life Pathogenesis
cycle of the Toxocara. VLM results from the After ingestion by dogs or cats, infective eggs
inflammatory response to the migration of hatch in the upper alimentary tract. The sec-
immature, second-stage larvae through the ond-stage larvae migrate through the intesti-
viscera of the host. nal walls and into the bloodstream and then
into the liver and lungs of the infected ani- totally asymptomatic or have symptoms and
mal. From the lungs, the larvae mature by signs related to specific organ dysfunction.
migrating through the tracheobronchial tree In VLM, the specific signs and symptoms
and passing into the upper alimentary tree. depend on the organ affected. Liver invasion
There, the mature worm can begin laying is an early event; hepatomegaly of varying
eggs, which pass out in the feces to begin degrees is almost always present. With more
the cycle anew. severe involvement, various combinations of
In humans, the initial stages of infection are abdominal pain, arthralgias, myalgias, weight
identical: Infectious second-stage larvae hatch loss, intermittent fever, pulmonary disease,
in the small intestine and begin migrating and neurologic disturbance may be seen. The
through bloodstream and lymphatics to vari- immediate hypersensitivity response to the
ous tissues, including the liver, heart, lungs, larvae manifests as symptoms of VLM. It is
brain, and eyes. Before the larvae can complete an environmental risk factor not only for
their transtracheal passage and maturation to asthma,31 but also for seizure disorder, func-
adult worms, however, host defenses block fur- tional intestinal disease, urticaria, eosino-
ther migration of the larvae by encasing them philic and reactive arthritis, and angioedema.
within an eosinophilic granulomatous reac- The natural course of VLM may be quite pro-
tion. The pathogenesis of VLM is the direct longed. The initial stage of the illness lasts sev-
result of the immunologic response of the eral weeks, beginning with low-grade fevers
body to the dead and dying larvae. Multiple and nonspecific symptoms and progressing to
eosinophilic abscesses may develop in the eosinophilia and hepatomegaly. Recurrent epi-
infected tissues. The larvae remain alive, infec- sodes of asthma or pneumonia may occur.
tive, and antigenic for an indefinite period. Over the next few weeks, intermittent high
The local inflammatory reaction appears as fevers occur along with the major manifesta-
an eosinophilic granuloma, and an open lung tions of the disease. Recovery may take 1 to
biopsy of a granulomatous lesion often shows 2 years, during which time the eosinophilia
Toxocara larvae. Host antibodies are generated resolves along with the hepatomegaly. The pul-
against excretory-secretory antigens of the lar- monary infiltrates resolve more rapidly.
vae.29 A group of glycoprotein antigens has Ocular larva migrans usually occurs in
been identified that contain protease, acetyl- older children and is typically manifested
cholinesterase, and eosinophil-stimulating as unilateral visual impairment. The degree
activity.30 of impairment relates to the specific area of
involvement. Blindness is common.
Clinical Manifestations
Any child with fever of unknown origin and Diagnosis
peripheral eosinophilia should be suspected The pulmonary involvement secondary to
to have VLM until proved otherwise. VLM is toxocariasis has been reported in 20% to
most common in young children because they 80% of infected children. Cough, if present,
have a greater opportunity of ingesting the is generally nonproductive. Wheezing is the
infectious eggs while in playgrounds. Children most frequent finding on chest examination,
are also less likely to follow good hygiene prac- although rhonchi and crackles also have
tices. The classic case occurs in a boy younger been described. Because of the wheezing,
than 5 years with a history of pica and expo- some patients are diagnosed initially with
sure to dogs. The extent of signs and symp- asthma. There is no typical chest radiograph
toms depends on the number and location of appearance. Descriptions of imaging studies
granulomatous lesions and the host’s immune range from patchy alveolar disease with pseu-
response. The initial symptoms may include donodular infiltrates on CT, to diffuse inter-
fever, anorexia, headache, lethargy, sleep and stitial pneumonitis, to an asymptomatic
behavior disorders, cough, wheeze, cervical pulmonary mass. A pattern similar to miliary
adenitis, and hepatomegaly. More recently, tuberculosis has been reported in severe cases.
so-called “covert toxocariasis” has been impli- The varied patterns seen on imaging studies
cated as responsible for a clinical presentation may reflect whether direct larval invasion of
that occurs after long-term exposure of migrat- lung tissue or a hypersensitivity reaction to
ing juvenile larval forms. Some individuals are larval antigens is the primary pathologic
process present in a particular patient. Al- diseases, such as detecting Ascaris and Tri-
though pulmonary symptoms are generally churis eggs in feces, indicates fecal exposure,
mild, acute respiratory failure has been re- however, increasing the probability of Toxo-
ported from Toxocara infection. cara involvement in the tissues.
Neutrophilia occurs during the first few
days, but rapidly gives way to the eosinophilia Treatment
characteristically seen in this disease. Eosino- For symptomatic pulmonary toxocariasis,
philia can range up to 50% to 90% of the total therapy with either albendazole or mebenda-
white blood cell count. Leukocytosis is gener- zole twice daily for 5 days is recommended
ally present, with extreme values of greater (see Table 13-2).8 Corticosteroids have been
than 100,000 cell/mm3 occasionally reported. used in patients with severe pulmonary
T. canis also may produce PIE syndrome involvement, possibly to treat the hypersen-
(pulmonary infiltrates and eosinophilia). sitivity component of the disease. Otherwise,
Other laboratory findings may be helpful treatment is symptomatic.
in supporting a diagnosis of VLM. Serum IgE
levels are greater than 900 IU/mL in 60% of
patients tested. Hypergammaglobulinemia Trematodes
is often reported, characterized by elevations
of one or all of the immunoglobulins. Paragonimiasis
Because of cross-reactivity between larval
and blood group antigens, many patients Etiology
develop high anti-A and anti-B isohemagglu- Paragonimiasis, also known as lung fluke dis-
tinin titers, which persist for months after ease, is caused by the genus Paragonimus.
the initial infection. Bronchoalveolar lavage There are more than 40 species, of which
may also show eosinophilia. only a few are considered relevant to humans.
A presumptive diagnosis of VLM rests on Most human disease is caused by Paragonimus
clinical signs and symptoms, history of westermani. In humans, the organism primar-
exposure to puppies, laboratory findings ily infects the lungs. Paragonimiasis is a
(including eosinophilia), and the detection zoonotic infection of carnivorous animals,
of antibodies to Toxocara. Antibody detec- including animals in the canine and feline
tion is the only means of confirming a clin- families, which also serve as reservoir hosts.
ical diagnosis of VLM or covert toxocariasis. Endemic areas for human paragonimiasis are
The currently recommended serologic test the Far East, Southeast Asia from India to
for toxocariasis is enzyme-linked immuno- Japan, Africa, and Latin America (Fig. 13-7).32
sorbent assay (ELISA) using the larval excre- The life cycle of these flukes involves two
tory-secretory antigens to detect the host’s intermediate hosts plus humans. The com-
antibodies. If a titer greater than 1:32 is con- plex life cycle involves seven distinct phases:
sidered positive, the diagnostic sensitivity is egg, miracidium, sporocyst, redia, cercaria,
approximately 78%, with a specificity of metacercaria, and adult (Fig. 13-8). Unem-
greater than 93%. A measurable titer does bryonated eggs from individuals previously
not indicate current clinical T. canis infec- infected with P. westermani are excreted in
tion, however. Because antibodies against the stool or expectorated in the sputum.
Toxocara are present for years, an antigen- The eggs embryonate and hatch in the exter-
capture ELISA has been developed to sepa- nal environment. These miracidia seek their
rate acute from dormant infection. A few first intermediate host, a snail, and penetrate
individuals tested have positive ELISA titers its soft tissue. Miracidia go through several
that apparently reflect the prevalence of developmental stages inside snails and even-
asymptomatic toxocariasis. The diagnosis tually later give rise to many cercariae, which
of toxocariasis does not rest on identifica- emerge from the snail. The cercariae invade
tion of the parasite. Because the larvae do the second intermediate host, a crustacean
not develop into adults in humans, a stool such as a crab or crayfish, where they encyst
examination would not detect any Toxocara and become metacercariae, the infective
eggs.28 Evidence of coexisting parasitic stage for the mammalian host.
Figure 13-7. Geographic distribution of Paragonimus species (dots). (Adapted from Martinez S, et al. Thoracic manifestations
of tropical parasitic diseases: a pictorial review. Radiographics 25:135-155, 2005.)
4a 4b 4c Cercariae invade the crustacean

5
and encyst into metacercariae i
Sporocysts Rediae Cercariae
6 Humans ingest
4 inadequately
cooked or pickled
crustaceans containing
metacercariae
Excyst in
duodenum
3 8
Miracidia hatch
and penetrate snail
Adults in cystic
cavities in lungs
lay eggs which
are excreted
in sputum.
Alternatively eggs
2 Embryonated eggs are swallowed
i = Infective stage d and passed with
d = Diagnostic stage 1 Unembryonated eggs stool.
Figure 13-8. Life cycle of Paragonimus westermani. (Adapted from Martinez S, et al. Thoracic manifestations of tropical
parasitic diseases: a pictorial review. Radiographics 25:135-155, 2005.)
Human infection with P. westermani occurs diagnosis of a viral syndrome. A peripheral

by eating raw or inadequately cooked or smear at this time would show eosinophilia.
pickled crab or crayfish that harbor metacer- The diagnosis of paragonimiasis is often
cariae of the parasite. The parasites excyst in not made in the acute stage of the disease.
the duodenum, penetrate through the intesti- The chronic stage usually follows 2 to 4 weeks
nal wall into the peritoneal cavity, and cross later. Most patients look well, and the disease
the diaphragm into the lungs, where they may resemble chronic bronchitis or bronchi-
become encapsulated and develop into adults. ectasis, with a persistent cough frequently
Within the lung, parasites migrate to the small worse in the morning hours that starts out
bronchioles and trigger an acute inflamma- dry and becomes productive and profuse.
tory process. This process results in necrosis The sputum may range from brown or rust
of lung parenchyma and formation of a in color to frank hemoptysis. Hemoptysis
fibrous capsule in which adult worms and can be frequent and fatal. Low-grade fever
ova are noted. These cystic areas frequently along with vague pleuritic chest pain may
can communicate with additional bron- be present. In uncomplicated pulmonary
chioles or bronchi.22,33 Worms can invade paragonimiasis, the chest examination may
other organs and tissues, such as the brain be normal, although progressive infection
and striated muscles. When this invasion may have detectable crackles, or digital club-
occurs, however, completion of the life cycle bing with chronic infection. Pulmonary
is not achieved because the eggs laid cannot paragonimiasis can be complicated by lung
exit these sites. Individuals infected as chil- abscess, pneumothorax, pleural adhesions,
dren may have infections that persist for 20 empyema, and interstitial pneumonia. Extra-
years. Animals such as pigs, dogs, and various pulmonary locations of the adult worms
feline species also can harbor P. westermani. result in more severe manifestations, espe-
As the life cycle of the fluke suggests, it can cially when the brain is involved.22,34
cause pulmonary and extrapulmonary disease. A normal chest radiograph is obtained in
The pathogenesis of pulmonary disease is a 21% of infected individuals.34 In others,
result of parasite and host factors. The lesions pleuropulmonary findings include migra-
are a result of direct mechanical damage by tory, frequently inconspicuous infiltrates
the flukes or their eggs or by toxins released that modify their appearance over time.
by the fluke. The host response adds to the Later, chest films may show fixed single or
damage in the lungs when the host immune multiple, patchy round opacities, noted
response assumes the form of eosinophilic either in the periphery or in the lung bases
infiltration and the subsequent development (Fig. 13-9). The pathognomonic radiographic
of a cyst of host granulation tissue around
the flukes. Besides the adult flukes, the cyst
also contains eggs and Charcot-Leyden crys-
tals. The cysts develop in the lung parenchyma
close to the bronchioles. The release of cyst
contents can cause bronchopneumonia, and
the cyst wall may fibrose and become calcified.
Pulmonary paragonimiasis has acute and
chronic stages with different clinical mani-
festations. The main clinical manifestations
of paragonimiasis are respiratory symptoms
and eosinophilia. When the flukes reach the
lungs, the patient can have cough, dyspnea,
or chest tightness or chest pain, and systemic
symptoms of fever, malaise, and night
sweats. The patient may recall being sick days
or weeks before the current illness, with fever,
diarrhea, and abdominal pain. Chills and Figure 13-9. Chest radiograph of a patient with Paragon-
urticarial rash may occur, leading to the imus westermani infection shows patchy round opacities.
biopsy may allow diagnostic confirmation

and species identification when an adult or
developing fluke is recovered.
Treatment
Praziquantel, given three times daily for
2 days, is the therapy of choice (see Table 13-2).
Infected individuals may transiently have
worsening of radiographic features in the lung
after treatment. Patients do not have concom-
Figure 13-10. Chest CT scan of a patient with Paragoni- itant exacerbation of respiratory symptoms,
mus westermani infection shows nodules. however.
picture shows a ring shadow with a crescent- Cestodes

shaped opacity along one side of the border.
Calcifications of cystic lesions are seen until Echinococcosis
healing occurs. Signs include pleural effusions,
pleural thickening, or hydropneumothorax; Human echinococcosis (hydatidosis, or hyda-
pleural effusions are reported in 5% to 71% tid disease) is caused by the larval stages of ces-
of patients with P. westermani infections. todes (tapeworms) of the genus Echinococcus.
Contrast-enhanced CT scan of the chest may Echinococcus granulosus, the most frequent
show single or multiple nodules (Fig. 13-10) hydatid disease in humans, causes cystic dis-
or fluid-filled cysts, occasionally accompanied ease. E. granulosus occurs practically world-
by burrow tracts, which are better visualized wide, and more frequently in rural, grazing
after the acute consolidation resolves.35 areas where dogs ingest organs from infected
animals. Echinococcus multilocularis occurs in
Diagnosis the Northern Hemisphere, including central
Diagnosis is based on microscopic demon- Europe and the northern parts of Europe, Asia,
stration of eggs in stool or sputum, but these and North America (Fig. 13-11). E. multilocu-
are not present until after 2 to 3 months of laris causes alveolar echinococcosis.
infection. Ova may frequently be detected The adult E. granulosus resides in the
when hemoptysis occurs. Bronchoalveolar small bowel of the definitive canine hosts
lavage occasionally may reveal ova. Concen- (Fig. 13-12). Other carnivores also may act
tration techniques may be necessary in as a host. Gravid proglottids release eggs that
patients with light infections. Pleural fluid are passed in the feces. After ingestion by a
may show increased eosinophils with rare suitable intermediate host, such as sheep
ova. Only one third of infected patients grazing on contaminated ground, the egg
have eggs detected in the stool.34 Lung hatches in the small bowel and releases an
Figure 13-11. Geographic distribution of hydatid disease from Echinococcus granulosus (solid dots), Echinococcus multilocu-
laris (black dots), and Echinococcus vogeli (grey dots). E. granulosus is the most common of the Echinococcus species. (Adapted
from Martinez S, et al. Thoracic manifestations of tropical parasitic diseases: a pictorial review. Radiographics 25:135-155, 2005.)
DEFINITIVE HOST IN HUMANS/

UNGULATED ANIMALS
Eggs penetrate the intestinal

Embryonated eggs found in feces wall and become oncospheres,
may be ingested or inhaled which go through circulation to
liver and lungs
Fox
Hydatid cysts in liver and

lungs. Protoscolices
develop within the cysts
Adults only in small
intestine of dogs
Dog
and foxes
Dogs and foxes (definitive hosts)

can be infected by ingestion of
protoscolices present in cysts in
viscera of intermediate hosts
Figure 13-12. Life cycle of Echinococcus species. (Adapted from Martinez S, et al. Thoracic manifestations of tropical
parasitic infections: a pictorial review. Radiographics 25:135-155, 2005.)
oncosphere. This oncosphere penetrates the organ in human hydatid disease. Multilocular
intestinal wall and migrates through the cysts form in the liver and clinically can result
circulatory system into various organs, espe- in abdominal pain, a mass in the hepatic area,
cially the liver and lungs, and develops into and biliary duct obstruction.
a gradually enlarging cyst capable of pro- Pulmonary involvement by Echinococcus
ducing protoscolices and daughter cysts. occurs by two routes. Transdiaphragmatic
Ingesting the cyst-containing viscera of the incursion into the lung is reported in 0.6% to
infected intermediate host infects the defini- 16% of cases of hepatic echinococcal disease.
tive host. After ingestion, the protoscolices Cyst adherence to the diaphragm or seeding
evaginate, attach to the intestinal mucosa, of the pulmonary parenchyma produces chest
and develop into adult organisms. The same pain, cough, and hemoptysis. Rupture of the
life cycle occurs with E. multilocularis, cysts into the pleural space can produce fever,
although the definitive hosts vary (foxes urticaria, eosinophilia, and anaphylactic shock,
and, to a lesser extent, other animals, includ- and cyst dissemination. Other organs (brain,
ing dogs). Humans become intermediate bone, heart) also can be involved, with result-
hosts through contact with a definitive ing symptoms. E. multilocularis affects the liver
host (usually a domesticated dog) or inges- as a slow-growing, destructive mass with occa-
tion of contaminated water or produce.36,37 sional metastatic lesions into the lungs.
Humans ingest eggs, with resulting release Hematogenous dissemination of the
of oncospheres in the intestine and the organism directly to the lungs is most com-
development of cysts in various organs. mon in children.37 Many hydatid cysts
E. granulosus infection may occur with silent acquired in childhood remain asymptom-
infection for many years before the enlarging atic, with the diagnosis made incidentally
cysts cause symptoms in the affected organs. on a chest radiograph. Cysts may be located
When the parasite traverses the intestinal wall in any lobes, but most are noted in the lower
and reaches the portal venous system and gut lobes. Symptomatic childhood disease can
lymphatics, the liver serves as an initial line manifest with a sudden cough paroxysm,
of defense and is the most frequently involved hemoptysis, or vague chest discomfort. After
rupture of a pulmonary cyst, expectoration Clinical manifestations of pulmonary toxoplas-

of parasites, cyst fluid, or membranes can be mosis include fever, dyspnea, and cough.42
seen. Bacterial superinfection of a ruptured Imaging of the chest typically shows reticulo-
pulmonary cyst is common.38 nodular infiltrates. The clinical presentation in
Abdominal radiograph and ultrasound can an immunocompromised individual can
document hepatic involvement. Calcification mimic that of pneumonitis caused by Pneumo-
of hepatic hydatid cysts is seen in 20% to cystis jiroveci (formerly Pneumocystis carinii).
30% of cases. CT has a high specificity in the Filarial infection (Brugia malayi, Wuchereria
diagnosis of unilocular or multilocular hydatid bancrofti, Brugia timori) can present with a clini-
cysts, with or without calcifications. Uncom- cal picture known as tropical pulmonary eosin-
plicated pulmonary cysts appear radio- ophilia, caused by the microfilaria stage in the
graphically as well-defined round, oval, or lungs.43,44 This clinical presentation is uncom-
polycyclic cysts measuring 1 to 20 cm in diam- mon during childhood, however. Clinical find-
eter.39 Large cavitary lesions with air-fluid ings in individuals with filariasis include mild
levels may be seen. Occasionally, cystic growth fever, weight loss, and lymphadenopathy.
may cause bronchial erosion with air flow Chest radiographs reveal small (<5mm), indis-
introduced between the cyst and bronchiole; tinct, frequently migratory nodular opacities
this can be seen as a thin, radiolucent crescent throughout all lung fields. Eosinophilia is
in the upper part of the cyst. After expecto- noted and may be strikingly elevated with
ration, retained membranes or remaining solid counts up to 50%. In the appropriate clinical
components can be recognized within the col- setting, a singular “coin lesion” noted on chest
lapsed cystic areas. CTcan clarify further many radiograph might be representative of infec-
of these findings noted on chest x-rays. tion with Dirofilaria immitis, the dog heart-
The diagnosis of echinococcosis relies worm (Figs. 13-13 and 13-14).45 Many cases
mainly on findings by ultrasound or other were seen in the southeastern United States,
imaging techniques supported by positive but increasingly cases are being diagnosed in
serologic tests. In seronegative patients with other areas of the country as the disease spreads
hepatic image findings compatible with echin- in dogs into these areas. Eosinophilia is rare in
ococcosis, ultrasound-guided fine needle individuals with dirofilariasis.
biopsy may be useful to confirm the diagnosis. Schistosomiasis caused by the trematodes
Precautions must be taken during aspiration to Schistosoma mansoni, Schistosoma japonica,
control allergic reactions or prevent secondary and Schistosoma haematobium is common
seeding in the event of leakage of hydatid fluid throughout the world with the exception of
or protoscolices.40,41 the United States. During early infection with
Surgery is the most common form of treat- these parasites, when transpulmonary migra-
ment for echinococcosis, although removal of tion occurs, patients may present with an
the parasite mass is usually not 100% effective. acute febrile illness associated with peripheral
After surgery, medication may be necessary to blood eosinophilia and diffuse nodular infil-
keep the cyst from recurring. The drug of choice trates in chest radiographs (Katayama fever).46
for treatment of echinococcosis is albendazole Such a clinical presentation can be confused
(E. granulosus). Some reports have suggested with miliary tuberculosis. The patient’s clini-
the use of albendazole or mebendazole for cal status and findings on chest films may
E. multilocularis infections (see Table 13-2). worsen in infected individuals given effective
therapy against the parasite. These findings
might be reflective of an allergic alveolitis.46
Other Parasites Causing
Pulmonary Disease
Summary
Toxoplasma gondii, an intracellular protozoan
parasite, may cause lung infection in immuno- The human lower respiratory tract can
compromised individuals, particularly those be affected by numerous parasitic agents.
with underlying human immunodeficiency Infections occur in adults and children. In
virus infection or after organ transplantation. individuals with parasitic pulmonary disease,
DEFINITIVE HOST HUMAN

ACCIDENTAL
HOST
Infected dog is bitten
by the mosquito
Dog
Mosquito
After six months, mature
parasites are found in the
right ventricle and
microfilaria in bloodstream
Microfilaria injected by
the mosquito mature in Injected larvae mature in
subcutaneous tissues the subcutaneous tissues
and may embolize to
the lungs
Figure 13-13. Life cycle of Dirofilaria immitis. (Adapted from Martinez S, et al. Thoracic manifestations of tropical parasitic
infections: a pictorial review. Radiographics 25:135-155, 2005.)
Figure 13-14. Dirofilariasis in an

asymptomatic 14-year-old girl with
a solitary pulmonary nodule. A,
Chest radiograph shows a nodule
with soft tissue opacity in the right
upper lung. B, Photomicrograph
obtained after surgical resection
shows an infarcted peripheral vessel
surrounded by necrotic lung tissue.
Some remnants of the parasites are
present in the lumen (arrows).
(Masson stain, original magnifica-
A B
tion 40.)
clinical manifestations and findings on imag- 2. Wilson CM: Respiratory distress caused by para-
sites. Pediatr Ann 22:443-446, 1994.
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the lung would be expected to occur in indi- for research and development. Lancet Infect Dis
2:564-573, 2002.
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areas of the world, but immigration and ease tions in guiding therapy for African children with
of travel might permit an infected individual malaria or pneumonia. Lancet 340:1140, 1992.
5. Shann F: The management of severe malaria.
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standing of the epidemiology, clinical fea- Chest Med 23:457-468, 2002.
7. Gachot B, et al: Acute lung injury complicating
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8. Moon TD, Oberhelman RA: Antiparasitic therapy
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cal Infectious Diseases, vol 2, 2nd ed. Philadelphia, 11. Shamsuzzaman SM, Hashiguchi Y: Thoracic amebi-
WB Saunders, 2006, p 1544. asis. Clin Chest Med 23:479-492, 2002.
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1977. ment of 39 cases in Manipur. Trans R Soc Trop
13. Adams EB, MacLeod IN: Invasive amebiasis, II: Med Hyg 80:967-971, 1986.
Amebic liver abscess and its complications. Medi- 33. Maclean JD, Cross J, Mabanty S: Liver, lung, and
cine 56:325-334, 1977. intestinal fluke infections. In Guerrant RL, Walker
14. Ravdin JI: Amebiasis. Clin Infect Dis 20:1453-1466, DH, Weller PF, eds: Tropical Infectious Diseases.
1995. Philadelphia, Churchill Livingstone, 2006.
15. Sarinas PSA, Chitkara RK: Ascariasis and hook- 34. Im JG, et al: Pleuropulmonary paragonimiasis:
worm. Semin Resp Infect 12:130-137, 1997. Radiologic findings in 71 patients. AJR Am J Roent-
16. Chan MS, et al: The evolution of potential global genol 159:39-43, 1992.
morbidity attributable to intestinal nematode 35. Lewall DB: Hydatid disease: Biology, pathology,
infections. Parasitology 109:373-387, 1994. imaging and classification. Clin Radiol 52:863-874,
17. Hotez PJ: Pediatric geohelminth infections: Trichur- 1998.
iasis, ascariasis, and hookworm. Semin Pediatr 36. Tanowitz HB, Weiss LM, Wittner M: Tapeworms.
Infect Dis 11:236-244, 2000. Curr Infect Dis Rep 3:77-84, 2001.
18. Martinez S, et al: Thoracic manifestations of tropical 37. Jaray M, et al: Hydatid disease of the lungs: Study of
parasitic infections: A pictorial review. Radio- 386 cases. Am Rev Respir Dis 146:185-189, 1992.
graphics 25:135-155, 2005. 38. Balikan JP, Mudarris FF: Hydatid disease of the
19. Chitkara R, Krishna G: Parasitic pulmonary eosino- lungs: A roentgenologic study of 50 cases. AJR Am
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Baltimore RS, eds: Pediatric Infectious Diseases, biol Infect Dis 20:87-94, 1997.
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351:799-807, 2004. 1995.
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23. Liu LX, Weller PF: Strongyloidiasis and other intes- 42. Boggild AK, Keystone JS, Kain KC: Tropical pulmo-
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30. Oteifa NM, Moustafa MA, Elgozamy BM: Toxocaria- able at: www.mic.ki.se/Diseases/C03.html.
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Infect 12:149-158, 1997.
CHAPTER 14
of Genetic Diseases
BETH A. PLETCHER
Congenital Anomalies 295 Bronchiectasis, Primary Ciliary Dyskinesia,

