Paediatric Respiratory Disease: Parenchymal Diseases

An Atlas of Investigation and Management
PAEDIATRIC RESPIRATORY DISEASE

Parenchymal Diseases
A Bush J Davies
CLINICAL PUBLISHING
An Atlas of Investigation and Management
PAEDIATRIC RESPIRATORY DISEASE

PARENCHYMAL DISEASES
Edited by Andrew Bush, MB BS(Hons), MA, MD, FRCP, FRCPCH Professor of Paediatric Respirology and Consultant Paediatric Chest Physician Department of Paediatric Respiratory Medicine Imperial College and Royal Brompton and Hareeld NHS Foundation Trust London, UK Jane C. Davies, MB ChB, MRCP, MRCPCH, MD(Hons) Reader and Honorary Consultant Department of Paediatric Respiratory Medicine Royal Brompton and Hareeld NHS Foundation Trust and Imperial College London, UK
CLINICAL PUBLISHING
OXFORD
Clinical Publishing an imprint of Atlas Medical Publishing Ltd Oxford Centre for Innovation Mill Street, Oxford OX2 0JX, UK Tel: +44 1865 811116 Fax: +44 1865 251550 E mail: info@clinicalpublishing.co.uk Web: www.clinicalpublishing.co.uk Distributed in USA and Canada by: Clinical Publishing 30 Amberwood Parkway Ashland OH 44805, USA Tel: 800-247-6553 (toll free within US and Canada) Fax: 419-281-6883 Email: order@bookmasters.com Distributed in UK and Rest of World by: Marston Book Services Ltd PO Box 269 Abingdon Oxon OX14 4YN, UK Tel: +44 1235 465500 Fax: +44 1235 465555 Email: trade.orders@marston.co.uk
Atlas Medical Publishing Ltd 2011 First published 2011 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Clinical Publishing or Atlas Medical Publishing Ltd Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention Clinical Publishing and Atlas Medical Publishing Ltd bear no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. A catalogue record for this book is available from the British Library ISBN-13 ISBN e-book 978 1 84692 086 8 978 1 84692 628 0
The publisher makes no representation, express or implied, that the dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publisher do not accept any liability for any errors in the text or for the misuse or misapplication of material in this work Project manager: Gavin Smith, GPS Publishing Solutions, Herts, UK Typeset by Phoenix Photosetting, Chatham, Kent, UK Printed and bound by Marston Book Services Ltd, Abingdon, Oxon, UK
Contents
Contributors Abbreviations 1. Congenital lung malformations 2. Neonatal lung disease
Chris Dewhurst, George K. Kokai, Gurdeep S. Mann, Nigel (Ben) Shaw Anne Greenough, Caroline May Anita K. Simonds
vi viii 1 11 25 37 51 69 79
3. Neuromuscular and chest wall disease (including non-invasive ventilation) 4. Interstitial lung disease
Andrew Bush, Andrew G. Nicholson Catherine Wynne, N.J. Sebire, Kieran McHugh, Julia Chisholm Samatha Sonnappa, Robert Dinwiddie
5. Primary and secondary thoracic tumours 6. Rare lung diseases Index
vi
Contributors
Andrew Bush, MB BS(Hons), MA, MD, FRCP, FRCPCH Professor of Paediatric Respirology and Consultant Paediatric Chest Physician Department of Paediatric Respiratory Medicine Imperial College and Royal Brompton and Harefield NHS Foundation Trust London, UK Julia Chisholm, BMBCh, PhD, FRCPCH Deputy Head Children and Young Peoples Unit Royal Marsden NHS Foundation Trust Sutton, UK Chris Dewhurst, MBChB, MRCPCH, PGCTLCP Consultant Neonatologist Neonatal Intensive Care Unit Liverpool Womens Hospital Liverpool, UK Robert Dinwiddie, MB, FRCP, FRCPCH Honorary Senior Lecturer Portex Unit, Respiratory Medicine UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust London, UK Anne Greenough, MD Professor of Neonatology and Clinical Respiratory Physiology Division of Asthma, Allergy and Lung Biology MRC-Asthma UK Centre in Allergic Mechanisms of Asthma Kings College London, UK George K. Kokai, FRCPath Consultant Paediatric Pathologist Department of Paediatric Histopathology Alder Hey Childrens Hospital NHS Foundation Trust Liverpool, UK Gurdeep S. Mann, MRCP, FRCR Consultant Radiologist Department of Radiology Alder Hey Childrens Hospital NHS Foundation Trust Liverpool, UK Caroline May, MB BS, BSc(Hons), MRCPCH Specialist Registrar in Neonatal Medicine Elizabeth Ward Neonatal Unit and Neonatal Transfer Service (NTS) The Royal London Hospital Whitechapel London, UK Kieran McHugh, FRCR, FRCPI, DCH Consultant Paediatric Radiologist Department of Radiology Great Ormond Street Hospital for Children London, UK Andrew G. Nicholson, DM, FRCPath Consultant Histopathologist and Professor of Respiratory Pathology Department of Histopathology Royal Brompton and Harefield Hospitals NHS Foundation Trust National Heart and Lung Institute Imperial College London, UK N. J. Sebire, MB BS, BClinSci, MD, DRCOG, FRCPath Professor of Paediatric Pathology Institute of Child Health and Great Ormond Street Hospital London, UK Nigel (Ben) Shaw, MB ChB, MRCPCH (UK), MD, MA (Clin Ed), FRCPCH Consultant in Neonatal and Respiratory Paediatrics Liverpool Womens Hospital and Royal Liverpool Childrens Hospital Alder Hey Liverpool, UK
Contributors vii
Anita K. Simonds, MD, FRCP Consultant in Respiratory Medicine National Heart and Lung Institute Royal Brompton and Harefield NHS Foundation Trust London, UK Samantha Sonnappa, MBBS, MD, DCH, MRCP, FRCPCH, PhD Clinician Scientist and Honorary Consultant in Respiratory Medicine UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust London, UK Catherine Wynne, BSc (Hons), MBChB, MRCPCH Consultant Paediatrician Department of Paediatrics Royal Alexandra Childrens Hospital Brighton, UK
viii
Abbreviations
ALL AML BAL b-HCG BPD CCAM chILD CT CXR DMD FEV1 FVC GBS GM-CSF HRCT ILD LCH LDH LPD MD MIBG acute lymphoblastic leukaemia acute myeloid leukaemia bronchoalveolar lavage beta-human chorionic gonadotropin bronchopulmonary dysplasia congenital cystic adenomatoid malformation interstitial lung disease in all age children computed tomography chest radiograph Duchenne muscular dystrophy forced expiratory volume in 1 second forced vital capacity Group B streptococcus (or Streptococcus agalactiae) granulocytemacrophage colony-stimulating factor high-resolution computed tomographic scan interstitial lung disease Langerhans cell histiocytosis lactate dehydrogenase lymphoproliferative disease muscular dystrophy metaiodobenzylguanidine scan MRI MYCN NEHI NHL NICU NIV PAP PAS PIE PL PPB pPNET RDS REM SFTP SMA SVC T-ALL T-IPPV UIP VC magnetic resonance imaging N-myc proto-oncogene protein neuroendocrine cell hyperplasia in infancy Non-Hodgkins lymphoma neonatal intensive care unit non-invasive ventilation pulmonary alveolar proteinosis periodic acid-Schiff [stain] pulmonary interstitial emphysema pulmonary lymphangiectasia pleuropulmonary blastoma peripheral primitive neuroectodermal tumour respiratory distress syndrome rapid eye movement surfactant protein (SP- prefix also commonly used) spinal muscular atrophy superior vena cava T-cell acute lymphoblastic leukaemia tracheostomy intermittent positive pressure ventilation usual interstitial pneumonia vital capacity
Chapter 1
Congenital lung malformations

Chris Dewhurst, George K. Kokai, Gurdeep S. Mann, Nigel (Ben) Shaw
Introduction
Congenital lung malformations comprise a rare but important group of disorders that may present at any age, from the previable fetus through to adulthood. They can range in severity from asymptomatic to incompatible with life. This collection of disorders can present in similar ways and may have a similar aetiology. In recent years more advanced radiological imaging has led to an increase in the number of lesions detected both antenatally and postnatally in asymptomatic individuals. The clinical dilemma is how best to manage this latter group.
Management is mainly symptomatic, although the rudimentary bronchus may act as a reservoir for infection and surgery is occasionally required. Pulmonary hypoplasia (1.2) is more common, and is usually secondary to intrauterine factors affecting pulmonary development (Table 1.1). The degree of underdevelopment of the lung(s) determines presentation, which ranges from apparent health through to severe, life-threatening respiratory distress. The lungs are often
Pulmonary agenesis, aplasia and hypoplasia

Pulmonary agenesis and aplasia are rare; they occur when the pulmonary bud fails to develop beyond the carina. This leads to complete absence of lung parenchyma, which in 30% of cases is bilateral and incompatible with life. If unilateral, the unaffected lung is usually normal but overinflates to fill the contralateral empty hemithorax. Antenatal ultrasound reveals increased echogenicity (bright lung) on the side of the abnormal pulmonary tissue (1.1). Children may present with respiratory distress shortly after birth or in later childhood with recurrent chest infections, wheeze or breathlessness; some remain asymptomatic and are diagnosed incidentally. The prognosis depends on the presence of other associated congenital anomalies (cardiac (14%), gastrointestinal (14%), skeletal (12%), vascular (9%) and genitourinary (9%)), which are more common with right-sided defects.
1.1 Antenatal ultrasound image of bright lung (between callipers). This is a non-specic marker and may indicate the presence of any of the congenital lung abnormalities. Serial ultrasound scans may also show regression of the lesion with a normal healthy lung being present after birth. The arrow indicates the heart.
2 Congenital lung malformations
(A)
(B)
1.2 (A) Frontal chest X-ray showing pulmonary hypoplasia. The lung volumes are small; the thorax is bell-shaped with crowding of the gracile ribs. (B) Normal neonatal chest X-ray showing adequate lung volumes.
stiff and difficult to ventilate. High ventilatory pressures, high frequency oscillatory ventilation or extracorporeal membrane oxygenation may be required. Air leaks, such as a pneumothorax (see Chapter 2) or pneumomediastinum are, therefore, relatively common in severe cases. The longterm prognosis is determined by the degree of hypoplasia and coexisting conditions.
Congenital diaphragmatic hernia

In congenital diaphragmatic hernia, the muscular diaphragm fails to develop normally allowing the abdominal components to herniate into the thorax
(1.3). The reduction in intrathoracic space results in underdevelopment of the fetal lung, which is often bilateral. Sixty per cent are detected antenatally and selected highrisk cases may be amenable to prenatal intervention, involving endotracheal obstruction to increase lung fluid volume. The amount of remaining healthy lung tissue and presence of associated anomalies determines the prognosis, with mortality remaining high (up to 60%). Postnatal management includes elective intubation and ventilation; nitric oxide, high frequency oscillatory ventilation and extracorporeal membrane oxygenation may be required, although trials have shown no benefit of the latter over conventional ventilation. Once stable, surgery is performed.
Congenital lung malformations 3
Table 1.1 Aetiology of pulmonary hypoplasia Reduced space available for fetal lung to develop Congenital diaphragmatic hernia CCAM Thoracic abnormalities (e.g. skeletal dysplasias, scoliosis) Pleural effusions Diaphragmatic eventration Renal agenesis (Potters syndrome) Urinary tract obstruction (posterior urethral valves) Oligohydramnios (prolonged rupture of membranes) Neuromuscular diseases (e.g. myotonic dystrophy, spinal muscular atrophy) Central nervous system lesions Phrenic nerve palsy Maternal depressant drugs Tetralogy of Fallot Hypoplastic right heart Pulmonary artery hypoplasia
Reduced lung uid volume
Reduced fetal breathing
Cardiac lesions with reduced pulmonary blood ow
Cystic lung disease

A common feature of one group of abnormalities is cystic lesions within the lungs. They may be single, multiple or contain adenomatous tissue (congenital cystic adenomatoid malformation, CCAM). They present in one of four ways; antenatally, at birth, in childhood or as an incidental finding.
Antenatally on ultrasound
1. Hyperechoic: solid lesions leading to bright lung (CCAM type III lesions see Table 1.2 or sequestration). 2. Cystic or mixed: type I/II CCAM, sequestration or a bronchogenic cyst (1.4). 3. Generalized hydrops caused by large lesions compressing the superior vena cava. It is often difficult to give an accurate diagnosis. Multicystic lesions may resemble congenital diaphragmatic hernia. Fetal magnetic resonance imaging (MRI; 1.5) may provide additional anatomical information. There are reports of lung cysts diagnosed in the antenatal period, which are not apparent after
birth. Some, however, can be seen after birth when high-resolution computed tomography (CT) scanning rather than chest radiography is used. Large lesions may be treated in utero by draining fluid-filled cysts or pleural effusions. More advanced fetal surgery to remove the lesion has also been performed with some success on babies who had been predicted to have a fatal outcome. The management of antenatally detected lesions that do not cause respiratory difficulties after birth remains controversial. Some clinicians advocate surgical removal (based on risk of infection and malignant transformation, although the incidence of the latter is unknown) while others advocate conservative management with follow-up and regular radiological review.
At birth
Large lesions can present at birth, which can put pressure on neighbouring structures. If compression of cardiovascular structures is significant, it may cause hydrops, pleural effusions or ascites. If lung tissue has been compressed in utero, pulmonary hypoplasia may have developed. Such lesions require surgical removal, which may be preceded by thoracocentesis to drain cysts or selective intubation and ventilation of the unaffected lung.
(A)
(B)
Infancy through to childhood

In this instance, the child may present with persistent cough, wheeze or recurrent chest infections (often involving the same area of lung). A chest radiograph may show an air-filled cyst (1.6) with or without a solid element, although the final diagnosis is usually made by high-resolution CT scan (1.7); the use of contrast may allow feeding/draining vessels to be seen. Most lesions will be removed once the infection has resolved.
Incidental nding
The best management of these lesions is controversial but large lesions are often removed because of concern of lifethreatening infections or malignancy occurring. Smaller lesions may be treated conservatively.
(C) 1.3 Left-sided Bochdalek congenital diaphragmatic hernia. (A) Radiographic appearance: multiple bowel loops are visible in the left hemithorax implying a degree of left pulmonary hypoplasia. Contralateral mediastinal shift is present which in this infant contributed to signicant right lung hypoplasia. The nasogastric tube terminates in the thorax consistent with an intrathoracic stomach. (B) Prenatal imaging of the same infant: coronal fetal T2W MR image showing normal bright lung parenchyma (arrow), contralateral shift of the heart (h) and an intrathoracic stomach (arrowhead). (C) Coronal fetal T1W MR image showing herniated and stomach (arrow) and bright meconium-laden bowel (arrowheads).
Congenital cystic adenomatoid malformations

The commonest form of congenital cystic lung lesions is CCAM (1.41.7), an adenomatous overgrowth of the terminal bronchiole that communicates abnormally with the tracheobronchial tree. CCAMs are divided into three main histological types (types IIII; see Table 1.2).
1.4 Antenatal ultrasound showing a mixed solid and cystic lung lesion (arrow). This appearance may indicate a type I/II CCAM, sequestration or a bronchogenic cyst.
1.6 Frontal chest X-ray showing a complex right lower zone hyperlucent area (arrows). On further imaging (1.7) this was conrmed as being a CCAM. A right intercostal chest drain was placed for a right pneumothorax resulting in subcutaneous emphysema along the right lateral chest wall.
1.5 Antenatal coronal T2W MR image of a hydropic fetus showing a large right-sided CCAM (arrow). Mass effect from the CCAM has impaired systemic venous return. Ascites (white arrowhead) and body wall oedema (black arrowhead) are present (image courtesy of Dr Ashley J. Robinson. FRCR FRCPC, Clinical Assistant Professor, University of British Columbia, Department of Radiology, BC Childrens Hospital, Canada)
1.7 Coronal reformatted MDCT image (lung window) of the patient in 1.6 showing a multi-macrocystic CCAM (type III) in the right lower lobe.
Table 1.2 Classication of CCAM Type I The commonest type of CCAM, which accounts for approximately two-thirds of the total number seen. Usually one cyst predominates, is >2 cm in size and is surrounded by smaller cysts. They may contain cartilage. One-quarter of all CCAMs are characterized by multiple, small cysts between 0.5 and 1 cm. These are lined with ciliated columnar epithelium, resemble bronchioles and are more frequently associated with other congenital anomalies such as cardiac, renal and chromosomal abnormalities. Multiple small (<5 mm) cysts characterize the type III lesions. These may be missed on antenatal ultrasound because the abnormal lung tissue may not be too dissimilar to normal lung tissue. lobar overinflation is more accurate. Congenital lobar emphysema may occur following a ball-valve-type obstruction and is most common in the left upper lobe. The cause may be intrinsic (e.g. absent cartilage, bronchial mucosal folds), extrinsic (compression from a thoracic mass) or, most commonly, idiopathic. Presentation may be antenatal (bright lung), at birth (approximately 30% with severe respiratory distress and mediastinal shift: it may be confused with tension pneumothorax) or as an asymptomatic, incidental finding. They are more common in males and in 20% of cases are associated with cardiac, renal or skeletal abnormalities. Management depends on clinical severity; surgical resection may be required, although there is no known risk of malignancy transformation,
Type II
Type III
Bronchogenic cyst
Bronchogenic cysts occur when an abnormal bud sprouts from the developing bronchial tree and develops into a separate thin-walled structure filled with fluid, air or both. They may also contain cartilage, smooth muscle or even gastro-oesophageal mucosa. They usually occur around the carina (1.8) and present with respiratory distress or infection. Surgical resection is usually required.
Congenital lobar emphysema

This is the term used for the massive overdistension of one or more lobes of the lung (1.9), although congenital
(A)
(B)
1.8 (A) Axial and (B) sagittal T2W MRI imaging of bronchogenic cyst (arrows) centred on the right lower lobe bronchus.
(A)
(B)
1.9 (A) Frontal chest X-ray showing congenital lobar overination, a clinical entity formerly referred to as congenital lobar emphysema. The left upper lobe is hyperlucent, hyperexpanded with attenuation of the bronchovascular markings. (B) Follow-up axial CT thorax (lung window) showing geographic area of hyperaeration (arrowheads) with minimal contralateral mediastinal shift. Lobar overination can result in signicant air-trapping and mass effect.
suggesting that intervention in asymptomatic individuals is unnecessary.
Pleural effusions
Neonatal pleural effusions (1.12) may be unilateral or bilateral and an isolated finding or associated with hydrops, pneumonia, congestive heart failure or Turners
Pulmonary sequestration
This term describes the presence of pulmonary tissue, which is separate from, although may be connected to, the normal bronchial system (1.10) and receives an anomalous blood supply (1.11). It occurs when an accessory lung bud develops from the primitive foregut and takes with it its own blood supply from the systemic circulation, usually the developing aorta. Ninety per cent are intrapulmonary, most commonly in the left lower lobe. Most present antenatally as bright lung but they may present later with neonatal respiratory distress, cough, haemoptysis or chest infections. Extrapulmonary sequestrations can have multiple arterial supplies and usually drain into the inferior vena cava or the portal vein. They do not communicate with normal lung tissue, are more likely to present neonatally and are associated with abnormalities in the cardiac/gastrointestinal systems. Management is mainly conservative, many of the lesions being asymptomatic and becoming smaller or disappearing during pregnancy or after birth. Surgery or embolization may be performed for larger lesions.
1.10 Frontal chest-X-ray showing a small radio-opaque sequestration in the left lower zone (arrowheads).
1.11 Axial contrast-enhanced CT image demonstrating the complex angio-architecture of an extralobar pulmonary sequestration (S) with abnormal arterial blood supply (arrow) directly from the descending thoracic aorta (Ao) and venous drainage (arrowhead) to the IVC.
1.12 Frontal chest X-ray of a hydropic infant showing large bilateral pleural effusions (lung edges marked by arrows) despite bilateral intercostal chest tube drainage. Note the marked generalised body-wall oedema. Ascites was present.
syndrome. Chylothorax, an effusion containing chyle or lymphatic fluid, can be spontaneous or acquired following birth trauma or surgery. The associated condition of congenital lymphangiectasia is discussed in Chapter 6. The effusions are clinically significant in about half of all cases at birth and may require ventilation and/or pleural drainage. If the fluid reaccumulates, dietary manipulation with medium chain triglycerides may be used to reduce the production of chyle. Somatostatins have also been used in a few cases of chylothorax with some success.
(50%), imperforate anus, Hirschsprung disease, biliary atresia and genitourinary defects. Chest X-ray may reveal a right-sided aortic knuckle or narrow or deviated trachea, and associated atelectasis or pneumonia may be seen. A barium oesophagram will demonstrate the degree of compression of the oesophagus; further imaging with echocardiography and either MRI or contrast-enhanced CT is indicated. Symptomatic rings require surgical division. Tracheomalacia commonly remains, causing persistent stridor for weeks or months.
Tracheal abnormalities
These occur as a result of aberrant embryological formation of the septum separating the trachea from the oesophagus. The most severe types are agenesis or atresia of the trachea, which are almost always fatal. Tracheal stenosis results from complete tracheal rings (lacking the posterior membranous portion). It is rare and presents at birth or later in life with biphasic stridor or dyspnoea; management is either conservative or interventional (dilatation or reconstruction). Tracheal webs occur when a thin layer of tissue partially obstructs the lumen, causing symptoms dependent upon the size of the remaining air passage. Most webs can be ruptured during bronchoscopy examination, with some requiring laser therapy or surgical resection.
Vascular rings
This is an anomalous configuration of the aortic arch and/ or associated vessels forming a ring around the trachea or oesophagus. The commonest is a double aortic arch formed from both the right and left fourth branchial arches. A pulmonary sling is created when the left pulmonary artery originates anomalously from the posterior aspect of the right pulmonary artery compressing the lower trachea and right mainstem bronchus; it may lead to stridor, obstructive emphysema or atelectasis of either lung. Associated defects include cardiac abnormalities

Tracheomalacia results from a structural weakness in the tracheal wall, sometimes with a widening of the membranous portion and can be primary or secondary to external obstruction (see Vascular rings above). Supportive treatment may be required such as continuous positive airway pressure or, less commonly, tracheostomy. Growth of the trachea will often eliminate symptoms by the age of 2 years. with deformities of the arm and hand. It is usually rightsided (75%) and may be associated with gastrointestinal, renal, cardiac or haematological problems. Surgery may be required depending on the defect present.
Other congenital lung anomalies

In Scimitar syndrome, an anomalous vein (the scimitar, 1.13) connects the pulmonary and systemic venous circulations, creating a left-to-right shunt. There is
Pulmonary arteriovenous malformation

Pulmonary arteriovenous malformations (abnormal communications between pulmonary arteries and veins) are uncommon. Two-thirds of cases are associated with hereditary haemorrhagic telangiectasia. They may present in infancy with cyanosis, congestive heart failure or even fulminant respiratory failure but more commonly present later in life with dyspnoea or haemoptysis. Physical signs may include clubbing, cyanosis, bruit and platypnea (improvement in dyspnoea on reclining). Classical radiological appearance is of a round mass of uniform density, frequently lobulated but sharply defined, more commonly in the lower lobes; they can be single (two-thirds) or multiple (one-third). Further investigations, including contrast (bubble) echocardiogram and/or cardiac catheterization, are usually required. Management ranges from conservative observation, therapeutic embolization or surgical resection.
(A)
Chest wall deformities

These range from asymptomatic pectus excavatum or carinatum through to life-threatening asphyxiating thoracic dystrophy (Jeunes syndrome). Jeunes is an autosomal recessive syndrome where failure of chest wall growth in utero results in a narrow chest cavity and pulmonary hypoplasia (see Chapter 3). Many patients die at birth, although there are increasing reports of prolonged survival. There is currently no recognized treatment although there have been several attempts to increase thoracic cavity volume surgically. Poland syndrome involves hypoplasia of the chest wall structures (pectoralis major and minor, serratus anterior, ribs and soft tissues) and is often associated
(B) 1.13 Contrast-enhanced MDCT images of Scimitar syndrome. (A) Coronal maximal intensity projection image showing vertical descent of an anomalous right lower lobe pulmonary vein (arrow) draining the right lower lobe via the IVC. (B) Corresponding 3D volume-rendered image showing anomalous vertical veins (arrowheads) draining into the IVC (arrow).
associated right lung hypoplasia with mediastinal shift and cardiac lesions (atrial septal defect, ventricular septal defect and aortic coarctation) occur in approximately 75% of cases. Presentation varies from an incidental finding to severe heart failure with pulmonary hypertension. Surgery, either division of the anomalous vessel or a right pneumonectomy, may be required.
Further reading
Barnes NA, Pilling DW. Bronchopulmonary foregut malformations: embryology, radiology and quandary. Eur Radiol 2003; 13: 265973. Horak E, Bodner J, Ingmar Gassner I, et al. Congenital cystic lung disease: diagnostic and therapeutic considerations. Clini Pediatr 2003; 42: 25161.
Shanmugam G. Adult congenital lung disease. Eur J Cardiothor Surg 2005; 28: 48389. Shanmugam G, MacArthur K, Pollock JC. Congenital lung malformationsantenatal and postnatal evaluation and management. Eur J Cardiothor Surg 2005; 27: 4552. Wallis C. Clinical outcomes of congenital lung abnormalities. Paediatr Respir Rev 2000; 1: 32835. Zach MS, Eber E. Adult outcomes of congenital lower respiratory tract malformations. Thorax 2001; 56: 6572.
Chapter 2
11
Neonatal lung disease

Anne Greenough, Caroline May
Introduction
Respiratory disorders are the commonest cause of neonatal unit admission and a major cause of neonatal mortality and morbidity. There are some generic investigations (Table 2.1); in particular, it is always important to exclude infection.
hence phosphatidylglycerol, a spreading agent, is required. Thus, relatively mature infants with impaired phosphatidylglycerol synthesis suffer from RDS. Histology of the lungs reveals hyaline membranes lining the terminal airways (2.1). Predisposing factors are shown in Table 2.2. Table 2.2 Predisposing factors for RDS Gestational age: surfactant synthesis increases with increasing gestational age and thus the incidence of RDS is inversely related to maturity at birth. Males are more likely to develop RDS; androgens delay surfactant maturation and the appearance of phosphatidylglycerol. Fetuses of women with diabetes have abnormal surfactant synthesis; insulin delays the maturation of type II pneumocytes with a decreased proportion of dipalmitylphosphotidylcholine, delayed appearance of phosphatidylglycerol and inhibition of SFTPA1 and SFTPB mRNA accumulation and SFTPA1 and SFTPB gene expression. Haemolytic disease of the newborn leads to b-islet cell hypertrophy, increased levels of insulin and delayed pulmonary maturity. Asphyxia, hypoxia, hypotension and hypothermia can impair surfactant synthesis and/or increase alveolar capillary leakiness. Exposure to cold results in impaired surfactant function; below 34C dipalmitylphosphotidylcholine cannot spread to form an adequately functioning monolayer. Genetic predisposition: specic alleles of SFTPA1 and SFTPB increase susceptibility to RDS.
Respiratory distress syndrome

Respiratory distress syndrome (RDS) due to surfactant deficiency affects about 1% of newborns. Surfactant is a complex mixture of phospholipids, primarily desaturated dipalmitylphosphotidylcholine and phosphatidylglycerol and surfactant proteins (SFTPA1, SFTPB, -C and -D). Dipalmitylphosphotidylcholine is primarily responsible for lowering surface tension, but is solid at body temperature,
Table 2.1 Routine investigations for acquired neonatal lung disorders Chest radiograph Arterial blood gases Blood culture Haemoglobin and white cell count Blood for electrolytes, calcium and albumin Measurement of coagulation Infants presenting in the immediate newborn period: Gastric aspirate and ear swab (the ear contains a pocket of amniotic uid) Placental histology and culture
12 Neonatal lung disease
fine granular opacification in both lung fields and an air bronchogram where the air-filled bronchi stand out against the atelectatic lungs; the appearance, however, can be mimicked by Group B streptococcal septicaemia and pneumonia. If disease is severe, the lungs may be so opaque that it is impossible to distinguish between the lung fields and cardiac silhouette (i.e. a whiteout).
Prophylaxis Antenatal agents

Corticosteroids (Table 2.3) significantly reduce the incidence of RDS, neonatal death, intracerebral haemorrhage and necrotizing enterocolitis. There is no benefit from thyrotrophic-releasing hormone. There is equivocal evidence for the use of Ambroxol.
2.1 Histology of hyaline membrane disease. Note the exfoliating, necrotic mucosa in the bronchioles (black arrows) and the hyaline amorphous material lining the alveoli (hyaline membranes, white arrows) (courtesy of Dr Pollina, Paediatric Pathologist, Kings College Hospital).
Management
Surfactant (Table 2.4) significantly reduces the incidence of RDS, pneumothoraces and the combined outcome of death and bronchopulmonary dysplasia (BPD) and improves survival. Prevent hypoxaemia, acidaemia and hypothermia, which inhibit surfactant synthesis. Avoid excessive fluid administration; babies with RDS have increased capillary leakiness, and pulmonary oedema will worsen hypoxaemia. Antibiotics must be given (e.g. penicillin and an aminoglycoside), as sepsis, particularly due to Streptococcus agalactiae (or Group B streptococcus, GBS) cannot be excluded until blood culture results are known at48 h.
Presentation
Infants with RDS present within the first 4 h of birth with: tachypnoea (respiratory rates >60/min); intercostal and subcostal indrawing, sternal retraction and nasal flaring; grunting during expiration, which occurs in other neonatal respiratory disorders; an association with a low lung volume; and a worsening dyspnoea over the first 2436 h after birth due to the disappearance of small quantities of surfactant present in an infant with RDS and the inhibitory effect of the exudation of plasma proteins on surfactant. At approximately 3648 h of age, endogenous surfactant synthesis commences and the infants respiratory status improves; this is associated with a spontaneous diuresis. Very premature infants, however, are often intubated at birth and given surfactant; they may never develop the classical signs listed above.
Investigations Chest radiograph

This should not be undertaken routinely in the first 4 h, as interpretation may be difficult because of retention of fetal lung fluid. The characteristic chest radiograph appearance (2.2) is of diffuse atelectasis resulting in
2.2 Chest radiograph of a 26-week gestation infant with RDS. There is diffuse atelectasis. The endotracheal tube tip is too low.
Neonatal lung disease 13

Prone positioning improves oxygenation. A high level of positive end expiratory pressure will restore the functional residual volume towards normal values, increase mean airway pressure and improve oxygenation.
Table 2.3 Guidelines for antenatal steroid use Should be considered for all women at risk of preterm labour between 24 and 36 weeks. Benet is maximal in infants delivered between 24 and 168 h of maternal therapy being started, but is still seen in infants whose mothers have received <24 h of treatment. Therefore, corticosteroids should be given unless immediate delivery is anticipated. Betamethasone (two doses 24 h apart) rather than dexamethasone is preferred, because it is associated with a lower incidence of periventricular leucomalacia. In the absence of chorioamnionitis, antenatal corticosteroids are recommended in pregnancies complicated by preterm and prolonged rupture of the membranes and in other complicated pregnancies, unless there is evidence that corticosteroids will have an adverse effect on the mother. Table 2.4 Surfactant administration Natural rather than a synthetic surfactant should be given, as they are associated with a lower pneumothorax rate and risk of mortality. Two doses should be given. Surfactant should be given prophylactically, rather than when RDS is established, as this decreases the risk of pneumothorax, pulmonary interstitial emphysema (PIE) and mortality.
High volume strategy

Restrict fluid intake diuretics. Broad-spectrum antibiotics (with careful monitoring for renal dysfunction) with aminoglycosides.
Transient tachypnoea of the newborn

This (2.3) occurs in between 4 and 5.7 per 1000 infants born at term and at least 10 per 1000 premature infants.
Predisposing factors
Caesarean section; affected infants have lower adrenaline levels than those exposed to labour and hence poorer lung fluid clearance. Maternal asthma (likely a genetic predisposition to beta-adrenergic hyporesponsiveness). Primary ciliary dyskinesia should always be considered.
Presentation
Within the first 4 h of birth: tachypnoea hyperinflation no grunting or recession.
Acute respiratory distress syndrome

This can occur following asphyxia, shock, sepsis (most common) or meconium aspiration syndrome.
Investigations Chest radiograph

Diffuse pulmonary infiltrates. In severe cases, there is a whiteout.
Management
Surfactant administration can improve oxygenation and is most effective if given early and in larger doses than used in RDS.
2.3 Chest radiograph of a 35-week gestation infant delivered by elective Caesarean section who had transient tachypnoea of the newborn. The radiograph demonstrates wet lungs with prominent perihilar vascular markings and oedema in the interlobar septa.
Management
Keep nil by mouth to reduce the risk of aspiration. Antibiotics as above. Respiratory support sufficient to achieve appropriate blood gases (usually <40% oxygen for <24 h).
Presentation Early onset

Infants with transplacentally acquired infection present at birth and those infected with organisms acquired from the birth canal within the first 48 h after birth. Progressive respiratory distress and signs of systemic sepsis. Non-specific signs: poor feeding and irritability. Fever or hypothermia. Most cases of GBS pneumonia present within the first 46 h; if the infant does not receive prompt treatment, the condition rapidly deteriorates such that they require intubation and ventilation for apnoea, and develop pulmonary hypertension. Infants with congenitally acquired listerial infection are often extremely ill at birth with severe pneumonia and hepatomegaly. Diarrhoea and an erythematous skin rash may occur. Characteristically, affected infants have small pinkish-grey cutaneous granulomas; these granulomas are widespread in lung, liver and nervous system.
Pneumonia
Early onset (within 4 days of birth) pneumonia is acquired transplacentally or during labour/delivery whereas late onset pneumonia usually occurs in ventilated, prematurely born infants; causative organisms differ (Table 2.5).
Risk factors for early onset pneumonia

Prolonged rupture of the membranes, premature labour and organisms present in the vagina. Chorioamnionitis, prolonged labour and frequent pelvic examinations in labour. Mothers with vaginal GBS but little or no circulating anti-GBS immunoglobulin. Maternal infection with Listeria monocytogenes acquired by infected food, especially dairy products. Increased risk in women with HIV.
Late onset
Increased requirement for respiratory support. Non-specific: feed intolerance, irritability temperature instability. or
Table 2.5 Organisms causing neonatal pneumonia Early onset Transplacentally acquired organisms include Listeria monocytogenes, Mycobacterium tuberculosis, Treponema pallidum, rubella virus, cytomegalovirus, herpes simplex virus, adenovirus and inuenza A virus. 6070% of cases of pneumonia caused by ascending infection are due to Streptococcus agalactiae (GBS). Escherichia coli is the second commonest cause of early neonatal sepsis. Other organisms that cause ascending infection include Haemophilus inuenzae, Streptococcus pneumoniae, Listeria monocytogenes, Klebsella pneumoniae, Candida albicans, adenovirus, cytomegalovirus, herpes simplex virus and echovirus. Late onset The commonest responsible bacteria are coagulase-negative staphylococci, S. aureus and gram-negative bacilli, including Klebsiella, E. coli and Pseudomonas. Viruses, including respiratory syncytial virus, inuenza virus, parainuenza virus, adenovirus and rhinovirus; viral pneumonia usually occurs when there are high levels of infection in the community. Fungal infections are a signicant problem if infants have had prolonged exposure to antiobiotics, particularly third-generation cephalosporins. Pneumonia occurs because of blood-borne spread.

Diagnosis Infection screen
This may be negative, particularly in late onset pneumonia. GBS is easy to culture and will usually grow from surface swabs and the gastric aspirate. In addition to the routine investigations described in Table 2.1, consider the following: examination of the first meconium passed for Listeria; serological testing of the mother and infant for syphilis or viral agents; if infection due to herpes is likely, viral cultures from maternal lesions and the infant.
Management Early onset

Initially treat with a combination of ampicillin or benzylpenicillin and an aminoglycoside. Modification may be necessary once the culture results are known or there is good reason to suspect a particular organism: Haemophilus influenzaeampicillin resistance is emerging and cefotaxime should be added; Escherichia colicefotaxamine or ceftriaxone; Listeriaampicillin plus gentamicin (Listeria are resistant to all third-generation cephalosporins). Antibiotic therapy should continue for at least 10 days and for 3 weeks if the pneumonia is due to Staphylococcus aureus and longer term in the presence of abscess formation. Empyema should be drained and intravenous antibiotics administered for at least 2 weeks. Prevent vertical transmission of GBS by giving intrapartum antibiotic prophylaxis (penicillin or ampicillin) to women identified by screening in pregnancy to carry GBS and/or have risk factors, such as: a previous infant with GBS disease; GBS bacteruria during pregnancy;
Chest radiograph
Lobar (2.4) or segmental consolidation, atelectasis or diffuse changes (2.5), including haziness or opacification. Pleural effusions may occur, particularly if pneumonia is the result of bacterial or fungal infection. Rarely, there is abscess or pneumatocoele formation; these complications are most likely to occur with staphylococcal or coliform pneumonia.
2.4 Chest radiograph demonstrating left upper lobe consolidation due to early onset pneumonia. The infants mother had been pyrexial in labour and there had been prolonged rupture of the membranes. The infant had respiratory distress form birth; this resolved during a course of antibiotics.
2.5 Chest radiograph of an infant of 41 weeks of gestational age who was born at home, under water. The radiograph demonstrates widespread changes and the GBS was grown from the blood cultures.
preterm labour; ruptured membranes for more than 18 h before delivery; and intrapartum fever.
Table 2.6 Chest radiograph appearances in meconium aspiration syndrome Initially there is widespread patchy inltration and overexpansion, meconium is sticky, and when inhaled creates a ball valve mechanism in the airways, resulting in gas trapping and predisposing to air leaks. Small pleural effusions occur in approximately 20% of patients. By 72 h of age, in severe cases, the appearance is often changed to that of diffuse and homogeneous opacication of both lung elds due to an inammatory pneumonitis with alveolar collapse. Air leaks, in particular pneumothorax and pneumomediastinum, are very common, occurring in approximately 20% of infants. The changes gradually resolve over the following week, but in severe cases the chest radiograph appearance may merge into the pattern seen in BPD.
Late onset
Initial treatment is third-generation cephalosporin and vancomycin (most likely coagulase-negative staphylococci). If the infant is already on antibiotics, the regimen should usually be changed and spectrum of cover broadened.
Meconium aspiration syndrome

Meconium staining of the amniotic fluid occurs in 820% of pregnancies. Five per cent of babies born through meconium-stained amniotic fluid develop meconium aspiration syndrome, a disease of term or post-term babies. Meconium staining of the liquor occurs in <5% of preterm pregnancies and suggests infection.
Presentation
Tachypnoea within the first hours after birth. Intercostal and subcostal recession and use of accessory respiratory muscles. Hypoxia due to ventilationperfusion imbalance and pulmonary hypertension. Widespread crackles. Overdistended chest due to gas trapping. The chest radiograph appearance varies according to the postnatal age of the patient (Table 2.6).
Management
Supplementary oxygen to maintain the saturation levels at 95% or the arterial oxygen level >10 kPa. Intubation and ventilation if the PaCO2 rises above 8.5 kPa (60 mmHg), particularly if the infant is hypoxic. If the infant has hypoxic ischaemic encephalopathy, control of the blood gases needs to be more rigid. Surfactant administration reduces the risk of requiring extracorporeal membrane oxygenation. Administering the surfactant by dilute surfactant lavage may be particularly effective in improving gas exchange. Broad-spectrum antibiotics should be given, because meconium predisposes to pulmonary infection, particularly with Escherichia coli.
Prevention
Avoidance of post-term delivery is the most important factor in reducing meconium aspiration syndrome. Intubation and suctioning should be restricted to newborns that have a heart rate <100 beats/min, poor respiratory effort and poor tone. Direct endotracheal suctioning is only indicated if meconium is seen below the cords. Compression of the neonatal thorax is not recommended, as it is unlikely to prevent gasping and may stimulate respiratory efforts. Aspiration of the stomach may prevent subsequent inhalation following vomiting or reflux of previously swallowed meconium.
Pulmonary hypertension of the newborn

This may be primary or secondary. Infants with primary pulmonary hypertension have no or very mild lung

disease and are described as having persistent pulmonary hypertension of the newborn, with right to left shunts at the level of the ductus arteriosus and the foramen ovale. Causes of secondary pulmonary hypertension are listed in Table 2.7. Table 2.7 Causes of secondary pulmonary hypertension Severe intrapartum asphyxia. Infection, particularly GBS. Pulmonary hypoplasia, particularly associated with congenital diaphragmatic hernia. Congenital heart disease: conditions that cause myocardial failure or obstruct the venous outows from the lungs. Medication: prostaglandin synthase inhibitors. Iatrogenic: overventilation. Alveolar capillary dysplasia. whereas in cyanotic congenital heart disease it will not rise above 56 kPa (37.545 mmHg). Alveolar capillary dysplasia should be suspected in infants with pulmonary hypertension unresponsive to maximal cardiorespiratory support. In such cases, a lung biopsy can establish the diagnosis.
Management
Minimize handling, which can precipitate severe hypoxaemia. Maintain an appropriate systemic blood pressure to minimize the rightleft shunt. Inhaled nitric oxide improves oxygenation and reduces the combined outcome of death or need for extracorporeal membrane oxygenation in infants with pulmonary hypertension at term or near term. A concentration of 5 p.p.m. should be used. There is currently insufficient evidence to recommend routine use of nitric oxide in prematurely born babies or in term babies with congenital diaphragmatic hernia. Systemic vasodilators can improve oxygenation but may cause systemic hypotension. If inhaled nitric oxide is unavailable, other vasodilators should only be given with careful blood pressure monitoring and prompt treatment for any hypotension.
Presentation
Usually within 12 h of birth. Cyanosis with only mild respiratory distress and rarely grunting. Loud second heart sound (increased pulmonary artery pressure) a soft systolic murmur due to tricuspid or mitral incompetence. Earlier onset (within 6 h of birth) in critically ill neonates with GBS, severe asphyxia or congenital diaphragmatic hernia.
Pneumothorax
Spontaneous pneumothoraces can occur immediately after birth due to the high transpulmonary pressure swings generated by the first spontaneous breaths although they are more common as a complication of respiratory disease or a congenital malformation. Approximately 510% of ventilated babies develop an air leak if they fight the ventilator. Rarely, pneumothoraces occur because of direct injury to the lung, perforation by suction catheters or introducers passed through the endotracheal tube or by central venous catheter placement.
Diagnosis
Hypoxaemia disproportionately severe for the radiological abnormalities (chest radiograph may be normal). Evidence of a right-to-left ductal shunt: a lower level of oxygenation in the distal aortic blood (umbilical artery catheter) compared with pre-ductal blood (right radial artery). Structurally normal heart on echocardiogram. The most important differential diagnosis is cyanotic congenital heart disease. The response to ventilation with 100% oxygen can help to distinguish the two conditions. In some infants with pulmonary hypertension, the arterial oxygen level will increase to >13 kPa (100 mmHg),
Presentation
Small pneumothoraces may be asymptomatic and picked up incidentally on a chest radiograph. A large pneumothorax will frequently cause marked respiratory distress, pallor, shock and desaturation.
A tension pneumothorax results in a shift of the mediastinum and abdominal distension due to displacement of the diaphragm. Pneumothorax causes and aggravates haemorrhage into the germinal layer and cerebral ventricles of preterm infants.
Chest radiograph appearance

A large pneumothorax is associated with absent lung markings and a collapsed ipsilateral lung; however, a stiff lung will not fully collapse (2.6). If the pneumothorax is under tension, there will also be eversion of the diaphragm, bulging intercostal spaces and mediastinal shift (2.7). A small pneumothorax may only be recognized by a difference in radiolucency between the two lung fields (2.8).
Management
Careful observation if asymptomatic. 100% inspired oxygen favours resorption of the extraalveolar gas (should not be used in infants at risk of retinopathy of prematurity).
2.6 Chest radiograph of a 26-week infant with RDS and a left-sided pneumothorax. There is free air, but the stiff left lung has not fully collapsed.
Drainage of a symptomatic or tension pneumothorax

If the infant is in extremis and there is no time to insert a chest drain, emergency aspiration should be undertaken with a butterfly needle (18 gauge) attached to a threeway tap held under water in a small sterile container. Otherwise a chest tube (French gauge 1014) should be inserted (Table 2.8; 2.9 and 2.10).
Pulmonary interstitial emphysema

The incidence of pulmonary interstitial emphysema (PIE) is inversely related to birthweight. It has rarely been described in spontaneously breathing infants and occurs mainly in neonates with RDS exposed to high peak inspiratory pressures and/or malpositioned endotracheal tubes.
Presentation
PIE may be diagnosed on a routine chest radiograph of a ventilated infant (2.11). More commonly, a ventilated infant becomes increasingly difficult to ventilate.
2.7 Chest radiograph of a 24-week infant with a large right pneumothorax. There is eversion of the right diaphragm and shift of the mediastinum to the left.
2.8 Chest radiograph of an infant with a rightsided pneumothorax indicated by differences in the radiotranslucency of the two hemithoraces.
2.9 Anteroposterior chest radiograph demonstrating a pneumothorax that has not been successfully drained; free air in the left hemithorax being demonstrated by a difference in the translucency of the two sides.
Table 2.8 Chest tube drainage of a pneumothorax The tip of the chest tube should lay retrosternally as this achieves the most effective drainage. The position of the drain should be checked on a lateral chest radiograph (2.9, 2.10). The tube should be connected to an underwater seal drain with suction of 510 cmH2O. Heimlich valves are useful during transport but should not be used for long-term drainage. The chest drain should be removed 24 h after there is no bubbling of gas into the water seal.

Hyperinflation and a characteristic cystic appearance (2.12), which may be diffuse, multiple or small, nonconfluent, cystic lucencies. At a later stage large bullae may appear.
2.10 A lateral decubitus chest radiograph demonstrates that the chest tube tip was not placed sufciently anteriorly.
Management
If the PIE is localized, the infant should be nursed in the lateral decubitus position with the affected lung dependent and hence underventilated; this promotes partial or complete atelectasis. Selective bronchial intubation to bypass the affected lung for 2448 h may be helpful if the PIE persists;
resection of the affected area may be necessary to alleviate respiratory distress. If the infant has widespread PIE, the positive end expiratory and peak-inflating pressures should be reduced to the minimum compatible with acceptable gases and the infant paralysed to try and avoid extension of the air leak. High-frequency jet, flow interruption or oscillatory ventilation or continuous negative pressures with intermittent mandatory ventilation have been anecdotally described as helpful.
Pulmonary oedema
Pulmonary oedema is most commonly seen in infants with a large left-to-right shunt from a patent ductus arteriosus.
Presentation
Tachycardia. Pale and sweaty. Poor volume peripheral pulses with reduced cardiac output.
Investigations
The chest radiograph demonstrates perihilar shadowing obscuring the vascular structures and linear septal shadows (Kerley B lines) in the lower part of the lungs; in the most severe cases, there may be fluid visible in the horizontal and oblique fissures, cardiomegaly and pericardial effusions. An echocardiogram is required.
Management
Restrict fluid input. Diuretics reduce the circulating volume and clinical manifestations of pulmonary oedema, but may critically lower cardiac output. Positive pressure ventilation may be needed to improve oxygenation. Treatment of any underlying structural or functional cause is essential.
2.11 A routine daily chest radiograph of a 25-week gestationventilated infant revealed early PIE. The infant is very oedematous.
Pulmonary haemorrhage
Pulmonary haemorrhage occurs most commonly in very low birthweight or growth-retarded babies who have heart failure secondary to a large pulmonary blood flow due to a patent ductus arteriosus. It can also occur following severe birth asphyxia, left heart failure, sepsis, fluid overload and clotting abnormalities.
Presentation
A massive pulmonary haemorrhage causes sudden deterioration and hypotension with a limp and unresponsive baby with copious bloody secretions from the airway. If secondary to heart failure, the infant may be tachycardic, with hepatosplenomegaly and a triple rhythm. Affected infants are dyspnoeic and cyanotic with widespread crackles and reduced breath sounds.
2.12 Chest radiograph demonstrating widespread severe PIE resulting in overdistension of the lungs with attened diaphragms.