Overview of Prenatal Lung Development 295 and Kartagener Syndrome 316
Lung Agenesis and Pulmonary Hypoplasia 296 Spontaneous Pneumothorax 320
Congenital Diaphragmatic Hernia 300 Inborn Errors of Metabolism 320
Segmentation Defects and Heterotaxy 305 Pulmonary Arterial Hypertension 322
Cystic Adenomatoid Malformations 306 Pulmonary Fibrosis 327
Bronchogenic Cysts and Other Cystic Pulmonary Embolism 327
Lesions 308 Cystic Fibrosis 329
Pulmonary Sequestration 309 CFTR 329
Bronchobiliary Fistulas 310 Mutations in CFTR and Their
Congenital Lobar Emphysema 310 Consequences 330
Tracheoesophageal Fistula and Tracheal Screening and Diagnosis 330
Agenesis 311 Clinical Manifestations 331
Pulmonary Lymphangiectasia and Other Lung Disease 332
Diseases of the Lymphatic Tree 311 Symptomatic Treatment 333
Pulmonary Arteriovenous Malformations and Curative Therapy 335
Hemangiomas 314 Miscellaneous Genetic Conditions 335
a1-Antitrypsin Deficiency 315 Summary 336
References 338
Many different pulmonary manifestations are Embryonic Period

seen in conjunction with genetic disorders. Prenatal lung development begins during the
Pulmonary findings have been noted with embryonic stage of fetal development, at 4
some cytogenetic conditions, many single weeks gestation, with lung buds emerging
gene or mendelian disorders, and numerous from the ventral side of the foregut, which
inborn errors of metabolism. In addition, con- is lined by endodermally derived epithelium.
genital lung anomalies are common, occurring The trachea is separated from the primitive
as isolated anomalies and as part of multiple esophagus beginning at week 5. Secondary
anomaly syndromes. Recognition of pulmo- bronchi then form, three on the right and
nary problems in patients with genetic dis- two on the left, which ultimately form the
orders may lead to prompt treatment and five lobes of the lungs. Developmental anom-
intervention, which ultimately might translate alies occurring during this period of develop-
into improved outcome. ment may include tracheal, laryngeal, and
esophageal atresia; tracheal stenosis; pulmo-
Congenital Anomalies nary agenesis; tracheoesophageal fistulas
(TEFs); and bronchial malformations.
Overview of Prenatal Lung
Development Pseudoglandular Period
The pseudoglandular stage is so called
Lung morphogenesis can be subdivided into because of the distinct glandular appearance
distinct periods on the basis of the morpho- of the lung from 6 to 16 weeks of gestation.
logic characteristics of the tissue (Table 14-1). During this period, branching of the airways
295
Table 14-1 Morphogenetic Periods of Human Lung Development
PERIOD GESTATIONAL AGE (WK) STRUCTURAL EVENTS

Embryonic 3-6 Lung buds, trachea, main stem, lobar, and segmental bronchi
Pseudoglandular 6-16 Subsegmental bronchi, terminal bronchioles, acinar tubules,
mucous glands, cartilage, smooth muscle
Canalicular 16-26 Respiratory bronchioles, acinus formation and
vascularization, type I and type II cell differentiation
Saccular and 26-36 (saccular); 36 to Dilation and subdivision of alveolar saccules, increase of gas-
alveolar maturity (alveolar) exchange surface area, further growth and alveolarization,
maturation of alveolar-capillary network
continues, and formation of the terminal Saccular and Alveolar Periods

bronchioles and primitive acinar structures Saccular and alveolar periods occur at 26 to 36
is completed by the end of this period. Surfac- weeks and 36 weeks through adolescence.
tant proteins A, B, and C are first detected dur- Increased thinning of the respiratory epithe-
ing this stage. Bronchial arteries arise from the lium and pulmonary mesenchyme, further
aorta and form along the epithelial tubules. growth of the lung acini, and development of
Various congenital defects may arise during the distal capillary network characterize these
this stage of lung development, including stages. In the periphery of the acinus, matura-
tracheobronchomalacia, pulmonary seques- tion of type II epithelial cells occurs in associa-
tration, cystic adenomatoid malformation, tion with increasing numbers of lamellar
ectopic lobes, cyst formation, and congenital bodies and increased synthesis of surfactant
pulmonary lymphangiectasia. The pleuroper- phospholipids. Pulmonary arteries enlarge
itoneal canal also closes early in the pseudo- and elongate in close relationship to the
glandular period. Failure to close the pleural increased growth of the lung. After birth,
cavity, often accompanied by herniation of alveoli expand a bit, but, more importantly,
the abdominal contents into the chest (con- lung growth remains active throughout the
genital diaphragmatic hernia [CDH]), leads first 10 years of life. There is a sixfold increase
to lung hypoplasia. in the number of alveoli during postnatal life.1
Before birth, fetal respiratory movements
Canalicular Period allow lung fluid that is constantly produced
The canalicular stage occurs at 16 to 26 to efflux into the amniotic fluid. These respira-
weeks of gestation. It is characterized by tory efforts promote further lung development
the formation of acinar structures in the dis- and strengthen the muscles of respiration. As
tal tubules, thinning of the mesenchyme, discussed in the next section, prenatal circum-
and formation of the capillary bed. By the stances that prevent adequate respiratory
end of this period, the terminal bronchioles movements before birth (i.e., oligohydram-
have divided to form two or more respira- nios, thoracic cage abnormalities, or neuro-
tory bronchioles, and each of these has muscular disease) may lead to life-threatening
divided into multiple acinar tubules, form- pulmonary hypoplasia.1
ing the primitive alveolar ducts and pulmo-
nary acini. At the end of this stage in
infants, gas exchange can be supported after Lung Agenesis and Pulmonary
birth. Abnormalities of lung development Hypoplasia
occurring during this period include pulmo-
nary hypoplasia (caused by diaphragmatic Primary pulmonary hypoplasia is occasion-
hernia or compression by thoracic or ab- ally reported as an isolated finding and has
dominal masses and prolonged rupture of been described in many sibships, suggesting
membranes causing oligohydramnios) and autosomal recessive inheritance in at least
renal agenesis, in which amniotic fluid pro- some cases.2 This serves as a reference point
duction is impaired. for some families who have given birth to
Chapter 14—Pulmonary Manifestations of Genetic Diseases 297
one child with pulmonary hypoplasia because Any renal abnormality, developmental or
risks for recurrence may be 25% in subsequent obstructive, leading to decreased urine output
pregnancies. in utero with concomitant oligohydramnios
Tracheal atresia accompanied by bilateral has the potential to cause pulmonary hypopla-
agenesis of the lungs is most likely to arise sia (see Chapter 6). The degree of oligohydram-
as an isolated defect, possibly secondary to nios and length of time the fetus is exposed to
a vascular event occurring very early in the limitation of movement likely determine the
embryonic period. Variable degrees of pul- severity of pulmonary hypoplasia and poten-
monary agenesis have been reported in many tial for long-term survival. Most instances of
sibships, however, with and without consan- oligohydramnios are not genetically deter-
guinity.3 Developmental anomalies of the mined, but instead are secondary to prolonged
lungs also have been described in association rupture of membranes. Late loss of amniotic
with other birth defects, as part of at least one fluid with a relatively short duration of fetal
possible mendelian disorder,4 and as an occa- constriction is less likely to cause significant
sional finding in a microdeletion syndrome respiratory compromise. In contrast, pro-
(Table 14-2). longed, severe oligohydramnios secondary to
More often, pulmonary hypoplasia identi- renal agenesis or sirenomelia results in the
fied at birth in association with severe respi- Potter sequence with severe pulmonary hypo-
ratory distress is found to be secondary to plasia and neonatal death.
another underlying defect or disorder. These In between these two extremes are variable
primary problems can be divided into three findings and prognoses associated with
broad categories: (1) renal problems leading decreased amniotic fluid volume. A common
to oligohydramnios, (2) skeletal dysplasia isolated birth defect in male fetuses, posterior
resulting in thoracic cage limitation and urethral valves, may result in oligohydram-
pulmonary insufficiency, and (3) neuromus- nios, bladder distention, hydronephrosis,
cular disorders leading to pulmonary hypo- and ultimately renal damage. In severe cases,
plasia owing to poor respiratory efforts in the bladder distention leads to anterior
utero. abdominal wall musculature hypoplasia and
Table 14-2 Genetic Conditions Associated with Primary Pulmonary Hypoplasia
GENE OR LOCUS
SYNDROME CLINICAL FEATURES MODE OF INHERITANCE IF KNOWN
Total anomalous pulmonary Right lung hypoplasia Autosomal dominant with Locus ¼ 4q12
venous return (scimitar Pulmonary hypertension incomplete penetrance
syndrome)4 (40% penetrant)
Total anomalous
pulmonary venous
return
Dextrocardia
Anophthalmia and Anophthalmia Possible autosomal Unknown
pulmonary hypoplasia Pulmonary hypoplasia recessive
(Matthew-Wood (with or without
syndrome)5 diaphragmatic hernia)
Velocardiofacial syndrome Pierre-Robin sequence Autosomal dominant with Locus ¼ 22q11.2;
(22q11.2 deletion Velopharyngeal many new or de novo cytogenetic
syndrome) insufficiency deletions microdeletion
Cardiac defects (especially
septal or aortic arch)
Unilateral pulmonary
dysgenesis
T cell defects
Hypocalcemia
Learning disabilities
Psychosis
renal failure (prune-belly syndrome). These secondary pulmonary hypoplasia. In addition

boys also may have respiratory compromise to severe and universally fatal skeletal dyspla-
that tends to correlate with the duration sias, such as achondrogenesis, osteogenesis
and severity of the oligohydramnios. imperfecta type 2, a few short-rib polydactyly
Suboptimal urine output associated with syndromes, and thanatophoric dysplasia,
many genetic conditions may be seen with there are many less severe skeletal dysplasias
varying degrees of pulmonary hypoplasia that may result in pulmonary compromise
at birth. Table 14-3 lists some of these syn- and respiratory difficulties at or shortly after
dromes. Bilateral or unilateral renal agenesis birth. The long-term prognosis for each
may occur as an isolated (nonhereditary) depends on the extent of the pulmonary
defect during early fetal development. hypoplasia and ability for the lungs to grow
In some instances, skeletal dysplasias with within the confines of the thoracic cage over
associated thoracic anomalies can result in time. Table 14-4 lists some of the skeletal
Genetic Conditions Associated with Renal Problems and Secondary Pulmonary

Table 14-3
Hypoplasia
GENE OR LOCUS
Hereditary renal agenesis Pulmonary hypoplasia Autosomal dominant (general Gene ¼ PAX2;
Renal agenesis recurrence risk of 1% in isolated locus ¼ 5q11.2-
cases—if parents have two q11.3
Other genitourinary normal kidneys)
anomalies
Potter facies
Secondary equinovarus
Autosomal recessive Pulmonary hypoplasia Autosomal recessive Gene ¼ PKHD1
polycystic kidney Enlarged cystic kidneys
disease (incidence with interstitial
1:16,000 live-born fibrosis
infants)
Hepatic and pancreatic
cysts
Potter facies
Meckel syndrome Pulmonary hypoplasia Autosomal recessive Gene ¼ MKS1 on
(Meckel-Gruber Polycystic kidneys with 17q; locus ¼
syndrome) or without renal 11q13 (MKS2);
agenesis 8q24 (MKS3)
Occipital encephalocele
Postaxial polydactyly
Nephronophthisis type 2 Pulmonary hypoplasia Autosomal recessive Unknown
Hyperechogenic
kidneys with cortical
microcysts and
tubulointerstitial
nephritis
Genitopatellar syndrome Pulmonary hypoplasia Autosomal recessive Unknown
Polyhydramnios (not
oligohydramnios)
Microcephaly, CNS
defects
Cardiac septal defects
Multicystic kidneys
Hydronephrosis
Joint flexion deformities
Mental retardation
CNS, central nervous system.

Table 14-4 Nonlethal Skeletal Dysplasias Associated with Pulmonary Hypoplasia
MODE OF GENE OR LOCUS

SYNDROME CLINICAL FEATURES INHERITANCE IF KNOWN
Camptomelic dysplasia Pulmonary hypoplasia Autosomal recessive Gene ¼ SOX
Cystic hygroma, lymphedema versus autosomal
dominant
Acromelia with short bowed
limbs, clubfoot, splayed toes
Polycystic kidneys
Asphyxiating thoracic Pulmonary hypoplasia or Autosomal recessive Unknown
dystrophy (Jeune syndrome) insufficiency
(incidence 1:100,000- Long, narrow thorax with rib
130,000 live-born infants) and clavicular anomalies
Polydactyly
Hepatic, renal, and pancreatic
cysts
Autosomal recessive Pulmonary insufficiency Autosomal dominant Gene ¼ DLL3 at
spondylocostal dysostosis Vertebral and rib anomalies 19q13; MESP2;
(Jarcho-Levin syndrome) with a crablike chest LFNG
Short neck with normal limbs
Spondylocostal dysostosis Pulmonary hypoplasia Autosomal recessive Unknown
with anal atresia and X-ray findings similar to
urogenital anomalies Jarcho-Levin syndrome
Single umbilical artery
Internal and external
genitourinary anomalies
Hydronephrosis
Spondyloepiphyseal dysplasia Pulmonary insufficiency Autosomal dominant Gene ¼ COL2A1
congenita secondary to restrictive lung
disease
Barrel chest with
platyspondylisis
Scoliosis, kyphosis, lordosis
Pectus carinatum
Coxa vara and clubfeet
Myopia and retinal
detachment
Cleft palate
Hypotonia
Rhizomelic chondrodysplasia Pulmonary insufficiency Autosomal recessive Gene ¼ PEX7
punctata type 1 Rhizomelic limb shortening
with epiphyseal
calcifications
Coronal vertebral clefts and
kyphoscoliosis
Microcephaly with seizures,
mental retardation, or
cortical atrophy
Sensorineural hearing loss
Congenital cataracts
Often lethal before age 2 years
dysplasias associated with respiratory difficul- forms of inborn errors of metabolism, myopa-
ties at birth, but with the possibility of long- thies, or neuropathies may be clinically indis-
term survival. tinguishable, unless specific diagnostic tests
Severe neuromuscular disorders associated are done. Table 14-5 summarizes genetic con-
with lack of fetal movement (fetal akinesia) ditions with neuromuscular underpinnings
may cause a host of problems in addition to that may result in secondary pulmonary
pulmonary hypoplasia. Prenatal history is hypoplasia.
often significant for polyhydramnios (believed
to be secondary to decreased fetal swallowing),
joint contractures, and clubfeet. Whether the Congenital Diaphragmatic Hernia
fetal akinesia is secondary to an inherent mus-
cle or peripheral nerve problem, or instead a CDH is a common anomaly and frequently
central nervous system problem, the clinical associated with secondary pulmonary hypo-
presentations are similar. Severe, congenital plasia. CHD is seen in approximately 1 in
Table 14-5 Neuromuscular Conditions Associated with Pulmonary Hypoplasia

Pena-Shokeir syndrome Pulmonary hypoplasia Autosomal recessive Unknown—may
(fetal akinesia Generalized joint contractures (about 50% of cases). represent many
deformation with clubfeet Empirical recurrence different genetic
sequence) risks for siblings may syndromes causing
Polyhydramnios be close to 10-15% suboptimal fetal
Intrauterine growth restriction movement
Facial dysmorphism
Small thorax and thin ribs
Hydrocephaly with or without
cerebellar hypoplasia
30% are stillborn
Frequently lethal in neonatal
period
Multiple pterygium Pulmonary hypoplasia Autosomal recessive Gene ¼ CHRNG
syndrome (Escobar Eventration of diaphragm
variant)6
Reduced facial movements
Severe joint contractures with
pterygia (webbing) of joints
and neck
Pathognomonic indentations
over elbows and knees
Reduced muscle mass
Genitourinary anomalies
Stuve-Wiedemann Pulmonary hypoplasia Autosomal recessive Gene ¼ LIFR
syndrome Pulmonary hypertension
Short neck; short stature
Dysphagia
Thin ribs, osteoporosis
Progressive scoliosis
Short, thick long bones
Flexion contractures of fingers,
elbows, and knees
Clubfeet
Hypotonia
Normal intelligence
Table 14-5 Neuromuscular Conditions Associated with Pulmonary Hypoplasia—Cont’d

Marden-Walker Pulmonary hypoplasia Autosomal recessive Unknown
syndrome Prenatal and postnatal growth
restriction
Microcephaly with CNS
malformations
Hypotonia and decreased
muscle mass
Fixed facial expression with
dysmorphism
Joint contractures, clubfeet
Radioulnar synostosis
Scoliosis, kyphosis
Renal microcysts and dysplasia
Cryptorchidism
Spinal muscular Pulmonary hypoplasia (in about Autosomal recessive. Gene ¼ SMN1
atrophy type 17 ¼ of infants with spinal Carried by about 1:40
muscular atrophy type 1) otherwise healthy
Above due to prenatal onset individuals
of hypotonia
Joint contractures
Feeding difficulties
Perinatal lethal Gaucher Pulmonary hypoplasia Autosomal recessive Gene ¼ GBA
disease Severe fetal hydrops (30% (enzyme acid
stillborn) b-glucosidase)
Polyhydramnios
Fetal akinesia
Hypertonia; joint contractures
Microcephaly
Facial dysmorphism
Small thorax
Cardiomegaly
Collodion skin
Usually lethal by age 3 mo
2000 live-born infants. This birth defect 80% are left-sided and result in abdominal
occurs as an isolated event and in association viscera sliding up into the pleural cavity
with more than 15 genetic syndromes (Fig. 14-1).10 Postnatal survival reportedly
(Table 14-6). CDH also is seen with numerous ranges from 39% to 95% after repair of CDH.
cytogenetic deletion and duplication syn- This large variation in mortality depends
dromes as one of many congenital anomalies; largely on the severity of the resulting pulmo-
15% of infants with CDH have a structural or nary hypoplasia and abnormal pulmonary
numeric cytogenetic abnormality. Prenatal or vasculature. If extracorporeal membrane oxy-
postnatal detection of a CDH would require a genation is required, the prognosis is not
thorough evaluation to look for dysmorphic favorable. The overall outcome of CDH is
features or additional birth defects that may recognized to be worse when it is found in
be diagnostic of a specific syndrome. association with certain syndromes, such as
CDH arises early in gestation when the Fryns syndrome.9 A recurrence risk for sibs of
pleuroperitoneal membranes fail to seal the a child with an isolated CDH, based on
pleuroperitoneal canal completely. Of CDHs, empiric data, is approximately 2%.11
Table 14-6 Genetic Conditions Associated with Congenital Diaphragmatic Hernia
GENE OR LOCUS
Congenital diaphragmatic Diaphragmatic hernia alone Autosomal dominant Gene ¼ ?NR2FZ;
hernia 1 locus ¼
15q26.1-q26.2
Congenital diaphragmatic Diaphragmatic hernia alone Autosomal recessive Locus ¼ 8p23.1
hernia 2
Congenital diaphragmatic Diaphragmatic hernia alone Autosomal dominant Gene ¼ ZFPM2
hernia 3 (8q22.3)
Anterior diaphragmatic Anterior diaphragmatic hernia X-linked or multifactorial Unknown
hernia M>F
Cornelia de Lange Diaphragmatic hernia Autosomal dominant Gene ¼ NIPBL
syndrome (Brachmann- Prenatal growth restriction
de Lange syndrome)
Abnormal cry at birth
Microcephaly and classic
facial dysmorphism
Congenital heart defects
Oligodactyly and other limb
defects
Mental retardation
Fryns syndrome Diaphragmatic hernia Autosomal recessive. Two Microdeletions ¼
Large for gestational age recognized 15q26.2 and
microdeletions 8p23.1
Coarse facies with excess hair
Small thorax
Distal limb and nail
hypoplasia
Gastrointestinal,
genitourinary, and CNS
malformations
Often stillborn or die as
neonates
Meacham syndrome Diaphragmatic hernia Unknown versus de novo Unknown
Pulmonary hypoplasia autosomal dominant
Pulmonary
rhabdomyomatous
dysplasia
Congenital heart defects
Males with ambiguous
genitalia or sex reversal
Simpson-Golabi-Behmel Diaphragmatic hernia X-linked recessive versus Gene ¼ GPC3
syndrome Lung segmentation defects X-linked semidominant
Prenatal and postnatal
overgrowth
Bulldog facies; macroglossia
Accessory nipples; 13 rib pairs
Cardiac and gastrointestinal
defects
Large, cystic kidneys
Umbilical hernia
Polydactyly, syndactyly
Clubfoot
Embryonal tumors
Table 14-6 Genetic Conditions Associated with Congenital Diaphragmatic Hernia—Cont’d
GENE OR LOCUS
Focal dermal hypoplasia Diaphragmatic hernia X-linked dominant (lethal Unknown
(Goltz syndrome) Ocular, dental, in males)
gastrointestinal, and
genitourinary defects
Syndactyly, polydactyly
Cutaneous linear or patchy
atrophy; papillomas with or
without telangiectasias
Absent or hypoplastic nails
Autosomal recessive cutis Diaphragmatic hernia Autosomal recessive Unknown
laxa Prenatal and postnatal
growth restriction
Cutis laxa
Emphysema and cor
pulmonale
Gastrointestinal and
genitourinary diverticula
Joint laxity
Arterial tortuosity
Aneurysms
Hernias
Decreased elastin fibers in
dermis
Epidermolysis bullosa with Diaphragmatic hernia Autosomal recessive Unknown
diaphragmatic hernia Epidermolysis bullosa
Reported infants died shortly
after birth
Syndromic Diaphragmatic hernia X-linked dominant (lethal Gene ¼ HCCS
microphthalmia (MIDAS Unilateral or bilateral in males). Also X (Xp22.3)
syndrome microphthalmia chromosome
[microphthalmia, microdeletion
dermal aplasia, Linear skin defects on face
sclerocornea]) and neck
Cardiac defects
Genital with or without anal
anomalies
CNS malformations
Syndromic anophthalmia Diaphragmatic hernia Autosomal recessive Gene ¼ STRA6
with mild facial Pulmonary dysplasia even in (15q24.1)
dysmorphism and normal absence of diaphragmatic
intrauterine growth defect
Bilateral anophthalmia
Cardiac and genitourinary
anomalies
Blepharophimosis with
unusual eyebrows
(trichoglyphic)
Large, low-set ears
Thoracoabdominal Diaphragmatic hernia X-linked recessive or Locus ¼ Xq25-
syndrome (X-linked Cleft lip with or without cleft X-linked dominant q26
midline defects including palate
pentalogy of Cantrell)
Cardiac defects
Omphalocele; ventral hernias
Hydrocephaly, anencephaly
Renal agenesis, hypospadias
(Continued)
GENE OR LOCUS
Donnai-Barrow syndrome Diaphragmatic hernia Autosomal recessive Unknown
(diaphragmatic hernia, Abnormal ears
exomphalos, absent
corpus callosum, Sensorineural deafness
hypertelorism, myopia, Myopia, ocular defects
and sensorineural Cardiac defects
deafness)
Ventral abdominal wall
defects
Agenesis of the corpus
callosum
Omphalocele, Diaphragmatic hernia Probable autosomal Unknown
diaphragmatic hernia, Omphalocele recessive
and radial ray defects
Single umbilical artery
Radioulnar synostosis with
thumb anomalies
Facial dysmorphism
Abnormal ears
Scoliosis
Diaphragmatic defects, Diaphragmatic hernia Autosomal recessive Unknown
limb deficiencies, and Omphalocele versus autosomal
ossification defects of dominant with gonadal
the skull Limb deficiencies with mosaicism
syndactyly
Cranial ossification defects
Denys-Drash syndrome Diaphragmatic hernia Autosomal dominant Gene ¼ WT1
(Wilms tumor and Ambiguous genitalia (M or F) (overlaps with WAGR (11p13)
pseudohermaphroditism and Frasier syndrome)
or true Gonadal dysgenesis (M or F)
hermaphroditism) Gonadoblastoma
Nephropathy, nephritic
syndrome leading to renal
failure
Wilms tumor
Agonadism with multiple Diaphragmatic hernia Autosomal recessive Unknown
internal malformations Omphalocele
(PAGOD syndrome
[pulmonary hypoplasia, Female external genitalia
hypoplasia of the without internal gonads
pulmonary artery, Dextrocardia
agonadism, Cardiac defects
omphalocele,
diaphragmatic defects Hypoplasia of lung even
and dextrocardia]) without diaphragmatic
defect
Perlman syndrome (renal Diaphragmatic hernia Autosomal recessive Unknown
hamartomas, Prenatal overgrowth
nephroblastomatosis,
and fetal gigantism) Polyhydramnios
Facial dysmorphism
Visceromegaly
Hyperinsulinism
Renal hamartomas
Nephroblastomatosis
Wilms tumor
GENE OR LOCUS
Pallister-Killian syndrome Diaphragmatic hernia Cytogenetic Mosaic tetrasomy
(mosaic tetrasomy 12p) Coarse facies with a 12p in skin
prominent forehead and fibroblasts
micrognathia (often not
seen in
Sparse eyebrows, large ears lymphocytes)
Short, webbed neck
defects
Ventral wall defects
Polydactyly
Profound mental retardation
and seizures
Stillbirth and neonatal
mortality common
Emanuel syndrome Diaphragmatic hernia Cytogenetic (results from Supernumerary
(supernumerary Prenatal growth restriction 3:1 segregation from a chromosome—
derivative 22 parent who is a a derivative 22
chromosome) Microcephaly balanced carrier of an with part of 11q
Preauricular tags and sinuses 11q23-22q11 attached
Cleft palate translocation)
Cardiac, genitourinary, and
anal defects
Mental retardation
Deletion 1q32.3-q42.38 Diaphragmatic hernia Cytogenetic Deletion ¼
1q32.3-1q42.3
Deletion 8p23.19 Fryns phenotype Cytogenetic Microdeletion ¼
Congenital diaphragmatic 8p23.1
hernia 2
Deletion 15q26.19 Fryns phenotype Cytogenetic Microdeletion ¼
Diaphragmatic hernia 15q26.2
CNS, central nervous system; F, female; M, male; WAGR, Wilms tumor, aniridia, genitourinary abnormalities, and mental
retardation.
Isolated CDH is generally believed to be a