Usually demonstrates a white out, with just an air bronchogram visible (2.13). Rarely, a lobar pattern of consolidation is found, suggesting that the haemorrhage has occurred only in part of the lung.
Bronchopulmonary dysplasia
Chronic oxygen dependency following birth has been called chronic lung disease or BPD; the consensus is now to use BPD as it better distinguishes the neonatal disease from other chronic respiratory conditions. The aetiology of BPD is multifactorial (2.14). The incidence is inversely related to gestational age. In babies who develop traditional BPD, there is progression from the initial exudative stage of diffuse alveolar damage in RDS to a regenerative and fibroproliferative reparative stage (2.15, 2.16). There are few reports describing the pathology of new BPD; they highlight dilated distal gas exchange structures, decreased alveolarization, minimal small airway injury and less prominent inflammation and fibrosis.
Management
Infants with a massive pulmonary haemorrhage should be intubated and ventilated; frequently peak inflation pressures above 30 cmH2O are necessary to achieve acceptable blood gases. A high positive end expiratory pressure should be used to help redistribute fluid and improve oxygenation. Neuromuscular blockade and sedation should be used until the haemorrhage is controlled. Although surfactant administration has been incriminated in increasing the risk of a pulmonary haemorrhage, once a haemorrhage has occurred a single dose of surfactant has been shown to improve oxygenation. Frequent suctioning is initially required to prevent copious bloody secretions blocking the endotracheal tube. Infection may cause a pulmonary haemorrhage; thus, broad-spectrum antibiotics should be administered, ensuring coverage against infection by Staphylococcus and Pseudomonas. Restrict fluid input, particularly if there is a coexisting patent ductus, and give diuretics if there is fluid overload.
Presentation
The majority are born very prematurely and at 23 months old remain dyspnoeic and require oxygen supplementation. Some may have had minimal or no initial respiratory distress, but then deteriorate and become chronically oxygen dependent. Infants with severe BPD may be oedematous and have signs of right heart failure. They have a chronic increased work of breathing. High risk of deterioration related to recurrent respiratory infections. Cor pulmonale develops in those who are chronically hypoxaemic. Copious endotracheal secretions, aspiration and tracheomalacia and/or bronchomalacia are common. Feeding difficulties and aspiration are common. Failure to thrive. Osteopenia and fractures can occur due to severe metabolic bone disease.
Chest radiograph
A variety of abnormalities is seen on the chest radiograph in the figure (2.17): small hazy lung fields in those least severely affected; large airway collapse; persistent atelectasis; interstitial shadows; lobar hyperinflation; gross cystic abnormalities.
2.13 Chest radiograph of a 25-week infant with a patent ductus arteriosus demonstrating widespread consolidation following a pulmonary haemorrhage.
Predisposed Infant Immaturity Family history Respiratory distress syndrome Severe Lung Disease Patent ductus arteriosis & fluid overload Pulmonary interstitial emphysema
High Level of Respiratory Support Volutrauma Oxygen support
Contributory Factors Infection Surfactant abnormalities Disturbance of elastase/protease Lung growth arrest
Bronchopulmonary Dysplasia 2.14 Multifactorial aetiology of BPD.
(A)
(B)
2.15 BPD: areas of emphysema alternating with areas of collapse and atelectasis. The enlargement on the right shows thick hypercellular intra-alveolar septa (courtesy of Dr Pollina, Paediatric Pathologist, Kings College Hospital).
(A)
(B)
2.16 BPD: the lung parenchyma shows markedly thickened alveolar septa with signicant septal brosis (>25 mmgrade 3 brosis). The picture to the right represents a normal lung of an infant of the same maturity as the infant whose specimen is on the left. Note in the normal lung, the alveolar septa are thin and slender with abundant blood vessels (courtesy of Dr Pollina, Paediatric Pathologist, Kings College Hospital).
In older babies, computed tomography scans give more detailed information than a chest radiograph; common findings are multifocal areas of hyperaeration and linear and triangular subpleural opacities.
Management
Aimed at minimizing lung damage: promoting weaning from ventilator; progressively lower concentrations of oxygen; keep free from infection. Treat chest infections promptly. Excessive fluid intake should be avoided. The optimum oxygen saturation level for infants with BPD remains controversial. We recommend that infants who are older than 1 month of age, should have an echocardiograph to determine whether they have pulmonary hypertension; if detected, then oxygen saturation is maintained at least at 95%; if pulmonary hypertension is not present then oxygen saturation is maintained at 92%. Babies with BPD may require prolonged ventilation; chronic use of either an oral or nasal endotracheal tube can result in cosmetic defects. Tracheostomy avoids those problems and eases nursing of an increasingly active
infant, but may be difficult to close in this population; thus, their use should be restricted to babies who remain fully ventilated after 3 months of age, or have profound cyanotic spells related to tracheobronchomalacia. On the neonatal intensive care unit (NICU), bronchodilators are rarely necessary and should be
2.17 Chest radiograph demonstrating severe BPD with widespread interstitial shadows and cysts. There is particularly overdistension of the left lung and attening of the diaphragm.
administered only to those who have symptomatic wheeze. We consider corticosteroids only for infants who are at least 2 weeks of age and have severe lung disease, remaining ventilator dependent and in high oxygen concentrations. Systemic corticosteroids are prescribed for 3 days and only continued, for a further 6 days in a reducing dose, if there has been an obvious clinical response (a significant reduction in respiratory support requirements).
Fluid regulation
A single dose of frusemide should be given to treat acute fluid overload. Regular chlorothiazide and spironolactone should be given to infants who have signs of incipient right failure or are poorly tolerant of a modest fluid volume regimen (120 ml/kg per day). If chronic diuretic therapy is given, acidbase balance, chloride and calcium levels must be carefully monitored and regular renal ultrasounds should be performed to check for the development of nephrocalcinosis.
Nutrition
Babies with BPD require a calorie intake approximately 2040% more than age-matched infants. Energy requirements above 150 kcal/kg are rare and usually associated with malabsorption. Large volume, enterally administered feeds are poorly tolerated and restriction to 120 ml/kg per day, using either a concentrated feed or calorie supplementation, is preferable. Administration of a nutrient-enriched formula (higher intake of protein, calcium, phosphorus and zinc), can achieve greater linear growth, radial bone mineral content and lean mass.
Further reading
Greenough A. Acute respiratory disease. In Robertons Textbook of Neonatology, 5th edition. Rennie JM, Roberton NRC (Eds). Edinburgh: Churchill Livingstone, 2011. Kinsella JP, Greenough A, Abman SH. Bronchopulmonary dysplasia. Lancet 2006; 367: 142131. Royal College of Obstetricians and Gynaecologists (RCOG). Antenatal Corticosteroids to Prevent Respiratory Distress Syndrome. Guideline No 7. London: Royal College of Obstetricians and Gynaecologists (RCOG), 2010. Suresh GK, Soll RF. Overview of surfactant trials. JPerinatol 2005; 2: 54044. Wiswell TE. Handling the meconium stained infant. Semin Neonatol 2001; 6: 22531.
Immunization
Routine immunizations, but a killed polio vaccine, should be given once BPD babies reach 2 months of age, even though they remain on the NICU. Immunization against influenza and immunoprophylaxis against respiratory syncytial virus should be considered, especially for babies receiving home oxygen therapy.
Chapter 3
25
Neuromuscular and chest wall disease (including non-invasive ventilation)

Anita K. Simonds
Introduction
The commonest inherited neuromuscular disorders are Duchenne muscular dystrophy (DMD) with a UK prevalence of 1 in 3500 live male births and spinal muscular atrophy (SMA), which occurs in approximately 1 in every 6000 births (with a heterozygote gene carrier frequency of 1:40). These conditions are often associated with developmental chest wall deformities such as scoliosis, which will be more severe if respiratory muscle and truncal weakness are present in infancy. A variety of other congenital disorders and syndromes are associated with scoliosis (e.g. congenital heart disease, neurofibromatosis, Marfan and KlippelFeil syndromes), and if progression of scoliosis is severe before lung growth is complete, these children may have additional alveolar and pulmonary vascular hypoplasia. Neuromuscular and chest wall conditions that predispose the individual to respiratory failure are shown in Table 3.1. Although the incidence of most of these disorders is relatively fixed, the prevalence is increasing, as many affected children that previously died prematurely are living longer and some surviving to adulthood. In Denmark, for example, the prevalence of DMD has risen to 1 in every 24 000 live births with a 1:80 autosomal recessive gene frequency, and mortality has fallen from 4.7 to 2.6 per 100 years at risk during 19772001. Improvements in outcome are likely due to a better understanding of the natural history of the disorders, proactive management of chest infections and ability to intervene with ventilatory support and secretion clearance assistance. In some of the more severely affected children, ventilatory assistance may be used as a palliative approach to reduce chest infections and allow the child to be managed at home.
Table 3.1 Probability of respiratory failure in neuromuscular and chest wall disease Inevitable DMD Type I SMA High cervical cord lesion Limb girdle muscular dystrophy (MD) 2C, 2D, 2F, 2I Nemaline myopathy Acid maltase deciency Type II SMA X linked myotubular myopathy Multicore myopathy Congenital myasthenia Congenital myotonic dystrophy Congenital/early onset scoliosis EmeryDreifuss MD, Becker MD, Bethlem myopathy Minicore, central core myopathy Facioscapulohumeral MD, mitochondrial myopathy Limb girdle MD 1, 2A, 2B, 2G, 2H
Frequent
Occasional
Unusual
Aetiology
In patients with severe respiratory muscle weakness and/or chest wall disease, pulmonary morbidity is the commonest cause of hospital admission and death. The pattern of respiratory muscle involvement may influence
26 Neuromuscular and chest wall disease (including non-invasive ventilation)
evolution of the condition and choice of treatment. For instance, in the muscular dystrophies there is early diaphragm involvement and weakness of the inspiratory and expiratory muscles tends to progress in tandem. In SMA, weakness of expiratory muscles often outstrips that of inspiratory muscles; difficulties with cough and secretion clearance may become a major problem before the development of sleep-disordered breathing. Consequently, individuals with SMA may benefit from cough assistance techniques before they require ventilatory support at night. It should also be noted that in other conditions (e.g. adolescent onset thoracic scoliosis), respiratory decompensation is rare, while in a further subgroup there may be huge phenotypic variation (e.g. nemaline myopathy and limb girdle muscular dystrophy), so ascertaining the prognosis can be difficult. A background of respiratory muscle weakness, restrictive ventilatory defect and increased work of breathing due to chest wall deformity may be compounded by bulbar weakness leading to aspiration, gastro-oesophageal reflux, feeding difficulties and failure to thrive.
Spinal muscular atrophy

SMA is conventionally classified as type 1 (never able to sit), type 2 (can sit but not stand) and type 3 (can walk). It is important to note that these designations apply to the maximal functional level reached (e.g. some walkers lose ambulation later in life). Within each group there can be a clear spectrum of ability (e.g. type 1 embraces babies diagnosed with a few weeks of birth with profound floppiness and major swallowing problem, and extends to other children who present with chest infections at >1 year of age (type 1.01.9)). Clearly, the feasibility of treatment such as noninvasive ventilation (NIV) is totally different in a child with preserved bulbar function presenting at 14 months compared with a baby diagnosed at 7 weeks with respiratory failure and feeding difficulties. A bell-shaped chest with pectus/chest wall deformity is common in children with type 1 and 2 SMA (3.1). A variant SMA with respiratory disease differs from typical SMA in that the diaphragm is affected early in the natural history, cranial nerves may be involved and the distribution of muscle weakness is more distal. Respiratory failure is virtually universal.
Specic diagnoses
Duchenne muscular dystrophy
Most children with DMD are diagnosed when they fail to meet motor milestones aged 23 years. Loss of ambulation is usual in early adolescence and although lung growth is normal to this point, lung volumes then tend plateau as respiratory muscle weakness progresses, and subsequently fall in the mid teenage years. Most boys develop sleep-disordered breathing in adolescence and overt ventilatory failure aged 1820 years. Steroid therapy appears to improve respiratory prognosis in DMD, although definitive trials are still in progress. Prednisolone seems to preserve muscle strength so a greater peak vital capacity (VC) is reached and cough efficacy is sustained for longer. If strength is maintained through the adolescent growth spurt, the risk of scoliosis is reduced and the need for ventilatory support may be delayed several years. Optimum dosing regimens, the best age range to apply steroid therapy and minimize adverse effects such as weight gain, glucose intolerance, growth retardation and osteoporosis are yet to be determined.
Chest wall disease

The most frequently seen chest wall disorder is scoliosis, which indicates lateral curvature of the spine (whereas kyphosis describes anteroposterior curvature). Scoliosis is measured by Cobb angle (3.2), but there is often a rotatory element too. A paralytic scoliosis often accompanies neuromuscular disorders due to vertebral, postural and respiratory muscle weakness. The commonest type of
3.1 Chest wall deformity in Type I spinal muscular atrophy.
Neuromuscular and chest wall disease (including non-invasive ventilation) 27

scoliosis is idiopathic, with onset during the adolescent growth spurt. More prevalent in females than males, adolescent onset idiopathic curves are unlikely to be associated with respiratory problems, as only minor reductions in VC and total lung capacity are seen. The vast majority of teenagers with genuine adolescent onset thoracic scoliosis do not need to be followed up long term, especially if VC is >50% of predicted after the pubertal growth spurt. However, high cervical and dorsal scolioses (seen more frequently in congenital disorders) are likely to have a worse impact on respiratory function, and if VC is <50% of predicted, individuals in this situation require follow-up as they are at risk of ventilatory decompensation over time. In addition, high-risk scoliosis includes those that are congenital or develop before the age of 5 years (i.e. before alveolar and pulmonary vascular bed development is complete) (3.3). Progression to respiratory failure is usually slower in chest wall disease than in those with respiratory muscle weakness, with the exception of conditions such as Jeunes syndrome (3.4), which is a rapidly progressive asphyxiating chest wall disease. anticipation of common problems (e.g. chest infections, sleep-disordered breathing), and prevention or prompt treatment where possible.
Investigations
The principles of assessment and timely management are: identification of high-risk cases; regular clinical review; measurement of respiratory function during the day and during sleep; and
3.3 Chest radiograph showing early onset scoliosis following surgical correction.
Cobb angle
3.2 Calculation of Cobb angle.
3.4 Chest radiograph: Jeunes syndrome.
Pulmonary function
The best and simplest measurement of respiratory capacity is forced VC expressed as absolute value and percentage of predicted for span or ulnar length (in individuals with scoliosis). In the young child unable to cooperate with formal measurement of lung function, a history of frequent chest infections, symptoms of reflux and dysphagia, chest wall deformity, markedly paradoxical breathing, weak cough and the extent of respiratory effort are important prompts for further investigation. Pulse oximetry is easily assessed at each clinic visit and any daytime value 94% is abnormal.
Respiratory muscle strength

Mouth pressures and sniff inspiratory pressure can also be measured relatively easily in children over the age of 6 years as indices of inspiratory muscle strength, though mouthpiece and nasal bung adaption may be required Cough can be roughly judged as weak, moderate or normal. Asking the child to cough and listening to the sound produced will provide a rough guide. Expiratory muscle function can be measured by mouth pressure assessment (Pemax), and whistle peak flow devices may be easier for children to use. Peak cough flow is a helpful measurement. It can be determined using a pneumotachograph, and even a simple peak flow meter will give a guide to cough ability. In adults, peak cough flow values of <270 l/min suggest cough impairment and values <160 l/min indicate significant weakness. Normal values for children have not yet been established, although as a rough rule of thumb values in a normal 10 year old should exceed 200 l/min. Some authorities recommend use of the cough assist devices in children with a Pemax of <60% of predicted.
should be carried out in children with a VC of <60% of predicted and considered at intervals that are more frequent if there is rapid progression of the underlying disease or development of new sleep-related symptoms. Sleep study methods range from simple home oximetry to polysomnography, including documentation of sleep stage and arousals. Normal oximetry overnight in a child who has slept reasonably well usually excludes a major degree of sleep-disordered breathing. Multichannel respiratory monitoring can be helpful in distinguishing obstructive and central events though in children with obstructive sleep-disordered breathing events tend to be obstructive hypopnoeas (i.e. related to partial airway obstruction, rather than apnoeas). Additional monitoring of CO2 is key to the diagnosis of nocturnal hypoventilation. End-tidal or transcutaneous measurements can be obtained continuously. The newer transcutaneous electrodes are more reliable than older models and can be safely left in place overnight.
Swallowing and feeding assessment

Swallowing and feeding problems are inevitable in the first year of life. Some neuromuscular conditions such as type 1 SMA occur later in the natural history of some conditions (e.g. DMD) and are variably present in others (e.g. congenital muscular dystrophy). They Table 3.2 Symptoms and signs of nocturnal hypoventilation/sleep-disordered breathing Symptoms Disturbed sleep, nightmares, daytime sleepiness Need for frequent turning Increased breathlessness at meals, on exertion and on transfers Morning grogginess/irritability, headaches Anorexia for breakfast Nocturnal gasping, erratic breathing Cyanosis on eating and during transfers from bed to chair or on exertion Sudden waking, nocturnal sweating
Sleep studies
Overnight monitoring of respiration is indicated in those with symptoms of nocturnal hypoventilation (Table 3.2) or at high risk of decompensation (Table 3.1). Sleepdisordered breathing in patients who have early diaphragm involvement evolves from an initial phase of rapid eye movement (REM)-related hypopnoeas via continuous hypoventilation in REM and non-REM sleep, to daytime ventilatory failure.The onset of sleep-disordered breathing tends to occur at an average VC of 60% of predicted, with continuous hypoventilation occurring at a VC <40% of predicted and daytime hypercapnia occurring when VC is <25% of predicted (3.5). Usually, annual sleep studies
Signs
100.0 90.0 80.0 70.0 SpO2% 60.0 50.0 40.0 30.0 20.0 10.0 0.0 0 2:00:00 4:00:00 Hours 6:00:00 Nocturnal hypoventilation
20.0 18.0 16.0 14.0 12.0 10.0 8.0 6.0 4.0 2.0 0.0 8:00:00 tcpCO2 kPa
SpO2% Max/Min tcpCO2
3.5 Overnight monitoring of arterial oxygen saturation (top) and transcutaneous carbon dioxide tension (bottom) demonstrating nocturnal hypoventilation. Dips in arterial oxygen saturation and peaks in transcutaneous carbon dioxide tension occur during rapid eye movement (REM) sleep.
may be accompanied by oesophageal reflux and other autonomic bowel problems (e.g. in hereditary sensory motor neuropathy). Swallowing and nutritional issues are closely linked to respiratory problems, as bulbar weakness may lead to aspiration pneumonia and frequent chest infections lead to poor weight gain and failure to thrive. It is also a common observation that swallowing function tends to deteriorate at the time of acute chest infections. Routine assessment of swallowing ability should include observation during mealtimes, and videofluoroscopy where problems are anticipated. The involvement of a specialist speech and language therapist is essential. Sensible measures include consistency modification of food, positional advice and optimization of oral intake with supplements. Percutaneous gastrostomy and jejunostomy are required to maintain nutritional intake and reduce risk of aspiration. In many situations, percutaneous gastrostomy or jejunostomy feeding may be combined with NIV. Particular care is required when placing a percutaneous gastrostomy to avoid respiratory complications.
Timing of initiation of non-invasive ventilation in chronic management

Oxygen therapy is inappropriate treatment in nocturnal hypoventilation as it is likely to provoke worsening CO2 retention. Original consensus guidelines recommended the initiation of NIV when daytime hypercapnia occurs. This leaves the child at risk from uncontrolled decompensation at the time of chest infections. With the hypothesis that intervention with NIV at the time the VC was between 25% and 50% of predicted would prevent respiratory failure, a multicentre French trial included boys with DMD with VC at this level and randomized them to NIV or control group. Interestingly this prophylactic approach was not successful as there was no reduction in lung volume decline or decrease in mortality in the NIV group. Indeed, there was a small excess of deaths from retained tracheobronchial secretions and cardiomyopathy. Preventative use of NIV is not in the patients interest, in DMD at any rate. More recently, a randomized controlled trial has been carried out of NIV in a mixed group of adults and children with congenital neuromusculoskeletal disease. Diagnoses included DMD, SMA and congenital muscular dystrophy. Entry criteria were nocturnal hypoventilation but with normal daytime PCO2. Patients were randomized to nocturnal NIV or control
Management
General principles of respiratory care are shown in Table3.3.
Table 3.3 Respiratory care plan Identify high-risk cases Immunizations and low threshold for antibiotics Physiotherapy advice Regular respiratory assessment: symptoms, signs, lung function, SaO2, cough assessment, sleep studies Nutrition, swallowing, oesophageal reux assessment Discussion of options for respiratory support in advance of need Regular ECG and echocardiogram in DMD (yearly): other disorders at high risk of cardiac disease include Becker muscular dystrophy (MD), EmeryDreifuss MD, congenital myopathies, limb girdle muscular dystrophy LGMD1B, LGMD1D, sarcoglycanopathies: angiotensin converting enzyme inhibitor and beta-blocker therapy as required Planned introduction of NIV and cough assistance as needed Rapid access to speciality care providers/multidisciplinary approach Observation of scoliosis, orthopaedic advice Perioperative management plan with advance liaison with anaesthetic team/ICU/surgical team if intercurrent surgery (e.g. for scoliosis) required Advance discussion of treatment escalation (e.g. tracheostomy ventilation, with negotiated care plan with agreed ceilings and minimum levels of care)
group; each group underwent 6-monthly sleep studies over 2 years. For the control group, safety criteria were set such that if individuals developed daytime hypercapnia, recurrent chest infections or failure to thrive, NIV was started. Whereas the NIV group generally progressed well, 70% of the control group fulfilled criteria to start NIV within a year and 90% within 2 years. Evolution of nocturnal arterial blood gas
tensions in both groups is shown in 3.6. Improvements in mean SaO2 and the period of time transcutaneous CO2 was <6.5 kPa only occurred in the NIV group. The main message is, therefore, if significant nocturnal hypoventilation is present, daytime ventilatory failure is likely within 12 months and virtually inevitable with 2 years. This provides time to discuss the need for NIV with families and plan the introduction around school
Group 1 Control Group 2 NIV 20 0 20 40 60 80 100 p=0.005 0 6 12 Months 18 p=0.024 24 5 4 3 2 1 0 1 2 3 0
Group 1 Control Group 2 NIV
p=0.005 6 12 Months 18
p=0.024 24
3.6 Changes in TcCO2 levels and mean SaO2 overnight in NIV and control groups.

holidays, family commitments, the childs preference, etc.
Types of ventilator
In nocturnal NIV, pressure preset devices (e.g. a bi-level ventilator) are most often used; however, in children who require 24-h ventilatory support, volume ventilators have a long track record. There is no evidence that one type of ventilator is superior, although trigger characteristics should be carefully checked, and from a risk-management perspective attention should be paid to provision of low- and high-pressure, low-volume, disconnection plus power failure alarms. Examples of typical non-invasive ventilators are shown in 3.7.
Other potential uses of non-invasive ventilation

While prophylactic NIV has little use in DMD, in SMA it may be more relevant to treat intermittent chest infections and facilitate recovery. In addition, NIV has been used intermittently to provide acute respiratory support in children with congenital myasthenia during acute episodes of weakness.
(A)
(B)
(C)
(D)
3.7a Non-invasive ventilators for home use. (A) Breas Vivo (Breas Medical). (B) Nippy ST (B&D Electromedical). (C) BiPAP Harmony (Philips Respironics). (D) VPAP III ST (ResMed).
Interfaces
The advantages and disadvantages of types of interface are indicated in Table 3.4. The development of suitable interfaces for small children has been a major problem. A range is now available (examples shown in 3.8 and 3.9), but the option of providing customized interfaces is important. This allows sufficient reduction of dead space. Importantly, it has also been shown that customized masks are less likely than commercial masks to cause mid-facial hypoplasia and facial pressure sores, which are crucial considerations. Mid-facial hypoplasia (3.10) seems more common in children started on NIV at a younger age and in those with weakness of the facial muscles where it probably accentuates aspects of facial maldevelopment, which may have occurred anyway. However, there is no doubt that mask pressure problems are a major limiting factor. Alternation of masks can also help, but all steps should be reasonably taken to avoid this problem.
3. Glottal closure. 4. Forced expiration. 5. Glottal opening. In neuromuscular disorders, the sensory component is rarely impaired. The inspiratory and expiratory components can be augmented using physiotherapy techniques, and by assisting this process using an Ambu bag or performing physiotherapy during NIV. The latter can be helpful to reduce tiring and maintaining arterial oxygen saturation during acute chest infections. A combination of cough assistance with the cough in-exsufflator and NIV has been shown to reduce pulmonary morbidity in patients with DMD compared with a group who received tracheostomy ventilation. The cough in-exsufflator device provides a positive pressure insufflation timed with the patients inspiration followed by a swing to negative pressure to enhance cough and secretion clearance. A number of studies have now shown that the cough in-exsufflator augments cough peak flow and is well tolerated even in small children (although there are sparse data in babies of less than about 6 months). Insufflation and exsufflation pressures do not appear related to age. Most practitioners start at positive and
Cough assistance techniques

Effective coughing comprises the following stages: 1. Sensation of need. 2. Big inspiration.
Table 3.4 Advantages and disadvantages of types of interface for children Interface Nasal mask Advantages Good for long-term use. Disadvantages Problems in children with mouth leaks, jaw contractures, or nasal pathology. Can be claustrophobic. Risk of aspiration after vomiting. Expensive. Available in size suitable for older child only. Limited range of sizes. Not appropriate for long-term use.
Full facemask
Can solve problems with mouth leak.
Total mask
Covers whole face, low effective dead space, preserves visual elds. Suitable for use in acute respiratory failure. No facial contact so has been used in children with leukaemia, clotting disorders. Can be used in older children. Helpful in patients wearing spectacles. Can help in those with nasal bridge sores. Improved t, as some patients may be impossible to t with a standard off the peg mask. Reduced dead space and risk of mid-facial hypoplasia.
Helmet
Nasal plugs
Can be unstable and slip off face. Not available in small enough sizes for young children. Need time to construct. Some variants may not last as long as commercial masks and, therefore, may cost more.
Customized
3.10 Lateral skull radiograph showing mid-facial hypoplasia in child with a congenital myopathy. 3.8 Non-invasive ventilation during sleep.
negative pressures of about 20 cmH2O and then increase gradually according to tolerance and effectiveness of cough achieved. Pressure swings of up to -40 to +40 are often required. The IMP Percussionaire device couples intermittent positive pressure breathing with high-frequency oscillation, and can deliver nebulized therapy. This can be applied by mouthpiece or mask and may mobilize peripheral secretions; however, further confirmation of benefit is required.
Tracheostomy ventilation
The key indications for tracheostomy ventilation are: swallowing dysfunction resulting in recurrent aspiration; marked ventilator dependency with minimal ventilator free time; NIV inadequate or poorly tolerated. As described above, the combination of NIV and cough assist devices can prove as effective or more effective than tracheostomy intermittent positive pressure ventilation (T-IPPV), so can be suitable in some children with, for example, severe SMA in whom invasive ventilation was previously the only option. In others with an acute chest infection requiring assisted ventilation, intubation may be
3.9 Nasal interface with mask leak to reduce dead space.
required. On recovery, many can be extubated on to NIV if bulbar function allows, but if a tracheostomy is needed gradual weaning on to NIV may be possible. Transition from NIV to T-IPPV in a child with a progressive disorder is an individual decision with many ramifications for the child and family. In each case the advantages and disadvantages for the child and family should be carefully considered so that a mutually acceptable decision can be reached. Potential advantages of T-IPPV include: better access to secretions; reduction in hospital admissions for aspiration pneumonia; and freedom of face from non-invasive mask. Disadvantages include: an inevitable increase in complexity of care package and competencies required from carers; acute risks of tracheostomy tube blockage and displacement; a reduction in speech quality; long-term complications such as haemorrhage; granulation tissue occlusion; and tracheal stenosis.
the child spending as much time at home with the family as possible should be the guiding principle.
Transition to adult care

It is vital children with neuromuscular disease and severe chest wall disease transfer smoothly to adult respiratory care. Worsening nocturnal hypoventilation occurs in the mid-teenage years in DMD and other conditions, and if successful transition has not occurred, uncontrolled respiratory decompensation is a potentially disastrous consequence. In view of the increasing number of children with neuromuscular disease and chest wall disorders surviving to adulthood there is increasing recognition that a network of adolescent neuromuscular clinics is required.
Further reading
Bushby K, Bourke J, Bullock R, Eagle M, Gibson M, Quinby J. The multidisciplinary management of Duchenne muscuar dystrophy. Current Paediatrics 2005; 15: 292300. Chatwin M, Bush A, Simonds AK. Outcome of goaldirected non-invasive ventilation and mechanical insufflation/exsufflation in spinal muscular atrophy type I. Arch Dis Child 2011; 96: 42632. Chatwin M, Heather S, Hanak A, Polkey MI, Simonds AK. Analysis of home support and ventilator malfunction in 1211 ventilator dependent patients. Eur Respir J 2010; 35: 3106. Chatwin M, Ross E, Hart N, Nickol A, Polkey MI, Simonds AK. Cough augmentation with mechanical insufflation/exsufflation in patients with neuromuscular weakness. Eur Respir J 2003; 21: 5028. Dubowitz V. Disorders of the lower motor neurone: the spinal muscular atrophies. In Muscle Disorders in Childhood. Dubowitz V. (Ed.). London: W.B. Saunders Company Ltd 1995, 32567. Fauroux B, Lavis J-F, Nicot F, Picard A, Boelle P-Y, Clement A, Vazquez M-P. Facial side effects during noninvasive ventilation in children. Int Care Med 2005; 31: 9659. Jeppesen J, Green A, Steffensen BF, Rahbek J. The Duchenne muscular dystrophy population in Denmark, 19772001: prevalence, incidence and
Anticipatory care plan

Respiratory complications likely to occur are ventilatory decompensation during chest infections or intercurrent events such as tendon lengthening or scoliosis surgery, or a gradual decrease in lung function over time associated with progressive respiratory muscle weakness. Interventions such as flu vaccination and pneumococcal immunization are helpful. Providing a reserve course of antibiotics to start when symptoms of a chest infection occur, or even rotating courses of antibiotics in children with recurrent intervention can be helpful (Table 3.3). Decisions should be made in advance about the appropriateness of escalating to invasive ventilation; the advantages and disadvantages listed above need to be weighed up and the natural history of the condition should be considered. This is particularly important in severe and progressive conditions such as type I SMA where NIV may be used, at best, to reduce morbidity associated with acute chest infection and palliate symptoms. Extended survival can be achieved, but improving quality of life and facilitating

survival in relation to the introduction of ventilator use. Neuromusc Disord 2003; 13: 80412. Miske LJ, Hickey EH, Kolb SM, Weiner DJ, Panitch HB. Use of the mechanical in-exsufflator in pediatric patients with neuromuscular disease and impaired cough. Chest 2004; 125: 140612. Tzeng AC, Bach JR. Prevention of pulmonary morbidity for patients with neuromuscular disease. Chest 2000; 118: 13906. Wang CH, Finkel RS, Bertini E, Schroth M, SimondsA, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A. Consensus statement for standard of care in spinal muscular atrophy. JChild Neurol 2007; 22: 102749.
Chapter 4
37
Interstitial lung disease

Andrew Bush, Andrew G. Nicholson
Introduction
These are rare conditions, and few centres see more than a handful of cases per year. The spectrum of diagnoses is much wider than that of adult interstitial lung disease (ILD); and they occur in the context of the growing and maturing lung and immune system, which may affect the manifestations of a particular disease. Thus, a surfactant protein (SP) Cdeficiency may present as a cellular nonspecific interstitial pneumonia in childhood, and usual interstitial pneumonia (UIP) in adults.
infancy may merit being considered separately (Table4.2); this is certainly useful to the clinician. Whether some disorders (the spectrum of alveolarcapillary dysplasia congenital alveolar dysplasia, and bronchopulmonary dysplasia, for example) belong under chILD is debateable (4.1), they certainly enter the differential diagnosis. The rest can be split into three groups: 1. Those with a known cause (Table 4.3). These include a subcategory of genetic diseases (Table 4.4) and neurocutaneous syndromes (e.g. tuberous sclerosis). Other known specific causes include drugs (particularly chemotherapy for malignant disease), radiation and graft-versus-host disease after bone marrow transplantation. 2. chILD associated with another condition, the cause of which may or may not be known (Table 4.5). 3. chILD with no known cause (Table 4.6). In some cases, investigation reveals a specific histological entity, for example, lymphangiectasia or other disease of pulmonary lymphatics. Lymphoid disorders may also present as chILD. The spectrum of follicular bronchiolitislymphoid interstitial pneumonia may be the presenting feature of a congenital or acquired immunodeficiency. The cause of the remainder of this group is unknown. Finally, there remains a large group of children with alveolitis of undetermined cause. In considering the classification of chILD, it is easy to confuse a list of differential diagnoses, in which, for example, lymphatic disorders belong, and should be all embracing, from a true classification. If the classification includes diseases that may be erroneously confused with chILD, but do not in fact belong in that group, it may cease to be useful.
Epidemiology
There are few good surveys, and the most comprehensive review of the spectrum of interstitial lung disease in all age children (chILD) was the report of the European Respiratory Society Task Force, and in children under age 2, the USA consensus group. The European Respiratory Society reviewed 185 cases, summarized in Table 4.1. They confirmed the predominance of cases in young children (age <2 years), and that nearly 10% cases have affected siblings. A surprising finding was seven cases of UIP, which is said to be almost unheard of in children. All were confirmed by lung biopsy, but there was no central standardized pathological review, so some caution in assessing the findings is necessary.
Classication
The best way of classifying these complex and disparate conditions is still debated, and none currently employed is perfect. Pragmatically, diseases that occur particularly in
38 Interstitial lung disease
Clinical presentation
This is very non-specific; tachypnoea and respiratory distress, sometimes with cyanosis, is typical. There may be feeding difficulties secondary to respiratory distress, and failure to thrive. Respiratory distress and crackles may be apparent on examination. Thus, history and physical examination may lead to the suspicion of chILD, but can usually not reliably confirm its presence.
Role of non-invasive tests

Blood tests: in some cases, a definite diagnosis can be made on serology or genetic testing (Table 4.7). However, this should not be allowed to delay further diagnostic tests, unless clinical suspicion is high. Echocardiography: to check pulmonary artery pressure and exclude congenital heart disease. Pulmonary veno-occlusive disease might be suspected if there was a disproportionate elevation of pulmonary artery pressure compared with the degree of parenchymal shadowing. Lung function: older children with chILD may have classical restrictive lung disease (reduced forced expiratory volume in 1 s (FEV1), reduced forced vital capacity (FVC), normal or increased FEV1/FVC ratio, low residual volume and total lung capacity). Physiological testing is certainly useful in children over about age 5 years, both in diagnosis and monitoring treatment. Much less is known about infant lung function testing in chILD; it should not be assumed that findings would be similar to those in older children.
Differential diagnosis
The non-specific presentation of chILD means that almost every diffuse lung disease of childhood enters the differential diagnosis. These include the aspiration syndromes (gastrooesophageal reflux, inco-ordinate swallowing, H-type fistula, laryngeal cleft); cardiac and non-cardiogenic pulmonary oedema; pulmonary vascular diseases; chronic bronchial sepsis and bronchiectasis; and infection and the sequelae (4.2), including exotic and tropical infections. Thus, specific further investigations are essential.
Table 4.1 Spectrum of childhood interstitial lung disease in Europe. Absolute numbers (percentages) are reported. Note the predominance of patients less than 2 years of age (with permission from Clement et al, 2004). Diagnostic entity Pulmonary haemosiderosis Pulmonary alveolar proteinosis Hypersensitivity pneumonitis Langerhans cell histiocytosis Sarcoidosis Pulmonary lymphangioleiomyomatosis Lymphocyte inltrative disorder Autoimmune-related interstitial lung disease Desquamative interstitial pneumonitis UIP Lymphoid interstitial pneumonitis Idiopathic pulmonary brosis Interstitial pneumonitis All patients (n = 177) 14 (8%) 14 (8%) 24 (14%) 3 (2%) 29 (16%) 1 (0.5%) 1 (0.5%) 3 (2%) 13 (7%) 7 (4%) 1 (0.5%) 46 (26%) 21 (12%) Patients <2 years (n = 56, 32% of total) 5 (9%) 7 (13%) 0 (0%) 3 (5%) 1 (2%) 0 (0%) 0 (0%) 0 (0%) 11 (20%) 2 (4%) 0 (0%) 12 (21%) 15 (27%)
Interstitial lung disease 39
Table 4.2 Classication of chILD between age 0 and 2 years (n = 165 interpretable biopsies in total) (adapted with permission from Deutsch et al, 2007). Category Diffuse developmental disorders (n = 11) Illustrative diseases Acinar dysplasia (n = 1) Congenital alveolarcapillary dysplasia (n = 2) Alveolarcapillary dysplasia with misalignment of the pulmonary veins (n = 8) Pulmonary hypoplasia (n = 7) Chronic neonatal lung disease (n = 20) Related to chromosomal disorders (n = 15) Related to congenital heart disease (n = 4) Pulmonary interstitial glycogenosis (n = 18) NEHI (n = 6) SFTPB gene mutations (n = 0) SFTPC gene mutations (n = 7) ABCA3 gene mutations (n = 6) Histology consistent with surfactant protein disorder but none detected (n = 5 in total) Pulmonary alveolar proteinosis (n = 2) Chronic pneumonitis of infancy (n = 1) Desquamative interstitial pneumonia (n = 1) Non-specic interstitial pneumonia (n = 1) Collagen vascular disease (n = 4) Storage disease (n = 1) Sarcoidosis (n = 0) Langerhans cell histiocytosis (n = 0) Malignant inltrates (n = 1) Infectious and post-infectious (n = 17) Environmental agents (n = 2 in total) Hypersensitivity pneumonitis (n = 2) Toxic inhalation (n = 0) Aspiration syndromes (n = 3) Eosinophilic pneumonia (n = 1) Opportunistic infections (n = 20) Iatrogenic (n = 3) Related to transplant and rejection (n = 0) Diffuse alveolar damage, unknown aetiology (n = 5) Arterial hypertensive vasculopathy (n = 8) Venous engorgement secondary to heart disease (n = 1) Veno-occlusive disease (n = 0) Lymphatic disorders (n = 0)
Growth abnormalities reecting decient alveolarization (n = 46)
Specic conditions of undened aetiology (n = 24) Surfactant dysfunction disorders (n = 18)
Disorders related to systemic disease processes (n = 6)
Disorders of the normal host, presumed immune intact (n = 23)
Disorders of the immunocompromised host (n = 28)
Disorders masquerading as ILD (n = 9)
(A)
(B)
4.1 (A) Alveolar capillary dysplasia, stained with anti-CD34 to highlight the vessels, which are poorly opposed to the alveolar epithelium. (B) Congenital alveolar dysplasia. The parenchyma is underdeveloped with abnormal growth and density of the alveolar walls.
Table 4.3 chILD associated with known causes Infective or post-infective disorders Environmental inhalants (toxic substances, antigenic dusts) Drug-induced disorders Radiation induced Neoplastic diseases Lymphoproliferative disorders Genetic disorders (see also Table 4.4) Degenerative disorders Neurocutaneous syndromes
Table 4.4 Genetic causes of chILD SFTPB, SFTPC, ABCA3 deciency GM-CSF receptor abnormalities Storage disorders (e.g. Gauchers disease, NiemannPick disease) HermanskyPudlak syndrome Lysinuric protein intolerance GM1 gangliosidosis Fabrys disease Neurobromatosis FOXP3 deciency Pulmonary alveolar microlithiasis (mutations in the SLC34A2 gene) STRA6 deciency Telomerase gene mutations (TERC, TERT) Brainlungthyroid syndrome
Table 4.5 chILD associated with other conditions Collagen vascular disease Pulmonary vasculitis syndromes Langerhans cell histiocytosis* Liver disease Bowel disease (e.g. granulomatous lung disease associated with Crohns disease) Renal disease (e.g. pulmonary brosis associated with chronic renal failure) Organ failure (cardiac, renal) Amyloidosis Graft-versus-host disease Adult respiratory distress syndrome (recovering phase) Hypereosinophilic syndromes Pulmonary veno-occlusive disease
*May be localized to the lung in older children.
4.2 Lung biopsy showing obliterative bronchiolitis. The pulmonary artery (white arrow) is normal; the accompanying airway (black arrow), which should be the same size, has been virtually completely obliterated (courtesy of Dr Liz Edwards).
Table 4.6 chILD of unknown cause Sarcoidosis Pulmonary alveolar proteinosis* Idiopathic interstitial pneumonia group Pulmonary haemorrhagic syndromes localized to the lung Congenital lymphatic disorders Normal histology
*Distinguish from congenital surfactant protein deciencies; pulmonary alveolar proteinosis is commoner in adults. May be strictly a mimic of ILD rather than considered a true ILD. The relationship with neuroendocrine cell hyperplasia in infancy (NEHI) (if any) has yet to be established.
from the high-resolution computed tomographic scan (HRCT). Occasionally, a child with an apparently normal CXR may in fact have changes suggestive of chILD (4.3). There are three other reasons for performing HRCT in this context: 1. Rarely, HRCT may be diagnostic. Specific patterns such as idiopathic pulmonary haemosiderosis (4.4), Langerhans cell histiocytosis, pulmonary microlithiasis (4.5), or pulmonary alveolar proteinosis (PAP; 4.6) may be identified, obviating the need for further tests. 2. To determine the optimal site for lung biopsy. 3. HRCT appearances should be correlated with the ultimate diagnosis, in the hope that in the future, more accurate interpretation of HRCT will obviate the need for lung biopsy. This last ambition will require multicentre and international collaboration.
Role of imaging
The chest radiograph (CXR) is usually non-diagnostic and, in general, has poor sensitivity and specificity, and correlates poorly with symptoms, histology or response to treatment. It may be normal, or show ground-glass shadowing with prominent air bronchograms, or coarse nodular or reticularnodular shadowing. In advanced cases, honeycombing is seen. In most cases, the definitive recognition that the tachypnoeic child has chILD will be
Role of bronchoscopy
A few conditions can be diagnosed on bronchoalveolar lavage (BAL). These include: pulmonary haemorrhage (haemosiderin-laden macrophages, which may be found in primary and secondary causes of pulmonary haemorrhage, 4.4C); Langerhans cell histiocytosis, which should be considered if there are >5% CD1a-positive cells;
Table 4.7 Blood testing that may be diagnostic of chILD Test Genetic analysis GM-CSF autoantibodies Antineutrophilic cytoplasmic antibody studies Angiotensin converting enzyme Serum precipitins Autoimmune serology Immune function testing, including HIV Diagnosis SFTPB, SFTPC, ABCA3 deciency Adult-type PAP Wegeners granulomatosis Sarcoidosis Avian granuloma, farmers lung Systemic lupus erythematosus, scleroderma, other connective tissue disorders Immunodeciency, opportunistic infection
Table 4.8 Illness severity score used in chILD Score 1 2 3 4 5 Symptoms No Yes Yes Yes Yes Hypoxaemia <90% sleep or exercise No No Yes Yes Yes Hypoxaemia <90% rest No No No Yes Yes Pulmonary hypertension No No No No Yes
(B) 4.3 (A) CXR of a 12-year-old girl. She had an undiagnosed illness at 18 months of age, being unwell with respiratory distress and failure to thrive. She recovered spontaneously but was subsequently noted to have digital clubbing. The CXR shows little in the way of abnormality. (B) HRCT scan in the same child, showing bibasal and predominantly subpleural, reticular nodular shadowing. A subsequent open lung biopsy showed a burned out desquamative interstitial pneumonitis.
(A)

a storage disease, suggested by cells with inclusion bodies; and One of the PAP syndromes if there are proteinaceous exudates and abnormal lamellar bodies on electron microscopy. Diseases within this last group are more reliably diagnosed on genetic analysis; BAL studies may be misleading. BAL is much more useful in excluding unsuspected opportunistic infections. BAL in children is too poorly characterized to make most specific chILD diagnoses, in contradistinction to the situation in adults.Transbronchial biopsy may be diagnostic in conditions characterized by very specific abnormalities, such as pulmonary alveolar microlithiasis (4.5), but provides insufficient tissue for analysis in more diffuse chILD.
Role of biopsy
Most children with chILD will require a lung biopsy for diagnosis, and this should not be delayed unless there is a realistic prospect that less invasive procedures will be diagnostic, or symptoms are so mild that treatment is not being contemplated. When a biopsy is performed, the destination of the tissue should be planned, including storing pieces for future use at -70C. Standard histology, immunohistochemistry, electron microscopy and culture of biopsy for mycobacteria and fungi in particular should always be performed. The limitations of transbronchial
(B) (A)
(C)
(D)
4.4 (A) CXR showing extensive conuent shadowing, particularly in the basal regions, in a 2-year-old child with iron-decient anaemia. (B) HRCT in the same child, showing bilateral, diffuse uniform ground-glass shadowing, typical of idiopathic pulmonary haemosiderosis. (C) BAL (Perls stain). There are aggregates of haemosiderin-laden macrophages. (D) Open lung biopsy in another case of pulmonary haemosiderosis showing macrophages within the alveolar spaces, which contain abundant brown pigment. Note there is no evidence of vasculitis.
(B)
(A) 4.5 (A) CXR shows diffusely hazy lung elds, with an element of nodularity. (B) Same case. The CT scan shows widespread nodular shadowing. (C) The alveolar microlithiasis shows abundant calcospherites lying both within alveolar spaces and the interstitium. Many of them have fractured during cutting due to their hard nature.
(C)
through a mini-thoracotomy or as a video-assisted thoracic surgery procedure will depend on the childs size and surgeons experience. The alternative to performing a biopsy is an empirical trial of treatment, usually oral steroids, performing a biopsy only in the non-responders. We do not believe this is optimal because:
4.6 Pulmonary alveolar proteinosis. The CT shows outlining of the secondary pulmonary lobules, giving a cobblestone appearance, on the background of diffuse ground-glass shadowing.
biopsy in chILD have been discussed above; other choices are percutaneous CT-guided biopsy (which has largely been discarded in most centres with the advent of videoassisted thoracic surgery, which many would regard now as the biopsy method of choice), and open lung biopsy through a mini-thoracotomy incision. Biopsy of the lung under direct vision is safe, well tolerated and should be regarded as the gold standard. Whether it is performed
much chILD does not to respond to high-dose steroids, which in any case may have major side effects; some conditions that may present as chILD may actually be made worse by corticosteroids (e.g. unsuspected opportunistic infections); increasingly, disease-specific therapies may be indicated (below) and so a precise diagnosis is important; there may be genetic implications for some conditions, mandating an accurate diagnosis; if open lung biopsy is undertaken after a failed trial of steroids, wound healing may be compromised; and steroid therapy may affect the histological features on biopsy, hindering diagnosis.