sporadic occurrence, although autosomal
dominant and autosomal recessive pedigrees
have been described. Several loci and putative
predisposition genes have been found in cases
of CDH, with cytogenetic deletions, duplica-
tions, and translocations often uncovering a
CDH locus (see Table 14-6).
Segmentation Defects and

Heterotaxy
During the embryonic stage, the right and left

bronchial buds begin to grow, subsequently
dividing into secondary bronchi. Normally,
the right lung bud divides into three segments,
and the left lung bud divides into two seg-
ments. Rarely, segmentation or lobulation
Figure 14-1. X-ray shows left sided diaphragmatic her- defects occur and may or may not be asso-
nia with loops of bowel in the left hemithorax. ciated with other visceral heterotaxies. Nearly
80% of children with right isomerism (bilateral encompasses variably sized cysts that, as they
right lung) have asplenia, leading to a risk for enlarge, compress adjacent lung tissue
overwhelming pneumococcal sepsis. A similar (Fig. 14-2). The reported incidence is 1 in
proportion with left isomerism (bilateral left 25,000 to 35,000. It is useful to divide these
lung) has multiple small spleens (polysplenia). cystic lesions into large cyst and small cyst
A few genetic syndromes have been associated types. The changes that have long been asso-
with these types of defects (Table 14-7). ciated with the “adenomatoid” type now are
recognized in various conditions with large
Cystic Adenomatoid Malformations airway obstruction and are more accurately
called “pulmonary hyperplasia.”
Cystic adenomatoid malformation of the lungs
is a developmental abnormality that results Large Cyst Type (Stocker Type 1)
from overgrowth of the terminal respiratory The type 1, or large cyst lesion usually man-
bronchioles modified by intercommunicating ifests in early infancy with progressive respi-
cysts. Cystic adenomatoid malformation ratory distress as the cystic region expands
Genetic Conditions Associated with Lung Segmentation Defects with or without

Table 14-7
Heterotaxy
GENE OR LOCUS
Smith-Lemli-Opitz Incomplete lobulation of lung Autosomal recessive Gene ¼ DHCR7
syndrome (RSH with or without lung (enzyme is 7-
syndrome) hypoplasia dehydrocholesterol
(Incidence Prenatal growth restriction reductase)
1:20,000-40,000)
Failure to thrive
Microcephaly, epicanthal folds
Broad alveolar ridges
Cardiac defects
Hypospadias and other
genitourinary defects
Two to three toe syndactyly
and polydactyly
Foot anomalies
Mental retardation, seizures
CNS defects
Pallister-Hall Abnormal lung lobulation Autosomal dominant. Gene ¼ GLI3 (7p13)
syndrome Intrauterine growth restriction Most cases are sporadic
(hypothalamic
hamartoblastoma, Microphthalmia, abnormal
hypopituitarism, ears
imperforate anus, Buccal frenula, cleft lip/palate
and postaxial Cardiac, genitourinary, and
polydactyly) anal defects
CNS hypothalamic
hamartoblastoma with
pituitary hypoplasia
Simpson-Golabi- See Table 14-5 See Table 14-5 See Table 14-5
Behmel syndrome
Asplenia with Right isomerism (bilateral right Autosomal recessive Locus ¼ 11q13
cardiovascular lung)
anomalies (Ivemark Asplenia
syndrome)
Severe cardiac defects (TAPVR)
Midline liver
Malrotation of the gut
Genetic Conditions Associated with Lung Segmentation Defects with or without

Table 14-7 Heterotaxy—Cont’d
GENE OR LOCUS
Situs inversus Left isomerism (bilateral left Autosomal recessive Locus ¼ 7p21
viscerum lung)
Polysplenia
Intrauterine growth restriction
Cardiac defects (PAPVR)
Severe Rubinstein- Abnormal lung lobulation Cytogenetic. Contiguous Microdeletion ¼
Taybi syndrome Accessory spleens gene syndrome, as 16p13.3; deletion
(chromosome opposed to a point size 400 kb to 3 Mb
16p13.3 deletion)12 Cardiac defects, especially mutation or nondeletion
hypoplastic left heart Rubinstein-Taybi
Renal agenesis syndrome
Neonatal seizures
CNS, central nervous system; PAPVR, partial anomalous pulmonary venous return; TAPVR, total anomalous pulmonary venous return.
A B
Figure 14-2. A, X-ray shows right upper lung cystic area filled with air after resorption of fluid from congenital cystic
adenomatoid malformation. B, CT scan shows septated cystic adenomatoid malformation in right upper lobe.
by air trapping with compression of adja- bronchioles with small amounts of smooth
cent lung tissue and ultimately mediastinal muscle, but no glands. Some of these
shift. Occasionally, these lesions are so large lesions may contain mucigenic epithelium.
that growth of the normal lung tissue is Increased risks for neoplasias, most com-
impaired, resulting with pulmonary hypo- monly bronchioloalveolar carcinoma, have
plasia related to this space-occupying lesion. been a rationale for the early surgical resec-
It is the most common type of cystic adeno- tion of these lesions even when there are
matoid malformation and has the best no clinical symptoms. This relationship is
prognosis because these malformations are presumed to be related to neoplastic change
usually localized and affect only part of in the mucigenic epithelium, which fre-
one lobe. Cysts are usually larger than quently is found as a minor component of
2 cm in diameter. They are lined by respira- the large cyst type of cystic adenomatoid
tory epithelium and have a wall resembling malformation.22
Small Cyst Type (Stocker Type 2) Bronchogenic Cysts and Other

The small cyst lesion has been recognized Cystic Lesions
widely in areas of lung in which there is air-
way obstruction during development, such Foregut cysts are closed epithelium-lined sacs
as bronchial atresia, isolated and with sys- developing abnormally in the thorax from
temic arterial connection and extralobar the respiratory tract and primitive developing
sequestration. On pathologic examination, gut. When these structures differentiate
these lesions show typical and distinctive toward airway and contain hyaline cartilage
features with regional replacement of the plates in the wall, they are called “broncho-
lung parenchyma by microcystic maldeve- genic cysts,” whereas structures developing
lopment. Mucigenic epithelium is rare. toward the gut are termed “enterogenous
Depending on the size and degree of pulmo- cysts.” Bronchogenic cysts are the most com-
nary compromise, infants may or may not mon cysts in infancy, although many do not
be symptomatic at birth. A small percentage manifest until adolescence or adulthood.
may be asymptomatic until later in child- Most are situated in the middle mediastinum
hood and often manifest with recurrent close to the carina, but do not communicate
pneumonia or chest pain. Cystic adenoma- with the trachea or bronchi. Less frequently,
toid malformations are usually isolated they are adjacent to the esophagus. They are
occurrences and are not thought to be usually single, unilocular cystic structures that
genetically determined. are filled with fluid or mucus, and more
A B
C
Figure 14-3. A and B, X-rays show thin-walled cyst in left lower lobe with air-fluid level. C, CT scan shows right upper
lobe bronchogenic cyst.
commonly are located on the right (Fig. 14-3). type mucosa, and with a pedicle that extends
Because of inadequate drainage, such cysts into the spinal canal. They are virtually
may be associated with recurrent infections always associated with vertebral defects in
and may appear as a consolidation or area the region of this communication. Rarely,
of atelectasis on chest x-ray. Bronchogenic congenital cystic lesions may be seen in con-
cysts also may be found within the lung hilum junction with genetic syndromes. There is a
and parenchyma. When located within the specific autosomal recessive disorder
lung, they are identical in their gross and described with multiple peripheral lung cysts
histologic appearance to cysts in the or fibrocystic pulmonary dysplasia as the pri-
mediastinum. mary feature (Table 14-8).
Similarly located cysts with enteric-type
mucosa, usually gastric or esophageal and
without cartilage plates within their wall, Pulmonary Sequestration
are enteric duplication cysts. Esophageal
cysts are more common. They are intramural Bronchopulmonary sequestration, some-
and do not involve the mucosa. Gastro- times referred to simply as “pulmonary
enteric cysts characteristically are not sequestration,” is a rare congenital malforma-
connected to the esophagus. In infants, they tion of the lower respiratory tract. It consists
are a common cause of a posterior mediasti- of a nonfunctioning mass of lung tissue that
nal mass. Neurenteric cysts are posterior receives its vascular supply from the systemic
mediastinal lesions, also lined by enteric- rather than pulmonary circulation, and it
Table 14-8 Genetic Conditions Associated with Pulmonary Cysts
GENE OR LOCUS
Cystic disease of the lung Cystic pulmonary lesions Autosomal recessive Unknown
Recurrent lung infections (especially common in
Yemenite and other
Spontaneous non-Ashkenazi Jews)
pneumothorax in the
neonate
Proteus syndrome Cystic pulmonary lesions Autosomal dominant Gene ¼ PTEN
(encephalocraniocutaneous Macrocephaly (some cases may be due (only some
lipomatosis) to somatic mosaicism cases)
Hemihypertrophy with for a gene mutation)
localized overgrowth
Variable cutaneous lesions,
including
lymphangiomas, lipomas,
epidermal nevi,
hemangiomas
High risk of thrombosis
Kyphoscoliosis
CNS malformations
Down syndrome (trisomy 21) Characteristic subpleural Cytogenetic Extra copy of
cysts13 chromosome
Facial dysmorphism 21
Short, broad neck
Cardiac, gastrointestinal,
and genitourinary defects
Brachydactyly, clinodactyly
Single palmar crease

lacks communication with the tracheobron- tracking into functional lung tissue or the
chial tree and alveoli. Sequestrations are classi- gastrointestinal tract. Surgical resection of a
fied anatomically. The intralobar variant, also pulmonary sequestration is generally recom-
known as intrapulmonary sequestration, is mended, and there are no strong genetic fac-
contained within otherwise normal lung and tors predisposing to the development of
lacks its own pleura, and the veins normally pulmonary sequestration.
drain into the pulmonary system. It is usually
found in the posterior basal segment of the
left lower lobe (Fig. 14-4). The less common Bronchobiliary Fistulas
extralobar sequestration, also known as extra-
Bronchobiliary fistulas often manifest with
pulmonary sequestration, is located outside
recurrent pulmonary infections and con-
the normal lung and has its own visceral
comitant atelectasis during early life. Rarely,
pleura, and the venous drainage, although
the diagnosis may not be made until after
variable, is commonly through the azygos
the second year of life. A bronchobiliary
system. These lesions generally receive a sys-
fistula represents a direct, congenital con-
temic arterial supply from the descending
nection between the bronchus of the right
thoracic aorta. They are commonly found
middle lobe and the left hepatic duct. When
beneath the left lower lobe. A rare variant of
the diagnosis of bronchobiliary fistula is
sequestration is bronchopulmonary-foregut
made, surgery is clearly indicated. These
malformation. With this anomaly, the seques-
are isolated occurrences with no recognized
tered lung tissue is connected to the
genetic associations.
gastrointestinal tract. Histologically, a pulmo-
nary sequestration is composed of cystic lung
tissue of embryonic origin. Rarely symptom- Congenital Lobar Emphysema
atic at birth, pulmonary sequestration may
appear as a cystic or solid infiltrate on chest Congenital lobar emphysema (CLE) is a devel-
x-ray. A pulmonary sequestration may opmental anomaly of the lower respiratory
become infected, with fistulas occasionally tract that is characterized by hyperinflation
A B
Figure 14-4. A, X-ray shows intralobar pulmonary sequestration (longer arrow) with anomalous artery arising from
aorta (shorter arrow). B, CT scan shows large pulmonary sequestration on the left with arterial blood supply coming
from aorta.
of one or more pulmonary lobes. Other terms distal esophagus connecting directly to the
for CLE include “congenital lobar overinfla- trachea, and accounts for approximately
tion,” “congenital large hyperlucent lobe,” 85% of cases. TEF occurs without esopha-
and “infantile lobar emphysema.” CLE is an geal atresia (H-type fistula) in only 5% of
uncommon cause of respiratory distress in cases. These defects result from failure of
infants. It has a marked predilection for the the tracheoesophageal ridges to fuse fully
left upper lobe. The most frequently identi- during early embryonic life, with incom-
fied cause of CLE is obstruction of the devel- plete separation of the esophagus from the
oping airway, which occurs in about 25% of trachea.1 One third of infants born with a
cases. Airway obstruction can be intrinsic or TEF have additional birth defects. TEFs
extrinsic, with the former more common. may be seen as part of multiple anomaly
This leads to a “ball-valve” effect, whereby a associations and in numerous mendelian
greater volume of air enters the affected lobe disorders (Table 14-9).
during inspiration than leaves during expira- The clinical presentation of TEF depends on
tion, producing air trapping. Intrinsic the presence or absence of esophageal atresia.
obstruction is often caused by defects in the In cases with esophageal atresia (95%), polyhy-
bronchial wall, such as deficiency of bron- dramnios occurs in approximately two thirds
chial cartilage. Intraluminal obstruction of pregnancies. Infants with esophageal atresia
caused by meconium or mucous plugs, granu- become symptomatic immediately after
lomas, or mucosal folds can result in partial birth, with excessive secretions resulting in
obstruction of a lower airway. Extrinsic com- drooling, choking, respiratory distress, and
pression may be caused by vascular anoma- the inability to feed. A fistula between the
lies, such as a pulmonary artery sling or trachea and distal esophagus often leads to
anomalous pulmonary venous return, or gastric distention and reflux of gastric con-
intrathoracic masses. tents through the TEF resulting in aspira-
CLE is often associated with hyperinflation pneumonia. Children with H-type
tion of the affected lung leading to compres- TEFs may present early if the defect is large,
sion of adjacent lung tissue and respiratory with coughing and choking associated with
distress. Although most cases of CLE are feeding as the milk is aspirated through the fis-
isolated occurrences, affected siblings and tula. Smaller defects of this type may not be
an affected mother and daughter have been symptomatic in the newborn period. These
described. CLE also has been seen in associ- patients typically have a prolonged history of
ation with cerebral (berry) aneurysms, cere- mild respiratory distress associated with feed-
bral calcifications, and cirrhosis in three ings or recurrent pneumonias. Treatment con-
brothers.14 The appropriate treatment of sists of surgical ligation of the fistula; patients
CLE in newborns with respiratory distress with esophageal atresia require esophageal
is surgical resection of the affected lobe. anastomosis.
Conservative management is reasonable in
infants who have no or minimal symptoms.
Pulmonary Lymphangiectasia and
Other Diseases of the Lymphatic Tree
Tracheoesophageal Fistula and
Tracheal Agenesis Congenital pulmonary lymphangiectasias
may be either secondary to prenatal obstruc-
TEF is a common congenital anomaly of the tion of the pulmonary lymphatic or venous
respiratory tract, with an incidence of about drainage or a primary defect. Primary pul-
1 in 3,500 live births. TEF typically occurs monary lymphangiectasias may be limited
with esophageal atresia. Esophageal atresia to the lung itself, or may manifest as part
and TEF are classified according to their ana- of more generalized lymphangiectasia. They
tomic configuration. Type A consists of a are frequently, but not always, associated
proximal esophageal blind pouch, with the with a chylothorax and may result in
Table 14-9 Genetic Conditions Associated with Tracheoesophageal Fistulas

Tracheoesophageal fistula with Tracheoesophageal fistula Autosomal Unknown and
or without esophageal atresia Esophageal atresia dominant deletion ¼ 17q22-
versus q23.3
multifactorial
X-linked VACTERL association Tracheoesophageal fistula X-linked versus Unknown
with hydrocephalus Hydrocephalus autosomal
recessive
Vertebral malformations
Anal atresia
defects
Radial dysplasia and thumb
anomalies
VATER association Tracheal agenesis Isolated cases Unknown. Fanconi
(occasional) (may find genes (group A, C,
Tracheoesophageal fistula similar defects D1, E, F and G)15
in children
Single umbilical artery with Fanconi
Vertebral defects anemia, which
Anal atresia is autosomal
recessive)
Cardiac and renal defects
Radial dysplasia and thumb
anomalies
Hemifacial microsomia Tracheoesophageal fistula Multifactorial Locus ¼ 14q32;
(Goldenhar syndrome) (5%) versus possible locus ¼
(incidence 1:3000-5000) Facial asymmetry, autosomal 22q11.2
microsomia dominant
Epibulbar dermoids
Microtia
Conductive hearing loss
Cardiac, vertebral, and renal
defects
CNS malformations
CHARGE syndrome Tracheoesophageal fistula Autosomal Gene ¼ CHD7
Anal atresia or stenosis dominant
External ear malformations
Sensorineural with or
without conductive
deafness
Ocular colobomas
Choanal atresia
Cleft lip with or without
cleft palate
Cardiac and renal defects
Genital anomalies
Posterior cleft larynx Common tracheoesophagus Autosomal Unknown
Posterior cleft larynx recessive
Opitz-Frias syndrome Tracheoesophageal fistula Autosomal Locus ¼ 5p13-p12
(hypertelorism with Pulmonary hypoplasia dominant and (duplication);
esophageal abnormality and X-linked 13q32.3—ter
hypospadias) Hypertelorism with (deletion); Xp22—
telecanthus p11.2 (deletion)
Table 14-9 Genetic Conditions Associated with Tracheoesophageal Fistulas—Cont’d

Cleft lip with or without
cleft palate
renal defects
Hernias
CNS defects with mental
retardation
Feingold syndrome Tracheoesophageal fistula Autosomal Gene ¼ MYCN
(oculodigitoesophagoduodenal Polyhydramnios dominant (2p24.1)
syndrome)
Microcephaly
Facial asymmetry
Hearing loss
Patent ductus arteriosus
Vocal cord paralysis
Asplenia or polysplenia
Hypoplasia of middle
phalanx of fingers 2 and 5
Syndactyly
Learning disabilities or
mental retardation
McKusick-Kaufman syndrome Tracheoesophageal fistula Autosomal Gene ¼ MKKS (20p12).
(occasional) recessive Allelic with Bardet-
Pulmonary hypoplasia Biedl syndrome
type 6
Females with
hydrometrocolpos
renal malformations
Syndromic microphthalmia 3 Esophageal atresia Autosomal Gene ¼ SOX2 (3q26.3-
Microphthalmia, dominant q27)
anophthalmia
Microcephaly
Cardiac, vertebral,
genitourinary, and CNS
defects
Multiple gastrointestinal Tracheoesophageal fistula Autosomal Unknown
abnormalities Duodenal atresia recessive
Hypoplasia of pancreas,
gallbladder, biliary ducts,
and intestines
Hypospadias
secondary pulmonary hypoplasia. Although (Table 14-10). Lymphatic hypoplasia of

most pulmonary lymphangiectasias are varied distribution underlies the yellow nail
isolated occurrences, primary pulmonary syndrome, and pulmonary lymphatic hyper-
lymphangiectasias have been reported in sib- plasia is part of Klippel-Trénaunay-Weber
lings and as part of several genetic syndromes syndrome (see Chapter 12).
Table 14-10 Genetic Conditions Associated with Pulmonary Lymphangiectasia
GENE OR LOCUS
Congenital pulmonary Pulmonary lymphangiectasia Autosomal recessive Unknown
lymphangiectasia Polyhydramnios
Hydrothorax, chylothorax
Facial edema
Ascites
Hypertelorism
Recurrent respiratory
infections
Frequently lethal in neonatal
period
Persistence of müllerian Pulmonary lymphangiectasia Autosomal recessive Unknown
derivatives with Polyhydramnios
lymphangiectasia and
postaxial polydactyly Facial dysmorphism
Short neck
Ventricular septal defect
Narrow thorax
Intestinal lymphangiectasia
Protein-losing enteropathy
Genitourinary anomalies in
males including residual
müllerian duct structures
(uterus and fallopian tubes)
Lymphedema- Pulmonary lymphangiectasia Autosomal recessive Unknown
hypoparathyroidism Short stature versus X-linked
syndrome recessive
Cataracts, ptosis, telecanthus
Mitral valve prolapse
Nephropathy
Hypoparathyroidism
Pulmonary Arteriovenous all ethnicities. Several genetic conditions

Malformations and Hemangiomas are associated with multiple pulmonary
AVMs and a high likelihood of vascular
Pulmonary arteriovenous malformations symptoms and mortality. Individuals from
(PAVMs) may manifest at birth or occasion- these high-risk families require increased
ally can develop postnatally. AVMs represent surveillance because they may have internal
direct arterial-to-venous communications and external AVMs, including pulmonary
without intervening capillary networks. lesions (Table 14-11).
They are frequently asymptomatic, but are a Other vascular lesions, such as hemangio-
significant cause of morbidity and mortality, mas, also may arise congenitally, but generally
especially if located in the central nervous carry less medical risk than AVMs. Super-
system, spinal cord, or internal organs. AVMs ficial capillary hemangiomas are extremely
can result in acute bleeding that may be diffi- common lesions noted at birth that often fade
cult to control. For most individuals with pul- with time. Larger cavernous hemangiomas
monary AVMs, however, they remain are sometimes associated with bleeding,
asymptomatic throughout their lives. Pul- infections, or ulceration, but are rarely life-
monary AVMs occur as frequently in females threatening. Although frequently cosmeti-
and males. They are seen in individuals of cally problematic, hemangiomas usually do
Table 14-11 Genetic Conditions Associated with Pulmonary and Other Arteriovenous Malformations

HHT (Osler-Weber-Rendu) Pulmonary AVMs (in lower lobes) Autosomal Gene ¼ ENG
type 1 Other internal organ AVMs dominant (9q34.1)
Congestive heart failure (high-output)
Polycythemia
Digital clubbing
Telangiectasias (face, tongue, lips,
conjunctiva, finger tips)
Epistaxis (most common presentation)
Gastrointestinal bleeding
Embolic complications
Cirrhosis of liver
Migraine headaches
HHT (Osler-Weber-Rendu) Same as HHT type 1, but with slightly Autosomal Gene ¼ ACVRL1
type 2 fewer pulmonary AVMs dominant (12q11-q14)
HHT (Osler-Weber-Rendu) Same as HHT type 1 Autosomal Locus ¼ 5q31
type 3 dominant
HHT (Osler-Weber-Rendu) Same as HHT type 1, but with fewer Autosomal Locus ¼ 7p14
type 4 nosebleeds and telangiectasias dominant
Juvenile polyposis HHT Pulmonary AVMs Autosomal Gene ¼ SMAD4
syndrome Other vascular features of HHT dominant (18q21.1)
Juvenile gastrointestinal polyps with
rectal bleeding
AVM, arteriovenous malformation; HHT, hereditary hemorrhagic telangiectasia.
not require surgical or medical treatment. choose to undergo molecular testing to deter-
Isolated internal hemangiomas also may mine their own status. Pulmonary AVMs
never pose serious medical risks. Pulmonary and hemangiomas are discussed further in
hemangiomas do occur, however, and may Chapter 12.
be identified incidentally. One genetic condi-
tion that is associated with multiple internal
hemangiomas and other angiomas is von a1-Antitrypsin Deficiency
Hippel–Lindau syndrome. This syndrome is
an autosomal dominant condition resulting a1-Antitrypsin is a member of the serine
in development of benign and sometimes proteinase inhibitor family and functions
malignant lesions. Although pulmonary to inhibit the activity of proteolytic enz-
hemangiomas are seen in some individuals ymes with a serine residue within the active
with von Hippel–Lindau syndrome, the clas- site. a1-antitrypsin deficiency is an autoso-
sic lesions seen are: cerebellar or spinal cord mal recessive condition associated with
hemangioblastomas, pancreatic and renal early-onset obstructive pulmonary disease
cysts, retinal angiomas, and pheochromocy- in childhood and adulthood. It is seen in
tomas. Renal cell carcinoma is a common about 1 in 5000 to 7000 whites residing in
malignancy in von Hippel–Lindau syndrome. North America; 1 in 1500 to 3000 Scandina-
Recognition of this serious genetic condition vians are affected.16 Although emphysema
enables aggressive screening measures and is rarely diagnosed in childhood, the diag-
provides patients and their families with nosis of a1-antitrypsin deficiency is some-
important medical and familial risk times made in infants with cholestatic
information. The VHL gene has been well jaundice and elevated liver function tests.
characterized, and at-risk individuals may In adulthood, the liver disease may progress
to fibrosis and cirrhosis. Avoidance of occurs most often in the setting of chronic lung
environmental triggers, such as smoke, dust, infections. Although cystic fibrosis (CF) is the
and fumes, may delay the onset of lung dis- most frequent genetic condition associated
ease in at-risk children and teens; this infor- with bronchiectasis, primary and secondary
mation should be included in counseling of immunodeficiencies and ciliary dysfunction
children diagnosed with a1-antitrypsin defi- also may result in chronic pulmonary infec-
ciency. Parents should be cautioned that tions and lung tissue destruction, especially in
even passive exposure to smoke poses signif- dependent areas of the lung. Because more
icant health risks to affected children. than two thirds of children with non–CF-
Although there is no cure for a1-antitrypsin related bronchiectasis have evidence of an
deficiency, a specific therapy is available and immune defect, primary ciliary dyskinesia, or
currently consists of a1-antitrypsin protein recurrent aspiration, evaluation of patients
replacement. Intravenous infusions of puri- with this finding should include immunologic
fied a1-antitrypsin can increase the level of and other diagnostic studies to rule out these
a1-antitrypsin and antineutrophil elastase other etiologies.17 Several genetic syndromes
activity in the lung epithelial lining fluid of with bronchiectasis as a major feature have
affected individuals. In the future, therapies been described that are associated with a pri-
such as this may become available to patients mary immunodeficiency (Table 14-12).
before alveolar destruction occurs and symp- Kartagener described a curious combina-
toms of chronic obstructive pulmonary dis- tion of situs inversus, chronic sinusitis, and
ease become apparent. bronchiectasis, which subsequently became
The diagnosis of a1-antitrypsin deficiency is known as the Kartagener triad. The term
made by measuring the plasma concentration “Kartagener syndrome” was later adopted
of a1-antitrypsin in an infant, child, or adult when additional features of rhinitis, nasal
with clinical signs of the condition. If the con- polyps, chronic otitis media, and reduced
centration is less than 50% of normal, consid- fertility were recognized. Kartagener syn-
eration should be given to performing a drome is now considered the most severe
Protease Inhibitor (PI) analysis either by iso- clinical expression of a spectrum of abnorm-
electric focusing or molecular mutation analy- alities of ciliary motility caused by defective
sis to confirm the diagnosis. Most affected cilia in several parts of the body that renders
individuals are homozygous for the Z allele. ciliary function ineffective. This entity has
Compound heterozygotes with a Z allele and been termed “immotile-cilia syndrome,”
a milder S allele may develop lung disease “dyskinetic cilia syndrome,” and, more appro-
when exposed to cigarette smoke, but gener- priately, “primary ciliary dyskinesia” (PCD).18
ally do not have liver involvement. The large airways and contiguous struc-
For couples who have an affected child, risks ture, such as nares, paranasal sinuses, and
to future children are on the order of 25%. middle ear, are lined by a ciliated, pseudos-
When an individual is diagnosed with a1-anti- tratified columnar epithelium. Ciliated cells
trypsin deficiency, siblings should be offered contain approximately 200 cilia. Each nor-
testing for their own medical information. mal cilium contains an array of longitudinal
When a prospective parent is known to carry microtubules, consisting of nine doublets
one or two abnormal a1-antitrypsin alleles, his arranged in an outer circle around a central
or her partner might wish to undergo PI typing pair. A network of structural proteins pro-
to determine their joint reproductive risks. vides linkages to maintain the 9þ2 pattern
of microtubules in healthy cilia. The protein
nexin links the outer microtubular doublet,
Bronchiectasis, Primary creating a circumferential network, and
Ciliary Dyskinesia, and radial spokes connect the outer microtubu-
Kartagener Syndrome lar doublets with a central sheath of protein
that surrounds the central tubules. Dynein
“Bronchiectasis” is the pathologic term for is attached to the microtubules as distinct
bronchial destruction, bronchial dilation, and inner and outer “arms” thought to participate
accumulation of infected secretions, which in the supply of energy for microtubular
Genetic Conditions Associated with Bronchiectasis Resulting from an

Table 14-12
Immunodeficiency
GENE OR LOCUS
Ataxia- Bronchiectasis Autosomal recessive. Gene ¼ ATM
telangiectasia Immune defects with thymus Heterozygotes may be at (11q22.3)
hypoplasia and decreased T cells, increased risk for certain
defective B cell differentiation, neoplasias
lymphopenia
Recurrent sinopulmonary infections
Short stature
Cutaneous and conjunctival
telangiectasias
Cerebellar ataxia and cerebellar
atrophy, dysarthria, seizures
Hypogonadism
Sensitivity to ionizing radiation
Risks for leukemia with or without
lymphoma
Increased AFP and CEA
Decreased IgA, IgE, and IgG2
Bloom syndrome Bronchiectasis Autosomal recessive. Gene ¼ RECQL3
Prenatal and postnatal growth Almost ⅓ of reported (15q26.1)
restriction cases are in Ashkenazi-
Jewish population
Microcephaly
Facial dysmorphism
Malar hypoplasia
Polydactyly, syndactyly, with or
without clinodactyly
Sun sensitivity
Facial telangiectasias
Cutaneous hyperpigmentation and
hypopigmentation
IgA, IgG, and IgM deficiency
Impaired lymphocyte response
Recurrent life-threatening infections
Increased risk for malignancy
Cytogenetic instability with
increased sister chromatid
exchanges
Young syndrome Bronchiectasis Autosomal recessive. Unknown.
(Barry-Perkins- Congenital cystic lung disease Should be differentiated Distinct from
Young syndrome) from congenital absence CFTR
Recurrent sinopulmonary infections of vas deferens owing to
Azoospermia owing to obstructed mutations in CFTR
vas deferens (cystic fibrosis) gene
Normal bronchial cilia on EM
AFP, a-fetoprotein; CEA, carcinoembryonic antigen; EM, electron microscopy.
sliding through adenosine triphosphatase and a recovery phase during which the cilia
activity (Fig. 14-5). Ciliary motion occurs bend backward and extend into the starting
within an aqueous layer of airway surface position for the stroke phase.
liquids and is divided into two phases: an PCD has been reported in many ethnic
effective stroke phase that sweeps forward, groups without racial or gender predilection.
Microtubular doublet
Central microtubule
Dynein arm
Ciliary
membrane
A B
Central sheath
Figure 14-5. A, Normal cilia contain Nexin link

nine outer microtubular doublets around a
central pair. B, Dynein arms control beats
within cilia; outer dynein arms are related Spoke
to beat frequency, and inner arms affect
the beat waveform. C, Radial spoke defect.
D, Microtubular transposition abnormality,
both clear, cilia structural variants. (Adapted
from Turcios, NL, Your patient may have
primary ciliary dyskinesia. J Respir Dis Pediatr
3:99, 2001.) C D
In most families, PCD seems to be transmit- secretions, with a buildup of mucus and
ted by an autosomal recessive pattern of bacteria in the respiratory tract.
inheritance; however, rare instances of auto- The clinical manifestations vary among
somal dominant or X-linked inheritance PCD patients and depend on age. The diag-
patterns have been reported. The incidence nosis of PCD should be considered in term
of PCD is 1 in 15,000 to 20,000 births. The newborns with respiratory distress or persis-
incidence of situs inversus is random within tent atelectasis/pneumonia with symptoms
affected families, suggesting that this pheno- resembling “wet lung” and no obvious pre-
type is not genetically determined. The disposing risk factors. The former presum-
numerous ultrastructural phenotypes sug- ably reflects the importance of functional
gest genetic heterogeneity. PCD seems to be cilia in clearing lung liquid shortly after
caused by mutations in at least three different birth.
genes. Not all individuals who carry two cop- Infants and older children with PCD may
ies of these gene mutations have the visceral present with atypical asthma that is nonre-
abnormalities, which greatly complicates sponsive to treatment or with an increased
diagnostic testing and genetic counseling of number of respiratory infections associated
these families. More recent advances in with chronic cough and expectoration of
molecular genetics have identified mutations mucopurulent sputum over time. The classic
that can be tracked in certain families. presentation of PCD includes chronic rhino-
Bronchiectasis may develop in young indi- sinusitis, recurrent serous otitis media (often
viduals, but is never present at birth; no indi- requiring multiple interventions, such as
vidual is born with full-blown Kartagener repeated courses of antibiotics and place-
syndrome. Although individuals with PCD, ment of myringotomy tubes), and recurrent
which includes Kartagener syndrome, are pneumonia. Nasal polyps and agenesis of
plagued by recurrent sinopulmonary infec- the frontal sinuses also are common in child-
tions and chronic otitis media, they do not hood. Situs inversus is a useful sign when PCD
have any recognized immunologic problem. is being considered, but as described earlier, is
Their infections are tied to structurally defec- present only in approximately 50% of
tive cilia, resulting in inability to clear patients with PCD.
The symptoms in adolescents and adults associated with anomalies such as cardiac
are similar to the symptoms in older children, defects, asplenia, and polysplenia. The pres-
but otitis media seems to be less prominent. ence of asplenia may add to the risk for infec-
Infertility is common in affected adults, tion in an already immunocompromised host.
especially in men owing to immotile sperm— Studies have shown that nasal nitric oxide
a modified cilium. Fatigue and headaches are is extremely low in PCD patients and may
common complaints and may be related to be useful for screening for PCD. The final
chronic sinusitis, although the headaches diagnosis of any of the PCDs, including
may persist even during infection-free periods. Kartagener syndrome, rests on electron
Cylindrical or saccular bronchiectasis may microscopic evaluation of respiratory cilia.
occur, even in childhood, usually affecting Scraping of the anterior aspect of the inferior
the middle and lower lobes and the lingula. nasal turbinate or biopsy of the bronchial
Patients with bronchiectasis have ausculta- epithelium at the time of bronchoscopy
tory crackles and may have wheezes that may provide an adequate sample for ultra-
mimic asthma. Common findings on chest structural analysis. The most frequent elec-
x-ray and computed tomography (CT) scan tron microscopic finding in patients with
are a moderate degree of hyperinflation, PCD is absence of, or abnormalities in, the
peribronchial thickening, atelectasis, and dynein arms; about 1 in 10 ciliary samples
bronchiectasis. Digital clubbing is uncom- has obvious abnormalities in the central pair
mon in patients younger than 18 years old. of microtubules or in the radial spokes.
Complete situs inversus may be an inci- Management of patients with PCDs
dental and clinically insignificant finding includes many of the same therapies used
in half of patients with PCD. Heterotaxy or for children with CF who have secondary
situs ambiguus results from failure of left-to- ciliary dysfunction. Table 14-13 outlines
right differentiation and occurs in about 1 many of the genes and loci recognized to
in 17 PCD patients. This condition may be be associated with bronchiectasis and PCD.
Table 14-13 Primary Ciliary Dyskinesia with or without Situs Abnormalities

Kartagener syndrome, Siewert Bronchiectasis Autosomal Gene ¼ DNAI1 (9p21-
syndrome (situs inversus, Dyskinetic cilia recessive p13); DNAH5 (5p15-
bronchiectasis, and sinusitis) p14); locus ¼ 7p21
Immotile sperm
Decreased fertility in males and
females
Recurrent sinopulmonary
infections
Dextrocardia
Situs inversus
Asplenia
Absent or abnormal dynein arms
of sperm and respiratory cilia
on EM
PCD 1 Bronchiectasis Autosomal Gene ¼ DNAI1 (9p21-
Dyskinetic cilia recessive p13). Allelic with
Kartagener
Recurrent rhinosinusitis
Chronic ear infections
Situs inversus (only in 20%)
Dynein arm defect on EM
PCD 2 Same as PCD 1 Autosomal Locus ¼ 19q13.3-qter
recessive
(Continued)
Table 14-13 Primary Ciliary Dyskinesia with or without Situs Abnormalities—Cont’d

PCD 3 Same as PCD1 Autosomal Gene ¼ DNAH5

recessive (5p15-p14). Allelic
with Kartagener
PCD 4 Same as PCD1 Autosomal Locus ¼ 15q13.1-
recessive q15.1
PCD 5 Same as PCD1 Autosomal Locus ¼ 16p12.2-
recessive p12.1
PCD 6 Same as PCD1 Autosomal Gene ¼ TXNDC3
recessive (17p14)
Dyskinetic cilia owing to Chronic sinopulmonary Autosomal Unknown
defective radial spokes infections recessive
Immotile sperm
Absence of ciliary axoneme
radial spokes on EM
Dyskinetic cilia owing to Chronic sinopulmonary Autosomal Unknown
transposition of ciliary infections recessive
microtubules Evidence of transposition of the
first doublet microtubule on
EM
Hypohydrotic ectodermal Recurrent pulmonary infections Autosomal Unknown
dysplasia with Hypohydrotic ectodermal recessive
hypothyroidism and ciliary dysplasia
dyskinesia
Primary hypothyroidism
Abnormalities of ciliary
microtubules on EM
X-linked retinitis pigmentosa Recurrent pulmonary infections X-linked Gene ¼ RPGR
with recurrent respiratory Retinitis pigmentosa recessive (Xp21.1)
infections
Normal male fertility
Inner dynein arm deficiency,
incomplete microtubules, and
ciliary disorientation on EM
EM, electron microscopy; PCD, primary ciliary dyskinesia.
Spontaneous Pneumothorax family history may help to uncover evidence

of a connective tissue disorder or a heritable
Spontaneous pneumothorax is usually an trait.
acute, sometimes life-threatening event,
occurring in otherwise healthy individuals.
Spontaneous pneumothorax occurs more Inborn Errors of Metabolism
often in tall, thin men and can be seen in indi-
viduals with certain underlying connective Although one would not typically associate
tissue disorders. Familial spontaneous pneu- inborn errors of metabolism with pulmonary
mothorax can be inherited as an autosomal problems, many storage and biochemical
dominant condition associated with sub- disorders cause respiratory complications.
pleural blebs and bullae, or can be a sporadic Because most of these conditions are systemic,
(nongenetic) occurrence. Table 14-14 sum- virtually all organs may be involved to a
marizes genetic associations with spontane- greater or lesser degree. Interstitial or restrictive
ous pneumothoraces. For any child, teen, or lung disease can be seen in some lysosomal
adult with a spontaneous pneumothorax, a storage disorders. Pulmonary hypertension or
focused physical examination and targeted pulmonary hypoplasia may be identified with
Table 14-14 Genetic Conditions Associated with Spontaneous Pneumothorax

Marfan syndrome Spontaneous pneumothorax Autosomal dominant. Gene ¼ FBN1
Pulmonary blebs At least ¼ due to (15q21.1)
new or de novo
Rarely emphysema gene mutations
Disproportionate tall stature
Long, narrow face
Severe myopia
Risk for retinal detachment
Aortic root dilation and risk for
aortic dissection
Pectus deformity
Kyphosis or scoliosis
Arachnodactyly
Joint hypermobility
Pes planus
Primary spontaneous Spontaneous pneumothorax Autosomal dominant Gene ¼ FLCN
pneumothorax Subpleural blebs and bullae (17p11.2)
(randomly distributed
throughout lungs in familial
instances)
More common in tall, thin men
Birt-Hogg-Dube Spontaneous pneumothorax Autosomal dominant Gene ¼ FLCN
syndrome Lung cysts (17p11.2). Allelic
(fibrofolliculomas with primary
with trichodiscomas Hair follicle hamartomas spontaneous
and acrochordons) Skin tags pneumothorax
Renal tumors
Ehlers-Danlos type IV Spontaneous pneumothorax Autosomal dominant Gene ¼ COL3A1
Pinched nose (2q31)
Premature tooth loss
Spontaneous bowel and uterine
rupture
Uterine and bladder prolapse
Easy bruising, prominent veins
Poor scar formation, thin skin
Distal interphalangeal joint
hypermobility
Acro-osteolysis
Autosomal recessive Neonatal pneumothorax Autosomal recessive Gene ¼ ADAMTS2
Ehlers-Danlos type VII Short stature (5q23)
Micrognathia
Blue sclera
Myopia
Gingival hyperplasia
Hypodontia and abnormal teeth
Hernias
Visceral rupture
Short limbs and digits
Significant joint laxity
Skin laxity and fragility
Easy bruising
Doughy, redundant skin
other inborn errors of metabolism. Organic Pulmonary Arterial

acidemias, aminoacidopathies, cholesterol Hypertension
ester storage diseases, disorders of glycosyla-
tion, and peroxisomal disorders have been Although pulmonary hypertension fre-
found to have pulmonary complications. quently results from other systemic problems,
Table 14-15 highlights some commonly recog- idiopathic pulmonary arterial hypertension
nized inborn errors of metabolism associated (previously termed “primary pulmonary
with pulmonary symptoms.
Table 14-15 Inborn Errors of Metabolism Associated with Pulmonary Manifestations
METABOLIC GENE OR
DISORDER ENZYME DEFICIENCY CLINICAL FEATURES INHERITANCE LOCUS
Mucopolysacchari- a-L-iduronidase. Restrictive lung disease Autosomal Gene ¼ IDUA
dosis type IH/S Lysosomal storage Recurrent upper recessive (4p16.3)
(Hurler-Scheie disorder— respiratory
syndrome) mucopolysacchari- infections
dosis
Short stature
Corneal clouding
Joint stiffness
Dysostosis multiplex
Hepatosplenomegaly
Declining or normal
IQ
Gaucher disease Acid b-glucosidase. Interstitial lung disease Autosomal Gene ¼ GBA
(pulmonary Lysosomal storage Restrictive lung recessive. Highly (1q21)
findings disorder— disease variable
associated with sphingolipidosis expression and
severe Pulmonary infiltrates incomplete
phenotype) (<1 in 20) penetrance.
Pulmonary Carrier frequency
hypertension in Ashkenazi-
Hepatosplenomegaly Jewish
population is
Bone pain, about 1:14
pathologic
fractures
Cutaneous
hyperpigmentation
Pancytopenia
Fabry disease a-galactosidase A. Mild obstructive lung X-linked recessive Gene ¼ GLA
Lysosomal storage disease (may be (Xq22)
disorder— mutation
sphingolipidosis dependent)
Mild short stature
Corneal dystrophy
Painful crises
Strokes, seizures
Angina,
hypertension
Left ventricular
hypertrophy
Abdominal pain
Renal failure
Acroparesthesias
Angiokeratomas
Table 14-15 Inborn Errors of Metabolism Associated with Pulmonary Manifestations—Cont’d
METABOLIC GENE OR
GM1 gangliosidosis Acid b-galactosidase. Pulmonary infiltrates Autosomal Gene ¼ GLB1
type I Lysosomal storage with foam cell recessive (3p21.33)
disorder— vacuoles filled with
sphingolipidosis fibrillar material
Respiratory
insufficiency
Short stature
Short neck
Cherry-red spots
(50%)
Gingival
hypertrophy
Kyphoscoliosis
Hepatosplenomegaly
Visceral foamy
histiocytes
Stiff joints
Dysostosis multiplex
Declining IQ
Krabbe disease Galactocerebroside b- Respiratory failure Autosomal Gene ¼ GALC
(globoid cell galactosidase. Intra-alveolar and recessive (14q31)
leukodystrophy) Lysosomal storage interstitial
disorder— macrophages
sphingolipidosis
Failure to thrive
Progressive
neurologic
deterioration,
seizures
Hydrocephalus
Optic atrophy,
blindness
Hyperirritability
Sensitive to sound
Peripheral
neuropathy
Farber disease Acid ceramidase. Respiratory Autosomal Gene ¼ AC or
Lysosomal storage insufficiency recessive ASAH (8p22-
disorder— Failure to thrive p21.3)
sphingolipidosis
Cherry-red spots
Hoarse cry
Irritability
Cognitive decline,
motor delays
Lipogranulomatosis
Periarticular
subcutaneous
nodules
Painful, enlarged
joints
Hepatosplenomegaly
Nephropathy
(Continued)
METABOLIC GENE OR
Wolman disease Acid cholesterol ester Pulmonary Autosomal Gene ¼ LIPA
hydrolase. hypertension recessive (10q24-q25)
Lysosomal storage Failure to thrive
disorder—other
Hepatosplenomegaly
Hepatic fibrosis
Malabsorption
Adrenal calcifications
Glycogen storage Undefined, but due to Pulmonary Autosomal Locus ¼
disease type Ic/Id a phosphate- hypertension recessive 11q23-q24
pyrophosphate Respiratory
translocase defect. infections
Glycogen storage
disorder Hypoglycemia
Growth delay
Hepatomegaly
Renal insufficiency
Xanthomas
Gout
Lactic acidemia
Zellweger Genetic heterogeneity. Pulmonary hypoplasia Autosomal Gene ¼ PEX1
syndrome Peroxisome Bell-shaped thorax recessive (7q21);
(cerebrohepato- biogenesis factors PEX2 (8q);
renal syndrome) and peroxisomal Breech presentation PEX3 (6q);
membrane protein Failure to thrive PEX5 (chr
and peroxisome Facial dysmorphism 12); PEX6
receptor. (6p); PEX12;
Peroxisomal disorder Nerve deafness PEX14 (chr
Corneal clouding 1); PEX26;
Cataracts, glaucoma locus ¼
7q11
Cardiac defects
Hepatomegaly
Neonatal jaundice
Hypospadias
Hydronephrosis
Stippled epiphyses
Clubfeet
Hypotonia, seizures
CNS defects
Elevated long-chain
fatty acids and
phytanic acid
Death in first year of
life
Congenital Dolichyl-P-glucose: Pulmonary hypoplasia Autosomal Gene ¼ ALG8
disorder of Glc-1-Man-9- Intrauterine growth recessive (11pter-
glycosylation GlcNAc-2-PP- restriction p15.5)
type Ih dolichyl-a-3-
(carbohydrate- glucosyltransferase. Feeding difficulties
deficient Carbohydrate- Low factor XI,
glycoprotein) deficient protein C, and
glycoprotein antithrombin III
disorder Protein-losing
enteropathy
METABOLIC GENE OR
Severe diarrhea
Hepatomegaly
Hypoalbuminemia
Ascites and edema
Assorted anomalies
Multiple Acyl-CoA Electron transfer Pulmonary hypoplasia Autosomal Gene ¼ ETFA
dehydrogenase flavoprotein- Respiratory distress recessive (15q23-
deficiency ubiquinone q25); ETFB
(glutaric aciduria oxidoreductase. Facial dysmorphism (19q13.3);
type II) Electron transfer Neonatal acidosis ETFDH
disorder— Jaundice (4q32-qter)
mitochondrial fatty
oxidation pathway Hypoglycemia
Hepatomegaly
Hypotonia
Renal cysts and other
genitourinary
defects
Glutaric aciduria
Homocystinuria Cystathionine Pulmonary embolism Autosomal Gene ¼ CBS
b-synthase. Amino Other thromboses recessive. About (21q22.3)
acid disorder— half are
methionine pathway Pectus deformities responsive to
Ectopia lentis vitamin B6
Arachnodactyly
Kyphoscoliosis
Osteoporosis
Joint contractures
Seizures, strokes
Learning disabilities
or mild mental
retardation
Elevated plasma and
urinary
homocystine
Lysinuric protein Amino acid Alveolar proteinosis Autosomal Gene ¼
intolerance transporter. Defect in Subpleural cysts recessive. More SLC7A7
transport of dibasic common in (14q11.2)
amino acids in the Acinar nodules Finnish
intestine, liver, and Thick pleural population
kidneys. Amino acid interstitial septa
disorder—amino Protein intolerance
acid transport
Failure to thrive
Malabsorption
Hepatomegaly
Cirrhosis
Osteopenia