Assessment of severity, including monitoring therapy
A useful score is summarized in Table 4.8. History and physical examination are likely too subjective to guide potentially toxic therapies. In the child old enough to perform spirometry and lung volumes, these should be used to follow therapy. Carbon monoxide transfer rises with acute pulmonary haemorrhage. For those children for whom pulmonary function tests cannot be performed or are unavailable, oxygen requirements, measured by overnight oximetry, may be useful. If there is pulmonary hypertension, serial echocardiograms are useful. The role of repeated CT scanning is less clear. BAL is generally too invasive and too poorly characterized in children to make it an attractive tool in most chILD. The exception may be in idiopathic pulmonary haemosiderosis, in which some investigators would perform BAL before discontinuing treatment, to ensure there is no evidence of ongoing occult bleeding.
4.7 A case of alveolar proteinosis showing widespread lling of alveolar spaces by acellular proteinaceous debris, within which a few macrophages are noted. There is a mild associated interstitial chronic inammatory cell inltrate. Many of these cases are now found to be associated with surfactant protein gene abnormalities.
Specic conditions
Only a limited number can be covered here; the reader is referred to recent reviews listed below.
Surfactant protein abnormalities/pulmonary alveolar proteinosis spectrum

The histological appearances of PAP, in which alveoli are filled with granular, eosinophilic material staining with periodic-acid Schiff, with preservation of lung architecture) (4.7) can be produced by a number of clinically distinct conditions: Surfactant protein abnormalities (above): SFTPB, SFTPC and ABCA3 mutations may lead to many histological appearances, in particular PAP when presentation is in the newborn period. Granulocytemacrophage colony-stimulating factor (GM-CSF) receptor abnormalities: clearance of surfactant by alveolar macrophages requires a functional GM-CSF receptor. Mutations in the a- and b-chains of the GM-CSF receptor have been shown to be a rare cause of PAP. GM-CSF autoantibody disease: this form of PAP is more classically seen in adults, but cases have been described in children. Diagnosis is confirmed by finding autoantibodies to GM-CSF in serum or BAL.
Metabolic disease: PAP may be a manifestation of lysinuric protein intolerance or a rare manifestation of NiemannPick disease. PAP has been rarely described in association with immunodeficiency (agammaglobulinaemia). The exact mechanisms are poorly defined; coincidence cannot be excluded. Macrophage blockade: this is seen exclusively in adults; causes include haematological malignancy and inorganic dust inhalation.
Surfactant protein B deciency

Defects in the gene encoding SFTPB were found to be associated with the congenital form of PAP (4.8).The SFTPB gene is located on chromosome 2; a number of mutations have been described, and the mutation frequency in the population is probably 1 per 13000 individuals. Typically, it presents as relentlessly progressive respiratory failure in a term baby, with radiographs showing ground-glass shadowing or established fibrosis. Diagnosis is established by absence of SFTPB staining of tracheal aspirates or lung biopsy, and genotype analysis. The only known therapy is lung transplantation, which has been performed successfully in a few infants, despite the development of antibodies against SFTPB after transplantation. The spectrum of SFTPB deficiency has broadened chILD in older children,
with survival for several years with a milder phenotype than the classical disease.
Surfactant protein C deciency

SFTPC deficiency may also present in the newborn period, but has also been found in adult and paediatric ILD of differing histology in large kindreds (4.9). It may
be that inherited surfactant protein problems are more common than hitherto considered, and may be sporadic, as well as inherited in an autosomal dominant fashion. The latter has variable penetrance and well parents of affected offspring have been described, some of who developed lung disease later in life.
Adenosine triphosphate-binding cassette transporter A3 deciency

The post-translational processing of surfactant proteins is complex and multistage, involving many different proteins, defects in which could cause a PAP-like picture. Newborns with severe surfactant deficiency of unknown cause may have mutations in the adenosine triphosphatebinding cassette transporter A3 (ABCA3). Lung ultrastructure shows markedly abnormal lamellar bodies. Milder forms may present in later childhood. Mutation analysis of SFTPB, SFTPC and ABCA3 genes should be considered as part of the routine examination for chILD of unknown cause, particularly if familial.
(A)
Chronic pneumonitis of infancy

This condition was first described more than 10 years ago. The CT appearances are non-specific (4.10A). It is characterized histologically by florid type 2 cell hyperplasia, and a proteinaceous alveolar exudate (4.10B). It is likely, on further investigation, that many of these children will prove to have a surfactant protein abnormality.
Pulmonary interstitial glycogenosis

This condition was first described in seven infants presenting with tachypnoea, hypoxaemia and diffuse infiltrates with
(B)
4.8 (A) SFTPB deciency in a neonate. There is a PAP-like histology, with a prominent proteinaceous intra-alveolar exudate. There is no staining for SFTPB (left inset). Compare with the positive control (right inset). (B) Electron micrographs in a case of SFTPB deciency (top panel) and control (bottom panel). Top panel: hyperplastic type II pneumocytes contain numerous apically polarized lamellar body-like structures (black arrow); multivesicular structures are also present. The alveolar space contains lamellar body-like structures, small multivesicular structures, and amorphous material. Bottom panel: control tissue from a 3-month-old child with pulmonary hypoplasia secondary to congenital diaphragmatic hernia. A type II pneumocyte contains well-organized lamellar bodies, some with a dense core matrix. There is minimal alveolar material (reproduced with permission from Dunbar et al, 2000).
(A)
(B)
4.9 Photomicrographs of representative lung tissue from extensive kindred of SFTPC deciency. (A) UIP. This lowpower view of an open lung biopsy in an adult patient shows coarse scarring with airspace dilatation and metaplastic cuboidal to columnar epithelium (left), normal alveolar tissue (right), and two broblast foci at the interface (arrowheads; haematoxylin and eosin 12.5). (B) Cellular non-specic interstitial pneumonia. Autopsy lung tissue from a child age 7 years shows homogeneous alveolar septal thickening by a cellular inltrate and intra-alveolar cells and granular material (reproduced with permission from Thomas et al, 2002).
(A)
hyperinflation. CT scan showed non-specific, groundglass appearances, and lung biopsy showed interstitial expansion by spindle cells containing periodic-acid Schiffpositive, diastase labile material consistent with glycogen (4.11). Five were treated with pulsed corticosteroids, one with additional hydroxychloroquine; six of seven did well. The authors proposed that this was an abnormality in lung cytodifferentiation involving interstitial mesenchymal cells, because abundant glycogen is not normally found in pulmonary interstitial cells. This condition has been described in twins, suggesting that inherited factors or the intrauterine environment may be important. Pathologists increasingly believe that these cells are not specific for pulmonary interstitial glycogenosis, and it is important not to overdiagnose this condition. Histological features of pulmonary interstitial glycogenosis may also be seen in other conditions.
(B) 4.10 (A) CT scan showing chronic pneumonitis of infancy. HRCT is non-diagnostic, and shows areas of ground-glass shadowing, and lucent areas crossed by broad strands. (B) A case of chronic pneumonitis of infancy shows interstitium widely expanded by plump spindle cells mixed with a mild inammatory cell inltrate. Alveolar walls show orid type 2 cell hyperplasia and focal proteinaceous debris is noted within alveolar spaces. Again, these cases are now often found to be associated with surfactant protein gene abnormalities.
Neuroendocrine cell hyperplasia of infancy

Another chILD that has so far only been recognized in infants is neuroendocrine cell hyperplasia of infancy. Infants present with respiratory distress and hyperinflation and ground-glass opacities are found on HRCT. Lung biopsies look essentially normal, unless they are stained for bombesin, which demonstrates hyperplasia in the form of increased numbers of neuroendocrine cells and bodies (4.12). Bombesin staining should be part of the evaluation of clinical ILD with an apparently normal lung biopsy.
Desquamative interstitial pneumonia

This is one of the commonest forms of chILD, true UIP being virtually unknown in childhood. It is characterized by interstitial expansion, and intra-alveolar macrophage aggregates. In most historical cases, no underlying cause has been identified, although these also are increasingly being associated with surfactant protein gene disorders.
4.11 Lung biopsy from 3-month-old infant born at term showing diffuse interstitial thickening with occasional macrophages within alveolar spaces. The cytoplasm of interstitial cells in lung biopsy contains masses of PASpositive material (arrow) indicative of glycogen.
4.13 A case of non-specic interstitial pneumonia shows mild loss of alveolar architecture with diffuse expansion of the interstitium by a mild degree of interstitial brosis associated with a mild to moderate degree of non-specic chronic inammation.
4.12 Neuroendocrine cell hyperplasia of infancy: the lung histology is essentially normal, but there is marked positive immunoreactivity for bombesin (arrow) (courtesy of Dr Leland Fan).
(A)
Non-specic interstitial pneumonia

In paediatrics, this is something of a repository of undiagnosable conditions (4.13). It may be the presentation of a genetic disorder. There is a uniform interstitial inflammation and fibrosis, and intra-alveolar macrophages, with no feature predominant. Cellular and fibrotic subdivisions are recognized.
The spectrum of lymphocytic abnormalities

This ranges from relatively benign conditions such as follicular bronchiolitis (4.14) and lymphoid interstitial pneumonia (4.15), through to primary pulmonary lymphoma, which is very rare in children. The finding of a lymphoid histology should prompt a full examination by an experienced paediatric immunologist.
(B) 4.14 (A) A 6-month-old infant presented with tachypnoea and failure to thrive. There is reticulonodular shadowing, with conuence basally. The appearances are non-diagnostic. (B) Same case as (A). The histology shows follicular bronchiolitis. In many such cases, an immunodeciency is detected on a detailed examination.

(non-evidence-based) approach in children is to try to induce remission using three once-daily pulses of 500 mg/ m2 methylprednisolone monthly for 6 months, sometimes with daily oral prednisolone if the child is very sick, and then assess response. If there has been continuing improvement with successive pulses, we would continue, otherwise we assume that the limit of steroid responsiveness has been reached. It is essential not to expose the child to risks of prolonged steroid therapy if there is no evidence of continued benefit. Most would add hydroxychloroquine 6 mg/kg to a maximum of 400 mg. If this medication were used, most would arrange ophthalmic checks. If the combination does not work, then second-line therapy with methotrexate, azathioprine, cyclophosphamide or even ciclosporin should be considered. In the absence of a specific diagnosis such as Wegeners granulomatosis, then there is no evidence to prefer any above the rest. Our own first choice is methotrexate.
(A)
Treatment for pulmonary hypertension

Some children have evidence of disproportionately severe pulmonary hypertension complicating interstitial lung disease, despite adequate oxygenation. They may benefit from treatment with either or both of the endothelin receptor antagonist, bosanten, or the phosphodiesterase V inhibitor, sildenafil.
(B) 4.15 (A) HRCT scan from an infant with respiratory distress. There is generalized ground glass, most marked basally. (B) Same case as (A); open lung biopsy. This shows lymphoid interstitial pneumonia with dense expansion of the alveolar walls by a lymphoid inltrate. This may be a manifestation of HIV infection, in which context there may be associated bronchiectasis.
Treatment of specic conditions

One reason for pursuing a specific diagnosis is that many conditions are not steroid sensitive, and the risk of side effects is unjustified; and a few rare conditions may be treated with specific therapies. Examples include: 1. Sarcoidosis: there is anecdotal evidence that the tumour necrosis factor-a receptor antagonist etanercept may be beneficial in resistant cases. Great care must be taken to exclude the diagnosis of tuberculosis, which may be worsened by this therapy. 2. Wegeners granulomatosis, neutrophilic capillaritis: cyclophosphamide is the treatment of choice; steroids may also be needed. 3. Pulmonary alveolar proteinosis (adult type, which may occur outside the neonatal period): large volume lung lavage has been used very successfully in a few children; in very small infants, doing the procedure on cardiopulmonary bypass may be safer. Nebulized and subcutaneous GM-CSF has also been successful. There is no evidence of benefit in PAP due to surfactant protein deficiency.
Treatment of interstitial lung disease

There is only the most meagre evidence base for therapy, due to the rarity and diversity of these conditions. The only non-controversial aspect is that hypoxaemic children should be given oxygen. Some children require several years of treatment, and then recover.
Non-specic therapies
The mainstay of therapy is corticosteroids. There is some evidence that pulsed methylprednisolone is safer and more effective than daily oral prednisolone. Our
It is likely that more anti-cytokine therapies for very specific conditions will develop in the future, making accurate diagnosis even more important.
Lung transplantation
This is the final resort for end-stage chILD. Considerations include the current severity and likely progression of the disease, and chances of recurrence in the transplanted lung. Relative contraindications include steroid therapy and osteoporosis; these are important reasons for withdrawing steroid therapy if it is no longer effective.
Prognosis
This is extremely variable, and it is virtually impossible to give sensible advice to the individual patient. Some deteriorate to the point of transplantation or death, whereas others, equally ill, make a complete recovery. As with so many rare lung diseases, much more work is needed. The organization of national and international networks to address this is welcome.
Key points
Bronchoscopy rarely gives diagnostic information in paediatric ILD. For most paediatric ILD, transbronchial or percutaneous lung biopsy gives insufficient tissue for diagnosis, and carries increased risk. Open lung biopsy or video-assisted thoracic surgery is the diagnostic investigation of choice.
Bush A, Nicholson A. Paediatric interstitial lung disease. In Interstitial Lung Disease, Eur Respir Monograph 46. duBois R, Richeldi L (Eds). 2008, 31954. Clement A, Allen J, Corrin B, et al. Task Force on chronic interstitial lung disease in immunocompetent children. Eur Respir J 2004; 24: 68697. Deutsch GH, Young LR, Deterding RR, et al.; Pathology Cooperative Group, Albright EA, Askin FB, Baker P, et al.; ChILD Research Co-operative. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med 2007; 176: 11208. Dunbar AE 3rd, Wert SE, Ikegami M, et al. Prolonged survival in hereditary surfactant protein B (SP-B) deficiency associated with a novel splicing mutation. Pediatr Res 2000; 48: 27582. Hartl D, Griese M. Interstitial lung disease in childrengenetic background and associated phenotypes. Respir Res 2005; 6: 32. Langston C, Patterson K, Dishop MK; chILD Pathology Co-operative Group, Askin F, Baker P, Chou P, et al. Aprotocol for the handling of tissue obtained by operative lung biopsy: recommendations of the chILD pathology co-operative group. Pediatr Dev Pathol 2006; 9: 17380. Milman N, Hoffmann AL. Childhood sarcoidosis: long-term follow-up. Eur Respir J 2008; 31: 5928. Thomas AQ, Lane K, Phillips J 3rd, et al. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med 2002; 165: 13228.
Further reading
Brody AS. Imaging considerations: interstitial lung disease in children. Radiol Clin North Am 2005; 43: 391403.
Chapter 5
51
Primary and secondary thoracic tumours

Catherine Wynne, N.J. Sebire, Kieran McHugh, Julia Chisholm
Introduction
Cancer in children is rare, affecting 1 in 500 children in the UK before the age of 15 years. The spectrum of disease differs from the adult population, with acute leukaemia, brain tumours and lymphoma forming the largest diagnostic groups (5.1). In contrast to the adult population, primary lung tumours are extremely uncommon, accounting for <1% of all paediatric cancers.
Malignant disease within the lung is more frequently the result of metastatic spread from primary disease elsewhere. This chapter discusses the clinical presentation, investigation and management of primary and secondary tumours within the lungs and chest. The diagnosis and management of respiratory complications of cancer therapy, including opportunistic infection in the immunocompromised patient, are mentioned as an important aspect of the care of children with cancer.
Leukaemias (32%) Lymphomas (10%) Brain and spinal tumours (24%) Sympathetic nervous system (7%) Retinoblastoma (3%) Renal tumours (6%) Hepatic tumours (1%) Bone tumours (4%) Soft-tissue sarcomas (7%) Gonadal and germ cell tumours (3%) Carcinoma and melanoma (3%) Other and unspecified cancers (1%) 0 50 100 150 200 Males Females 250 300
Average number of cases per year 5.1 Annual average number of cases of paediatric cancer by diagnostic group and sex, ages 014, Great Britain 198998. Reproduced from Toms JR (ed). Cancer Stats Monograph 2004. London: Cancer Research UK, 2004.
52 Primary and secondary thoracic tumours
Clinical presentation of tumours involving the chest

Respiratory symptoms and signs are the commonest presenting features of primary tumours within the chest and occur with extrapulmonary malignant disease affecting the mediastinum, chest wall or haematological systems. By contrast, metastatic lung disease is usually detected by routine investigations after diagnosis of a primary tumour. A careful clinical history and examination may point to the site of malignant disease within the chest or underlying diagnosis in systemic disease or primary disease outside the chest (Table 5.1).
Investigation of paediatric malignant chest disease

The aim is to establish a firm diagnosis and determine the extent of tumour by appropriate staging investigations. It is important to involve a paediatric oncologist or haematologist at an early stage of investigation. Complex imaging and diagnostic tissue sampling are usually performed at a specialist oncology centre affiliated to the UK Childhood Cancer and Leukaemia Group or an equivalent national body, so that the full complement of diagnostic tests (particularly cytogenetic and molecular genetic testing) can be done. An outline of the types
Table 5.1 Typical presenting features of malignant chest disease Site of malignancy Malignant differential diagnosis Possible presenting symptoms Cough Shortness of breath Wheeze Stridor Haemoptysis Metastatic disease often asymptomatic with symptoms relating to primary tumour elsewhere Potential examination ndings Dyspnoea Hypoxia Wheeze Stridor Deviated trachea Reduced/ asymmetric chest expansion Reduced air entry Crepitations Bronchial breathing Increased respiratory rate Dyspnoea Hypoxia Stridor Superior vena cava (SVC) obstruction Other features
Lung elds
Metastatic lung disease Primary lung tumour Leukaemic inltration Lymphoproliferative disease (LPD) Langerhans cell histiocytosis (LCH)
Look for evidence of solid tumour elsewhere or haematological malignancy Ask about history of immunodeciency or previous solid organ/bone marrow transplant (LPD)
Anterior mediastinum
T-cell acute lymphoblastic leukaemia (T-ALL) Non-Hodgkins lymphoma (NHL) Hodgkins disease Germ cell tumour Thymic tumour Carcinoid LCH (rare)
Cough Shortness of breath Stridor Symptoms worse when supine
History of sweats, weight loss, fever (lymphoma) Fever, pallor, bruising, petechiae, lymphadenopathy, hepatomegaly, splenomegaly (haematological malignancy)
Primary and secondary thoracic tumours 53
Table 5.1 Typical presenting features of malignant chest disease (continued) Posterior mediastinum Neuroblastic tumours (ganglioneuroma, ganglioneuroblastoma, neuroblastoma) Incidental nding on chest X-ray (common) Shortness of breath Symptoms of spinal cord compression secondary to intraspinal extension Unilateral Horners syndrome Dullness/reduced air entry posteriorly in chest Unilateral Horners syndrome Always examine limbs for evidence of spinal cord compression Fever, sweats, hypertension (resulting from catecholamine release) History of lethargy, weight loss, bone pain (metastatic skeletal disease) Look for evidence of neuropathic bowel or bladder if spinal cord involvement suspected Examine for: signs of pleural effusion, pneumothorax, soft tissue swelling/ mass in chest wall; lymphadenopathy; intra-abdominal mass Lymphadenopathy suggests locoregional spread
Pleura
Metastatic lung disease Tumour invasion from lung Mesothelioma Malignant pleural effusion
Cough Dyspnoea Chest pain Symptoms may relate to primary tumour elsewhere
Dyspnoea Reduced/ asymmetrical chest expansion Reduced oxygen saturations
Chest wall
Soft tissue sarcoma Ewings/ peripheral primitive neuroectodermal tumour (pPNET) Rhabdoid tumour LCH Chest wall tumour with local invasion Bone sarcoma Metastatic disease
Pain Swelling Dyspnoea
Localized chest wall swelling or signs of intrathoracic mass
Ribs
Pain Swelling
Localized swelling and tenderness
Look for primary tumour site or other features of LCH (e.g. fever, scalp or skin rash; hepatomegaly; splenomegaly, aural discharge; proptosis)
of investigation needed for suspected malignant chest disease is shown in Table 5.2. Many procedures/investigations require sedation or general anaesthesia, particularly for young children. A full clinical assessment must be performed by a paediatrician and anaesthetist to determine whether the child is fit for the procedure, particularly in children with a mediastinal mass, airway compromise or respiratory distress. In some cases, it is necessary to initiate treatment guided by clinical diagnosis before completing investigations.
Primary lung tumours

Table 5.3 shows the relative frequencies of benign and malignant lung tumours in children. Diagnosis is made by tumour biopsy or primary surgical excision, and management varies according to the specific tumour type. Follow-up is particularly important and should consist of regular clinical reviews for at least 5 years after completion of treatment, with regular chest X-rays. Bronchoscopy may also be useful in monitoring for recurrence of endobronchial disease.
Table 5.2 Diagnostic investigations in suspected paediatric malignant disease Procedure Blood tests Investigation Full blood count and blood lm Clotting screen Urea and electrolytes Calcium, phosphate Urate Lactate dehydrogenase (LDH) Serum a-fetoprotein, b-HCG Differential diagnosis Leukaemia/lymphoma Other considerations Capillary/venous blood gas (if signs of respiratory distress) Cerebrospinal uid if haematological malignancy suspected (intrathecal chemotherapy should be given at time of lumbar puncture).
Tumour lysis syndrome in leukaemia/lymphoma Lymphoma; elevated in many tumours Malignant teratoma, hepatoblastoma Neuroblastoma Haematuria or suspected renal tumour Primary lung tumour Metastatic lung disease Pleural/chest wall malignancy + local spread Mediastinal tumour Pulmonary infection Primary lung tumour Metastatic lung disease Pleural/chest wall malignancy with local spread LPD Pulmonary infection
Urine tests
Homovanillic acid/ vanillylmandelic acid Urinalysis/urine microscopy and culture Chest X-ray
Imaging
Anteroposterior/ posteroanterior and lateral lms if suspected malignancy
CT scan of chest
CT scan is imaging of choice for pulmonary metastases. For other indications, particularly the chest wall and mediastinum, MRI may be preferred in some centres
Table 5.2 Diagnostic investigations in suspected paediatric malignant disease (continued) CT or MRI scan of abdomen Wilms tumour Neuroblastoma Other renal tumours (rhabdoid, clear cell sarcoma) Other abdominal tumours Osteosarcoma Ewings sarcoma Neuroblastoma with suspected intraspinal extension Acute lymphoblastic leukaemia (ALL) Acute myeloid leukaemia (AML) Non-Hodgkins lymphoma Metastatic solid tumour LCH ALL AML Non-Hodgkins lymphoma Metastatic solid tumour LCH Primary lung tumours Wilms tumour Neuroblastoma Soft tissue sarcoma Other solid tumours Haematological malignancy Solid tumours Biopsy of suspected Wilms tumour is not performed in some countries Peripheral blood can be sent for immunophenotype if patient unt for diagnostic procedure Ultrasound scan of abdomen should be performed prior to CT or MRI scan
MRI scan of abnormal limb
Plain X-rays of affected area should be performed
MRI of spine
Bone marrow aspirate
Morphology Cytogenetics Immunophenotype Minimal residual disease if ALL suspected
Bone marrow trephine
Histopathology, immunohistochemistry
Trucut or open biopsy of primary tumour
Histopathology Cytogenetics Molecular genetics
Lymph node biopsy
Histopathology
Can be performed when primary site inaccessible for safe biopsy. Bone marrow is investigation of choice if leukaemia suspected Valuable if unsafe to lay patient at/give general anaesthetic. May be diagnostic. May be required for symptomatic relief
Pleural uid tap
Histopathology Microscopy, biochemistry and culture
Primary lung tumours Metastatic lung tumours Haematological malignancy
Benign tumours
Inflammatory myofibroblastic tumour (5.2) is the commonest benign lung tumour: all others are very uncommon (Table 5.3).
Malignant tumours Carcinoid tumour