hypertension”) can occur as a mendelian of these conditions. An IPAH gene has been
disorder (autosomal dominant and autoso- identified in selected families, which codes
mal recessive) and as part of other well- for the BMPR2 protein, which resides on
described genetic syndromes. There seems chromosome 2 within band q33. Table 14-16
to be a relationship between systemic vascu- presents genetic conditions associated with
lar development and idiopathic pulmonary idiopathic pulmonary arterial hypertension.
arterial hypertension in some, but not all, See Chapter 4 for further information.
Table 14-16 Genetic Conditions Associated with Primary Pulmonary Hypertension
GENE OR LOCUS
PPH PPH Autosomal dominant. About Gene ¼ BMPR2 (2q33)
PFTs with restrictive 6% of cases of PPH are
pattern genetic. Females more
often affected than males
Arterial hypoxemia
RVH and failure
Increased pulmonary
arterial pressure
and pulmonary
vascular resistance
Arterial fibrosis and
medial
hypertrophy
Thrombosis
Autosomal recessive Same as PPH Autosomal recessive Unknown
PPH
Familial persistent Neonatal pulmonary Autosomal recessive Susceptibility gene ¼ CPS1
pulmonary hypertension (T1405N polymorphism)
hypertension of the Abnormal
newborn pulmonary lobules
Increased muscular
wall in arterioles
Lethal in infants
Lymphedema and PPH Autosomal dominant Unknown
cerebral arteriovenous AVM
anomaly
Cranial bruit
Lymphedema
Familial pulmonary PPH Autosomal recessive Unknown
capillary Pulmonary capillary
hemangiomatosis hemangiomatosis
Familial cirrhosis PPH Autosomal recessive Gene ¼ KRT8 (12q13);
Congenital or KRT18 (12Q13)
childhood cirrhosis
Esophageal varices
Edema
Liver with
panlobular
swelling, fibrosis,
and micronodular
cirrhosis
Increased hepatic
copper
Table 14-16 Genetic Conditions Associated with Primary Pulmonary Hypertension—Cont’d
GENE OR LOCUS
VATER-like defects with Pulmonary Autosomal recessive Unknown
pulmonary hypertension
hypertension, Short stature
laryngeal webs, and
growth deficiency Blue sclera
Cardiac defects
Laryngeal webs
Pectus excavatum
Rib and vertebral
anomalies
Absent kidney
Polydactyly
Rowley-Rosenberg Pulmonary Autosomal recessive Unknown
syndrome hypertension
Growth deficiency
Muscle atrophy
Decreased adipose
tissue
RVH and cor
pulmonale
Aminoaciduria
Increased plasma
unesterified fatty
acids
AVM, arteriovenous malformation; PFT, pulmonary function test; PPH, primary pulmonary hypertension; RVH, right ventricular
hypertrophy.
Pulmonary Fibrosis and increased use of central venous catheters.

In teenagers, pleuritic chest pain seems to be
Idiopathic pulmonary fibrosis is usually a the most common presenting complaint.
sporadic occurrence, often identified in Other complaints include dyspnea, cough,
adults. Approximately 2% of patients are and hemoptysis. Unexplained persistent
identified to have a familial form of the dis- tachypnea can be an important indication of
ease. In addition, several genetic syndromes pulmonary embolism in pediatric patients.
have pulmonary fibrosis as part of the clinical More than 95% of children with venous
picture. Table 14-17 summarizes some syn- thromboembolic disease have at least one
dromes associated with pulmonary fibrosis. underlying clinical condition. Central venous
catheters are the most frequent clinical risk
factor. Other underlying clinical conditions
Pulmonary Embolism associated with pediatric thromboembolic
disease are congenital heart disease, infection,
Thromboembolic events, including pulmo- surgery, malignancy, kidney disease, trauma,
nary embolism, are uncommon in pediatric immobility, systemic lupus erythematosus,
patients. As individuals age, the risk of devel- sickle cell disease, antiphospholipid syn-
oping a deep vein thrombosis and subsequent drome, ventriculoatrial shunts, and medica-
pulmonary embolism increases. The inci- tions, including estrogens and asparaginase.
dence of pulmonary embolism is decreased Although most thrombi occur in otherwise
in children compared with adults. The inci- low-risk individuals, patients with genetic
dence of pulmonary embolism may be disorders that increase their risk for throm-
increasing, however, as a result of prolonged bosis are considered to have thrombophilia.
survival of children with chronic diseases For many years, it has been known that
Table 14-17 Genetic Conditions Associated with Pulmonary Fibrosis
GENE OR LOCUS
Idiopathic pulmonary Idiopathic pulmonary Autosomal dominant. Most Susceptibility gene ¼
fibrosis (Hamman-Rich fibrosis are sporadic SPA1 polymorphism
disease) Alveolar 6A(4); locus ¼ 4q31
inflammation with possible candidate
gene ELMOD2; 8p21
Digital clubbing
Increased risk for
alveolar cell
carcinoma
Hermansky-Pudlak Interstitial pulmonary Autosomal recessive. Carrier Gene ¼ HPS1 (10q23.1-
syndrome (albinism fibrosis frequency in Puerto Rico q23.2); AP3B1 (5q14.1);
with hemorrhagic Restrictive lung is about 1:20, a little HPS3 (3q24); HPS4
diathesis and disease higher in the northwest (22q11.2-q12.2); HPS5
pigmented region of the country (11p15-p13); HPS6
reticuloendothelial Oculocutaneous (10q24.3); DTNBP1
cells) albinism (6p22.3); locus ¼ 19q13
Nystagmus, low
vision
Epistaxis
Inflammatory bowel
disease
Platelet dysfunction
Absent platelet dense
bodies
Pulmonary alveolar Progressive pulmonary Autosomal recessive. About Gene ¼ SLC34A2
microlithiasis fibrosis 2
=3 are sporadic and ⅓ (4p15.31-p15.2)
Intra-alveolar familial
calcifications
PFTs with restrictive
lung changes
Chest x-ray with
“sandstorm”
appearance
X-linked dyskeratosis Pulmonary fibrosis X-linked recessive Gene ¼ DKC1 (Xq28)
congenita Restrictive lung
disease
Short stature
Cytopenias, bone
marrow failure
Recurrent infections
Risks for squamous
cell carcinomas
and other
malignancies
Optic atrophy
Leukoplakia, dental
caries
Nail dystrophy
Skin atrophy and
reticulated
pigmentation
Sparse hair
Cirrhosis
Hypospadias,
cryptorchidism
Renal anomalies
Autosomal dominant Same as X-linked Autosomal dominant Gene ¼ TERC (3q21-q28)
dyskeratosis congenita dyskeratosis
congenita
PFT, pulmonary function test.

deficiencies of protein S, protein C, or anti- of African-Americans, however, and natives

thrombin are thrombophilic. More recently, of Middle Eastern countries, India, and Paki-
the Arg506-to-Gln506 mutation in factor V stan. More recent data from the CF Founda-
(commonly known as factor Leiden) has been tion Patient Registry suggest an incidence of
identified and found to confer an eightfold 1 in 3000 white births, 1 in 6000 Hispanic
increased risk for thrombosis in individuals births, and 1 in 10,000 African-American
heterozygous for the disorder. This risk is births. CF is caused by mutations in a single
much higher when factor Leiden is present gene, known as the cystic fibrosis trans-
in the homozygous state. Factor Leiden is membrane regulator (CFTR), which func-
present in about 5% of the white population. tions as a chloride channel on the apical
Similarly, a common mutation in the pro- membranes of epithelial cells lining the air-
thrombin gene is the factor II polymorphism ways, pancreatic ducts, sweat ducts, intes-
known as 20210G!A, present in about 2% tines, biliary tree, and vas deferens.
of whites, which causes a modest increased
risk for deep vein thrombosis and pulmonary CFTR
embolism. Individuals who carry one copy
of the factor V Leiden mutation and one The absence or underfunctioning of CFTR in
prothrombin mutation have a much more sig- CF patients is the basis for the cellular defects,
nificant risk of developing a deep vein throm- and explains some, but not all, of the various
bosis or pulmonary embolism or both. organ dysfunctions in CF. In addition to its
In addition to the thrombotic risks noted function as an apical chloride channel, CFTR
with homocystinuria as outlined in Table 14- regulates other apical membrane conduc-
14, there are a few genetic conditions that tance pathways. Numerous other cellular
are thrombogenic. Sporadic protein S, protein functions have been ascribed to CFTR: It
C, or antithrombin III deficiencies are often downregulates transepithelial sodium trans-
noted during episodes of thrombosis. Occa- port, in particular, the epithelial sodium chan-
sionally, these deficiencies may be transmit- nel, which accounts for increased sodium
ted through the family as autosomal absorption in CF airways; it also regulates cal-
dominant traits. In these cases, the family his- cium-activated chloride channels and potas-
tory may be very compelling, with multiple sium channels, and may serve important
affected individuals in several generations, functions in exocytosis and the formation of
with individuals having more than one molecular complexes in the plasma mem-
thrombotic event over their lifetime. Protein brane. In airway epithelial cells of patients
S deficiency is seen in about 1 in 50 indi- with CF, chloride impermeability caused
viduals with deep vein thrombosis. Infants by abnormal or absent CFTR and increased
who are homozygous for protein C or anti- sodium absorption caused by the epithelial
thrombin III mutations are at incredibly high sodium channel dysfunction cause a twofold
risk for neonatal thrombosis and pulmonary increase in the transepithelial potential differ-
embolism, and may die in the newborn period ence. More recent data suggest that CFTR also
if untreated. Recognition of patients with transports HCO3 or regulates its transport
strong family histories of thrombosis may through epithelial cell membranes.
allow for (1) better preoperative and postoper- The role of CFTR in epithelial cells seems to
ative planning, (2) ordering of appropriate extend well beyond chloride permeability. In
diagnostic studies, (3) discussion of risk fac- human CF, and in mice with targeted dele-
tors, and possibly (4) referral to a hematologist tions of the CFTR gene, the absence of CFTR
for discussion of therapeutic options and influences the expression of several other gene
management strategies. products, including proteins important in
inflammatory responses, maturational proces-
sing, ion transport, and cell signaling. These
Cystic Fibrosis other proteins are potential modifiers of the
CF phenotype and may help explain the sub-
CF occurs wherever Europeans have settled. stantial differences in clinical severity among
CF has been reported in significant numbers patients with the same mutations in CFTR.
Mutations in CFTR and Their clinically important mutations (e.g., N1303K,

Consequences G85E, and G91R) lead to misfolded CFTR pro-
teins that are prematurely degraded.
The CFTR gene encompasses approximately About 5% to 10% of CFTR mutations result
180,000 base pairs on the long arm of chro- in premature truncation or nonsense alleles,
mosome 7. The protein contains 1480 amino designated by “X”; with G542X, CFTR is not
acids. More than 1500 disease-associated synthesized (class I defect). As a result of a
mutations have been described in the coding genetic founder effect, specific CFTR muta-
sequence, messenger RNA splice signals, and tions are particularly common among indi-
other regions. These mutations can be classi- viduals of Ashkenazi Jewish descent. Other
fied on the basis of the mechanism by which CFTR mutations encode properly processed,
they are believed to cause disease (Fig. 14-6). full-length CFTR protein that lacks normal
The most common mutation, known as ion channel activity. The G551D mutation
DF508, is present in approximately 70% of (class III) is believed to possess little or no chlo-
defective CFTR alleles and in 90% of patients ride channel function in vivo because of abnor-
with CF in the United States, and is categor- mal function of a nucleotide-binding domain,
ized as inadequately processed (class II defect). resulting in defective regulation. The A455E
CFTR with the DF508 mutation is missing a mutation (class IV) retains partial CFTR ion
phenylalanine (F) residue at position 508. channel activity, a feature that probably
The defective protein retains substantial explains the less severe pulmonary phenotype.
chloride channel function in cell-free lipid Other mutation classes include reduced num-
membranes, but when synthesized by the bers of CFTR transcripts (class V) and defective
normal cellular machinery, the protein is rap- CFTR stability at the cell surface (class VI).
idly recognized as misfolded and is quickly
degraded. This degradation occurs well before
CFTR can reach its crucial site of action at Screening and Diagnosis
the cell surface. Similar to DF508, several other
Most U.S. states and several countries screen
newborns for CF by measuring immunoreac-
tive trypsinogen, a pancreatic enzyme precur-
sor, in dried blood spots. Asymptomatic
CFTR CFTR
newborns identified by neonatal screening
have elevated blood immunoreactive trypsi-
nogens, most likely secondary to pancreatic
ductular obstruction and leakage of enzyme
Class IV Class VI
into the circulation. This screening test has a
Accelerated
Class III
turnover
substantial false-positive rate, however, and
Cl− as such, cannot be used as a confirmation of
a diagnosis of CF. Instead, the diagnosis of CF
Golgi
complex is best confirmed by performing a genotype
or a sweat test.
Class II Genotyping that reveals two known CF-
Proteosome causing mutations confirms the diagnosis.
Molecular tests can readily detect a specific
Endoplasmic
mutation, and some vendors can sequence
reticulum
the entire gene. Among the more than
1500 recognized mutations, however, many
Class I Class V are “private” mutations that occur in only a
single family. A patient in whom two CF
Nucleus mutations are not identified by commercial
genotyping still can have CF.
Figure 14-6. CFTR mutations classes I through VI.
(Adapted from Rowe SM, Miller S, Sorcher EJ: Cystic fibrosis. The diagnosis also can be made when the
N Engl J Med 352:1992-2001, 1998, 2005.) sweat chloride concentration is greater than
60 mEq/L in the presence of typical clinical Clinical Manifestations

features (chronic pulmonary disease, pancre-
atic insufficiency, or both). A family history Many clinical findings prompt consideration
(sibling or first cousin who has CF) signifi- of the diagnosis of CF (Fig. 14-7). After birth,
cantly increases the index of suspicion for CF because of the presence of the high protein
in a symptomatic child or infant with an ele- concentration in meconium, newborns with
vated immunoreactive trypsinogen on new- CF can present with meconium ileus or
born screening, and should immediately meconium plug syndrome. About 15% of
prompt diagnostic testing. The sweat test is patients who have CF present in the neonatal
very reliable and is an excellent discriminant period with meconium ileus (obstruction of
for CF, if it is performed by experienced per- the distal ileum or proximal colon with
sonnel, and the samples are handled carefully inspissated meconium). Meconium ileus is
to avoid evaporation or contamination. About virtually diagnostic of CF, so the patient
5% of patients who have CF exhibit sweat should be treated presumptively as having
chloride values less than 60 mEq/L. The CF until a valid sweat test or genotype can
sweat test is performed by iontophoresis of be obtained. Meconium plug syndrome, in
pilocarpine into the skin to stimulate sweat- which there is transient distal colonic
ing. Sweat is collected for chloride quantifica- obstruction, also may be the presenting man-
tion by titrimetric analysis. Technical errors ifestation of CF. A few affected infants pre-
tend to produce elevated values, so a “posi- sent with prolonged obstructive jaundice,
tive” result must always be confirmed by a sec- presumably secondary to obstruction of
ond sweat test or CFTR molecular analysis. If extrahepatic bile ducts by thick bile along
neither of these procedures is diagnostic, with intrahepatic bile stasis.
another test of CFTR function, such as mea- An increased concentration of electrolytes
surement of the nasal potential difference, in the sweat may result in hyponatremic or
should be performed. There is a small subset hypochloremic dehydration secondary to
of patients (often adults) who have atypical salt depletion, or hypokalemic metabolic
clinical manifestations, a normal or borderline alkalosis secondary to chronic salt loss. CF
sweat test result, and equivocal CFTR molecu- should always be considered in any child
lar results (zero or one mutation identified) in who presents with dehydration and severe
whom a definite diagnosis cannot be made. hypoelectrolytemia that is not accounted
Prenatal diagnosis of CF can be accom- for by gastrointestinal losses. Because of their
plished in pregnancies known to be at high ratio of surface area to volume, infants
increased risk because of a positive family his- who have CF are prone to heat prostration.
tory, or through routine antenatal screening During infancy and beyond, a common
programs. In cases where the genotype of presentation of CF is failure to thrive. Any
the parents is known, the diagnosis of CF child who fails to gain weight despite a good
can be confirmed or excluded by direct muta- appetite, and especially if the child produces
tion analysis performed on fetal cells frequent, bulky, foul-smelling, oily stools,
obtained by chorionic villus sampling after should be evaluated for CF. These children
10 weeks’ gestation, or cultured amniotic may develop abdominal cramps after feeding
fluid cells performed between 15 and 18 and begin to refuse food, with resultant
weeks gestation. There is currently no bio- decreased oral intake that worsens the malnu-
chemical assay for the protein gene product. trition. There also may be excessive flatus.
In pregnancies not known to be at These symptoms are usually the result of pan-
increased risk for CF, the diagnosis is some- creatic insufficiency (failure of the pancreas to
times suggested by prenatal ultrasound find- produce sufficient digestive enzymes), which
ings, including a hyperechoic bowel pattern impairs the breakdown and absorption of fats
suggestive of intestinal obstruction. Meco- and protein. Affected infants also may present
nium peritonitis secondary to small bowel with hypoproteinemia with or without
perforation in utero also can be detected by edema, anemia, and manifestations of defi-
prenatal ultrasound. Only 7% of such cases ciency of the fat-soluble vitamins A, D, E,
are associated with CF, however. and K, which are poorly absorbed in the
Biliary cirrhosis
Prolonged jaundice
Microgallbladder
Gallstones
Pancreatic insufficiency
Growth delay
Cystic fibrosis Vitamin deficiency: A, D, E, K
Hypoproteinemia and edema
Meconium ileus Clinical Recurrent pancreatitis
Rectal prolapse manifestations
Azoospermia Nasal polyps

Congenital bilateral absence Recurrent wheezing/pneumonia
of vas deferens Bronchiectasis
Mucoid P. aeruginosa
Hyponatremic/Hypochloremic
Figure 14-7. Clinical manifesta- Dehydration
tions of cystic fibrosis. Chronic metabolic alkalosis
presence of severe steatorrhea. In patients In approximately 50% of CF patients, the

with CF who are malnourished, connective diagnosis is first considered because of pul-
tissue quality may be poor and support for monary symptoms. Although the lower respi-
the rectum may be inadequate; this, com- ratory tract is almost invariably involved,
bined with abnormal stools, may lead to rectal manifestations may not appear until months
prolapse. The association of rectal prolapse or years after birth. CF should be considered
with CF is so strong that this finding alone is in every patient with recurrent pneumonia,
an indication for obtaining a sweat test. refractory asthma, bronchiectasis, and empy-
Another gastrointestinal manifestation of CF ema. Isolation of mucoid Pseudomonas from
is idiopathic pancreatitis. the lung should prompt diagnostic investiga-
Nasal polyps occur frequently in patients tion for CF.
with CF and may be present at a very early The diagnosis of CF also can be consid-
age. Occasionally, opacification of all the para- ered in the absence of clinical features. An
nasal sinuses on radiography suggests the individual with an affected sibling has a 1
diagnosis of CF. in 4 chance of having the disease. First cous-
Men with CF are frequently infertile ins of a CF patient have about a 1 in 120
because of glandular obstruction of the vas chance of having the disease.
deferens in utero, which causes involution
of the wolffian duct, vas deferens, and asso-
ciated structures. CFTR mutations also can Lung Disease
cause infertility in otherwise normal men
as a result of the CF variant, called congeni- Pulmonary involvement in CF accounts for
tal bilateral absence of the vas deferens. much of the morbidity and almost all of
Similarly, obstruction of bile canaliculi fre- the mortality from CF. Although the lungs
quently causes hepatic damage and, in some are histologically normal at birth, patients
patients, overt cirrhosis. soon acquire bacterial infections that are
difficult to eradicate. In the first year of life, Symptomatic Treatment