This is the commonest endobronchial tumour in children and arises from Kulchitsky cells. It frequently presents with pneumonia, related to pulmonary obstruction. Non-specific systemic symptoms may occur, but carcinoid syndrome (with symptoms of, e.g., paroxysmal flushing and diarrhoea) is rare. Investigations include 5-hydroxyindoleacetic acid measurements in serum and urine, chest X-ray and computed tomography (CT) scan, abdominal ultrasound scan and octreotide scintigraphy. The treatment of choice is surgical resection, although laser ablation has been used in adults. Most case series include adults and children and show variable survival rates, with 10-year survival rates ranging from 56% to 82%. Neuroendocrine carcinoma is closely related to carcinoid tumour but extremely rare. The primary site
(B)
Inammatory myobroblastic tumour (pulmonary inammatory pseudotumour, plasma cell granuloma)

This slow-growing tumour may present with pneumonia or cough. A chest radiograph may reveal a solitary nodule in the lung, or occasionally lobar hyperexpansion or collapse/atelectasis due to an endobronchial lesion. The treatment of choice is complete surgical resection, although this may not be feasible in extensive disease. Even after surgery, local relapse can occur. Laser ablation, radiotherapy, corticosteroids and non-steroidal anti-inflammatory drugs have been used, but without convincing results.
(A)
(C)
5.2 Inammatory myobroblastic tumour. (A) Axial CT showing a large inammatory myobroblastic tumour in the right lower lobe, encasing the ipsilateral pulmonary vein (arrow). (B) Macroscopic photograph of tumour resection, including rib and lung with inltrating white tumour. (C) Photomicrograph demonstrating inammatory myobroblastic tumour. There is a proliferation of spindle cells in a variably collagenous background with numerous admixed inammatory cells.
Table 5.3 Incidence of primary lung tumours in children Tumour type Benign primary lung tumours Inammatory myobroblastic tumour Hamartoma Neurogenic tumour Leiomyoma Granular cell tumour Mucous gland adenoma Benign teratoma Bronchial chondroma Papilloma Pulmonary capillary haemangiomatosis Sclerosing haemangioma Malignant primary lung tumours Carcinoid Bronchogenic carcinoma Mucoepidermoid carcinoma Pleuropulmonary blastoma Leiomyosarcoma Rhabdomyosarcoma Fibrosarcoma Adenoid cystic carcinoma Haemangiopericytoma Teratoma Plasmacytoma Myxosarcoma Frequency 70% 12% 6% 5% 3% 1% <1% <1% <1% <1% <1% 33% 28% 9% 8% 6% 5% 4% 2% 1% <1% <1% <1%
of this slow-growing tumour, can be lung, thymus or caecum and it can metastasize to bone. An association with common variable immunodeficiency has been reported. Histologically, tumour cells are mixed with fibrous tissue and stain positive for chromogranin, cytokeratin, Leu-7 and synaptophysin. It does not appear to be a chemosensitive tumour and surgical resection is the treatment of choice.
Bronchogenic carcinoma of the lung

This is very rare in children compared with adults, but has been reported in all age groups, including infants. The majority of patients have never smoked. Tumours are most commonly undifferentiated, but adenocarcinoma (5.3) and squamous cell carcinoma can occur. Most cases are treated with radical surgery and radiotherapy, following adult treatment guidelines. Prognosis is uncertain.
(A)
5.4 Mucoepidermoid carcinoma. Contrast-enhanced CT showing a left paraspinal mass lesion, mimicking a neuroblastoma, but which was seen to be encroaching into the left lower lobe bronchus and causing left lower lobe collapse more inferiorly, typical of an endobronchial tumour.
(B) 5.3 Adenocarcinoma of the lung. (A) Coronal CT at mediastinal window settings showing enhancement of the cardiac chambers and major vessels. The non-enhancing soft tissue in the mediastinum is widespread adenopathy, which was partially occluding the right main bronchus. (B) Photomicrograph demonstrating malignant adenocarcinoma cells within a pulmonary vessel in a case of disseminated carcinoma.
Common presenting features include fever, cough and haemoptysis. Radiological investigations may reveal a solitary lesion, focal consolidation or atelectasis (5.4). Histologically, the tumours have a mixed solid and cystic composition with areas of squamous, transitional and goblet cells. In children, the majority are low grade and treated by surgical resection; spread is rare. High-grade tumours, invading local tissues, have been treated with radiotherapy. Recurrence is rare in patients <30 years of age and paediatric cases reported in the literature have survived up to 21 years after treatment.
Pleuropulmonary blastoma
Pleuropulmonary blastoma (PPB; 5.5) is a malignant tumour of embryonic origin that only occurs in children. There is evidence of a previous pulmonary cyst in about 35% of cases. In about 25% of cases, PPB has been associated with cystic nephroma, nephroblastomatosis, cystic adenomatous malformation and thyroid carcinoma, either in the affected patient or in a close relative. Children with PPB have an increased risk of developing other embryonal tumours of childhood although there is no consensus on whether screening for other tumours is necessary. Familial PPB has been documented and in some families with PPB and other associated tumours, a mutation has been recently discovered in the DICER1 gene. Three histological types of PPB are recognized, of increasing tumour aggressiveness: type I (cystic); type II (mixed solid and cystic components); and type III (solid). Patients commonly present with cough, fever and
One specific subtype of bronchogenic carcinoma reported in children is the a-fetoprotein secreting fetal lung adenocarcinoma. It can occur in teenage children, although most commonly occurs in Japanese adults. Despite being initially chemo- and radiosensitive, it follows an aggressive course and has a poor prognosis. Bronchioalveolar carcinoma is also reported; it may arise from congenital cystic adenomatous malformation and usually appears as a solitary lung nodule, which is often found incidentally. Surgical resection is an effective treatment.
Mucoepidermoid tumours
These tumours, affecting adults and children, are derived from the salivary glands that line the trachea and bronchi.

of eosinophilic spindle cells with cigar-shaped nuclei. Surgical resection is the usual treatment.
Cylindroma
These malignant tumours arise from mucus-secreting cells of the bronchial mucosa and are histologically similar to salivary gland tumours. Treatment is surgical excision.
Lung involvement in systemic disease Lymphoproliferative disease

This malignancy occurs in the setting of immune dysfunction, including congenital immunodeficiencies (e.g. severe combined immunodeficiency, X-linked agammaglobulinaemia, X-linked lymphoproliferative disorder, WiscottAldrich and many others) and in acquired immunodeficiency states such as HIV and posttransplantation. It is usually of B-cell lineage and in acquired immunodeficiencies is usually driven by the EpsteinBarr virus. Clinical features include fever, malaise, weight loss, lymphadenopathy, hepatosplenomegaly and parenchymal lung involvement.Treatment options may include reduction in immunosuppressive therapy, chemotherapy, monoclonal antibodies against CD20 and cytotoxic T lymphocytes.
5.5 Pleuropulmonary blastoma. Photomicrograph of PPB, immunostained for desmin, highlighting the inltrating population of malignant cells with a small round cell phenotype, reminiscent of rhabdomyosarcoma.
shortness of breath. They may have non-specific symptoms, such as headache, vomiting and weight loss. The tumours typically metastasize to brain and bone, but can involve spinal cord, liver, ovary, pancreas, kidney, adrenal glands and soft tissue. Poor prognostic features include primary tumour size >5 cm, local or distant spread, especially to mediastinum, pleura or central nervous system and histological subtypes II or III. Complete surgical resection is the treatment of choice. Many advocate use of chemotherapy in all cases although some patients with type I PPB have been successfully treated with surgery alone. PPB is a chemosensitive tumour and if the diagnosis is confirmed by biopsy and the patient is clinically stable, neoadjuvant chemotherapy may be used to facilitate delayed complete surgical resection. Adjuvant chemotherapy is always recommended for all type II and III tumours where there has been primary resection, with second-look surgery for any residual mass. Radiotherapy has been used instead of chemotherapy in patients with minimal residual disease following surgery, but there is no proven benefit. Follow-up should include monitoring of brain and bone in addition to the primary site, as metastatic relapse frequently occurs at these sites.
Langerhans cell histiocytosis

This can occur at any age, but incidence peaks between the ages of 1 and 3 years. It is more common in males. It is not a true malignancy, but rather is thought to represent an abnormal immunological response, characterized by the clonal proliferation of dendritic cells with epidermal Langerhans cell phenotype. Single system disease affects bone, skin or lymph nodes; lung involvement is usually part of multisystem disease, which may also involve thymus, liver, spleen, bone, soft tissue, bone, bone marrow, thyroid gland and central nervous system. It usually presents with nonspecific features, such as fever, weight loss, failure to thrive or skin rash, and sometimes with lymphadenopathy, hepatosplenomegaly, aural discharge or proptosis. Lung disease may occur in isolation in smokers. Typical presenting features of respiratory involvement are persistent cough and shortness of breath. Bilateral reticulonodular interstitial shadowing can be identified on chest radiograph, with nodules and cystic lesions on CT scan (5.6). In later stages of the disease, the number of cysts increase and a honeycomb appearance of the lungs develops. Rupture of these cysts may result in pneumothoraces.
Leiomyosarcoma
Primary leiomyosarcoma can occur in the lung, heart or mediastinum. There is an association with HIV infection. Microscopically, these slow-growing tumours consist
Respiratory function tests show reduced compliance and lung volume. Lung fibrosis may occur. Diagnosis is made by biopsy of involved tissue (e.g. lymph node, bone marrow and lung) with the finding of Langerhans cells, which are positive for CD1a, langerin and S100; Birkbeck granules may be seen on electron microscopy. Lung disease in isolation or as part of multisystem disease is treated with chemotherapy, including prednisolone and vinblastine. Advice to stop smoking is essential.
foregut cyst presenting as a mass in the middle mediastinum may be confused for a tumour.
Non-Hodgkins lymphoma
The mediastinum is the primary tumour site in approximately 30% of cases of non-Hodgkins lymphoma (5.7), most commonly T-cell lymphoma. Presenting symptoms are attributable to the mediastinal mass, to associated pleural or pericardial effusions, or to systemic manifestations. Diagnosis can be confirmed by histopathological examination of pleural fluid or the primary tumour biopsy or from tissue from other sites of disease such as bone marrow or lymph node. Respiratory distress may be exacerbated by lying supine, so caution should be exercised in planning further investigations and administering general anaesthetic and, in some
Tumours of the mediastinum

Anterior and middle mediastinum
The commonest anterior mediastinal tumours are lymphoma, germ cell tumour and thymoma. A congenital
(A)
(B)
(C)
(D)
5.6 Langerhans cell histiocytosis. (A) Heterogeneous appearance to the thymus (arrow) on CT with stippled higher attenuation (likely early calcication) is characteristic of Langerhans cell histiocytosis involvement of the thymus. (B) CT scan of the lungs of a 4-month-old baby, showing numerous ill-dened nodules, with one larger right-sided air-lled cyst, likely due to cavitation of a larger nodule. (C) Higher-power photomicrograph of same lung biopsy specimen, composed predominantly of cells with a histiocytic morphology, pale eosinophilic cytoplasm and grooved nuclei. (D) Cells with a histiocytic morphology clearly highlighted by immunohistochemical staining for langerin.CD1a.

an association between Kleinfelters syndrome (XXY) and mediastinal germ cell tumour. Occasionally, ectopic production of sex hormones or insulin can lead to presentation with precocious puberty or hypoglycaemia before the onset of respiratory symptoms. Investigation should include serum a-fetoprotein (raised in malignant teratoma) and b-human chorionic gonadotrophin (raised in choriocarcinoma). If tumour markers are not raised and imaging is characteristic of mature or immature teratoma, primary surgical resection can be considered. Otherwise, a biopsy should be taken and treatment planned accordingly. Biopsy can be delayed until after the start of chemotherapy if the risk of a general anaesthetic is too high. Treatment of malignant tumours includes platinumbased chemotherapy and surgical resection of residual tumour. Approximately 90% of children with extracranial malignant germ cell tumours survive long term.
5.7 Non-Hodgkins lymphoma. Coronal CT post-contrast enhancement, section through the superior vena cava and pulmonary artery, showing a left-sided large non-Hodgkins lymphoma mass lesion, with some lower attenuation medially due to an associated pericardial effusion.
cases, it is necessary to initiate treatment before obtaining a histopathological diagnosis and completing staging investigations. Staging investigations include bone marrow aspirate/biopsy and lumbar puncture for cerebrospinal fluid cytology; the disease is categorized as lymphoblastic leukaemia if the bone marrow contains >25% blasts. Chemotherapy is the treatment of choice for T-cell and B-cell lymphomas and leukaemias. Prognosis is good with cure rates of 7080%.
Posterior mediastinum
A number of different tumours can arise in the posterior mediastinum. These include benign tumours such as neurofibroma, schwannoma and rarely their malignant counterparts, including malignant schwannoma and malignant peripheral nerve sheath tumour. However, the vast majority of posterior mediastinal tumours are neuroblastic tumours.
Hodgkins lymphoma
The anterior or middle mediastinum is a common site of involvement in Hodgkins lymphoma (5.8). Patients usually present with painless lymphadenopathy but may have fever, night sweats and weight loss (B symptoms). Clinical and radiological findings may include lymphadenopathy at multiple sites above and/or below the diaphragm, including mediastinal adenopathy, and splenomegaly with focal splenic lesions. Disease can occur outside the reticuloendothelial system and may include parenchymal lung disease, bone marrow or liver involvement. Treatment is with chemotherapy with or without radiotherapy and prognosis is generally good although there is an increased risk of secondary malignancy after treatment for Hodgkins disease.
Neuroblastic tumours
These neurogenic embryonal tumours are seen predominantly in young children. The tumours show variable degrees of differentiation towards ganglion cells with a spectrum ranging from neuroblastoma, with malignant cells predominating, to ganglioneuroma, in which all cells are mature. Primary mediastinal disease is frequently detected incidentally on a routine chest X-ray done for other reasons (5.10) but symptomatic disease may present with respiratory distress, dysphagia, spinal cord compression or occasionally Horners syndrome. The child may also present with systemic symptoms related to high levels of catecholamines or metastatic disease. Investigation is outlined in Table 5.4. Current treatment for neuroblastic tumours is determined primarily by the age of the patient, the staging and tumour biology (MYCN amplification). It is treated by multi-agent chemotherapy, surgery, radiotherapy or combination therapy. Surgery alone is often the treatment of choice
Germ cell tumours

The mediastinum is the primary tumour site in approximately 6% of germ cell tumours in children and is commonly seen in adolescent males (5.9). There is
(A)
(B)
(C)
(D)
(E)
5.8 Hodgkins disease. (A) Chest X-ray showing a lobulated widened mediastinum due to conglomerate adenopathy. (B) Axial CT post-contrast enhancement in an 11-year-old showing a relatively homogeneous anterior mediastinal mass compressing the left brachiocephalic vein as that vein traverses through the mass. The trachea is also compressed posteriorly. (C) Coronal image from a positron emission tomography examination showing increased uptake of the tracer, uorine deoxyglucose, in the mediastinum, upper abdomen and right side of the pelvis due to widespread Hodgkins disease. (D) Photomicrograph of a mediastinal lymph node involved by Hodgkins disease, classical subtype. (E) Higher power view of previous photograph, demonstrating classical ReedSternberg cells within a mixed cellular background.
(A)
(B)
5.9 Germ cell tumour. (A) Axial CT post-contrast enhancement showing a large, mainly left-sided, mass lesion that contains large amounts of fatty tissue (arrow 1) and calcication (arrow 2). Note the fatty components of the mass have similar attenuation to subcutaneous fat. (B) Photomicrograph of a needle core biopsy of a mediastinal teratoma demonstrating brous tissue within which are areas of squamous and respiratory type epithelium in a disorganized pattern. No immature elements or frankly malignant elements are present.
(B) (A)
(D)
(C)
(E)
5.10 Neuroblastic tumours. (A) Chest X-ray in a 1-year-old showing widening of the superior mediastinum. Note there is posterior rib separation and erosive change affecting the medial aspect of the right fourth rib posteriorly, indicating an aggressive posterior mediastinal lesion. (B) Axial CT post-contrast enhancement showing anterior displacement and encasement of the descending thoracic aorta, typical of neuroblastomas. Note: it is often difcult on CT to assess whether there is intraspinal invasion of this tumour. (C) Metaiodobenzylguanidine (MIBG) scan images, in a child with a thoracic neuroblastoma primary, of the pelvis and lower limbs showing scattered MIBG uptake in the skeletonany skeletal uptake of MIBG is abnormal, indicating metastatic disease. (D) Photomicrograph of a post-treatment neuroblastic tumour demonstrating nests of immature neuroblasts within a brillary stroma and focal brous tissue septi. Focal dystrophic calcication is also present. The features are those of a post-treatment, poorly differentiated neuroblastoma. (E) Photomicrograph of a ganglioneuroma in the chest demonstrating predominant spindle cell, schwannian stroma, with scattered well-differentiated ganglion cells but no immature neuroblasts or neurobrillary stroma.
for benign ganglioneuroma. The prognosis is variable; generally very good for localized tumours but poor in patients with metastatic disease or amplification of the MYCN oncogene. Infants with stage 4S neuroblastoma may present with respiratory failure secondary to massive hepatomegaly from metastatic liver involvement. The disease tends to regress spontaneously in this patient group and prognosis is very good if the infant can be supported through the acute proliferative phase of the disease. Chemotherapy is used to induce regression in symptomatic infants.
Thymoma
Thymomas are usually slow-growing tumours. They are often found incidentally on chest X-ray, but otherwise present with symptoms suggestive of a mediastinal mass or a paraneoplastic syndrome (myasthenia gravis, red cell aplasia, hypogammaglobulinaemia). Some children may have finger clubbing. There is an association with EpsteinBarr virus infection. Thymomas are subdivided into low- and high-grade tumours. Treatment is based upon adult guidelines and depends on disease stage, usually involving surgery. Chemotherapy with or without radiotherapy is used for higher stage tumours.
Tumours of the thymus

Thymolipoma
These are slow-growing benign tumours, which account for <10% of thymic tumours. They often present at an advanced stage, with breathlessness or refractory asthma. They may be associated with myasthenia gravis. Histologically, the tumour is composed of mature thymic and adipose tissue. Following biopsy to confirm the diagnosis, complete surgical resection should be performed.
Carcinoid
Thymic carcinoid tumours present with symptoms from a mediastinal mass or bronchial obstruction. Complete surgical resection is the treatment of choice and confers a good prognosis. However, in metastatic disease, the prognosis is poor and there is no chemotherapy regimen of established benefit.
Tumours of the pleura

Mesothelioma
Mesothelioma is extremely rare in children. In contrast to adults, where there is a strong link, asbestos exposure has only been reported in a few paediatric cases. The tumour derives from the mesothelial cells covering the pleura and peritoneum. Pleural mesothelioma usually presents with chest pain or with a symptomatic pleural effusion. Diagnosis is based upon CT or magnetic resonance imaging scans and tumour biopsy. Treatment should include surgical resection and chemotherapy. Doxorubicin, cyclophosphamide, cisplatin and mitomycin-C have all been found to be effective in combination regimens. Intrapleural cisplatin and radiotherapy can also be used. The prognosis is poor.
Table 5.4 Investigations in neuroblastoma Diagnostic tests Chest X-ray (posteroanterior and lateral) CT or MRI scan of primary tumour site; Abdominal ultrasound Urine homovanillic acid/ vanillylmandelic acid (+ dopamine/other catecholamines) Tumour biopsy including tumour biology for MYCN Staging CT or MRI scan of abdomen Bilateral bone marrow aspirates and trephine biopsies MIBG scan
Tumours of the chest wall

Bone scan if MIBG scan negative Chest wall tumours are rare in children and most are malignant tumours of either the Ewings sarcoma family or rhabdomyosarcoma. Occasionally lymphoma can present as a chest wall mass. Hamartoma and fibromatosis are very rare benign chest wall tumours.
MIBG, Metaiodobenzylguanidine scan.