many types of bacteria, including enteric
organisms, can be recovered from the lungs Knowledge about the functional basis of CF
of an infant with CF, but later in childhood, has led to many new strategies for curative
two organisms predominate: Staphylococcus treatment, but at present, treatment for the
aureus and Pseudomonas aeruginosa. Stap- most part remains symptomatic. Prevention
hylococcus colonization comes and goes; of bacterial lung infection is considered a
methicillin-resistant S. aureus is being seen primary objective in CF treatment. Epide-
increasingly at some CF centers. Pseudomo- miologic studies have suggested that trans-
nas eventually colonizes the lungs of most mission of P. aeruginosa and other pathogens
CF patients, reaching a prevalence of 80% occurs either by direct patient-to-patient con-
by age 18 years. P. aeruginosa specifically tact or from various environmental reservoirs.
adapts to the pulmonary microenvironment Improved hygiene measures and segregation
in patients with CF through the formation regimens have been implemented in several
of macrocolonies (or biofilms) and the pro- CF centers to limit cross-infection.
duction of a capsular polysaccharide (an Improved antibiotic treatment regimens tar-
alginate product) that inhibits penetration geting CF-specific respiratory tract infections
by antimicrobial agents and confers the are regarded as the main reason for the increas-
mucoid phenotype. Acquisition of the ing life expectancy of patients with CF that has
mucoid phenotype has been associated with been achieved over the last decades. Although
accelerated decline of pulmonary function. most patients are initially colonized with
Later in life, some patients acquire a Bur- S. aureus, the rate of S. aureus infection in
kholderia cepacia infection, which is asso- patients with CF decreases with age, whereas
ciated with poor lung function and poor the rate of P. aeruginosa increases, rendering
prognosis. this latter microorganism the major patho-
Pulmonary inflammation is another major gen in this disease. After an initial transient
cause of the decline in respiratory function colonization period with nonmucoid strains,
in patients with CF and may precede the untreated patients generally become chron-
onset of chronic infection. An exaggerated ically infected with mucoid strains of
and sustained inflammatory response to bac- P. aeruginosa. Even with intensive antibiotic
terial and viral pathogens, characterized by regimens, mucoid P. aeruginosa cannot be
neutrophil-dominated airway inflammation, eradicated, probably because of poor pene-
is an accepted feature of lung disease in CF. tration of antimicrobials into anaerobic
Inflammation is present even in clinically sputum plugs and rapid development of
stable patients with mild lung disease and mutant strains, which show enhanced resis-
in young infants diagnosed through new- tance to antibiotics.
born screening. To minimize adverse effects and to
Elevated levels of interleukin-8, interleukin- achieve optimal airway concentrations of
6, tumor necrosis factor-a, and leukotriene B4, antibiotics, the inhalation route has been
along with reduced levels of anti-inflamma- used for patients with CF. Long-term use of
tory cytokines and proteases, have been inhaled tobramycin has had positive effects
found in the airways of patients with CF. An in improving lung function and reducing
elevated ratio of arachidonic acid to docosa- exacerbations in patients who have moder-
hexaenoic acid was found in mucosal scrap- ate to severe lung disease with airways
ings from patients with CF compared with chronically infected with P. aeruginosa.
scrapings from normal individuals and from The results have been released of clinical
patients with inflammatory bowel disease; trials using azithromycin to treat patients
the altered ratio cannot be explained by a sys- older than 6 years of age with CF who also
temic inflammatory process alone. These and were chronically infected with P. aeruginosa.
other inflammatory mediators, such as man- The azithromycin group experienced benefit
nose-binding protein and a1-antitrypsin, in pulmonary function, decreased pulmonary
influence the progression of lung disease. exacerbations, reduction in the use of oral
antibiotics, decreased hospitalizations, and patients with mild lung disease as a prophy-
weight gain compared with the placebo lactic agent. The major disadvantage of ibu-
group. The mechanism of action is unknown; profen relates to its narrow therapeutic
however, the benefits of long-term azithromy- window, which means that serum concentra-
cin therapy in patients with CF are thought to tions of the drug have to be carefully titrated
be due primarily to a decreased inflammatory in all patients. Low concentrations might
reaction associated with bacterial infections. increase neutrophil influx into the lung, and
Azithromycin should be considered for CF high concentrations are associated with an
patients who are older than 6 years of age increased risk of gastrointestinal and renal
and who are chronically colonized with toxicity.
P. aeruginosa. Viscid airway secretions are characteristic
Currently, the strategy to combat pulmo- of CF lung disease. Mucolytics such as N-
nary P. aeruginosa infection in patients with acetyl cysteine have little effect on lung
CF is early antibiotic treatment. In the early disease in patients with CF. By contrast,
phase of P. aeruginosa colonization, antibiot- long-term use of dornase alfa has been re-
ics may prevent or delay the shift to chronic ported to reduce sputum viscosity, modestly
mucoid infection. The combination of improves pulmonary function, and reduces
inhaled tobramycin, colistin, or aztreonam the number of pulmonary exacerbations in
with oral ciprofloxacin, or inhaled tobramy- patients with moderate to severe lung dis-
cin or inhaled colistin alone has been used ease. Also, a short-term clinical trial using
to treat early P. aeruginosa colonization. an inhaled 7% saline solution reported an
Pulmonary exacerbations are common in improvement in lung function. Although
patients with CF. Specific antibiotics are hypertonic saline solution has the potential
selected on the basis of a recent throat swab to cause bronchospasm in CF patients, this
or sputum culture. Therapy with oral antibio- may be preventable by pretreating with a
tics is often used for mild exacerbations. Par- b2-adrenergic inhaled bronchodilator.
enteral antibiotics are used in combination Retained secretions play an important role
for the treatment of moderate to severe pul- in the pathophysiology of CF pulmonary
monary exacerbations. Inhaled antibiotics disease. They physically obstruct the air-
are sometimes used in combination with par- ways, aggravating infection and directly
enteral antibiotics. Pulmonary exacerbations causing hyperinflation and ventilation/per-
also have been associated with respiratory fusion mismatching. They also contain high
viral infections. concentrations of inflammatory chemical
It is now widely acknowledged that an mediators, which can cause bronchospasm
intense, neutrophil-dominated chronic air- and progressive parenchymal injury. Various
way inflammation plays a crucial role in airway clearance techniques are available.
the pathophysiologic sequence leading to Conventional chest physiotherapy is the
parenchymal destruction and fibrosis. Theo- technique of chest percussion and postural
retically, strategies for the treatment of drainage. Despite the absence of controlled
CF-associated inflammation should include studies, clinical experience supporting chest
drugs that have direct effects on neutrophils physiotherapy seems to be convincing. As
and may block specifically proinflammatory patients become older and more indepen-
mediators, or target neutrophil-specific activ- dent, they frequently seek airway clearance
ities. Although treatment with inhaled methods that can be performed without
steroids theoretically should reduce inflam- assistance. Several alternative modalities
matory effects, results of a controlled study have been developed, including active cycle
instead showed a beneficial effect, primarily breathing, positive expiratory pressure de-
in airway hyperreactivity, whereas clear vices, high-frequency chest wall oscillator
improvement in pulmonary function and vest, the FlutterW valve, and intrapulmonary
reducing exacerbations was not shown. Ibu- percussive devices.
profen is the only other anti-inflammatory Most patients with CF have bronchial
drug that has proven moderate benefit in hyperreactivity at least some of the time.
Bronchodilators have become a standard mutation. New compounds that correct this
component of the therapeutic regimen. fundamental processing abnormality in CFTR
Short-acting b2-adrenergic agents are the most should undergo clinical testing in the near
commonly prescribed. They are often used to future.
provide symptomatic relief and, before chest Many agents also have been shown to
physiotherapy, to facilitate airways clearance. suppress premature stop codons in CFTR
Long-acting aerosolized b2-adrenergic agonists (class I) mutations, including the surprising
combined with inhaled steroids also may be finding that ribosomally active drugs, such
helpful in patients with CF and asthma. Anti- as gentamicin, may be capable of correcting
cholinergic bronchodilators, such as ipratro- premature stop codons in human subjects.
pium, may be beneficial for some patients High-throughput screening programs specif-
with CF. Some patients apparently benefit ically designed to identify drugs that acti-
from combination therapy of a b-adrenergic vate residual CFTR activity (class III and IV
agonist and an anticholinergic agent. mutations) also have been successful.
Physical activity augments airway clear- Luminal chloride secretion of airway epi-
ance by forcing deep breathing and, for thelial cells occurs through CFTR and alterna-
many individuals, producing broncho- tive chloride channels. An increased activity
dilation and facilitating cough and airway of the alternative epithelial chloride channel
clearance. In addition, appropriate physical in the lower airways may compensate for
exercise enhances cardiovascular fitness, reduced or absent CFTR function and poten-
increases functional capacity, and improves tially improve clinical status in CF patients.
quality of life. For these reasons, with the Two components are currently in clinical
exception of patients whose clinical condi- trials that have been shown to stimulate chlo-
tion precludes it, all patients with CF should ride secretion through this pathway: denufo-
be encouraged to exercise. Aerobic activities, sol and peptide drug Moli1901.
such as swimming, jogging, and cycling, are Important advances have improved under-
the most commonly recommended forms of standing of the role of the CFTR protein in
exercise. the progression of suppurative pulmonary
failure in CF. These discoveries are ushering
in a new era of translational research that
Curative Therapy incorporates specific therapeutic targets and
new cellular pathways. Progress in research
Insight into the cellular consequences of defec- on CF will continue to rely on an improved
tive CFTR suggests a role for tailored therapies, understanding of CFTR function and its rela-
a predominant theme in clinical research on tionship to mucociliary clearance, airway
CF. Robotic drug screening of more than 1 mil- secretion, and other ion channels. Clinical
lion random compounds has led to the discov- advances directed at the correction of CFTR
ery of compounds that correct the DF508 function predict an optimistic future for
abnormality by restoring the mutant protein patients with CF and their families. Discus-
to its normal position at the cell surface (par- sion about pancreatic, nutritional, and gastro-
tially restoring chloride channel function). intestinal system manifestations and their
The more recently elucidated crystal structure complications is beyond the scope of this
of nucleotide-binding domain 1 localizes the chapter. The reader may wish to consult sev-
crucial phenylalanine 508 residue to a loop eral more recent reviews to learn more about
on the external surface of the domain. Because these other aspects of CF management.19,20
of this structure, drug screening laboratories
can test the specificity of DF508-correcting
compounds by cocrystallization with the CFTR Miscellaneous Genetic
protein. Curcumin, a nontoxic compound and Conditions
the major constituent of the spice tumeric, has
been shown to correct DF508 processing in In addition to the many genetic conditions
many in vitro model systems and prolong life previously discussed, there are a few outliers
in mice that are homozygous for the DF508 that defy classification into specific categories
of lung disease. Surfactant protein B (SP-B) ABCA3 deficiency is the most recently
deficiency has been recognized as a rare recognized inborn error of surfactant metab-
genetic cause of lung disease.21 It is inherited olism, but may eventually prove to be the
as an autosomal recessive condition. It is most common genetic defect associated
encoded on a single gene (SFTPB) on chro- with surfactant production. The clinical
mosome 2. SP-B is primarily produced by phenotype is similar to that of SP-B defi-
alveolar type II epithelial cells. Pathology ciency, with death usually resulting from
findings in lung tissue from SP-B-deficient respiratory failure within 3 months of life.
infants include nonspecific interstitial fibro- More research is needed to clarify the role
sis and alveolar type II epithelial cell hyper- of ABCA3 in surfactant metabolism, its con-
plasia. Characteristic electron microscopic tribution to lung disease, and the potential
findings include absence of lamellar bodies. roles of other ABC transporters in type II cell
Affected infants are typically full-term and and surfactant metabolism.
generally present with symptoms and signs Table 14-18 includes some supplemental
of surfactant deficiency, with chest radio- conditions of clinical interest with specific
graphs resembling those of premature infants pulmonary findings.
with respiratory distress syndrome. Although
the lung disease in SP-B-deficient infants is
often severe, affected infants may have initi- Summary
ally mild symptoms not requiring mechani-
cal ventilation. Their respiratory disease is Myriad pulmonary complications have been
progressive, however, and death usually identified in association with cytogenetic
results from hypoxic respiratory failure with- and mendelian disorders. Lung development
in 3 to 6 months, even with optimal medical in early embryonic life is a complex process
management. Transient improvement may that is closely tied to development of the gas-
be seen in response to treatment with sys- trointestinal tract. Intrinsic or extrinsic factors
temic steroid or exogenous surfactant; how- that impair lung expansion within the fetal
ever, the only effective treatment is lung thorax may lead to significant pulmonary
transplantation. hypoplasia and subsequent respiratory dis-
Surfactant protein C (SP-C) deficiency also tress at birth. The degree of pulmonary com-
is a rare autosomal recessive disorder asso- promise often predicts long-term survival
ciated with lung disease.21 Clinical features despite aggressive intervention at birth. Most
in infants and adults with SP-C mutations pulmonary defects are isolated occurrences,
have included chronic respiratory symptoms but children born with lung anomalies should
(tachypnea, cough, cyanosis in room air) and be evaluated for additional malformations
failure to thrive. The age of onset varies, with and syndromic features. Identification of
some infants developing respiratory distress additional anomalies or the diagnosis of a spe-
immediately after birth, and other individuals cific syndrome may provide important long-
remaining apparently asymptomatic well into term prognostic information, in addition to
adulthood. The lung disease in some children guidance for medical management. Making a
seems to be triggered or exacerbated by viral syndromic diagnosis also may provide essen-
infections. The diagnosis should be consid- tial information to the parents and extended
ered in an infant with progressive forms of family about recurrence risks and may guide
interstitial lung disease, particularly with family planning decisions.
biopsy findings interpreted as desquamative Multisystem disorders, which include
interstitial pneumonitis, chronic pneumoni- lung findings, should alert the clinician to
tis of infancy, or nonspecific interstitial pneu- the possibility of a genetic condition or
monitis. Electron microscopic findings also inborn error of metabolism. Gene muta-
reveal absence of lamellar bodies. All SP-C tions that affect ciliary function, impair
mutations associated with human lung dis- collagen or other connective tissue synthe-
ease identified to date would result in the pro- sis, or result in vascular abnormalities also
duction of an abnormal protein that is likely may affect pulmonary function. Thinking
to be misfolded. broadly about possible genetic conditions
Table 14-18 Genetic Conditions Associated with Miscellaneous Pulmonary Findings
GENE OR LOCUS
Tuberous sclerosis Pulmonary Autosomal dominant. New Gene ¼ TSC1 (9q34);
lymphangiomatosis or de novo mutations in TSC2 (16p13.3);
Cardiac rhabdomyoma about 80% of patients possible locus ¼ 11q23;
with TSC1 and 60% of possible locus ¼ 12q22-
Facial angiofibromas patients with TSC2 q24
Hypopigmented “ash-
leaf” spots
Subependymal nodules
and intracranial
calcifications
CNS giant cell
astrocytomas
Renal cysts
Seizures
Mental retardation
Diffuse Micronodular pulmonary Autosomal dominant Locus ¼ 6p21.3 (most
panbronchiolitis lesions susceptibility locus with telomeric portion of
Chronic pulmonary shared haplotypes in HLA-B locus)
disease affected East Asian
patients
Sinobronchial infections
Familial Pleuritis Autosomal dominant or Gene ¼ MEFV (16p13)
Mediterranean fever Episodic fevers autosomal recessive.
Seen with increased
Pericarditis frequency among
Hepatosplenomegaly Sephardic and Armenian
Abdominal pain and Jews
peritonitis
Nephrotic syndrome
Renal amyloidosis
Hereditary pancreatitis Hemorrhagic pleural Autosomal dominant Gene ¼ PRSS1 (7q35);
effusions SPINK1 (5q32); CFTR
Pancreatitis (7q31.2) rare
heterozygotes with
Recurrent fevers pancreatitis, but the
Portal or splenic vein same gene seen with
thrombosis cystic fibrosis, which is
Diabetes identified in
homozygotes
Familial dysautonomia Breath-holding spells Autosomal recessive. Seen Gene ¼ IKBKAP (9q31)
(hereditary sensory Recurrent aspiration almost exclusively in
and autonomic Ashkenazi Jews
neuropathy type III Failure to thrive
or Riley-Day Alacrima
syndrome) Decreased lingual
fungiform papillae
Gastroesophageal reflux
and cyclic vomiting
Hypertension
Autonomic dysfunction
Episodic fevers
Hypotonia
Hyporeflexia
Acrocyanosis
Absent flare with
intradermal injection
of histamine

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Index
Page numbers followed by f indicates figures and followed by t indicates table.
A Alveolar ventilation, 122 Ash-leaf macule, 260f, 337t

Accessory inspiratory muscles, Amebiasis, 276–280, 278t Aspergillosis, 40, 61
185, 186t American Academy of Pediatrics, 16 Assisted coughing, 197
ACE. See Angiotensin-converting American College of Rheumatology Asthma, 179–180, 251, 254
enzyme (ACR), JRA classification, 217 cardiac, 84
Acetylcholine, 185 American Thoracic Society, on and GERD, 105
Acquired immunodeficiency asthma, 105 and obesity, 179–180
syndrome, 284 AML. See Acute myeloid leukemia Ataxia telangiectasia, 58t, 59, 317t
Acquired tracheobronchomalacia, 20 ANAs. See Anti-nuclear antibodies Atrial septal defect (ASD), 81, 83t
ACR. See American College of ANCA. See Antineutrophil Autoimmune cell cytopenias, 57
Rheumatology cytoplasmic antibody(ies) Autoimmune disorders, 62
ACS. See Acute chest syndrome Ancylostoma braziliense, 282 Autosomal recessive cutis laxa, 303t
Activated partial thromboplastin Ancylostoma caninum, 282 AVMs. See Arteriovenous
time, 129 Ancylostoma duodenale, 281, 282 malformations
Acute chest syndrome (ACS), 147, Anemia, 127–128 Azathioprine, 207, 208, 226, 249
148–150 chronic, 147
Acute idiopathic polyradiculitis, 190 normochromatic normocytic, 127
Acute lung injury (ALI), 131 Aneurysm thrombosis, 252
Acute lupus pneumonitis (ALP), Aneurysmal dilation, 253 B
202, 203t, 204t, 205, 206, 207 Angioedema, 286 Bacterial pneumonia, 30–32, 31t
Acute lymphoblastic leukemia Angiomyolipomas, 260 Bacterial sepsis, 149
(ALL), 64, 135, 136, 137 Angiotensin-converting enzyme BAL. See Bronchoalveolar lavage
Acute myeloid leukemia (AML), 135, (ACE), 8 Barium esophagogram, 90, 90f
136, 138–139 Ankylosing spondylitis, 226–228 Barium swallow, 103–104,
Acute pancreatitis, 114 Antenatal chorioamnionitis, 6 103t, 104f
Acute renal failure, 130–131, 130t Antenatal corticosteroids, 13 Basophils, 54
Acute respiratory distress syndrome Anterior horn cell disorders, Baylisascaris procyonis, 285
(ARDS), 114–116, 125, 189–190 Beclomethasone, 16
131, 276f Antibiotic therapy, 72, 192 Behçet disease, 251–252
Acute respiratory failure, 157 Antibodies Benzimidazole drugs, 281
Acute respiratory infections, antineutrophil cytoplasmic, 243f Bicarbonate-carbonic acid system,
29–41 anti-nuclear, 211 122
Adjunctive corticosteroids, 34 antiphospholipid, 208 Bilevel positive airway pressure
Adrenal disorders, 172 Antibody underproduction, 52t (BiPAP), 187, 189, 195
Aerosol therapy/technology, Anticardiolipin antibodies, 208 Biopsy(ies)
142–143 Anticholinergic bronchodilators, bronchoscopic transbronchial,
Agonadism, 304t 334 248
Airway(s) Antileukemia treatment, 139 lung, 42, 216f
clearance of, 196–197 Antimetabolites, 162 open lung, 75
compression of, 91, 92, 92t Antimicrobial sensitivity, 202 transbronchial, 38
hyperreactivity of, 180 Antineutrophil cytoplasmic transthoracic needle aspiration, 75
inflammatory, 219 antibody(ies) (ANCA), 243–244, in Wegener granulomatosis, 248
intraparenchymal, 92 243f, 244f, 248–251 BiPAP. See Bilevel positive airway
malacia, 91 Anti-nuclear antibodies (ANAs), 211 pressure
mucosa, 20 Antiphospholipid antibodies, 208 Birt-Hogg-Dube syndrome, 321t
mucosal edema, 131 a1-Antitrypsin deficiency, Blalock-Taussig shunt, 94
rare diseases of, 210t 315–316 Blau syndrome, 228
reactive, disease with, 150 Aortic stenosis, 88 Bleomycin toxicity, 158, 158t,
vascular compression of, causes Apparent life-threatening events 159–162
of, 89t (ALTEs), 99, 105–106 Bloom syndrome, 317t
viscid, 334 Arteriovenous malformations Bombesin-like peptides, 7
ALI. See Acute lung injury (AVMs), 262, 263, 314–315, BOOP. See Bronchiolitis obliterans
Alkalinization, 126 315t with organizing pneumonia
Alkylating agents, 66t, 67, 162 Arthralgias, 124, 245t Botulism, 191–192
ALL. See Acute lymphoblastic Arthritis BPD. See Bronchopulmonary
leukemia enthesitis-related, 227, 227t dysplasia
Alloantigens, 73 juvenile rheumatoid, 217–220 Breathing disorders, 127
ALP. See Acute lupus pneumonitis reactive, 286 Bronchial circulation, 80
ALTEs. See Apparent life-threatening rheumatoid, 218 Bronchial malformations, 295
events seronegative, 57 Bronchial stenosis, 20
Alveolar damage, 206 Ascariasis, 280–281 Bronchial-associated lymphoid
Alveolar hemorrhage, 155, 202, 247 Ascaris eggs, 280 tissues, 53
Alveolar hyperplasia, 260 Ascaris lumbricoides, 274, 280, Bronchiectasis, 43, 316–319,
Alveolar period, of lung 281, 281f 317t, 319t
development, 296, 296t ASD. See Atrial septal defect Bronchiolar disease, 110
Aseptic inflammatory process, 219 Bronchiolitis obliterans, 41
339
340 Index
Bronchiolitis obliterans syndrome, Bronchopulmonary dysplasia Chloroquine-associated retinopathy,

72 (BPD) (Continued) 231
Bronchiolitis obliterans with tracheal stenosis/bronchial Chronic granulomatous disease, 61
organizing pneumonia (BOOP), stenosis/granuloma Chronic interstitial edema, 87
73, 109, 210, 226 formation, 20 Chronic lung disease, in HIV
Bronchiolitis, obliterative, 71–73 vitamin A, 15 infection, 41–43
Bronchitis, 51 Bronchoscopic transbronchial Chronic lung disease of infancy
plastic, 96 biopsy, 248 (CLDI), 1–27
recurrent, 90 Bronchoscopy, 150 Chronic obstructive pulmonary
suppurative, 109 flexible, 75, 91 disease, 73
Bronchoalveolar lavage (BAL), 33, Bronchospasm, 104 Chronic pulmonary venous
72, 74, 75, 140, 153, 206 Brugia species, 292 hypertension, 86f
Bronchobiliary fistulas, 310 Bruton tyrosine kinase, 51 Chronic renal failure, 124–126, 124t
Bronchodilator therapy, 13 Burkholderia cepacia, 61, 333 Chronic sickle cell lung disease,
Bronchogenic cysts, 308–309, 308f Burkitt lymphoma, 136 150–151
Bronchopulmonary dysplasia Churg-Strauss syndrome, 242t,
(BPD), 1 250–251, 251t
antenatal corticosteroids, 13 Circulation
bombesin-like peptides, 7 C bronchial, 80
bronchodilator therapy, 13 Café au lait macules, 258, 258f, 259t cardiovascular, 79–80
caffeine, 17 Caffeine, 17 lymphatic, 80
cardiopulmonary function, Calcium channel blockers, 225t mature pulmonary, 80
10–11 Campylobacter jejuni, 190 pulmonary, 79–80
cardiovascular monitoring/ Canadian Pediatric Society, 16 Cisplatin-doxorubicin regimen,
oxygenation, 21 Canalicular period, of lung with methotrexate, 142
chest radiograph, 9 development, 296, 296t Classic bronchopulmonary
classic, 2f Cancer therapy, pulmonary dysplasia, 2f
clinical course, 9–10 complications of, 64–67 CLDI. See Chronic lung disease of
clinical features, 9 Candida, 40, 70 infancy
coordination of care/discharge Candida albicans, 50, 54 Clostridium botulinum, 191
planning, 21–22 Capillary permeability changes, 115 CMV. See Cytomegalovirus
corticosteroids, 13 Carbon monoxide diffusion Coarctation of aorta, 88–89
definitions of, 2–4 capacity, 109, 160, 209 Cogan syndrome, 242t
development/vision/hearing, 21 Cardiac catheterization, 96 Complement system/deficiencies,
diagnostic criteria, 3t Cardiac dysrhythmias, 179 61–62
diuretics, 12–13 Cardiac involvement, in DMD, 194 Computed tomography (CT),
epidemiology, 4 Cardiac rhythm disturbances, 178 72, 146
fluid management, 12 Cardiac sphincter, 102 Congenital anomalies, 100–102,
fluid restriction, 14 Cardiopulmonary function, in BPD, 295–316
genetic factors, 7–8 10–11 Congenital diaphragmatic hernia,
glottic/subglottic damage, 20 Cardiovascular circulation, 79–80 101, 300–305, 302t–305t
growth, 19 Cardiovascular lesions with Congenital lobar emphysema,
high-frequency oscillatory increased work of breathing, 310–311
ventilation, 11, 14 80–96 Congenital lymphedema, 256
hyperoxia/oxidant stress, 5–6 Cardiovascular monitoring/ Congenital myotonic dystrophy,
infection, 6–7 oxygenation, 21 193
inflammation, 7 Cavitations, 124 Congestive heart failure, 84
inhaled corticosteroids, 13, 16 Cellular immunity deficiencies, COP. See Cryptogenic organizing
inhaled nitric oxide, 16–17 53–59 pneumonia
management of, 11–13 Cercariae, 287, 288f Corticosteroids, 13, 39, 42, 231
mechanical ventilation/ Cerebral palsy, 15 adjunctive, 34
volutrauma, 6 Cestodes, 290–292 antenatal, 13
minimal ventilation, 14 CFTR. See Cystic fibrosis in bronchopulmonary dysplasia, 13
monitoring, 21 transmembrane regulator and inhaled, 16
neurodevelopment, 18–19 gene in SLE, 208
nutrition, 7 Charcot-Leiden crystals, 96, 281 systemic, 15–16
and fluid management, 12 CHARGE syndrome, 312t Crohn disease, 108, 109
outcome, 17–20 Chemotherapeutic agents, 66–67, Cryoprecipitate, 157
pathogenesis, 4–8 66t. See also specific agent, e.g. Cryptococcus, 74
pathology, 8–11 Cyclophosphamide and Cryptogenic organizing pneumonia
physical examination, 9 Cytotoxic drugs (COP), 73, 155, 156
prenatal events, 5 Chemotherapy, 63 CT. See Computed tomography
prevention, 13–17 high-dose, with radiotherapy, 156 Curative therapy, in genetic
pulmonary function, 18 lung toxicity of, 158–162 disorders, 335
respiratory care, 11–12 Chest radiograph, 9 Cushing syndrome, 172
respiratory infections, 18 of infant, 9f Cutis laxa, 264
schematic representation of, 10f Chest wall mobility, 194–195 Cyanotic spells, 186
superoxide dismutase, 17 Chest wall restriction, 227 Cyclic neutropenia, 62
systemic corticosteroids, 13, Childhood vasculitis, 242t Cyclophosphamide, 162, 206, 207,
15–16 Chlamydia pneumoniae, 148–149 208, 213, 224, 233
Index 341
Cyclophosphamide therapy, Dermatologic disease(s), with Disease(s) (Continued)