Ewings sarcoma
This is primarily a tumour of adolescents and young adults arising from bone (5.11). Identical tumours also arise in soft tissue, when they are known as peripheral primitive neuroectodermal tumours. Most patients present with a painful chest wall mass arising from a rib or within the chest wall often associated with systemic symptoms. The tumour may metastasize to the lungs, bones and bone marrow. Treatment involves chemotherapy, surgical resection of the primary tumour and sometimes radiotherapy. Five-year survival rates are 5070%, but less good when pulmonary metastases are present. The prognosis is poorer in alveolar rhabdomyosarcoma than in other types with a 5-year survival rate of about 70% in localized disease and only 1020% in metastatic disease.
Fibrosarcoma
The chest wall can be affected in the adolescent age group, where the tumour behaves more aggressively than the congenital infantile fibrosarcoma. Histologically, the tumour comprises fibroblasts, which may be spindleshaped or small and round. The treatment of choice is complete surgical excision, with radiotherapy if there is residual disease. Chemotherapy is not particularly effective, but has been used in unresectable disease. The prognosis is poor in adolescents.
Rhabdomyosarcoma
Primary chest wall rhabdomyosarcoma is uncommon and is usually associated with the alveolar subtype. The patient often presents with a painless lump, but may have an associated pleural effusion. Spinal involvement can result in neurological symptoms and signs. Approximately 20% of patients have metastases at diagnosis. Common sites for metastasis are lung, bone, bone marrow and lymph nodes. Treatment includes multiagent chemotherapy, surgery and usually radiotherapy. Definitive surgical resection is usually delayed until chemotherapy has been given to maximize the likelihood of complete excision. Local tumour control is the key issue affecting event-free survival.
Chondrosarcoma
These tumours typically arise in the anterior chest wall, but may also arise from the scapula, lungs and bronchi. They tend to present with a mass, which may be painful or painless. Bone destruction and soft tissue involvement are common. Treatment consists of surgical resection with chemotherapy or radiotherapy.
Malignant rhabdoid tumour

These rare tumours usually occur in young children. The most common sites are the kidney and brain (5.12). Treatment of extracranial disease is usually based upon soft tissue sarcoma chemotherapy guidelines. Surgical resection and radiotherapy may also be used. Prognosis is poor.
Haemangiopericytoma
These rare soft tissue sarcomas only occur in infants and may involve the chest wall. The prognosis is good after complete surgical resection.
Metastases
Tumours metastasizing to the lung
Many paediatric malignant solid tumours can metastasize to the lung (5.13). The commonest among these are Wilms tumour, osteosarcoma, rhabdomyosarcoma, hepatoblastoma, clear cell carcinoma of the kidney and thyroid carcinoma. Although neuroblastoma is a common paediatric malignancy, lung metastasis is rare in this condition.
5.11 Ewings tumour/peripheral primitive neuroectodermal tumours. Photomicrograph of primitive neuroectodermal tumours/Ewings tumour, composed of inltrating sheets of closely packed small ovoid cells with little cytoplasm, characterized by a high nuclear/cytoplasmic ratio and CD99 positivity on immunostaining.
(A) 5.13 Lung metastases in Wilms tumour. This patient has been placed in the prone position for percutaneous biopsy under CT guidance of a peripheral, posteriorly located, metastasis. Note a small pneumothorax has already been caused by the biopsy needle.
metastatic tumour and may involve surgical resection of residual operable lung lesions. For some tumour types, such as Wilms tumour and rhabdomyosarcoma, whole lung radiotherapy may be indicated.
(B) 5.12 Rhabdoid tumour. (A) Coronal CT scan showing a large mass lesion occupying the whole right hemithorax, displacing the trachea with endotracheal tube in situ, to the left. (B) Photomicrograph demonstrating extrarenal rhabdoid tumour composed of sheets of ovoid cells, some of which exhibit characteristic eosinophilic cytoplasmic inclusions. Diagnosis may be conrmed by INI1 immunostaining.
Tumours metastasizing to the mediastinum

Adenopathy in the middle mediastinum can occur in both haematological malignancy and in metastatic solid malignancies in children.
Respiratory infection associated with oncological conditions

Treatment of malignancy can result in a number of different treatment-related respiratory complications (Table 5.5). Infective complications are common and may be life threatening; they require careful evaluation and treatment. Lower respiratory tract infection is documented in 13% of episodes of paediatric febrile neutropenia. Causes include the usual spectrum of childhood lower respiratory tract infections but also opportunistic infections. Pneumocystis jiroveci infection occurs in the setting of prolonged immunosuppression and lymphopenia, particularly during treatment for haematological malignancy. Routine prophylaxis with cotrimoxazole has reduced its incidence significantly.
Metastases may be discovered on chest X-ray or CT scan during diagnostic and staging investigations. Occasionally patients may present with symptoms and signs related to lung metastases rather than the primary tumour, but this implies very advanced lung disease. Patients with potential lung metastases must have posteroanterior and lateral chest X-rays with CT scan for full evaluation. Most small (510 mm) nodules in the lung in a child with a known primary tumour are metastases but a minority is not. It is usually impractical to biopsy these small lesions, so they should simply be observed during follow-up. Treatment will usually involve intensive chemotherapy regimens aimed at treating both the primary and
Table 5.5 Respiratory complications of treatment for malignancy Short-term effects Pneumothorax related to central venous catheter insertion Pulmonary oedema due to uid overload and/or hypoalbuminaemia Diffuse alveolar haemorrhage Acute bleomycin toxicity Pulmonary veno-occlusive disease Bacterial pneumonia Viral pneumonia (including measles, chicken pox, inuenza A, respiratory syncytial virus) Pneumocystis jiroveci infection Cytomegalovirus pneumonitis Fungal infection especially Candida sp, Aspergillus sp. Chemotherapy related Reduced lung function Fibrosis (implicated agents: bleomycin; busulfan; cyclophosphamide; melphalan; methotrexate) Radiotherapy related Pneumonitis Lung brosis Restrictive lung disease due to restricted chest wall growth (or uncommonly scoliosis) Surgery related Loss of lung volume secondary to lung resection or scoliosis aware of the potential respiratory complications of cancer therapy.
Late effects
Viral pneumonitis from cytomegalovirus, varicella and measles is well documented and can be extremely serious. Respiratory syncytial virus, influenza A and adenovirus can be fatal after allogeneic bone marrow transplant for haematological malignancy. Fungal infections, most commonly Candida or Aspergillus, can also occur, particularly in the setting of prolonged neutropenia or after bone marrow transplant procedures and these infections remain difficult to treat even with the introduction of newer antifungal agents.
Further reading
Al-Qahtani AR, Di Lorenzo M, Yazbeck S. Endobronchial tumors in children: institutional experience and literature review. J Pediatr Surg 2003; 38: 7336. Fink G, Krelbaum T, Yellin A, et al. Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest 2001; 119: 164751. Kantar M, Cetingul N, Veral A, et al. Rare tumors of the lung in children. Pediatr Hematol Oncol 2002; 19: 4218. Pinkerton CR. Malignant germ cell tumours in childhood. Eur J Cancer 1997; 33: 895902. Webber SA, Naftel DC, Fricker FJ, et al.; Pediatric Heart Transplant Study. Lymphoproliferative disorders after paediatric heart transplantation: a multi-institutional study. Lancet 2006; 367: 2339.
Conclusions
A number of different tumours can affect the chest and lungs in children. Careful investigation and staging to determine differential diagnosis is essential before deciding whether tissue biopsy or primary excision should be undertaken; subsequent management is decided by the final diagnosis. Early involvement of specialist paediatric oncology services in planning the investigation and treatment of such tumours is mandatory. All clinicians involved in the care of children with cancer must be
Chapter 6
69
Rare lung diseases

Samatha Sonnappa, Robert Dinwiddie
Introduction
A number of rare diseases can affect the lungs in childhood and adolescence with the potential to cause serious longterm morbidity and mortality. The conditions are often misdiagnosed because of the relative infrequency with which each illness is encountered in clinical practice. This chapter describes systemic disorders with predominant pulmonary involvement, including: rheumatoid disorders affecting the lung such as systemic lupus erythematosus, dermatomyositis, scleroderma and Wegeners granulomatosis; sarcoidosis; pulmonary lymphangiectasia (PL) and lymphangiomatosis; sickle cell disease, mucopolysaccharidoses and respiratory papillomatosis. Although specific, targeted therapy is available for only some of these conditions, long-term lung damage can be contained if the disease activity can be controlled. Treatment for most is aimed at suppression of the underlying inflammatory and immune-mediated processes with corticosteroids, antifibrotic and immunosuppressive agents. A substantial minority of cases are refractory to treatment, leading to significant lifelong impairment of lung function and subsequent mortality.
Systemic lupus erythematosus Pathogenesis and presentation

Systemic lupus erythematosus is a chronic, multisystem, collagen vascular disease involving particularly the skin, central nervous system, kidneys and the lungs. The autoimmune process in the lung is manifest by pneumonitis, vasculitis and haemorrhage and leads to pulmonary fibrosis in severe cases. Other complications include pleural effusions, bronchiolitis obliterans and respiratory muscle weakness; the latter is often most marked in the diaphragm resulting in an apparent rapid loss of lung volume (shrinking lungs) (6.1), resulting in acute respiratory insufficiency. Presenting clinical features include breathlessness on exercise or at rest, cough, chest pain and fever.
Rheumatoid disorders
Multisystem involvement is the hallmark of these disorders and pulmonary involvement may be insidious. The underlying diagnosis is usually established before there is evidence of pulmonary involvement although, occasionally, lung disease may be the presenting feature.
6.1 Chest X-ray in systemic lupus erythematosus showing small volume lungs and some pleural uid on the right (arrow).
70 Rare lung diseases
Investigations
Lung function tests: reduced vital capacity, airway obstruction and reduced gas transfer if there is interstitial lung involvement. A fall in forced vital capacity >20% on going from seated to the supine position is very sensitive and specific for diaphragm weakness. Chest X-ray changes include reticular shadowing, volume loss, patchy consolidation and presence of pleural fluid. Computed tomography (CT) appearances include interstitial infiltration, honeycombing, traction bronchiectasis and ground-glass changes (6.2). Presence of lupus cells in pleural fluid is highly specific (seen with Wright staining).
Both the disease itself and immunosuppressive therapies lead to a significant risk of acute opportunistic lung infection with organisms such as Gram-positive and -negative bacteria, Pneumocystis jiroveci, candida, aspergillus, cytomegalovirus and mycobacteria.
Dermatomyositis Pathogenesis and presentation

Juvenile dermatomyositis is a chronic, multisystem inflammatory disease manifesting primarily in the lungs as vasculitis, although fibrosing alveolitis and pulmonary fibrosis are also described. There may also be intrapulmonary cysts that can predispose to spontaneous pneumothorax and pneumomediastinum. Musculoskeletal system involvement can lead to pharyngeal dysmotility resulting in recurrent aspiration pneumonitis. Clinical presentation is with cough, fever and breathlessness on exercise and at rest.
Diagnosis
Positive antinuclear antibody titre. High titres of antibodies to double-stranded DNA. Lung biopsy may be necessary to confirm the diagnosis.
Investigations Treatment
Analgesia. High-dose systemic corticosteroids. Plasmapheresis in severe cases. Immunosuppressive agents such as cyclophosphamide, ciclosporin, methotrexate or infliximab. Lung function tests: a restrictive pattern with reduced lung volumes and impaired gas transfer. Chest X-ray and CT (6.3) demonstrate diffuse interstitial infiltration. Videofluoroscopy may confirm aspiration if there is pharyngeal involvement.
6.2 A chest CT in an 11-year-old boy with systemic lupus erythematosus, showing extensive interstitial lung disease. Diffuse ground-glass attenuation, cystic changes and diffuse brosis with some honeycombing is seen.
6.3 A chest CT in a 10-year-old girl with juvenile dermatomyositis showing diffuse interstitial disease evidenced by widespread subpleural reticular change and ground-glass shadowing.
Rare lung diseases 71

Diagnosis
Raised antinuclear antibody titres. Elevated muscle enzymes. Typical electromyography. Muscle biopsy. Chest X-ray shows chest wall abnormality and in severe cases reticular shadowing. A chest CT may show honeycomb shadowing and cystic degeneration of the lungs as the disease process progresses.
Diagnosis Treatment
Systemic corticosteroids. Immunosuppressive agents such as methotrexate, azathioprine, ciclosporin or cyclophosphamide. Elevated antinuclear antibody titres. Raised antibodies to double-stranded DNA. High immunoglobulin levels. Tissue biopsy.
Scleroderma Pathogenesis and presentation

Scleroderma is a multisystem connective tissue disorder particularly affecting the skin, kidneys and lungs. Respiratory manifestations include interstitial pneumonitis, pulmonary hypertension, constriction of the chest wall due to thickening of the skin (6.4), diaphragmatic dysfunction and chronic aspiration pneumonitis secondary to oesophageal dysmotility. Histopathologically, there may be vasculitis and hyperplasia of connective tissue and alveolar walls.
Treatment
Systemic corticosteroids. Antifibrotic drugs such as D -penicillamine. Immunosuppressive agents such as cyclophosphamide and ciclosporin. Pulmonary hypertension is treated with vasodilating agents, including prostaglandins, sildenafil and bosentan. Pulmonary complications of the disease are major contributory factors to long-term morbidity and mortality.
Investigations
Lung function tests: a mixed restrictive and obstructive defect and impaired diffusing capacity for carbon monoxide.
Wegeners granulomatosis Pathogenesis and presentation

Wegeners granulomatosis is a multi-organ, granulomatous vasculitis most commonly affecting the skin and kidneys. There may be sinusitis (6.5) and the airways may be affected by necrotizing granulomatous lesions leading to subglottic and tracheobronchial stenosis. Presenting features include stridor, cough chest pain and haemoptysis.
6.4 Chest X-ray in scleroderma showing bilateral interstitial shadowing, thoracolumbar scoliosis, marked rib crowding and chest wall deformity.
6.5 CT of the sinuses in a 12-year-old girl with Wegeners granulomatosis showing involvement of maxillary and ethmoid sinuses with complete opacication of the right maxillary sinus (arrow).
Investigations
Lung function tests: a mixed restrictive and obstructive picture and decreased gas transfer. Chest X-ray and CT scan may show nodules or patchy interstitial parenchymal change in both lung fields. Sinus involvement can be confirmed on paranasal X-ray or CT (6.5).
Sarcoidosis Pathogenesis and presentation

Sarcoidosis is a chronic, multisystem, granulomatous disease with prominent pulmonary, lymph node and eye involvement, most often seen in adolescents. Respiratory disease may be the presenting symptom, or occur many years after the diagnosis has been established. The precise aetiology is unclear but current opinion suggests that an environmental antigen initiates an immune-mediated response via CD4 lymphocytes in genetically susceptible individuals. Less common pulmonary changes include pneumothorax, pleural effusion, pleural thickening, lymph node calcification and cavity formation in the parenchyma. The disease is manifest clinically by the onset of a variety of non-specific symptoms, including fever, weight loss, anorexia, lethargy and headache. Respiratory symptoms include cough, dyspnoea and exercise limitation.
Diagnosis
Presence of c-antineutrophil cytoplasmic antibodies has a reported sensitivity and specificity >90% for active disease. Presence of necrotizing granulomas and acute vasculitis on tissue biopsy (6.6).
Treatment
Supportive management, including dilatation/stenting of tracheobronchial stenosis (6.7) or tracheostomy. Systemic corticosteroids. Immunosuppressive agents such as cyclophosphamide, ciclosporin, azathioprine, chlorambucil and tacrolimus. Intravenous immunoglobulins. Disease progression results in pulmonary fibrosis, which can lead to chronic respiratory failure. Most cases will go into remission with current treatment; over one-third of these will relapse within 5 years and require further therapy. Antineutrophil cytoplasmic antibody titres are useful in monitoring disease activity and tailoring therapy.
Investigations
Lung function tests: reduced vital capacity, functional residual capacity, carbon monoxide gas transfer. In more advanced cases, oxygen desaturation, which may only be manifest on exercise initially. Chest X-ray typically shows bilateral hilar adenopathy and interstitial shadowing most prominent peripherally (6.8). A chest CT is vital to delineate the nature and extent of the disease (6.9).
Diagnosis
Presence of epithelioid, non-caseating granulomas in tissue biopsy (6.10). High erythrocyte sedimentation rate. Elevated CD4 lymphocytes in bronchoalveolar lavage.
(A)
(B)
(C)
6.6 Photomicrograph of a lymph node biopsy in Wegeners granulomatosis demonstrating a mixed inammatory inltrate with giant cell formation (arrow) (haematoxylin and eosin, original magnication 250) (courtesy of Dr N.J. Sebire).
6.7 (A) Chest X-ray in a 15-year-old girl with Wegeners granulomatosis showing left upper and lower lobes collapse secondary to bronchial stenosis. A left bronchial stent is seen (arrow). (B,C) Imaging at bronchoscopy demonstrating the left main bronchus stent and balloon dilatation (arrows) for recurrence of stenosis secondary to granulomatous lesions.

Raised levels of serum angiotensin-converting enzyme. Granulomatous pulmonary infections (tuberculosis and atypical mycobacteria) are an important differential. The long-term prognosis in children is good if pulmonary fibrosis can be prevented; 6070% show spontaneous remission and only 1020% develop significant longterm lung damage.
Treatment
Systemic corticosteroids. Inhaled corticosteroids, hydroxychloroquine, methotrexate, cyclophosphamide, ciclosporin, colchicine and antitumour necrosis factor-a have been used with variable results.
Pulmonary lymphangiectasia
Pathogenesis and presentation
PL is characterized by abnormal dilation of the pulmonary lymphatic vessels draining the subpleural and interstitial spaces of the lungs. The primary form is due to developmental abnormalities of the pulmonary lymphatic system and presents in the neonatal period. Causes of secondary PL include lymphatic obstruction or increased lymph production. It may be localized to the lungs or a part thereof, or represent a more generalized abnormality of the lymphatic system. There is a well-described association with congenital ichthyosis, Noonan, Down, Turner, Fryn and yellow nail syndromes. It is more common in males and a few familial cases have been described. The primary form can present prenatally with hydrops, polyhydramnios and intrauterine pleural effusion or in the neonatal period with respiratory distress and chylous pleural effusion(s). The secondary forms present non-specifically with cough, wheeze, tachypnoea, breathlessness and pleural effusion or may be picked up when investigating for a generalized lymphatic disorder.
6.8 Chest X-ray in sarcoidosis showing hilar lymphadenopathy and bilateral interstitial and reticular shadowing.
6.9 A chest CT in sarcoidosis showing diffuse bilateral interstitial changes.
6.10 Photomicrograph of lung biopsy in sarcoidosis demonstrating a nodular, interstitial inltrate with non-caseating bare granuloma formation, including numerous giant cells (haematoxylin and eosin, original magnication 100) (courtesy of Dr N.J. Sebire).
Investigations
Chest X-ray shows hazy reticulonodular interstitial shadowing and hyperinflation with or without pleural effusions (6.11). CT shows bilateral patchy ground-glass infiltrates, crazy paving appearance and thickened interlobular septae (6.12). Pleural tap shows evidence of chylous fluid. Lung biopsy shows dilated endothelial-lined lymphatic vessels and increased connective tissue content (6.13).
these problems, however, many do make reasonable progress in later childhood and into adult life.
Pulmonary lymphangiomatosis
Lymphangiomatosis occurs due to systemic overgrowth of the lymphatics and presence of multiple haemangioma. Lungs, heart, bones, spleen and skin are commonly affected with a predilection for thoracic and neck
Treatment
Supportive management, including draining pleural effusions, although reaccumulation is common. Trial of medium-chain triglyceride diet. Pleurodesis and pleurectomy. Anti-acidic and prokinetic agents for reflux if indicated. The prognosis for PL depends on its underlying aetiology. Neonatal PL previously carried a significant mortality but with modern neonatal intensive care, this has greatly improved. The secondary form has a variable outcome depending on whether or not the underlying problem (e.g. heart disease) can be treated. In all cases, nutritional and growth problems are common in the early years of life as are recurrent cough and wheeze and an increased incidence of lower respiratory tract infection. Despite
6.12 A chest CT showing bilateral pleural effusions, patchy consolidation and thickened interlobular septae.
6.11 Chest X-ray in a neonate with PL showing extensive hazy reticulonodular interstitial shadowing.
6.13 Photomicrograph of lung biopsy in PL demonstrating dilated lymphatic channels (black arrows) running along the brous septae (white arrows) (haematoxylin and eosin, original magnication 40). (Courtesy of Dr N.J. Sebire.)

involvement. Presentation is usually in late childhood with a gradual onset of wheeze, breathlessness and exercise limitation. Chylous effusions are common.
Sickle cell disease

Sickle cell disease is one of the commonest haemoglobinopathies and is inherited in an autosomal recessive fashion. The lungs may be affected either acutely, acute chest syndrome or long term by sickle cell chronic lung disease. Acute chest syndrome presents with fever, chest pain and the appearance of fresh infiltrates on the chest X-ray (6.15). It is precipitated by either vasoocclusion or pulmonary infection or both simultaneously. Patients with sickle cell disease may have functional asplenia and impaired complement-mediated immunity, which predisposes to common respiratory pathogens such as Streptococcus pneumoniae, Haemophilus influenzae and Mycoplasma pneumoniae. Sickle cell chronic lung disease reflects the long-term damage of recurrent infections and localized pulmonary infarction. Patients with sickle cell disease can also suffer from a number of other respiratory complications, including obstructive sleep apnoea, airway hyper-reactivity and thromboembolism due to hypercoagulability and the presence of fat emboli in the lungs. In advanced cases, pulmonary hypertension becomes an important complication.
Investigations
Chest radiography often demonstrates interstitial infiltration, pleural and pericardial effusions and lytic bone lesions in the ribs (6.14). A chest CT reveals diffuse interlobular septal thickening with involvement of mediastinal fat and perihilar regions. Bone biopsy shows lymphangiomatous lytic lesions. Lymphangiography reveals multiple thoracic duct lesions, dilated lymphatic channels and lung and bone involvement.
Treatment
Supportive management, including draining pleural effusions. Pleurectomy and pleurodesis. Radiotherapy, interferon and etoposide have been tried with varying degrees of success. The overall prognosis is not good and life expectancy post-diagnosis is about 57 years.
6.14 Chest X-ray in a child with pulmonary lymphangiomatosis. Right-sided pleural effusion and loss of rib density over whole of chest wall is seen.
6.15 Chest X-ray in sickle cell crisis showing bilateral diffuse inltrates and extracorporeal membrane oxygenation cannulae in situ.
Investigations
Lung function tests: restrictive/obstructive airway changes and reduced diffusion capacity. Chest radiology demonstrates interstitial infiltrates that can be acute or chronic (6.15).
Treatment
Cautious rehydration during painful crises for acute chest syndrome (overhydration predisposes to acute pulmonary oedema). Pain relief. Correction of hypoxaemia. Blood transfusion.
Mucopolysaccharidoses
The mucopolysaccharidoses are a group of multisystem genetic disorders in which there is an abnormal deposition of mucopolysaccharides (glycosaminoglycans) in various organs. Respiratory manifestations are usually secondary to skeletal abnormalities resulting in progressive truncal deformity and immobility. Rarely, interstitial lung disease may be caused by gradual pulmonary deposition. Accumulation in the upper airway results in obstructive sleep apnoea and secondary pulmonary hypertension. Hypoventilation and central apnoeas are seen in patients with atlanto-axial instability. Pulmonary involvement is demonstrated clinically by breathlessness on exercise and eventually at rest. The chest wall can also become involved in the infiltrative process leading to further restriction of lung function.
6.16 Chest and spine anteroposterior and lateral views in a 5-year-old girl with Hurler syndrome (mucopolysaccharidosis type I) showing severe kyphoscoliosis and gibbus. Spinal xation rods are seen extending from mid-cervical to mid-lumbar level.
Treatment
Supportive management, including tracheostomy and continuous positive airway pressure support. Bone marrow transplantation. Specific enzyme replacement to correct underlying deficiency.
Respiratory papillomatosis
Recurrent respiratory papillomatosis is a rare benign neoplasm of the airways but a potentially fatal disease caused by human papillomavirus types 6 and 11. Human papillomavirus is usually passed by vertical transmission from mother to child. Papillomas may develop anywhere in the upper or lower respiratory tract and resultant symptoms range from hoarseness of voice and stridor to respiratory distress secondary to airway obstruction. The course of the disease is variable, from spontaneous remission to aggressive papillomatous growth, with malignant transformation occurring rarely in chronic invasive papillomatosis.
Investigations
Lung function tests: an obstructive or restrictive disease pattern. Typical skeletal abnormalities affecting the respiratory system include spine involvement with scoliosis, kyphosis and severe gibbus, rib flaring and pectus carinatum (6.16). Magnetic resonance imaging of the spine and brainstem delineates the skeletal abnormalities and cervical cord compression. Sleep studies are recommended if signs of cervical myelopathy or obstructive sleep apnoea are present.
Investigations
Papillomas are easily visualized by airway endoscopic procedures, including indirect laryngoscopy and laryngobronchoscopy (6.17).
(A)
(B)
6.17 Bronchoscopic images showing (A) a clump of supraglottic papillomas, and (B) papillomas causing partial obstruction of the right main bronchus. (Courtesy of Mr D. Albert.)
Chest X-ray shows patchy consolidation, atelectasis and cystic changes. A chest CT may show extensive parenchymal destruction and atelectasis in severe cases (6.18).
6.18 A chest CT in the same child demonstrating extensive destruction of the lung parenchyma by papillomatous growth.
Treatment
Surgical debulking by carbon dioxide or potassiumtitanyl-phosphate laser to maintain safe airway. Airway support: tracheostomy in severe cases. Adjuvant antiviral therapy for children requiring frequent laser therapy, including systemic a-interferon therapy, intravenous ribavirin, and intralesional and intravenous cidofovir.
Further reading
Arceci RJ, Shahlaee AH. Histiocystic disorders of the lung. In Kendigs Disorders of the Respiratory Tract in Children. Chernick V, Boat TF, Wilmott RW, Bush A (Eds). Philadelphia: Saunders/Elsevier 2006, 93748. Caboot JB, Allen JL. Pulmonary complications of sickle cell disease in children. Curr Opin Pediatr 2008; 20: 27987. Dinwiddie R, Sonnappa S. Systemic diseases and the lung. Paediatr Respir Rev 2005; 6: 1819. Faul JL, Berry GJ, Colby TV, et al. Thoracic lymphangiomas, lymphangiectasis, lymphangio-
matosis, and lymphatic dysplasia syndrome. Am J Respir Crit Care Med 2000; 161: 103746. Fauroux B, Clement A. Paediatric sarcoidosis. Paediatr Respir Rev 2005; 6: 12833. Henry MM, Noah TL. Sarcoidosis. In Kendigs Disorders of the Respiratory Tract in Children. Chernick V, Boat TF, Wilmott RW, Bush A (Eds). Philadelphia: Saunders/Elsevier 2006, 92736. Mathiesen PR, Zak M, Herlin T, Nielsen SM. Clinical features and outcome in a Danish cohort of juvenile dermatomyositis patients. Clin Exp Rheumatol 2010; 28: 7829. Platzker ACG. Pulmonary involvement in rheumatoid diseases of childhood. In Kendigs Disorders of the Respiratory Tract in Children. Chernick V, Boat TF, Wilmott RW, Bush A (Eds). Philadelphia: Saunders/ Elsevier 2006, 94977. Shetty AK, Gedalia A. Childhood sarcoidosis: a rare but fascinating disorder. Pediatr Rheumatol Online J 2008; 6: 16.
Index
Note: page numbers in italics refer to Figures and Tables
ABCA3 deficiency 40, 46 abscesses, neonatal pneumonia 15 acid maltase deficiency 25 acute respiratory distress syndrome 13 adenocarcinoma 58 adenoid cystic carcinoma 57 adult respiratory distress syndrome 41 agammaglobulinaemia, PAP 45 alpha-fetoprotein 61 alveolar capillary dysplasia 17 histology 40 alveolar rhabdomyosarcoma 65 Ambroxol 12 amyloidosis 41 antenatal ultrasound bright lung 1 congenital lobar emphysema 6 pulmonary sequestration 7 cystic lung disease 3, 5 anterior mediastinal tumours 601 antibiotics in meconium aspiration syndrome 16 in neonatal pneumonia 1516 in pulmonary haemorrhage 21 in RDS 12 anticipatory care plans, neuromuscular disorders 34 aortic arch anomalies 8 arteriovenous malformations 9 asthma, maternal, transient tachypnoea of the newborn 13 autoimmune-related interstitial lung disease 38 azathioprine, in chILD 49 Becker muscular dystrophy 25 benign tumours 56 incidence in children 57 betamethasone, antenatal use 13 Bethlem muscular dystrophy 25
biopsy in chILD 434 in malignant disease 55 bombesin staining, chILD 47 bone marrow, examination in malignant disease 55 bosentan, in chILD 49 brainlungthyroid syndrome 40 bright lung, antenatal ultrasound 1 congenital lobar emphysema (congenital lobar overinflation) 6 pulmonary sequestration 7 bronchial chondroma 57 bronchioalveolar carcinoma 58 bronchoalveolar lavage (BAL), in chILD 41, 43 bronchodilators, in bronchopulmonary dysplasia 234 bronchogenic carcinoma, incidence in children 57 bronchogenic cysts 6 MRI appearance 6 bronchopulmonary dysplasia 21 histology 223 management 234 multifactorial aetiology 22 presentation 21 radiographic appearance 21, 23 Caesarean section, transient tachypnoea of the newborn 13 calorie requirements, in bronchopulmonary dysplasia 24 cancers by diagnostic group and sex 51 see also malignant chest disease carbon dioxide monitoring, sleep studies 28, 29 carcinoid syndrome 56 carcinoid tumour 56 incidence in children 57 thymic 64 CD4 lymphocytes, sarcoidosis 72
80 Index
central core myopathy 25 chest tube drainage, neonatal pneumothorax 19 chest wall, malignant disease 54 chest wall deformities 9 chest wall tumours 645 chlorothiazide, in bronchopulmonary dysplasia 24 chondrosarcoma 65 chronic pneumonitis of infancy 46 CT appearance 47 histology 47 chylothorax 8 ciclosporin, in chILD 49 Cobb angle, scoliosis 27 cobblestone CT appearance 44 collagen vascular diseases 41 congenital alveolar dysplasia, histology 40 congenital cystic adenomatoid malformation (CCAM) 3, 4 classification 6 MDCT image 5 prenatal MRI 5 radiographic appearance 5 congenital lobar emphysema (congenital lobar overinflation) 67 radiographic and CT appearances 7 congenital malformations 1 bronchogenic cysts 6 MRI appearance 6 chest wall deformities 9 cystic lung disease 34 diaphragmatic hernia 2 prenatal MRI 4 radiographic appearances 4 pleural effusions 78 pulmonary agenesis and aplasia 1 pulmonary arteriovenous malformation 9 pulmonary hypoplasia 12 aetiology 3 pulmonary sequestration 7 CT appearance 8 Scimitar syndrome 910 tracheal abnormalities 89 vascular rings 8 corticosteroids in bronchopulmonary dysplasia 24 in chILD 49 empirical use 44
in Duchenne muscular dystrophy 26 guidelines for antenatal use 13 in pulmonary interstitial glycogenosis 467, 48 RDS prophylaxis 12 cotrimoxazole, Pneumocystis jiroveci prophylaxis 667 cough, assessment of strength 28 cough assistance techniques 323 cough-in exsufflator device 323 Crohns disease 41 customized face masks, advantages and disadvantages 32 cyanotic congenital heart disease, differentiation from pulmonary hypertension of the newborn 17 cyclophosphamide, in chILD 49 cylindroma 59 cystic lung disease antenatal detection and management 3 incidental finding 4 presentation at birth 3 presentation in infancy and childhood 4 dermatomyositis 701 CT appearance 70 desquamative interstitial pneumonitis 38, 47 imaging 42 diabetic mothers, risk of RDS 11 diaphragmatic hernia, congenital 2 prenatal MRI 4 radiographic appearances 4 DICER1 gene mutations 58 dipalmitylphosphotidylcholine 11 diuretics, in bronchopulmonary dysplasia 24 Duchenne muscular dystrophy (DMD) 25, 26 echocardiography, in chILD 38 EmeryDreifuss muscular dystrophy 25 empyema, management 15 EpsteinBarr virus 59, 64 Escherichia coli antibiotic sensitivities 15 neonatal infection 14 etanercept, in sarcoidosis 49 Ewings sarcoma 65 expiratory muscle function assessment 28 Fabrys disease 40 facemasks, advantages and disadvantages 32
Index 81
facioscapulohumeral muscular dystrophy 25 feeding assessment, neuromuscular disorders 289 fibrosarcoma 57, 65 flow interruption ventilation, in pulmonary interstitial emphysema 19 fluid administration, in RDS 12 fluid regulation, in bronchopulmonary dysplasia 24 follicular bronchiolitis 37, 49 forced vital capacity 28 FOXP3 deficiency 40 furosemide, in bronchopulmonary dysplasia 24 fungal infections 67 neonatal 14 ganglioneuroma, histology 63 gastrostomy, percutaneous 29 Gauchers disease 40 germ cell tumours 61 histology 62 imaging 62 GM1 gangliosidosis 40 GM-CSF autoantibody disease 45 GM-CSF receptor abnormalities 40, 45 GM-CSF therapy 49 graft-versus-host disease 41 granular cell tumour 57 Group B streptococcus intrapartum antibiotic prophylaxis 1516 maternal infection 14 neonatal pneumonia 14 haemangiopericytoma 57, 65 haemolytic disease of the newborn, risk of RDS 11 Haemophilus influenzae, antibiotic sensitivities 15 hamartoma 57 helmets, NIV, advantages and disadvantages 32 hereditary haemorrhagic telangiectasia 9 HermanskyPudlak syndrome 40 high frequency ventilation, in pulmonary interstitial emphysema 19 high volume strategy, acute respiratory distress syndrome 13 high-resolution computed tomography (HRCT), in chILD 41, 42 Hodgkins lymphoma 61 histology 62 imaging 62 -human chorionic gonadotrophin 61 human papillomavirus, respiratory papillomatosis 767 Hurler syndrome, radiographic appearance 76 hyaline membrane 11 histology 12 hydroxychloroquine, in chILD 49 hypereosinophilic syndromes 41 hypersensitivity pneumonitis 38 hypoplastic right heart 3 hypoxic ischaemic encephalopathy, in meconium aspiration syndrome 16 idiopathic pulmonary fibrosis 38 immunizations, in bronchopulmonary dysplasia 24 immunodeficiencies, lymphoproliferative disease 59 IMP Percussionaire device 33 infection screening, neonates 15 inflammatory myoblastic tumour 56, 57 influenza immunization, in bronchopulmonary dysplasia 24 interstitial lung disease (chILD) ABCA3 deficiency 46 associated conditions 41 chronic pneumonitis of infancy 46, 47 classification 37 between 0 and 2 years 39 clinical presentation 38 desquamative interstitial pneumonitis 47 differential diagnosis 38 disease of unknown cause 41 epidemiology 37 genetic causes 40 investigations biopsy 434 blood testing 38, 42 bronchoscopy 41, 43 imaging 41 non-invasive tests 38 known causes 40 lymphocytic abnormalities 49 monitoring therapy 45 neuroendocrine cell hyperplasia of infancy 47, 48 non-specific interstitial pneumonia 48 prognosis 50 pulmonary alveolar proteinosis 45 pulmonary interstitial glycogenosis 467
82 Index
interstitial lung disease (chILD) contd severity assessment 45 severity score 42 spectrum of disease 38 surfactant protein abnormalities 45 surfactant protein B deficiency 456 surfactant protein C deficiency 46 treatment 4950 interstitial pneumonitis 38 intubation, in meconium aspiration syndrome 16 jejunostomy, percutaneous 29 Jeunes syndrome 9 radiographic appearance 27 Kerley B lines 20 Kleinfelters syndrome 61 Langerhans cell histiocytosis 38, 41, 5960 BAL 41 leiomyoma 57 leiomyosarcoma 59 incidence in children 57 limb girdle muscular dystrophy 25 Listeria monocytogenes antibiotic sensitivities 15 maternal infection 14 lobar emphysema, congenital 67 lower respiratory tract infections, complications of malignancy 667 lung function tests, in chILD 38 lung lavage, in PAP 49 lung transplantation, chILD 50 SP-B deficiency 456 lymphangiectasia 734 radiographic appearance 74 lymphangiomatosis 745 radiographic appearance 75 lymphocyte infiltrative disorders 38 lymphoid interstitial pneumonia 37, 38, 50 lymphoproliferative disease 59 lysinuric protein intolerance 40, 45 macrophage blockade 45 malignancy associated respiratory infection 667
respiratory complications of treatment 67 malignant chest disease chondrosarcoma 65 clinical presentation 523 Ewings sarcoma 65 fibrosarcoma 65 germ cell tumours 61, 62 haemangiopericytoma 65 Hodgkins lymphoma 61 investigations 52, 545 Langerhans cell histiocytosis 5960 lymphoproliferative disease 59 mesothelioma 64 metastases 656 neuroblastic tumours 61, 63, 64 non-Hodgkins lymphoma 601 primary lung tumours 54 bronchogenic carcinoma 578 carcinoid tumour 56 cylindroma 59 incidence in children 57 leiomyosarcoma 59 mucoepidermoid carcinoma 58 neuroendocrine carcinoma 567 pleuropulmonary blastoma 589 rhabdoid tumour 65, 66 rhabdomyosarcoma 65 MBG (metaiodobenzylguanidine) scan, neuroblastic tumours 63 meconium aspiration syndrome 16 radiographic appearance 16 mediastinal tumours 534 germ cell tumours 61, 62 Hodgkins lymphoma 61 metastatic 66 neuroblastic tumours 61, 63, 64 non-Hodgkins lymphoma 601 mesothelioma 64 metastatic tumours 656 methotrexate, in chILD 49 methylprednisolone, in chILD 49 middle mediastinal tumours 601 mid-facial hypoplasia 32 radiographic appearance 33 minicore myopathy 25 mitochondrial myopathy 25 mouth pressures 28
Index 83
mucoepidermoid carcinoma 58 incidence in children 57 mucopolysaccharidoses 76 radiographic appearance 76 mucous gland adenoma 57 multicore myopathy 25 myasthenia, congenital 25 NIV 31 myotonic dystrophy, congenital 25 myxosarcoma 57 nasal masks 33 advantages and disadvantages 32 nasal plugs, advantages and disadvantages 32 nemaline myopathy 25 neonatal lung disorders acute respiratory distress syndrome 13 bronchopulmonary dysplasia 214 meconium aspiration syndrome 16 pneumothorax 1718 pulmonary haemorrhage 201 pulmonary hypertension of the newborn 1617 pulmonary interstitial emphysema 1819 pulmonary lymphangiectasia 74 pulmonary oedema 20 routine investigations 11 transient tachypnoea of the newborn 1314 see also respiratory distress syndrome (RDS) neonatal pneumonia causative organisms 14 diagnosis 15 management early onset disease 1516 late onset disease 16 presentation 14 radiographic appearance 15 risk factors 14 neuroblastic tumours 61, 64 histology 63 imaging 63 investigations 64 neuroendocrine carcinoma 567 neuroendocrine cell hyperplasia of infancy 47 histology 48 neurofibromatosis 40 neurogenic tumour 57 neuromuscular disorders 25 anticipatory care plans 34 cough assistance techniques 323 Duchenne muscular dystrophy (DMD) 26 investigations 27 pulmonary function assessment 28 respiratory muscle strength assessment 28 sleep studies 28 swallowing and feeding assessment 289 Jeunes syndrome 27 non-invasive ventilation (NIV) interfaces 32 timing of initiation 2930 types of ventilator 31 patterns of respiratory muscle involvement 256 respiratory care plan 30 scoliosis 267 spinal muscular atrophy (SMA) 26 tracheostomy ventilation 334 transition to adult care 34 neutrophilic capillaritis, treatment 49 NiemannPick disease 40, 45 nitric oxide, in pulmonary hypertension 17 nocturnal hypoventilation 28, 29 initiation of NIV 2930 non-Hodgkins lymphoma 601 non-invasive ventilation (NIV) 33 interfaces 32 in neuromuscular disorders 31 TcCO2 and Sa O2 changes 30 timing of initiation 2930 types of ventilator 31 non-specific interstitial pneumonia 48 nutrition, in bronchopulmonary dysplasia 24 obliterative bronchiolitis, histology 41 oligohydramnios 3 opportunistic infections in sickle cell disease 75 in systemic lupus erythematosus 70 in treatment of malignancy 667 oscillatory ventilation, in pulmonary interstitial emphysema 19 oxygen saturation levels, bronchopulmonary dysplasia 23 oxygen therapy in meconium aspiration syndrome 16 in neonatal pneumothorax 18
84 Index
papillomas 57 see also respiratory papillomatosis peak cough flow 28 pectus excavatum/carinatum 9 percutaneous gastrostomy/ jejunostomy 29 peripheral primitive neuroectodermal tumours 65 persistent pulmonary hypertension of the newborn 1617 phosphatidylglycerol 11 phospholipids, surfactant 11 plasma cell granuloma (inflammatory myoblastic tumour) 56 plasmacytoma 57 pleura, malignant disease 54, 64 pleural effusions malignant 53, 64, 65 neonatal 78 in pneumonia 15 radiographic appearance 8 pleural fluid, examination in malignant disease 55 pleuropulmonary blastoma 589 incidence in children 57 pneumatocoele, in neonatal pneumonia 15 Pneumocystis jiroveci infection 667 pneumonia see neonatal pneumonia pneumothorax, neonatal 1718 chest tube drainage 19 radiographic appearance 18, 19 Poland syndrome 9 polio immunization, in bronchopulmonary dysplasia 24 positive end expiratory pressure, in acute respiratory distress syndrome 13 posterior mediastinal tumours 61, 64 posterior urethral valves 3 Potters syndrome 3 prednisolone in chILD 49 in Duchenne muscular dystrophy 26 prenatal intervention in cystic lung disease 3 endotracheal obstruction 2 preterm labour, corticosteroids 13 primary ciliary dyskinesia 13 pulmonary agenesis and aplasia 1 pulmonary alveolar microlithiasis 40 histology 44 imaging 44
pulmonary alveolar proteinosis (PAP) 38, 41, 45 BAL 43 CT appearance 44 histology 45 treatment 49 pulmonary arteriovenous malformation 9 pulmonary artery hypoplasia 3 pulmonary capillary haemangiomatosis 57 pulmonary function assessment, neuromuscular disorders 28 pulmonary haemorrhage, neonatal 201 radiographic appearance 21 pulmonary haemorrhagic syndromes 41 pulmonary haemosiderosis 38 BAL 43 histology 43 imaging 43 monitoring therapy 45 pulmonary hypertension, in chILD 49 pulmonary hypertension of the newborn 1617 causes of secondary pulmonary hypertension 17 pulmonary hypoplasia 12 aetiology 3 in congenital diaphragmatic hernia 2 Jeunes syndrome 9 pulmonary inflammatory pseudotumour (inflammatory myoblastic tumour) 56 pulmonary interstitial emphysema (PIE) 18 management 19 radiographic appearance 19, 20 pulmonary interstitial glycogenosis 467 histology 48 pulmonary lymphangiectasia 734 CT appearance 74 histology 74 radiographic appearance 74 pulmonary lymphangioleiomyomatosis 38 pulmonary lymphangiomatosis 745 radiographic appearance 75 pulmonary oedema, neonatal 20 pulmonary sequestration 7 CT appearance 8 radiographic appearance 7 pulmonary sling 8 pulmonary vasculitis syndromes 41 pulmonary veno-occlusive disease 41 pulse oximetry 28
Index 85
radiotherapy, in pleuropulmonary blastoma 59 ReedSternberg cells 62 renal agenesis (Potters syndrome) 3 renal failure 41 respiratory distress syndrome (RDS) 11 acute 13 adult 41 investigations 12 management 12 surfactant administration 13 predisposing factors 11 presentation 12 prophylaxis 12 guidelines for antenatal steroid use 13 radiographic appearance 12 respiratory muscle strength assessment, neuromuscular disorders 28 respiratory papillomatosis 767 bronchoscopic appearance 77 CT appearance 77 respiratory syncytial virus, immunoprophylaxis in BPD 24 rhabdoid tumour 65, 66 rhabdomyosarcoma 57, 65 ribs, malignant disease 54 right-to-left shunts, pulmonary hypertension of the newborn 1617 sarcoidosis 38, 41, 723 CT appearance 73 histology 73 radiographic appearance 73 treatment 49 Scimitar syndrome 910 CT appearance 9 scleroderma 71 radiographic appearance 71 sclerosing haemangioma 57 scoliosis 25, 267 Cobb angle 27 early onset disease 27 SFTP genes see surfactant protein abnormalities; surfactant protein B deficiency; surfactant protein C deficiency sickle cell disease 756 radiographic appearance 75 sildenafil, in chILD 49 sinuses, Wegeners granulomatosis 71 SLC34A2 gene mutations 40 sleep-disordered breathing neuromuscular disorders 28 symptoms and signs 28 sleep studies, in neuromuscular disorders 28, 29 sniff inspiratory pressures 28 somatostatins, in chylothorax 8 spinal muscular atrophy (SMA) 25, 26 chest wall deformity 26 prophylactic NIV 31 spironolactone, in bronchopulmonary dysplasia 24 Staphylococcus aureus pneumonia, antibiotic therapy 15 STRA6 deficiency 40 surfactant 11 surfactant administration 12, 13 in acute respiratory distress syndrome 13 in meconium aspiration syndrome 16 in pulmonary haemorrhage 21 surfactant protein abnormalities 45 RDS susceptibility 11 surfactant protein B deficiency 40, 456 histology 46 surfactant protein C deficiency 40, 46 histology 47 swallowing assessment, neuromuscular disorders 289 systemic lupus erythematosus CT appearance 70 diagnosis 70 investigations 70 pathogenesis and presentation 69 radiographic appearance 69 treatment 70 telomerase gene mutations 40 teratomas 57 histology 62 tetralogy of Fallot 3 thymic tumours 64 thymolipoma 64 thymoma 64 thyrotrophic-releasing hormone, in RDS prophylaxis 12 tracheal agenesis and atresia 8 tracheal stenosis 8 tracheal webs 8 tracheomalacia 9 vascular rings 8
86 Index
tracheostomy in bronchopulmonary dysplasia 23 in neuromuscular disorders 334 transbronchial biopsy, in chILD 43 transient tachypnoea of the newborn management 14 predisposing factors 13 presentation 13 radiographic appearance 13 tumours of anterior and middle mediastinum 601, 62 of chest wall 645 clinical presentation 52 lung involvement in systemic disease 5960 pleural 64 of posterior mediastinum 61, 63, 64 primary 54 benign 56 malignant 569 thymic 64
usual interstitial pneumonia (UIP) 37, 38 histology 47 vascular rings 8 vasodilators, in pulmonary hypertension 17 ventilation in bronchopulmonary dysplasia 23 in meconium aspiration syndrome 16 in pneumothorax 17 in pulmonary interstitial emphysema 1819 viral pneumonia, neonatal 14 viral pneumonitis 67 Wegeners granulomatosis 712 CT of sinuses 71 histology 72 radiographic appearance 72 treatment 49 Wilms tumour, lung metastases 66 X linked myotubular myopathy 25

Paediatric Respiratory Disease: Parenchymal Diseases

Caricato da

Informazioni sul documento

Titolo originale

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

Paediatric Respiratory Disease: Parenchymal Diseases

Caricato da

Copyright:

Formati disponibili

An Atlas of Investigation and Management

PAEDIATRIC RESPIRATORY DISEASE

An Atlas of Investigation and Management

PAEDIATRIC RESPIRATORY DISEASE

5. Primary and secondary thoracic tumours 6. Rare lung diseases Index

Congenital lung malformations

Pulmonary agenesis, aplasia and hypoplasia

2 Congenital lung malformations

Congenital diaphragmatic hernia

Congenital lung malformations 3

Reduced lung uid volume

Reduced fetal breathing

Cardiac lesions with reduced pulmonary blood ow

Cystic lung disease

4 Congenital lung malformations

Infancy through to childhood

Congenital cystic adenomatoid malformations

Congenital lung malformations 5

6 Congenital lung malformations

Congenital lobar emphysema

Congenital lung malformations 7

suggesting that intervention in asymptomatic individuals is unnecessary.

8 Congenital lung malformations

Congenital lung malformations 9

Other congenital lung anomalies

Pulmonary arteriovenous malformation

Chest wall deformities

10 Congenital lung malformations

Neonatal lung disease

Respiratory distress syndrome

12 Neonatal lung disease

Prophylaxis Antenatal agents

Investigations Chest radiograph

Neonatal lung disease 13

High volume strategy

Transient tachypnoea of the newborn

Acute respiratory distress syndrome

Investigations Chest radiograph

14 Neonatal lung disease

Presentation Early onset

Risk factors for early onset pneumonia

Neonatal lung disease 15

Management Early onset

16 Neonatal lung disease

Meconium aspiration syndrome

Pulmonary hypertension of the newborn

Neonatal lung disease 17

18 Neonatal lung disease

Chest radiograph appearance

Drainage of a symptomatic or tension pneumothorax

Pulmonary interstitial emphysema

Neonatal lung disease 19

Chest radiograph appearance

20 Neonatal lung disease

Neonatal lung disease 21

22 Neonatal lung disease

High Level of Respiratory Support Volutrauma Oxygen support

Bronchopulmonary Dysplasia 2.14 Multifactorial aetiology of BPD.

Neonatal lung disease 23

24 Neonatal lung disease

Neuromuscular and chest wall disease (including non-invasive ventilation)

26 Neuromuscular and chest wall disease (including non-invasive ventilation)

Spinal muscular atrophy