223, 249 pulmonary manifestations rare airway, 210t
Cyclosporine, 71 (Continued) reactive airway, 150
Cylindrical bronchiectasis, 319 neurofibromatosis type 1, renal, 121–132
Cyst(s) 258–259 rheumatoid, 201–240
bronchogenic, 308–309, 308f pseudoxanthoma elasticum, sickle cell, 147–152
foregut, 308 265–266 sight-threatening ocular, 231
gastroenteric, 309 tuberous sclerosis complex, Werdnig-Hoffman, 189
parenchymal, 265 259–261, 260f Wolman, 324t
pulmonary, 309t xanthoma disseminatum/ xanthoma disseminatum, 266
small, 308 Erdheim-Chester disease, 266 Disorders. See also Genetic disorder(s),
Cystic adenomatoid malformations, yellow nail syndrome, 256–258 with pulmonary manifestations
306–308 Desmopressin, 267 adrenal, 172
Cystic fibrosis, 112f, 171, 174, 174f, Development/vision/hearing, 21 anterior horn cell, 189–190
316, 329–335 Dexamethasone, 15, 16 autoimmune, 62
clinical manifestations of, Diabetes, 170–172 breathing, 127
331–332, 332f Diabetic ketoacidosis, 171 growth hormone, 172
screening/diagnosis, 330–331 Dialysis-related hypoxemia, 121, hematologic, 147–154
Cystic fibrosis transmembrane 129–130, 130f histiocytic, 152–154
regulator and gene (CFTR), Diaphragmatic excursion, 65 of muscles, 192–193
317t, 329 Diffuse alveolar hemorrhage of neuromuscular junctions,
mutations of, 317t, 330, (DAH), 155 191–192
330f, 332 Diffuse panbronchiolitis, 337t oncologic, 154–163
Cystic kidneys, bilateral, 2 Diffusing capacity for carbon of peripheral nerves, 190
Cytomegalovirus (CMV), 31t, 35, monoxide (DLCO), 109, post-transplant
36, 54, 60t, 70 160, 209 lymphoproliferative, 67
Cytotoxic drugs, 159–162 DiGeorge syndrome, 57, 177 of reproductive system, 177
Dilated bronchial anastomotic sleep, 175, 193
vessels, 86 Diuretics, 12–13
Dilated intercostals, 88 DLCO. See Diffusing capacity for
D Dirofilaria immitis, 292 carbon monoxide
DAH. See Diffuse alveolar Disease(s). See also Endocrine/ DMD. See Duchenne muscular
hemorrhage metabolic disease(s); dystrophy
Damage Neuromuscular disease(s); Donnai-Barrow syndrome, 304t
alveolar, 206 Parasite(s)/parasitic disease(s) Doppler ultrasonography, 138
drug-induced pulmonary, 158 affecting lung and kidney, Dornase alfa, 334
glottic/subglottic, 20 123–124, 123t Down syndrome, 309t
Defect(s) Behçet, 251–252 Drug(s)
atrial septal, 81 bronchiolar, 110 benzimidazole, 281
lung segmentation, 305–306, chronic lung, 1–27, 41–43 cytotoxic, 140
306t Crohn, 108, 109 lung disease from, 159
T cell, 55t dermatologic, pulmonary lupus from, 202, 211–212, 211t
ventricular septal, 81 manifestations of, 256–272 myelosuppressive, 73
Deficiency(ies) Erdheim-Chester, 266 nonsteroidal anti-inflammatory,
antitrypsin, 315–316 gastroesophageal reflux, 99–106 202, 268
in cellular immunity, 53–59 gastrointestinal, 98–117 for parasitic lung infections,
complement, 61–62 Gaucher, 301t, 322t 278t–279t
dehydrogenase, 325t graft-versus-host, 50, 155 for pediatric cancer treatment,
GM-CSF, 140–141, 142 hematologic/oncologic, 135–163 toxicity of, 158t
phagocyte number, 59–62 Hodgkin, 64, 135–137, 284 pulmonary damage from, 158
vitamin, 12 idiopathic/sporadic pulmonary D-transposition of great
Dehydrogenase deficiency, 325t veno-occlusive, 87f arteries, 94
Denys-Drash syndrome, 304t immunosuppressive, 49–76 Duchenne muscular dystrophy
Dermatologic disease(s), with inflammatory, 62 (DMD), 184, 192–194
pulmonary manifestations, inflammatory airway, 219 Dynein, 316
256–273 inflammatory bowel, 57, 98, Dyskeratosis congenita, 271–272
cutis laxa, 264 108–111 Dystrophy
dyskeratosis congenita, interstitial lung, 202 congenital myotonic, 193
271–272 Kawasaki, 241, 242t, 243 Duchenne muscular, 184,
Ehlers-Danlos syndrome, 256, kidney, 327 192–194
264–265, 321t Krabbe, 323t
erythema multiforme, 267–269 Kugelberg-Welander, 189
hereditary hemorrhagic mixed connective tissue, 212–215,
telangiectasia, 256, 261–263, 214t E
263t neonatal Graves, 176 Early-onset pathologic pulmonary
Hermansky-Pudlak syndrome, oncologic, 135–147, 154–163 changes, 160f
267, 328t parenchymal, 109, 230 Early-onset sarcoidosis, 232
Klippel-Trenaunay-Weber pleural, 109 EBV. See Epstein-Barr virus
syndrome, 263–264 primary immunodeficiency, 51 Echinococcosis, 279t, 290–292
mastocytosis, 269–271 pulmonary, 248 Echinococcus, 291
342 Index
Echinococcus granulosus, 279t, Esophageal peristalsis, 99 Genetic disorder(s), with pulmonary

291, 292 Ethambutol, 34, 35 manifestations, 295–338
Echinococcus multilocularis, 279t, Ewing sarcoma, 64 bronchiectasis, 43, 316–319,
290, 292 Ewing sarcoma family of tumors 317t, 319t
Echocardiography, 113 (ESFT), 143–144 congenital anomalies, 100–102,
Edema Exercise fitness, 181 295–316
airway mucosal, 130 Extracardiac shunts, 81 curative therapy, 335
angio, 286 Extracorporeal membrane cystic fibrosis, 112f, 171, 174,
chronic interstitial, 87 oxygenation, 301 174f, 316, 329–335
pulmonary, 81–83, 84, 125, 155 Extralobar sequestration, 309 inborn errors of metabolism,
EDS. See Ehlers-Danlos syndrome Extremely-low-birth-weight (ELBW) 320–322, 322t
Ehlers-Danlos syndrome (EDS), infants, 3 miscellaneous genetic conditions,
264–265, 321t Extubation/decannulation, 197–198 335–336
Eisenmenger syndrome, 85 pulmonary arterial hypertension,
Elastolysis, generalized, 264 209t, 322–326
ELBW. See Extremely-low-birth- spontaneous pneumothorax,
weight infants F 320, 321t
Electrophysiologic studies, 191 Fabry disease, 322t symptomatic treatment, 333–335
ELISA. See Enzyme-linked Failure GER. See Gastroesophageal reflux
immunosorbent assay acute renal, 130–131 GERD. See Gastroesophageal reflux
ELISPOT. See Enzyme-linked acute respiratory, 157 disease
immunospot assay chronic renal, 124–126 Glossopharyngeal breathing, 198
Emanuel syndrome, 305t congestive heart, 84 Glottic/subglottic damage, 20
Emphysema respiratory muscle, 186t Glucocorticoids, 220
congenital lobar, 310–311 Falciparum malaria, 274–275 Glucose tolerance, 171
pulmonary, 264 Familial cirrhosis, 326t Glutathione-S-transferase (GST), 5
Empyema, 257 Familial dysautonomia, 101f, 337t Glycogen storage disease, 324t
Endocrine/metabolic disease(s), Familial Mediterranean fever, 337t Glycosylation, 171
170–181 Familial pulmonary capillary disorder of, 322t
adrenal disorders, 172 hemangiomatosis, 326t GM-CSF deficiency, 140–141
diabetes, 170–171 Farber disease, 323t Goodpasture syndrome, 124,
growth hormone disorders, 172 Feingold syndrome, 313t 207, 243
hyperthyroidism, 175–176 Fetal lung growth, kidney and, 121 Graft-versus-host disease (GVHD),
hypothyroidism, 174–175, 181 Fibrinous pleuritis, 125 50, 155
obesity-hypoventilation Fibroblast proliferation, 222 Granuloma, 250
syndrome, 177–181 Fibrosarcoma, 147 in CLDI, 20
pseudohypoaldosteronism, Fibrosis noncaseating, 229
172–174 cystic. See Cystic fibrosis Graves disease, neonatal, 176
reproductive system, 177 extensive interstitial, 222 Growth hormone disorders, 172
End-of-life care, 199 pulmonary, 159, 161, 326t, GST. See Glutathione-S-transferase
Endoscopic retrograde 327, 328t Guillain-Barré syndrome, 190
cholangiopancreatography Flexible bronchoscopy, 75, 91 GVHD. See Graft-versus-host
(ERCP), 116 Flow-volume loops, 136 disease
Endothelins, 111–112 Focal dermal hypoplasia, 303t
Entamoeba histolytica, 276, 278t, Forced vital capacity (FVC),
279–280 186–187
Enthesitis-related arthritis, 227t Foregut cysts, 308 H
Enzyme-linked immunosorbent Fryns syndrome, 301, 302t HAART. See Highly active
assay (ELISA), 287 Full overnight polysomnography, 187 antiretroviral therapy
Enzyme-linked immunospot assay Functional asplenia, 151 Haemophilus influenzae, 31t, 50, 53,
(ELISPOT), 33 Fungal infections, 40–41 149, 151
Eosinophilia, 251 FVC. See Forced vital capacity type b, 30, 31
Eosinophilic microabscesses, 251 Hamman-Rich disease, 328t
Epidermolysis bullosa, 303t Heart transplantation, 70
Epigastric discomfort, 105 Heiner syndrome, 98, 106–108
Epithelial Naþ channel mutations, G Hematologic disorders, 147–154
173–174 Gangliosidosis, GM1, 323t Hematologic/oncologic diseases,
Epoprostenol, 215 Gastroenteric cysts, 309 135–163
Epstein-Barr virus (EBV), 59 Gastroesophageal reflux (GER), 98 Hematopoietic stem cell
ERCP. See Endoscopic retrograde Gastroesophageal reflux disease transplantation, 154–156
cholangiopancreatography (GERD), 99–106 Hemodialysis-related hypoxemia,
Erdheim-Chester disease, 266 Gastroesophageal reflux-associated 129–130
Erythema multiforme, 267–269 pulmonary involvement, 100f Hemoptysis, 205, 262, 269
Erythema nodosum, 253 Gastroesophageal sphincter, 102 Hemorrhage
Erythrocyte sedimentation rate, 231 Gastrointestinal bleeding, 262 alveolar, 155, 202, 247
Escherichia coli, 62 Gastrointestinal disease, 98–117, diffuse alveolar, 155
ESFT. See Ewing sarcoma family of 285 pulmonary, 245, 246
tumors Gaucher disease, 301t, 322t Hemosiderosis, 106, 107, 108f
Esophageal atresia, 311 Gemcitabine, 162 Henderson-Hasselbalch equation,
Esophageal dysmotility, 211t Gene therapy, 59 122
Index 343
Henoch-Schönlein purpura, 245, Hypertrophy, medial smooth Inflammation, 5, 7

246–247 muscle, 215 BPD, 7
Hepatoblastoma, 146 Hypoalbuminemia, 125 monophasic, 206
Hepatopulmonary syndrome, Hypocalcemia, 177 pulmonary, 333
111–114 Hypocapnia, 122 vascular, 241
Hereditary hemorrhagic Hypocarbia, 6 Inflammatory airway disease, 219
telangiectasia (HHT), 256, Hypoparathyroidism, 177, 181 Inflammatory bowel disease (IBD),
261–263, 263t Hypoplasia 57, 98, 108–111
Hereditary pancreatitis, 337t focal dermal, 303t Inflammatory disease, 62
Hermansky-Pudlak syndrome (HPS), primary pulmonary, 297t Inflammatory microenvironment,
267, 328t pulmonary, 94, 296–300, 300t 180
Herpesvirus, 36 secondary pulmonary, 298t–299t Inflammatory pseudotumor, 147
Heterotaxy, 305–306, 319 Hypopnea, 179 Influenza, 36
HFOV. See High-frequency Hypothyroidism, 174–175, 181 Inhaled bronchodilators, 42
oscillatory ventilation Hypoventilation, 174 Inhaled corticosteroids, 16
HHT. See Hereditary hemorrhagic Hypoxemia, 37, 79, 94, 112, 113, Inhaled nitric oxide, 16–17
telangiectasia 129–130, 130f, 139 Injury(ies)
High-dose chemotherapy/ Hypoxia, 175 acute lung, 131
radiotherapy, 156 Hypoxic vasoconstriction, 80 kidneys, mechanical
High-frequency oscillatory ventilation-induced,
ventilation (HFOV), 11, 14 131–132
Highly active antiretroviral therapy laryngeal, 20
(HAART), 28–30, 30t, 34–36, 40 I progressive parenchymal, 334
High-potency topical steroids, 270 IBD. See Inflammatory bowel disease transfusion-related acute lung,
Histamine H1/H2 blockers, 270 Idiopathic pneumonitis syndrome, 156–157
Histamine release, 269 155 Inspiratory muscle aids,
Histiocytic disorders of lung, Idiopathic pulmonary arterial 195–196
152–154 hypertension, 95–96 Intercostal muscle paralysis, 188
Histoplasma, 74 Idiopathic pulmonary fibrosis, 326t Interleukin–12, 142
HIV. See Human immunodeficiency Idiopathic pulmonary-renal Internal hemangiomas, 315
virus syndrome, 253 Interstitial lung disease
Hodgkin disease, 64, 135–137, 284 Idiopathic/sporadic pulmonary (ILD), 202
Home oxygen therapy, 19 veno-occlusive disease, 87f Interstitial pneumonitis, 42
Homocystinuria, 325t ILD. See Interstitial lung disease Intra-abdominal pressure, 131
Hookworm, 281–282 Immune inflammatory response, Intrahepatic bile stasis, 331
HPS. See Hermansky-Pudlak 229 Intraluminal impedance testing,
syndrome Immune reconstitution 103t
HPV. See Human papillomavirus inflammatory syndrome (IRIS), Intraparenchymal airways, 92
Human immunodeficiency virus 41, 42–43 Intrapulmonary bleeding, 107
(HIV), 28–48, 208 Immunodeficiency syndromes, Intravenous immunoglobulin
Human lung development, 296t 58t, 60t (IVIG), 32
Human papillomavirus (HPV), 36 Immunoglobulin deficiencies, Intravenous methylprednisolone,
Hurler-Scheie syndrome, 322t 50–53, 317t 206
Hyaline membranes, 206 Immunoglobulin production, 50–53 Intrinsic nitric oxide synthesis
Hydrocortisone therapy, 15 Immunomodulatory therapy, 215 pathway, 111–112
Hydronephrosis, 297 Immunosuppressive agents, 68t, 211 Iontophoresis, 331
Hydroxychloroquine, 226 Immunosuppressive diseases, 49–76 IRIS. See Immune reconstitution
Hydroxyurea, 151 Inborn errors of metabolism, inflammatory syndrome
Hypercalciuria, 229, 232 320–322, 322t IVIG. See Intravenous
Hypereosinophilia, 270 Increased pulmonary venous immunoglobulin
Hyperglycemia, 15 pressure, 83–87, 83t, 85t
Hyper-IgE syndrome, 60t, 61 Increased venous admixture, 92–94
Hyperinfection, 284 Indirect immunofluorescence, 244f
Hyperinsulinemia, 172 Induced lung disease, 159 J
Hyperkalemia, 173 Infant botulism, 191 JDMS. See Juvenile
Hyperleukocytosis, 65, 139 Infection(s) dermatomyositis
Hyperoxia/oxidant stress, 5–6 acute respiratory, 29–41 Jeune syndrome, 299t
Hyperreactivity of airways, 180 BPD, 6–7, 18 JLS. See Juvenile localized
Hypersensitivity, immediate, 286 chronic pulmonary, 42 scleroderma
Hypertension, 15 hyper, 284 Job syndrome, 61
chronic pulmonary venous, 86f mycobacterial, 32–35 Juvenile dermatomyositis ( JDMS),
idiopathic pulmonary arterial, nosocomial, 6 225–226
95–96 opportunistic respiratory, 32f characteristics of, 226t
portal, 111 parasitic lung, 277t Juvenile localized scleroderma ( JLS),
portopulmonary, 111 pneumocystis, 37–40 220, 221, 221t
primary pulmonary, 322, 326, 326t pulmonary, 66 Juvenile myasthenia gravis, 191
pulmonary, 10, 151–152, 263, 320 respiratory, 18 Juvenile rheumatoid arthritis,
pulmonary arterial, 209t, 225t, s. aureus, 32f 217–220
322–326 urinary tract, 131 Juvenile systemic sclerosis, 220,
Hyperthyroidism, 175–176 viral, 35–37 221, 222t
344 Index
K Lung metastases, 144 Metastatic nodules, 142

Kaposi sarcoma, 136 Lupus Methotrexate, 162, 208
Kartagener syndrome, 316–319, 319t drug-induced, 202, 211–212 cisplatin-doxorubicin regimen
Kasukawa criteria, 212 systemic. See Systemic lupus with, 142
Kawasaki disease, 241, 242t, 243 erythematosus pneumonitis, 232–233
Keratosis obturans, 257 Lymphatic circulation, 80 Methylprednisolone, 111, 206
Kidney. See Renal Lymphedema, 326t MIC. See Maximum insufflation
Kidney disease, 327 congenital, 256 capacity
Kidney injury, mechanical primary, 257 Micro-Ouchterlony technique,
ventilation–induced, 131–132 Lymphoblastic lymphoma, 137f 107
Klebsiella aerobacter, 211 Lymphocytes, 115 Microphthalmia syndrome, 303t
Klebsiella pneumoniae, 30, 31t Lymphocytic interstitial pneumonia Microscopic polyangiitis, 242f, 243,
Klippel-Trenaunay-Weber (LIP), 41–42, 42f, 216 249–250
syndrome, 263–264 Lymphoid interstitial pneumonitis, Miliary tuberculosis, 32, 33f
Kommerell diverticulum, 89 216t, 219 Milk scan, 103t
Kostmann syndrome, 61 Lymphoma, 135, 284 Minimal ventilation, 14
Krabbe disease, 323t Burkitt, 136 Mixed connective tissue disease
Kugelberg-Welander disease, 189 lymphoblastic, 137f, 138f (MTCD), 212–215
Lysinuric protein intolerance, 325t pulmonary manifestations of,
Lysosomal trafficking protein, 267 214t
MMR. See Measles, mumps, rubella
L vaccine
Lactate dehydrogenase (LDH), 37 Model End-Stage Liver Disease
Langerhans cell histiocytosis (LCH), M score, 111
152–154, 153t M. bovis, 34 Monocyte chemoattractant
Large left-to-right shunts, 81–87, 82f Macroaggregated albumin (MAA), protein–1, 222
treatment of, 85 113 Mononeuritis multiplex, 251
Laryngeal injury, with intubation, 20 Macrolide antibiotics, 72 Monophasic inflammation,
Laryngeal nerves, 101 Magnetic resonance 206
Laryngomalacia, 101 cholangiopancreatography, Mounier-Kuhn syndrome, 265
LCH. See Langerhans cell 116 MPO. See Myeloperoxidase
histiocytosis Magnetic resonance imaging MRI. See Magnetic resonance
LDH. See Lactate dehydrogenase (MRI), 90 imaging
Left ligamentum arteriosum, Malacia of airways, 91 MTCD. See Mixed connective tissue
89, 90 Malaria, 274–276 disease
Left ventricular outflow obstruction, Malignancies, 65t. See also Oncologic MTP-PE. See Muramyl tripeptide
87–88 diseases phosphatidylethanolamine
Lesions Malnutrition, and PCP, 38 Mucopolysaccharidosis, 322t
cardiovascular with increased Mannose-binding lectin (MBL), 61 Mucosal barrier, 155
work of breathing, 80–96 Marden-Walker syndrome, 301t Mulberry tumors, 259
noncalcified, 142 Marfan syndrome, 321t Multinucleated giant cells, 249f
plexiform lung, 83f Mastocytosis, 269–271 Multiorgan dysfunction, 115
renal, 261 Mature pulmonary circulation, 80 Muramyl tripeptide
small cyst, 308 Maximum insufflation capacity phosphatidylethanolamine
vascular, 209 (MIC), 187 (MTP-PE), 142
Leukocytosis, 217, 276 Maximum voluntary ventilation, Muscles
Leukostasis, 138 179 accessory inspiratory, 185
Liddle syndrome, 172 MBL. See Mannose-binding lectin hypertrophy, 70
Lifelong prophylaxis, 40 McKusick-Kaufman syndrome, 313t inspiratory, 195–196
LIP. See Lymphocytic interstitial Meacham syndrome, 302t intercostal, 188
pneumonia Measles, mumps, rubella vaccine respiratory, 185
Liver transplantation, 70–71 (MMR), 36 aids, 194
Löffler pneumonitis, 281 Mebendazole, 282 dysfunction, 189t
Löffler syndrome, 281 Mechanical insufflation- failure, 186t
Lung(s). See also Pulmonary exsufflation, 197 fatigue, 187–194
biopsy, 41, 75, 216f Mechanical ventilation and function, 185–187
disease. See Lung disease volutrauma, 6 Muscular disease, 188
and kidneys, physiologic Meckel syndrome, 298 Mutations
connections between, Medial smooth muscle hypertrophy, CFTR gene, 115
121–123 215 epithelial Naþ channel,
morphogenesis, 295 Mediastinal adenopathy, 223 173–174
segmentation defects of, 306t Mediastinal lymphadenopathy, 218 Myasthenia gravis, 191
toxicity, 158–162, 158t Medroxyprogesterone, 261 Mycobacterial infection,
transplantation, 63, 71–72 Meigs syndrome, 177 32–35
Lung disease, 332–333 Mesalamine, 109 Mycoplasma pneumoniae, 148,
chronic, 41–43 Metabolic acidosis, 122 190, 268
chronic sickle cell, 150–151 Metabolism, inborn errors of, 320–322, Myeloperoxidase (MPO), 244
genetic disorders, 332–333 322t–325t. See also Endocrine/ Myelosuppressive drugs, 73
of infancy, 1–27 metabolic disease(s) Myotonic dystrophy, 193
interstitial, 202 Metacercariae, 287 neonatal, 193
Index 345
N Nonirradiated blood products, 57 Paragonimiasis, 287–290

N-acetyl cysteine, 150, 334 Non–Langerhans cell histiocytosis, Paragonimus, 287, 288f
NADPH. See Nicotinamide adenine 266 Paragonimus westermani, 279t,
dinudeotide phosphate Nonlethal skeletal dysplasia, 299t 287–290, 288f, 290f
Nasal polyps, 332 Nonsteroidal anti-inflammatory Parasite(s)/parasitic disease(s),
Nasopharyngeal washes, 74–75 drugs, 202, 268 274–294
Nasopharynx, 246 Nonsteroidal immunosuppressants, cestodes, 290–292
National Institutes of Health 266 nematodes, 280–287
on asthma, 105 Normal alveolar ventilation, protozoa, 274–280
and rituximab, 226 195–196 trematodes, 287–290
Natural killer (NK) cells, 53, 54, Normal cough, 197 Parasitic lung infections, drugs for,
55t–56t, 57 Normochromatic normocytic 277t
Necator americanus, 281 anemia, 127 Parenchymal cysts, 265
Neisseria meningitidis, 53 Nosocomial infection, 6 Parenchymal disease, 109, 230
Nemaline myopathy, 101f NPPV. See Non-invasive intermittent Parry-Romberg syndrome, 220, 221t
Nematodes, 280–287 positive-pressure ventilation Patchy pneumonia, 107
hookworm, 281–282 Nutrition, 7 Patent ductus arteriosus (PDA),
N. americanus, 281 BPD, 7 81, 83t
strongyloidiasis, 282–285 PCD. See Primary ciliary dyskinesia
toxocariasis, 285–287 PCP. See Pneumocystis pneumonia
Neonatal Graves disease, 176 PDA. See Patent ductus arteriosus
Neonatal hyperthyroidism, 176f O Peak inspiratory pressure, 196
Neonatal intensive care units Obesity, and asthma, 179–180 Pena-Shoeir syndrome, 300t
(NICUs), 4 Obesity-hypoventilation syndrome, Pentamidine, 38
Nephrocalcinosis, 12 177–181 Percutaneous balloon angioplasty,
Nephrotoxicity, 67 Obliterative bronchiolitis, 71–73 89
Neuroblastoma, 64, 145–146 Ocular larva migrans, 285, 286 Peripheral eosinophilia, 286
Neurodevelopment in BPD, 3, 18–19 Oligohydramnios, 297 Peritoneal dialysis, 125
Neurofibromatosis type 1, 258–259 Omphalocele, 304t Perlman syndrome, 304t
Neuromuscular disease(s), 184–200 Oncologic diseases, 135–147 PET. See Positron emission
cardiac involvement, 194 complications related to, tomography
disorders of muscles, 192–193 135–141, 154–163 PFTs. See Pulmonary function tests
disorders of neuromuscular Oophorectomy, 261 Phagocyte number deficiencies,
junction, 191–192 Open lung biopsy, 75 59–62
disorders of peripheral nerves, 190 Opitz-Frias syndrome, 312t–313t Phosphodiesterase type 5 inhibitor,
end-of-life care, 199 Opportunistic respiratory infections, 225t
extubation/decannulation, 32f Pirfenidone, 267
197–198 Oropharyngeal discoordination, 100 Plasmodium species, 276f
management, 194–198 Oropharynx, 246 Plastic bronchitis, 96
muscular disease, 188 Orthopnea, 136 Pleural disease, 109
outcomes, 198–199 Osler-Weber-Rendu syndrome, 261, Pleural effusion, 84f
physiology, 184–185 315t Pleural thickening, 160
respiratory muscle fatigue, Osteohypertrophy, 263 Pleuritic chest pain, 128
187–194 Osteopenia, 12 Pleuroperitoneal shunting, 257
respiratory muscle function Osteosarcoma, 141–143 Pleuropulmonary blastoma (PPB),
assessment, 185–187 Oxidant stress, 201 146–147
sleep evaluation in, 193–194 Oxidative stress, 12 Pleuropulmonary manifestations,
Neuropsychiatric disability, 258 Oxygen steal, 139 218
Neutrophilia, 287 Oxygenation, 150 Plexiform lesion, 83f
Neutrophils, 59 Oxyhemoglobin desaturation, 196 Plexiform neurofibromas, 258
influx, 334 Pneumococcal conjugate vaccine,
recruitment, 53 35
NHL. See Non-Hodgkin lymphoma Pneumococcal pneumonia, 224
Nicotinamide adenine dinudeotide P Pneumococcal sepsis, 306
phosphate (NADPH), 61 PAH. See Pseudohypoaldosteronism; Pneumocystis infection, 37–40
NICUs. See Neonatal intensive care Pulmonary arterial with other pathogens, 44
units hypertension; Pulmonary Pneumocystis jiroveci, 37, 42, 50, 54,
NK cells. See Natural killer cells arterial pressure 57, 59, 70, 211
NK-T cells, 53–54, 57 Palivizumab prophylaxis, 36 Pneumocystis pneumonia (PCP), 29,
Nocturnal noninvasive ventilation Pallister-Killian syndrome, 305t 35t, 37f, 38
(NIV), 187 Pancreatitis, 114–117 Pneumonia
Noncalcified lesions, 142 acute, 114 bacterial, 30–32
Noncaseating granuloma, 229 clinical management, 116–117 bronchiolitis obliterans with
Non-Hodgkin lymphoma (NHL), 64, diagnostic approach, 116 organizing, 73, 210
135–137, 138f etiology, 114 cryptogenic organizing, 155
Noninfectious pulmonary hereditary, 337t lymphocytic interstitial, 41–42,
complications, 79, 202, 203t pathophysiology, 115–116 42f, 216
Non-invasive intermittent positive- pulmonary manifestations, Mycoplasma, 148, 190, 267
pressure ventilation (NPPV), 114–115 patchy, 107
194, 195f, 198 Paradoxical breathing, 186 pneumococcal, 224
346 Index
Pneumonia (Continued) Protozoa, 274–280 Pulmonary manifestations/

Pneumocystis, 29, 35t, 37t, 38 amebiasis, 276–280 complications (Continued)
recurrent, 99 malaria, 274–276 of inborn errors of metabolism,
viral, 32f Proximal skin sclerosis, 220 322t–325t
Pneumonitis Pseudoglandular period, of lung of neuromuscular diseases,
bleomycin-induced, 161 development, 295–296, 296t 184–199
interstitial, 42 Pseudohypoaldosteronism (PAH), of non-HIV immunosuppressive
Löffler, 281 170, 172–174 diseases, 49–76
lymphoid interstitial, 216t, 219 Pseudomonas, 50, 332, 333 of parasitic diseases, 274–293
methotrexate, 232–233 Pseudomonas aeruginosa, 173, 174, of renal disease, 121–132
resulting from antirheumatic 333, 334 of rheumatoid disease, 201–233
therapy, 232–233 Pseudoxanthoma elasticum, of systemic vasculitis, 241–254
Pneumothorax, 264, 320, 321t 265–266 Pulmonary nodules, 142
Polymorphonuclear leukocytes, 223 PTLD. See Post-transplant Pulmonary paragonimiasis, 289
Polymorphonuclear neutrophils, lymphoproliferative disorder Pulmonary parenchyma, 252
157 Pulmonary alveolar microlithiasis, Pulmonary sequestration, 309–310
Polysomnography, 103t, 104, 187 328t Pulmonary valve, 91
Portopulmonary-hypertension, 111 Pulmonary alveolar proteinosis, Pulmonary vascular resistance,
Port-wine stains, 263, 264f 140–141, 140f 81, 91
Positron emission tomography Pulmonary angiography, 262f Pulmonary venous pressure, 83–85,
(PET), 136 Pulmonary arterial hypertension 83t, 85t
Postdiphtheritic neuropathy, 190 (PAH), 209t, 225t, 322–326 Pulmonary-renal syndrome(s),
Postextubation stridor, 20 Pulmonary arterial pressure, 82f, 244–246, 245f, 245t
Postmortem pleuropulmonary 83t, 202 idiopathic, 253–254
evaluation, 219 Pulmonary arteries, 82 Pyloric stenosis, 102
Post-transplant lymphoproliferative Pulmonary arteriovenous
disorder (PTLD), 67 malformations, 314–315
PPB. See Pleuropulmonary blastoma Pulmonary calcification, 126
PPHTN, 111 Pulmonary capillary blood, 122 R
Prader-Willi syndrome, 179 Pulmonary circulation, 79–80 Radiation therapy/radiotherapy,
Praziquantel, 290 Pulmonary cysts, 309t 153, 161, 162–163
Prenatal lung development, Pulmonary edema, 81–83, 84, 125, Rapid eye movement (REM) atonia,
295–296 155 178
Pressure Pulmonary embolism, 124t, 263, Rare airway diseases in SLE, 210t
bilevel positive airway, 187, 189, 327–328 Rasburicase, 137–138
195 Pulmonary emphysema, 264 RDS. See Respiratory distress
increased pulmonary venous, Pulmonary fibrosis, 159, 161, 327, syndrome
85–87 328t Reactive airway disease, 150
intra-abdominal, 131 Pulmonary function tests (PFTs), 18, Reactive arthritis, 286
NPPV, 194, 195f, 198 98, 207 REM. See Rapid eye movement
peak inspiratory, 196 Pulmonary hemorrhage, 245, 246 Renal diseases, 121–132
pulmonary arterial, 82f, 83t, 202 Pulmonary hypertension, 10, Renal dysplasia, 2
pulmonary microvascular, 125 151–152, 263, 320 Renal insufficiency, 126
pulmonary venous, 83–85, diagnostic classification, 95t Renal lesions, 261
83t, 85t Pulmonary hypoplasia, 94, 296, 300 Renal transplantation, 70
respiratory system, 180f neuromuscular conditions Reproductive system disorders, 177
Primary ciliary dyskinesia (PCD), associated with, 300t–301t Respiratory acidosis, 123t
316–319, 319t–320t Pulmonary infections, 66 Respiratory distress syndrome
Primary immunodeficiencies, 50–62 Pulmonary inflammation, 333 (RDS), 1
with antibody underproduction, Pulmonary leukostasis syndrome, Respiratory infections, 18
52t 138–140 Respiratory muscle aids, 194
Primary lung neoplasms, 146–147 Pulmonary lymphangiectasia, Respiratory muscle dysfunction,
Primary lymphedema, 257 311–313, 314t 189t
Primary pulmonary hypertension, Pulmonary lymphatic drainage, 10 Respiratory muscle failure, 186t
322, 326, 326t, 327t Pulmonary manifestations/ Respiratory muscle fatigue,
Primary pulmonary hypoplasia, complications, 322t–325t. 187–194
297t See also specific disorders Respiratory muscle function,
Primary pulmonary Langerhans cell of cardiac diseases, 79–97 185–187
histiocytosis, 147, 153–154 of chronic lung disease of infancy, Respiratory syncytial virus (RSV), 35
Primary spontaneous 1–22 Respiratory system pressure-volume
pneumothorax, 321t of dermatologic diseases, curves, 180f
Progesterone, 179 256–272 Restrictive syndrome, 192
Progressive parenchymal injury, 334 of endocrine/metabolic diseases, Rhabditiform larvae, 282
Proinflammatory cytokines, 6 170–181 Rhabdomyosarcoma (RMS), 64, 144
Prophylaxis, 35, 40, 59, 62, 71 of gastrointestinal diseases, Rheumatoid arthritis, 218
Prostacyclins, 225t 98–117 juvenile, 217–220
Protein of genetic disorders, 295–336 Rheumatoid disease(s), 201–240
intolerance, 325t of hematologic/oncologic ankylosing spondylitis, 226–228
lysosomal trafficking, 267 diseases, 154–163 juvenile dermatomyositis,
surfactant, 336 of HIV infection, 28–43 225–226
Index 347
Rheumatoid disease(s) (Continued) Solid tumors, 141–146 Syndrome(s) (Continued)

juvenile rheumatoid arthritis, Spinal muscular atrophy (SMA), Klippel-Trenaunay-Weber,
217–220 184, 301t 263–264
pneumonitis resulting from Spontaneous pneumothorax, 320, Liddle, 172
antirheumatic therapy, 321t Löffler, 281
232–233 Sputum, 74–75 Marfan, 321t
sarcoidosis, 228–232 Staphylococcus, 50 McKusick-Kaufman, 313t
scleroderma, 220–224 Staphylococcus aureus, 30, 31f, 60t, Meacham, 302t
Sjögren syndrome, 215–216 61, 62, 67 Meckel, 298
systemic lupus erythematosus, methicillin-resistant, 30 Meigs, 177
124, 202–211, 205f, 210t Stem cell transplant (SCT), 50, Microphthalmia, 303t
Rheumatology medications, and 72–73 Mounier-Kuhn, 265
pneumonitis, 232–233 Sternocleidomastoids, 185 obesity-hypoventilation, 177–181
Rifampin, 34 Stevens-Johnson syndrome (SJS), Opitz-Frias, 312t–313t
Riley-Day syndrome, 101f, 337t 267–269 Pallister-Killian, 305t
Rituximab, 72, 159t, 236 extensive skin necrosis, 269f Parry-Romberg, 220
RMS. See Rhabdomyosarcoma Streptococcus pneumoniae, 30, 31t, 36, Perlman, 304t
Rowley-Rosenberg syndrome, 327t 50, 53, 57, 59, 62, 149, 150, 151 Prader-Willi, 179
RSV. See Respiratory syncytial virus Streptococcus pyogenes, 62 pulmonary leukostasis, 138–140
Rubinstein-Taybi syndrome, 307t Streptococcus viridans, 67 pulmonary-renal, 244–246, 245f,
Strongyloides, 281, 283 245t, 253
Strongyloides stercoralis, 274, 282, respiratory distress, 1
283, 283f, 284, 284f restrictive, 192
S Strongyloidiasis, 282–285 Rowley-Rosenberg, 327t
Salbutamol, 13 STS. See Soft tissue sarcomas shrinking lung, 124, 209, 222
Saline, inhaled, 334 Stuve-Wiedemann syndrome, 300t Simpson-Golabi-Behmel, 302t
Salivagram, 103t, 104 Subcutaneous fat, 265 Stevens-Johnson, 267–269
Sarcoidosis, 228–232 Superior vena cava (SVC), 64, 136 Stuve-Wiedemann syndrome,
SCD. See Sickle cell disease syndrome, 136–138 300t
Schistosoma species, 292 Superoxide dismutase, 17 superior vena cava, 64, 136–138
SCID. See Severe combined Supplemental oxygen, 213 thoracoabdominal, 303t
immunodeficiency Suppurative bronchitis, 109 vasculitis, 243
Scleroderma, 220–224 Surfactant protein, 336 vena cava compression, 137f
Scleroderma-renal crisis, 213 Surgery, fundoplication, 106 Wiskott-Aldrich, 57, 58t, 59
SCT. See Stem cell transplant Surgical palliation, 93 yellow nail, 256–258
Secondary immunodeficiencies, Sweat test, 331 Young, 317t
62–73 Syndrome(s) Zellweger, 324t
Secondary organ dysfunction, 66 acquired immunodeficiency, 284 Syndromic anophthalmia, 303t
Secondary pulmonary hypoplasia, acute chest, 147, 148–150 Syndromic microphthalmia, 313t
298t–299t acute respiratory distress, Systemic corticosteroids, 15–16
Serologic diagnosis, 250 114–116, 125, 276f Systemic lupus erythematosus, 124,
Seronegative arthritis, 57 Birt-Hogg-Dube, 321t 202–211, 203t–204t, 205f
Seronegative enthesitis, 227 Blau, 227 noninfectious complications of,
Serositis, 217 Bloom, 317t 203t
Serratia marcescens, 61 bronchiolitis obliterans, 72 rare airway diseases, 210t
Serum chitotriosidase, 231 Churg-Strauss, 250–251, 251t Systemic vasculitis (vasculitides),
Severe combined immunodeficiency Cogan, 242t 241–254
(SCID), 50 defined immunodeficiency, 58t Behçet disease, 251–252
Shrinking lung syndrome, 124, Denys-Drash, 304t Churg-Strauss syndrome, 242t,
209, 222 DiGeorge, 57, 177 250–251, 251t
Sickle cell disease (SCD), 147–152 Donnai-Barrow, 304t Henoch Schönlein purpura, 245,
Sight-threatening ocular disease, drug-induced lupus, 211t 246–247
231 Ehlers-Danlos, 256, 264–265, idiopathic pulmonary-renal
Simpson-Golabi-Behmel syndrome, 321t syndrome, 253–254
302t Eisenmenger, 85 microscopic polyangiitis, 249–250
Single unilocular cystic structures, Emanuel, 305t pulmonary-renal syndromes,
308 Feingold, 313t 244–246, 245f, 245t
Sjögren syndrome, 215–216 Fryns, 301, 302t Takayasu arteritis, 241, 252–253
SJS. See Stevens-Johnson syndrome Goodpasture, 124, 207, 243 Wegener granulomatosis, 121,
Skeletal dysplasias, 298 Heiner, 98, 106–108 123–124, 242t, 247–249,
Skin rash, 243 hepatopulmonary, 111–114 248t, 249f
Sleep apnea, 127, 178 Hermansky-Pudlak, 267, 328t Systemic ventricle obstruction,
Sleep hypoventilation, 188 hyper-IgE, 60t, 61 87–89
muscular disorders and, 193 hyperleukocytosis, 65
Sleep-disordered breathing, 175 idiopathic pneumonitis, 155
SMA. See Spinal muscular atrophy idiopathic pulmonary-renal, 253
Small cysts, 308 immune reconstitution T
Small pulmonary artery, 94 inflammatory, 41, 42–43 T cell defects, 55t
Soft tissue sarcomas (STS), 144–145 immunodeficiency, 58t, 60t Tachypnea, 217, 280
Solid malignancies, 141 Kartagener, 316–319, 319t Takayasu arteritis, 241, 252–253
348 Index
Tamoxifen, 261 Transplant-related pulmonary Ventilation (Continued)

TEFs. See Tracheoesophageal fistulas complications, 67–73 non-invasive intermittent
Temporal arteritis, 241 Transthoracic Doppler positive-pressure, 194, 195f,
TEN. See Toxic epidermal necrolysis echocardiography, 224 198
Tetralogy of Fallot, 92f, 93–94 Transthoracic needle aspiration, 75 normal alveolar, 195–196
Theophylline, 179 “Tree in bud” CT pattern, 110, 110f Ventricular septal defect (VSD), 81,
Therapy. See also Chemotherapy Trematodes, 287–290 83t
antibiotic, 192 Tricuspid atresia, 93 Very-low-birth-weight (VLBW)
macrolide, 72 Trimethoprim-sulfamethoxazole infants, 3
bronchodilator, 13 (TMP-SMX), 31t, 32, 39t, 40, 44 Video-assisted thoracoscopy, 207
cancer, 64–67 prophylaxis with, 39, 211 Viral infections, 35–37
curative, 335 Tuberculosis, 33f, 34, 42, 44, Viral pneumonia, 37f
gene, 59 125–126, 233 Visceral larva migrans (VLM),
highly active antiretroviral, 28 Tuberous sclerosis, 259–261, 285–287
home oxygen, 19 260f, 337t Viscid airway secretions, 334
hydrocortisone, 15 complex, 259–261, 260t Vitamin A, 15
immunomodulatory, 215 Tumor necrosis factor, 233 Vitamin deficiency, 12
pneumonitis resulting from VLBW. See Very-low-birth-weight
antirheumatic, 232–233 infants
radiation, 156, 161, 162–163 VLM. See Visceral larva migrans
transfusion, 152 U Vomiting, versus reflux, 102–103,
Thoracentesis, 137 Ulcerative colitis, 110 102t
Thoracoabdominal syndrome, 303t Ultrasonography, 116 von Hippel-Lindau syndrome, 315
Thoracoscopy, 142, 207 Uncinaria stenocephala, 282 VSD. See Ventricular septal defect
Thromboembolism, 74 Upper motor neuron, 188–189
Thrombotic risks, 329 Ureaplasma urealyticum, 7
Thymoma, 64 Urinary tract infection, 131
Thyromegaly, 176 Urine output, suboptimal, 298 W
Thyrotoxicosis, 176 Urinothorax, 126–127 Wegener granulomatosis, 121,
Tinidazole, 280 Urticaria pigmentosa, 270 123–124, 242t, 247–249, 248t,
TLC. See Total lung capacity 249f
TMP-SMX. See Trimethoprim- Weight loss, 179
sulfamethoxazole Werdnig-Hoffman disease, 189
Tonsillectomy, 179 V Wilms tumor, 145
Total lung capacity (TLC), 217 Vaccines Wiskott-Aldrich syndrome, 57
Toxic epidermal necrolysis (TEN), measles, mumps, rubella, 36 Wolman disease, 324t
267–269 pneumococcal conjugate, 36 World Health Organization stage,
Toxicity Varicella-zoster virus, 36 for lymphocytic interstitial
chemotherapy-induced lung, Vascular anomalies, respiratory pneumonia, 42
158–162 manifestations of, Wuchereria bancrofti, 292
lung, 158t pathophysiology of, 91–92
renal, 70 Vascular compression of airway, 86f
Toxocara canis, 285, 287 Vascular endothelium, 59
Toxocara catis, 285 Vascular inflammation, 241
X
Toxocariasis, 285–287 Vascular lesions, 209 Xanthoma disseminatum disease,
Toxoplasma gondii, 274, 292 Vasculitis. See also Systemic 266
Tracheal agenesis, 311 vasculitis X-linked agammaglobulinemia, 51
Tracheal atresia, 297 childhood, 242t X-linked dyskeratosis congenita,
Tracheal compression, 136–138 definition of, 241–244 328t
Tracheal stenosis, 247 syndromes, 243
Tracheobronchial glands, 63 VATER-like defects, 327t
Tracheobronchomalacia, 19–20 Vena cava compression syndrome,
Tracheoesophageal fistulas (TEFs), 137t
295, 311, 312t Venous thrombosis, 208 Y
Tracheomalacia, 100 Ventilation Yellow nail syndrome, 256–258,
Transbronchial biopsy, 38 alveolar, 122 257f
Transepithelial potential difference, high-frequency oscillatory, 11, 14 Young syndrome, 317t
329 maximum voluntary, 179
Transfusion therapy, 152 mechanical, 6
Transfusion-related acute lung glottic/laryngeal injury and, 20
injury, 156–157 minimal, 14 Z
Transient neonatal myasthenia, 191 nocturnal noninvasive, 187 Zellweger syndrome, 324t

Pulmonary Manifestations of Pediatric Diseases

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PULMONARY MANIFESTATIONS OF PEDIATRIC DISEASES ISBN: 978-1-4160-3031-7

Copyright # 2009 by Saunders, an imprint of Elsevier Inc.

Library of Congress Cataloging-in-Publication Data

Acquisitions Editor: Dolores Meloni

Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Nelson L. Turcios, M.D.

Robert J. Fink, M.D.

JAMES M. ADAMS, M.D. TED M. KREMER, M.D.

JOSEPH LEVY, M.D.

BETH A. PLETCHER, M.D. ANN R. STARK, M.D.

JAMES M. STARK, M.D., PH.D.

JACQUELINE R. SZMUSZKOVICZ, M.D.

JOSEPH C. SHANAHAN, M.D. MARLYN S. WOO, M.D.

HEATHER J. ZAR, M.D., PH.D.

Chronic Lung Disease of Infancy

Historical Overview 1 Minimal Ventilation 14

Historical Overview RDS and required prolonged mechanical ven-

Figure 1-1. A, Classic bron-

Diagnostic Criteria for Bronchopulmonary Dysplasia Proposed by National Institute of

*Whichever comes first.

mechanisms, and inadequate fluid clearance airway remodeling, hyperreactivity, and

elastic tissue maturation was shown in a Physical Examination

Figure 1-3. A, Chest radiograph

then supplemental oxygen alone, until they Cardiopulmonary Function

Fluid Restriction because of excess adverse events in infants

Vitamin A development of BPD at 36 weeks PMA and

Caffeine has been shown to reduce the fre- Summary

Network and evaluated at 18 to 22 months Growth

Monitoring occlusion, to assess the severity of pulmo-

Cardiovascular Monitoring Growth

susceptibility to bronchopulmonary dysplasia. 85. Goodman G, et al: Pulmonary hypertension in

Epidemiology 28 Chronic Pulmonary Infections 42

Respiratory complications in children in- pneumonia-specific mortality rates are three

Table 2-1 Impact of HAART on Opportunistic Respiratory Infections

INFECTION PRE-HAART RATE9 POST-HAART RATE5

INFECTION PATHOGENS FIRST-LINE THERAPY

treatment failure and mortality compared inactivated vaccines (diphtheria, pertussis,

Respiratory disease also may result from infec-

uncommon, reported in 2.8% of foreign- young children.6,43 Primary and secondary

Alternatively, therapy with four drugs (isoni-

papillomas should be removed. Adjuvant chest retractions.77 Infants younger than 6

Table 2-4 Treatment of Pneumocystis Pneumonia in Children*

DRUG DOSE ROUTE COMMENTS

*Corticosteroids should be added for children with hypoxia.

amphotericin B recommended for the acute Persistent or recurrent pneumonia is an

Lymphocytic Interstitial Pneumonia

increases. Corticosteroids are tapered to 0.5

Non-specific interstitial pneumonitis may

Chronic Pulmonary Infections

Chronic infection, resulting from recurrent

mycobacterial infection or from a florid and aggressive treatment of intercurrent infec-

Primary Immunodeficiencies 50 Diagnosis and Treatment of

Infection in an immunocompromised child defenses for even an immunocompetent host.

in healthy individuals during routine blood Patients with X-linked agammaglobulin-

Pulmonary Manifestations of Pediatric Diseases

levels of IgG and IgA, resulting in an defense. Bronchial-associated lymphoid tis-

This disease phenotype is the consequence deficiency. DiGeorge syndrome is usually

or opportunistic organisms (P. jiroveci).3,37 Treatment

Pulmonary Manifestations of Pediatric Diseases

Specific Diseases the reduced nicotinamide adenine dinucleo-

Factors Predisposing to Infection and Pulmonary Complications after Cancer Therapy

CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus.