Immunocompromised Hosts

David Kramer, M.D.

1
 Primary Immunodeficiency Disorders When the neutrophil count falls below 500, and especially when it
stays that way for days and weeks at a time, the risk of an infec-
tious complication is 40% to 60%, and if the patient remains
profoundly neutropenic the risk can actually approach 100%.

Within that context, it is also possible to differentiate in this patient

population between lower and higher-risk patients according to the
DISORDER DEFICIENCY duration of their neutropenia. Lower risk patients are being defined
as those who are neutropenic for less than 10 days, higher risk for
Humoral Deficiency Decreased phagocyte efficiency, failure of lysis greater than 10 days.

Syndromes and agglutination of bacteria, inadequate neu- Now, in a neutropenic patient, it is important to recognize there are
tralization of toxins other alterations of the host defense matrix that can alter the risk
for developing an infectious complication. So the presence of oral
Cellular Immunodefi- Absence or impaired delayed hypersensitivity, or GI mucositis which intersects the integrity of the integumentary
barriers can lead to both colonization and a risk-free infection.
ciency absent T cell cooperation or function These can be influenced by the type and intensity of a chemother-
apy that is being administered. They can lead to both new acquisi-
Neutropenia Decreased neutrophil numbers tion of organisms, as well as to alterations of the endogenous
microflora, which of course contribute to the risk for developing an
Phagocytic defects Decreased adhesion, chemotaxis, opsonization, infectious complication. These risks can be aggravated by indwell-
ing catheters, as well as devices, and further deter by changes in
phagocytosis, killing
phagocyte function as well as alter cellular and humoral immunity,
some of which are the result of a chemotherapy or radiation that is
Complement deficien- Defective membrane attack mechanisms
administered and others emanate from underlying diseases.
cies
In the 1990s gram-positive organisms predominate, particularly the
coagulase, and coagulase negative staphylococci. Staph aureus is
certainly a contender for the lead spot in some centers, but virtually
in all, coagulase negative staphylococci are number one. It is
important to remember that the enterococci has increased in
frequency, particularly those that are resistant to vancomycin, and
this has become a problem. And this underscores the importance
of not overusing vancomycin.

There have been tremendous changes in the distribution of gram-

negative organisms. Two decades ago, gram-negative organisms
dominated the course of the disease in this population. Among the
gram-negatives, Pseudomonas aeruginosa was the most note-
worthy. In fact, when this organism is present, it still carries a very
serious prognosis. In some ways, numerically replacing Pseudo-
monas are multiply resisting gram-negatives, particularly the beta-
lactamase inducible Enterobacter, Citrobacter, Serratia, which
have caused outbreaks and significant infections in some centers
treating cancer patients.

This patient population like other immunocompromised hosts is

vulnerable to a wide array of potential infectious agents, including
anaerobes. Those are quantitatively the most numerically signifi-
cant organisms in our body and the GI tract. They infrequently
account for singular infections, but they are part of mixed infec-
tions, especially in the oral cavity and the perianal area.

Mycobacteria infections, including MTB are seen in cancer pa-

tients, albeit infrequently. Among the atypical mycobacteria,
chelonei and fortuitum are the cause of the catheter-related infec-
tions; and Mycobacteria kansasii is the cause of pneumonic infec-
tions.

Viruses in this patient population include the herpes virus, simplex,

cytomegalovirus, varicella zoster. The respiratory viruses have also
emerged as important pathogens, particularly respiratory syncytial
virus or parainfluenza virus, adenovirus, especially in patients you

2
 Secondary Immunodeficiency Disorders see in high doses of chemotherapy, or in those undergoing bone
marrow transplantation.

It is important to include Candida and Aspergillus among the most

important of the pathogens. Pneumocystis remains and important
cause of infection in patients with cancer, including Hodgkin, and
lymphomas, leukemias. Toxoplasmosis can be associated with a
DISORDER DEFICIENCY meningoencephalitis in this patient population as well as
Strongyloides, which can cause hyperinfection syndrome with
HIV/AIDS Altered cellular immunity, polymicrobial sepsis as part of its manifestation.
In terms of the common sites for infection, the primary portal is the
dysgammaglobulinemia, phagocytic defects or GI tract, but the most important physical sites are the oral cavity,
neutropenia skin, perianal area, and respiratory tract.

Cancer Neutropenia, lymphopenia, humoral deficien- It is important to remember with this patient population, particularly
those who are neutropenic, the signs and symptoms of infection
cies, altered physical integrity can be subtle and muted. Physical evidence for infection certainly
early-on in the course of the disease may not be apparent. And
Immunosuppressive Impaired cellular immunity and/or neutropenia while it is true that fever is usually associated with infection in the
neutropenic patient, it is not impossible for a serious infection to
therapies
occur in a patient who is neutropenic and afebrile. And one syn-
drome that is particularly notable is that associated with
Transplantation Varies with solid organ vs bone marrow and Clostridium septicum, which can cause life-threatening infections
includes deficiencies in cellular and phagocytic with fasciitis, and which may not be associated with fever early in
its course in the neutropenic patient.
immunity

Malnutrition Impaired cellular immunity, complement activ-

ity

3
 Other Secondary Immunodeficiency States

• Indwelling catheters (central venous, urinary catheter, Cerebrospinal

fluid)
• Burns
• Inhalation Therapies (steroids or contaminated solutions)
• Surgical Wounds
• Fistula-sinus communications (neurocutaneous, neuroenteric, otic,
facial sinus-meningeal sinus tract, facial sinus fracture)
• Intravenous drug use
• Prosthetic devices (cardiac valves, pacemakers)

4
 Other Secondary Immunodeficiency States
Malnutrition
Cystic Fibrosis
Diabetes Mellitus
Nephrotic syndrome
Uremia
Cirrhosis, ascites
Prolonged Antibiotic Therapy
Spinal cord injuries
Sickle Cell Anemia
Periodontitis
Congenital Heart Disease
Urinary Tract Anomalies
Kartagener syndrome
Eczema
Protein-losing enteropathy
(lymphangiectasia)
Chronic blood product
transfusions
5
Pathogens Associated With Anatomic Disruption

Site Bacteria Fungi Other

Oral cavity Alpha strap; an- Candida spp HSV

aerobic

Esophagus Staph; colonizing Candida spp HSV, CMV

bacteria

Lower GI Enterococci, Candida spp Strongyloides

Enterobacteri-
aceae
Bacteroides,
Clostridia

Skin (Catheter) Staph, Strep, Candida,

Corynebacteria, Aspergillus
Bacillus, Atyp Malassezia
Mycobacteria, Furfur
Gram-negatives

Urinary Tract Enterococci, Candida

Enteric Bacteria,
Pseudomonas

6
 Pathogens Associated with Defects in Cellular
Immunity

Bacteria Fungi Viruses Other

Legionella Cryptococcus VZV, HSV, CMV, P. carinii

Nocardia Histoplasma EBV, hepatitis T. gondii
Salmonella Coccidiodes Live virus vaccines Cryptosporidia
Mycobacteria Candida vaccinia, measles Strongyloides
Listeria

7
Pathogens Associated With Humoral, Complement
or Reticuloendothelial Defects

Defects Bacteria Viruses Other

Immunoglobulin S. pneumonia, Enteroviruses, Giardia lamblia

abnormalities Staphylococ- (Including Po-
cus, lio)
Hemophilus,
Neisseria,
Enteric
organisms

Complement S. pneumonia,
abnormalities Staphylococ-
cus,
Hemophilus,
Salmonella,
DF2

Splenectomy S. Pneumonia, Babesia

Hemophilus,
Salmonella,
DF2

8
Clinical Features of Primary Immunodeficiencies –
Newborns and Infants

Diagnosis Clinical Features

DiGeorge syndrome Hypocalcemia, heart disease, unusual fa-

cies

Congenital asplenia Cyanosis, heart disease, midline liver

Leukocyte adhesion defi- Delayed umbilical cord separation,

ciency syndrome leukocytosis, recurrent infectious

SClD (also AIDS) Diarrhea, pneumonia, thrush, FTT

SCID with GVH Maculopapular rash, alopecia,

lymphadenopathy, hepatosplenomegaly

Wiskott-Aldridge syndrome Melena, draining ears, eczema

Chediak-Higashi syndrome Oculocutaneous albinism, recurrent

infections, neutropenia

C3 deficiency Recurrent pyogenic infections, sepsis

Congenital Neutropenias Chronic gingivitis, recurrent aphthous

ulcers, skin infection

9
Clinical Features of Primary Immunodeficiencies –
Six Months to Five Years

Diagnosis Clinical Features

X-linked lymphoproliferative syn- Severe mononucleosis

drome

X-linked agammaglobulinemia Paralytic disease post immuniza-

tion

Hyper IgE syndrome Recurrent skin and systemic staph,

coarse facial features

Chronic mucocutaneous candidiasis Persistent thrush, nail dystrophy,

endocrinopathy

Specific granule deficiency Recurrent skin abscesses

10
Clinical Features and Primary Immunodeficiencies
– Older than Five Years

Diagnosis Clinical Features

X-linked agammaglobulinemia Progressive dermatomyositis with

ECHO encephalitis

Ataxia-telangiectasia Sinopulmonary Infections, neurological

deterioration, telangiectasis

Chronic granulomatous disease Lymphadenopathy, dermatitis,

pyloric-antinial obstruction,
pneumonias, small bone osteomyelitis

C6, C6, C2, C8 deficiency Recurrent Neisseria meningitis

Common variable immunodefi- Sinopulmonary infectious,

ciency malabsorption, splenomegaly,
autoimmunity

11
 Risk Factors for Infection in Fever and
Neutropenia

• Primary risk factor is the depth and duration of neutropenia

- Neurophil counts < 500/mm3 and especially less than 100/mm 3
- 48-60% of neutropenic patients who become febrile have an estab-
lished or occult infection
• Duration of neutropenia

LOW RISK HIGH RISK

Duration <10 days Duration >10 days

• Factors which may modify the risk or patterns of infection associated

neutropenia
- Oral or GI mucositis
- Type and intensity of therapy (including transplantation)
- Endogenous microflora
- Indwelling catheters (or devices)
- Altered qualitative phagocytic function
- Altered cellular or humoral immunity

12
 Current Pathogens Associated with
Fever and Neutropenia

• Gram-positive organisms predominate.

- Coagulase negative Staphylococci are the most frequent
- S. aureus is second (in some centers MRSA are important)
- Viridans streptococci comprise up to 39% of bacteremias
- Enterococci, especially resistant to vancomycin
• Risk factors associated with Viridans Streptococci
- Profound neutropenia (PMN's <100/mm3)
- High-dose cytosine arabinoside
- Oropharyngeal mucositis
- Treatment with H2 antagonists
- Quinolone or trimethoprim-sulfa prophylaxis
• Complications include ARDS (3-33%), shock (7-18%), endocarditis
(7-8%) and death (6-30%)

13
Current Pathogens Associated with Fever and
Neutropenia

• Among Gram-negatives, P. aeruginosa has declined

- P. aeruginosa was isolated in less than 20 of >1000 episodes of
febrile neutropenia during the past decade.
- However, when infection with Pseudomonas occurs, it still
carries a serious prognosis.
• Multiply-resistant Gram-negatives (especially Enterobacter) have
emerged as pathogens at several centers.

14
Current Pathogens Associated with Fever and
Neutropenias

• Anaerobes (as mixed infections) are important in oral cavity and GI

infections
• Mycobacteria, both MTb and atypicals need to be considered
• Viruses
- Herpes viruses (HSV, CMV, VZV, HHV 6)
- Respiratory viruses (RSV, PIV, Adenovirus, Measles)

15
Current Pathogens Associated with Fever and
Neutropenia

• Fungi (especially in high-risk patients)

- Candida (both acute and chronic infections)
- Cryptococcus (both CNS and extra-neuronal infections)
- Aspergillus and Mucor
- Regional isolates - eg, Fusarium, Trichosporon
• Parasitic Infections
- Pneumocystis carinii
- Toxoplasmosis gondii
- Strongyloides stercoralis

16
 Common Sites of Infection in Fever and
Neutropenia

• Primary portal of entry is usually the GI tract

• Other important portals and sites include
- Oral cavity - especially periodontal disease
- Skin - including catheter sites
- Perianal area
• Respiratory tract

17
 Initial Evaluation of Fever and Neutropenia Underscoring the fact that if there are signs or symptoms that
suggest infection, even in the absence of fever, the patient should
be treated as if infected. A careful comprehensive physical exami-
nation is critical and needs to be repeated frequently.

That exam should focus on the specific sites of infection. The most
important oral cavity, the lower esophagus, the lungs, perianus,
skin, and one should always consider exit sites from catheters.
• Signs end symptoms can be muted and subtle, especially during the
early stages of infection in profoundly neutropenic patients In terms of the initial evaluation of the patient who is a febrile
neutropenic, it is safe to say that blood cultures are useful, cer-
• Profoundly neutropenic patients can sometimes have a life-threaten- tainly for screening evaluations, but their yield is relatively low.
Only about 10% to 15% of newly febrile neutropenic patients will
ing infection and yet be afebrile - usually there is a localizing actually have a bacteremia
symptom that heralds a serious underlying process (eg, C.
septicum).
• Careful and comprehensive physical exam should be repeated at
least daily
• Exam should focus specifically on periodontium, pharynx, lower
esophagus, lungs, perineum, skin, catheter entry and exit sites
• Blood cultures - including from catheter (all ports) are important
• Routine surveillance cultures are not indicated but may be indicated
in centers with increased incidence of certain nosocomial infections
• Other cultures should be guided by signs or symptoms of infection

18
 Initial Evaluation of Fever and Neutropenia
• Initial chest radiographs have a low yield in patients without respira-
Other evaluation techniques: Initial chest x-rays tend to have a low-
yield in the absence of pulmonary symptoms. They do serve as
valuable baselines for patients who are likely to have prolonged
periods of neutropenia. The use of imaging studies, particularly CT
and MRI, can be especially helpful in patients with protracted
neutropenia who are at-risk for certain sites of infection, particu-
larly in the lungs, liver, and spleen.

tory symptoms. Baseline chest radiographs could prove helpful in

patients with high-risk neutropenia
• Imaging studies - ultrasound, CT, MR - can be useful in patients with
prolonged neutropenia and/or persistent fever (eg, chest CT for
Aspergillus, liver CT/MR for hepatic candidiasis)

19
Initial Management of Fever and Neutropenia
• Prompt initiation of broad-spectrum therapy when the neutropenic
patient becomes febrile, coupled with appropriate modification of the
initial regimen
• There is no "ideal regimen" - variables include the risk status of the
patient, local microflora and their sensitivity patterns, toxicity, prefer-
ence and cost
• Options, based on current patterns of infection and available antibi-
otics
- Combination regimens (eg, third-generation cephalosporin plus
aminoglycoside and/or vancomycin)
- Monotherapy (eg, third generation cephalosporin, carbapenem,
extended-spectrum ampicillin/sulbactam)
- Monobactams for patients with beta-lactam allergy
- For low-risk patients
# Outpatient parenteral therapy
# Oral therapy
The most important underlying principle in the management of the
cancer patient or neutropenic patient who becomes febrile, is
indeed prompt initiation of a broad spectrum antibiotic therapy.
This needs to encompass the most common organism, so gram-
positive and gram-negatives in particular. Having said that, there
really is not an ideal regimen. It depends upon the status of the
patient, the local microflora, their sensitivity patterns, toxicity,
preference, and cost.
There are a number of choices that have been advocated, ranging
from combination regimens to more simplified approaches. With
regard to combination regimens, the standards include third gener-
ation cephalosporins coupled with aminoglycosides. The alterna-
tives are single-agents, particularly selective third generation
cephalosporins. They should have antipseudomonal activity if they
are going to be used as monotherapy, or the carbapenems and the
extended spectrum penicillins that have beta-lactamase inhibitors
associated with them.
Outpatient therapy is already being employed in selecting popula-
tions, low-risk patients populations who present with fever and
neutropenia.
If one were to look at all of the data that has been collected, I think
you can say that either monotherapy or combination therapy are
reasonable choices for the curable management of the febrile
neutropenic patient.
While aminoglycosides have been part of the regimen in many
centers, at least our own experience based upon thousands of
episodes of fever and neutropenia, suggest that it is really not
necessary to give aminoglycosides early on.
Vancomycin should not be employed for empirical therapy. The
risk for developing resistant organisms outweighs the benefits for
empirical vancomycin. The only settings in which Vancomycin
should be employed empirically are those settings that include
patients with a clinically obvious catheter site infection, patients
with colonization with resistant organisms, an individual who has
persistent positive cultures despite appropriate antibiotic therapy,
or who presents with hypotension or evidence of cardiovascular
impairment. Aside from that, pathogen directed vancomycin is
really the way to proceed in this patient population.
The reason why Vancomycin became popularized is that indwell-
ing catheters have been increasingly used for the last couple of
years in the management of children and adults with cancer. With
that has come an increase in the incidence of gram-positive infec-
tions. There is no question that placing a catheter in a patient
increases the risk for developing a bacteremia and that
bacteremia could be due to a coagulase negative or positive staph,
it could be due to other gram-positives, gram-negatives, or to a
fungi, most notably Candida.
The principles of management of these catheters, particularly the
subcutaneously planted port, while we generally think of the need
to remove these devices, in this clinical setting most of these
infections can be treated without device removal. So a simple
bacteremia can be treated without device removal. It is important
to remember if a double or triple lumen catheter is in place, rotate
the antibiotics in each of the ports because colonization can be in
20

Antimicrobial Agents for Fever and Neutropenia
only one of them.
There are times where it is important to remove catheters. They
include patients who have either a tunnel infection, who have
persistent positive cultures despite 48 hours of appropriate antibi-
otic therapy. Some of the bacillus species require catheter re-
moval, even though the organisms are sensitive. Candida is an
absolute indication for device removal.

• Antifungal agents Antibiotic therapy can be discontinued in low-risk patients who

- Amphotericin B - still the gold standard.
- Liposomal formulations of amphotericin B (expensive)
- Fluconazole
- Itraconazole
• Antiviral agents
- Acyclovir, valacyclovir, famciclovir
have evidence of recovery of neutrophil counts and who are
afebrile. In those patients, monitoring your outcome is probably all
that is needed. On the other hand, for high-risk patients, meaning
those with profound neutropenia, and particularly for persistent
fever, continuation of antibiotic therapy is necessary and should be
coupled with an antifungal and other agents to support the patient
during the course of neutropenia.
Sites of infection often involve the oral cavity or the esophagus
and the lungs, as well as other organ site infections, especially
around the perianal area.

- Foscarnet
Cutaneous infections can be caused by a panoply of organisms
- Ganciclovir from bacteria to viruses or fungi. The predominant bacteria that
are responsible for cutaneous manifestations of infection are due
- Ribavirin to staph, strep, Pseudomonas, which is associated with ecthyma
- Amantadine, rimantadine gangrenosa. Fungal infections can include a number of cutaneous
lesions ranging from pustules associated with disseminated
candidiasis. Local signs of necrotizing infection appear with
Aspergillus, Mucor or Fusarium.

Viral infections can be associated with a number of vesicular and

erythematous rashes as well.

21
Initial Management of Fever and Neutropenia
• Ceftazidime was as effective as piperacillin + tobramycin for overall
response (63 vs 61%), including in patients with profound
neutropenia
- Infection related mortality was comparable: 6% for ceftazidime
vs 8% for piperacillin + tobramycin
- Adverse events were more common for the combination (20%)
than monotherapy (8%) group
Pulmonary infections. These are divided into focal versus dissemi-
nated infections, according to whether a patient is neutropenic or
non-neutropenic. There are a number of non-infectious complica-
tions that always need to be considered when you are evaluating a
patient who has developed new pulmonary infiltrates.
The approach to the management of these patients doesn’t de-
pend upon whether you are dealing with focal consolidation, where
one is generally thinking about bacteria or fungi, or a diffuse and
interstitial process where one certainly thinks about bacteria, but is
more naturally attracted to either pneumocystic or viral infections.
In terms of other respiratory tract disease, otitis media can be due
to common organisms, but they can otitis also be associated with
fungi, particularly Aspergillus. When negative infections occur,
external otitis can occur.
22
Initial Management and Subsequent Modifications

• Either monotherapy or combination therapy permit a highly success-

ful outcome for patients who present with fever and neutropenia
• Vancomycin is not Indicated for empirical therapy except in centers
with high Incidence of MRSA or alpha strep
• Other situations in which empirical vancomycin might be appropriate
Include
- Clinically obvious catheter infection
- Known colonization with pen/cephalosporin resistant
pneumococci
- Positive blood culture with Gram positive bacteria
- Hypotension or evidence of cardiovascular impairment

23
 Reducing Catheter-related Infections

• Major problem is bacteremias, especially coagulase-positive staph,

other gram positives, gram negatives and Candida.
- Most simple bacteremias can be treated without catheter
removal.
- Need to rotate antibiotics to multiple ports
- Need to remove catheters for tunnel infections, persistent
bacteremias or candidemia
• Infection be reduced by subcutaneous devices vs externalized
devices.

24
 Oral Therapy For Low-risk Patients

• Studies demonstrate a benefit with oral therapy or potentially simpli-

fied parenteral therapy (eg, ceftriaxone)

25
Should Antibiotics Be Continued Until Resolution
of Neutropenia?

• Disconnection of antibiotic therapy is feasible for low-risk patients

who have evidence of bone marrow recovery, it is not acceptable for
patients with persistent profound neutropenia
- In such patients, discontinuation of antibiotics can be associated
with significant clinical deterioration
• For high-risk patients, addition of antibiotics, antifungal and other
agents is the rule

26
Initial Management and Subsequent Modifications

• Modifications are particularly frequent for patients with prolonged

neutropenia
• Modifications represent an important adjunct to therapy rather than a
failure of the primary regimen
• Clinical Events Requiring Modification of Therapy
- Breakthrough bacteremia or fungemia
- Catheter associated soft tissue infection
- Severe oral mucositis or necrotizing gingivitis
- Esophagitis
- Diffuse or interstitial pneumonitis
- New pulmonary infiltrate despite antibiotic therapy
- Perianal tenderness or cellulitis
- Prolonged or recurrent fever with persistent neutropenia

27
 Skin Infections in Fever and Neutropenia

• Can be caused by bacteria, viruses and fungi

• Predominant bacteria include staph, strep, Pseudomonas (causing
ecthyma gangrenosa - also seen with Aeromonas)
• Fungal infections include candida (local or disseminated),
Aspergillus (at catheter sites or disseminated), Mucor, Fusarium
• Virus infections can be caused by HSV, VZV (can sometimes be
chronic)

28
 Pulmonary Infections in Fever and Neutropenia

Pneumonia Infectious Non-infectious

Focal consolidation Gram positive or Hemorrhage,

(Lobar or segmental) negative bacteria, infarction, atelectasis,
Legionella, Anaerobes, radiation, drug-related,
Mycobacteria, Crypto, tumor
Histo, Coccidiodes,
Aspergillus

Diffuse Interstitial Bacteria, viruses, Edema, ARDS, Drug-

P. carinii, MTB related, radiation,
Disseminated fungi, lymphatic metastasis
Chlamydia,
mycoplasma

Nodular Infiltrate Aspergillus, other Tumor

(+/- cavitation) mycoses, Nocardia,
Bacteria (Gram posi-
tive and negatives,
anaerobes), MTB

29
 HEENT Infections in Fever and Neutropenia
Sinusitis in a patient who is immunocompromised can be caused
by a fungal infection, especially Aspergillus or Mucor, which can
cause severe infections.

• Otitis media can be caused by routine bacteria or caused by gram

negatives or fungi (Aspergillus)
• Sinusitis can be recurrent (eg, patients with obstructive tumors)
• Can also be caused by fungi including Aspergillus, Mucor, Fusarium,
Pseudallescheria boydii.

30
Gastrointestinal Tract Infections in Fever and
The gastrointestinal tract is the most common port of entry of
Neutropenia organs, but there are certain syndromes that are associated with
the GI tract that are noteworthy. This includes mucositis and
esophagitis, gram-positive and gram-negative infections, as well
as anaerobes, but also, especially for esophagitis, Candida and
viruses appear.

In terms of intraabdominal processes, the syndrome of neutropenic

colitis generally presents as right lower quadrant pain, and is
• Mucositis/Esophagitis - due to gram-positive, gram-negative and
generally due to gram negative bacteria, particularly Pseudomonas
anaerobic bacteria. Candida and viruses (especially HSV, CMV) may aeruginosa. It can be rapidly progressive and sometimes needs
surgical intervention, although the general approach is to try and
be contributing factors. treat patients with appropriate antibiotic therapy.
• Intraabdominal Infections
Clostridial infection which can be due to Clostridium septicum, but
- Typhlitis or neutropenic colitis (due to gram negative bacteria, also perfringens and tertium can cause significant infections and
with perfringens and septicum, a fasciitis is especially noteworthy.
especially Pseudomonas)
- Clostridial infections (C. perfringens, C. septicum, C. tertium) Invasive mycoses are very relevant to the compromised host.
Mycoses have emerged as major problems in this patient popula-
- Pseudomembranous and antibiotic associated colitis (C. tion. Invariably the Candida stands at the top of the list.
Aspergillus, Mucor, Cryptococcus, Fusarium, Trichosporon as well
difficile)
as histo, blasto and cocci.
- Hepatosplenic candidiasis
Candida may cause a broad array of symptoms and syndromes
• Perianal cellulitis that can occur, from superficial candidiasis to deep infection, and
deep infections most importantly disseminated infection.

With regard to Candida esophagitis, as I mentioned already, the

differential diagnosis includes other organisms, particularly sim-
plex and Cytomegalovirus, as well as bacteria. The diagnosis can
only be made by biopsy. Now in many situations biopsy is contra-
indicated and therefore intervention with either oral therapy, in the
form of fluconazole, or systemic therapy, in the form of lower
doses of amphotericin, can lead to resolution of this syndrome
relatively promptly.

Fungemia can be related to catheter-related infections. In the

presence of fungemia, devices must be removed. A positive
culture for Candida in an immunocompromised patient should
always be taken seriously. An effective therapy means, especially
if there is a device in place, its removal together with appropriate
antifungal therapy.

Even with removal of the device, continued shedding of organisms

can occur because of the presence of a suppurative phlebitis,
which can remain in place even when the catheter is taken out.

31
Assessment of High-risk Patients with Persistent
Fever

• Frequent meticulous physical examination is essential

• Consider ultrasound of liver/spleen (especially in patients with
persistent fever who are recovering their white count)
• Consider chest CT in patients with persistent fever/neutropenia who
become candidates for empirical antifungal therapy

32
Fungal Infections and Immunocompromised Hosts

• Invasive mycoses are major problems for immunocompromised

hosts
• Candida is the most common
• Depending on the host and geographic location, other important
mycoses can include Aspergillus, Mucor, Cryptococcus, Fusarium,
Blastomycetes, Coccidioides

33
 Fungal Infections and Phagocytic Deficiencies

Disorder Deficit Infections

Chronic Impaired production of Invasive Aspergillosis

Granulomatous oxidative metabolites
Disease

Myeloperoxidase Defective Intracellular kill- Candidiasis

Deficiency ing

Granulocyto- Quantitative deficit of Candidiasis, invasive

penia phagocytes Aspergillosis
Zygomycosis,
Trichonosporosis,
Fusariosis,
Pseudallescheriasis

Corticosteroid Impaired phagocytosis invasive Aspergillosis,

therapy of conidia by Candidiasis,
macrophages Zygomycosis
and defective damage
to hyphae by neutrophils

34
 Fungal Infections and Altered Cellular Immunity

Disorder Deficit Infections

Severe Combined Depletion of T- and B- Candidiasis,

Immunodeficiency cell precursors Cryptococcosis

DiGeorge syndrome Thymic hypoplasia Candidiasis,

Cryptococcosis,
Histoplasmosis

Chronic Impaired recognition or Mucosal candidiasis

Mucocutaneous T-cell response to
Candidiasis Candida antigens

Acquired Immune Defective cell-mediated Mucosal candidiasis,

Deficiency Syn- and humoral immunity; Cryptococcosis,
drome impaired neutrophil Aspergillosis,
function Histoplasmosis,
Coccidioidomycosis

35
 Candidiasis
• More than 80 species, less than 10 of which are medically important
• C. albicans is responsible for >60% of candidiasis
• Colonization is 25-70%
- 5-15% of newborns to first week, increasing to 46% by 18
months
- Major sites include oral cavity, GI tract, and vagina
• Other clinically relevant species of Candida
- C. tropicalis - a cause of disseminated infection in compromised
hosts.
- C. parapsilosis - second to C. albicans as a cause of
endocarditis.
- C. glabrata - rare cause of endocarditis and disseminated infec-
tion in compromised hosts and catheter associated fungemia.
Resistant to azoles.
- C. lusitaniae - can be a cause of fungemia and deep infection.
Resistance to amphotericin B reported.
The diagnosis of disseminated candidiasis is still a challenge.
The best technique available to us is the lysis centrifugation, a
technique that has permitted us to make the diagnosis of
candidemia in close to 60% to 70% of the patients, as compared
to about 20% of the patients who do not have blood cultures but
the lysis centrifugation technology. Newer techniques, and partic-
ularly non culture-dependent techniques like enolase or arabinitol
and PCR, are still experimental and not part of any standard regi-
men.
The clinical presentation in this patient population of disseminated
candidemia rests on the presence of fever. That may be all you
have. So persistent fever of babies may be the only symptom of
disseminated candidiasis. If one does have evidence of skin
lesions, particularly papules or chronic lesions that are available
for biopsy, that can help you to diagnose infection earlier on.
Myositis can be part of this syndrome, so muscle pain, in addition
to fever in a neutropenic patient is suggestive of disseminated
candidiasis. The sites of dissemination include many organs from
the skin to the kidneys, lungs, GI tract, liver, spleen, and the central
nervous system. Very similar to what one sees in neonatal
candidiasis. The drug of choice is a polyene, particularly
amphotericin. Either amphotericin B or, depending upon the
setting, the liposomal or lipid associated formulation of
amphotericin. The duration of therapy really depends upon whether
or not there is evidence of organ infection. In the absence of
organ infection, treating a patient or a child for between 30 to 40
mg/kg and in an adult for one-half to a gram of amphotericin is
appropriate therapy. If there is evidence of organ infection, higher
doses and longer courses are needed. This syndrome is charac-
terized by new or persistent fever, the presence of abdominal pain,
or right upper quadrant tenderness, an elevated alkaline
phosphatase and leukocytosis.
The clinical presentation includes “bulls eye” lesions on either
ultrasound or CT and the MR scan, which may be the most sensi-
tive way of diagnosing this syndrome. These lesions are generally
not visible in children with neutropenia, so if you had a patient who
was surveyed during the time they had neutropenia, they had a
negative CT or MR scan and is still febrile at the time of resolution
of neutropenia, it would be important to go back and repeat those
studies. Definitive diagnosis requires biopsy because blood cul-
tures will often be negative. Therapy can require protracted
courses of antibiotics with either amphotericin or fluconazole. And
if one is using amphotericin on very long courses in high doses,
5FC may also be necessary. Lipid-associated formulations of
amphotericin may allow for a greater degree of dose intensity.
Cryptococcus. This is much more of a problem in adult HIV pa-
tients and adult cancer patients. Cryptococcus can be a problem in
children as well. It can be associated with primary infection of the
lungs, characterized by a diffuse miliary disease, which can be
rapidly progressive in a child with cancer, leading to death if not
recognized and treated. The most common manifestation of
Cryptococcus is Meningoencephalitis, which often is indolent and
can be associated with headaches, nausea, dizziness and irritabil-
ity. A heightened index of suspicion for the diagnosis is essential
because fever is generally low-grade. Patients can deteriorate
quite rapidly and have a high degree of mortality.
36
 Nuchal rigidity is rare. There often is evidence of increased
intracranial pressure, as well as cranial nerve palsies. The differ-
Candidiasis ential diagnosis includes a variety of different
meningoencephalides and the CSF is a critical part of the evalua-

Ecology tion, particularly looking for Cryptococcal antigen which can be

found in large numbers of patients.

• Other clinically relevant species of Candida

- C. kruesei - a cause of breakthrough infection in patients
receiving fluconazole
- C. guillermondii
- C. kefyr (C. pseudotropicalis)
• Lacks an apparent sexual life cycle
• Changes in colony morphology can occur during sequential episodes
of infection
• Two major serotypes - A and B
- Higher prevalence of B serotype in immunosuppressed patients
• Numerous environmental sources, including soil, water, plants,
foods and beverages

37
 Candidiasis: Laboratory Diagnosis

• Characteristic features include budding yeast cells, pseudohyphae,

or hyphae in tissue. Yeast cells and pseudohyphae commonly
measure 3-5 um in diameter
• C. glabrata has smaller yeast forms and does not produce
pseudohyphae or hyphae
• Wet mount (KOH) or fluorescent microscopy with calcofluor wet
specimens
• Organisms well demonstrated with Gram, Giemsa or Wrights stains

38
 Candidiasis: Laboratory Diagnosis

• Blood cultures are optimized with lysis centrifugation (Isolator), also

planted on Sabouraud's agar (with antibiotics but without
cycloheximide)
• Cultures from other clinical sites should be placed on Sabouraud's
agar and incubated at 300C. Culture plates should be held for 2-3
weeks
• Candida produces white to cream-colored colonies

39
 Candidiasis: Clinical Syndromes

• Superficial Candidiasis
- Skin, hair, nails, mucous membranes
- Ocular candidiasis
• Deep Candidiasis
- Esophagitis Arthritis
- GI/Peritonitis Osteomyelitis
- Respiratory tract Endophthalmitis
- Urinary tract CNS
- Acute Hematogenously disseminated
- Chronic disseminated (hepatosplenic)
- Suppurative phlebitis
- Endocarditis
- Neonatal candidiasis

40
 Ocular Candidiasis

• Keratoconjunctivitis due to Candida is a complication of the long-

term use of steroid eye drops
• Other risk factors include breaks in the corneal epithelium
• Characterized by cheesy discharge in the conjunctival sac

41
 Candida Esophagitis

• At risk populations include patients with congenital or acquired

immunodeficiency disorders, cancer patients, mechanical problems
(achalasia, peptic esophagitis)
• May be asymptomatic or associated with burning retropharyngeal
chest pain
• May or may not be associated with oral lesions
• Typical lesions are white mucosal plaques, generally in the distal
third of the esophagus. Lesions can be edematous and hemorrhagic
• Differential diagnosis includes H. simplex, CMV, bacteria
• Diagnosis can only be confirmed by biopsy
• Therapy
- Topical - clotrimazole is best
- Oral - ketoconazole or fluconazole
- Systemic
# Low-dose amphotericin (0.1 mg/kg/d for 5 days)
# Conventional amphotericin (0.5-1.0 mg/kg/d)
# Liposomal amphotericin (for recalcitrant or resistant
organisms)

42
 Gastric Candidiasis

• Stomach is second to esophagus as a site for GI candidiasis

• Lesions may involve the intestine and, in the case of leukemia
patients, may be deeply invasive and serve as a nidus for dissemina-
tion

43
 Candida Peritonitis

• Peritonitis can occur with peritoneal dialysis (risk is 7%) or postoper-

atively
• Symptoms include abdominal pain, with or without nausea, vomiting
or low-grade fever
• Dialysate should be examined microscopically and cultured
• Peritoneal fluid should be examined, especially in the post-op patient
• Therapy
- It is prudent to remove the device
- Approximately 25% can be cured without catheter removal
- If dissemination has occurred, amphotericin should be adminis-
tered
- Although amphotericin can be added to the dialysate or infused,
it is associated with pain and can lead to fibrosis
- Recommendations are for IV amphotericin + oral 5 FC.

44
 Urinary Tract Candidiasis

• Urinary Tract accounts for 49% of nosocomial candida infections.

Candida is the causative organism in 7%
• Risk factors include indwelling catheter and predisposing illnesses
(eg, diabetes mellitus, immunosuppression)
• Symptoms of lower tract infection (dysuria, frequency) and fungus
galls or bezoars (primarily in diabetics) may occur
• Colony counts >104 suggest the diagnosis
• Removal of the catheter may ameliorate symptoms
• Therapeutic recommendations include instillation of amphotericin B
(which can be painful) to fluconazole
- Note that ketoconazole is not excreted into the urine in an active
form
• Because of the high volume of blood flow, the kidney is commonly
involved in disseminated candidiasis
• Ascending infection can be associated with obstruction, renal stones,
nephrostomy tubes, ureteral stents or with diabetes
• Symptoms can be indistinguishable from bacterial pyelonephritis
- Persistent fever in a patient receiving broad-spectrum antibiotics
- Blood cultures are positive in <50%, even with disseminated
candidiasis

45
 Urinary Tract Candidiasis

• Microabscesses are primarily in the renal cortex

• Candiduria is helpful but not definitive
- Presence of hyphae is not necessarily indicative of invasive
disease
• Imaging studies (CT, MR) may reveal evidence of abscesses,
often in association with lesions elsewhere
- Lesions may not be apparent during neutropenia
- Can be found in intravenous drug users
• Intravenous amphotericin in the recommended therapy
- Short courses have been used, although longer courses are
preferred for proven renal abscesses
- Fluconazole has also been used

46
 Bone And Joint Candidiasis

• Prosthetic and rheumatoid joints can be infected hematogenously

or during surgery
• Arthritis can occur in neonates or neutropenic patients
• Symptoms are indolent, and joint fluid is variable
• Osteomyelitis is generally hematogenous, clinically indolent, and
most commonly involves the lumbar vertebrae
• Therapy includes surgical debridement and intravenous
amphotericin B

47
 Catheter-associated Candidiasis

• Fungemia is a sequelae of intravascular catheters in

immunocompetent and immunosuppressed hosts
• Positive cultures should never be ignored. In neutropenic patients
they often signify disseminated infection.
• Effective therapy mandates removal of the catheter and systemic
therapy
• Suppurative phlebitis can cause of treatment failure and may require
surgical therapy

48
 Candida Endocarditis and Pericarditis

• Subacute endocarditis can occur following candidemia, especially in

patients with valvular defects or prosthetic devices
- Lesions can become large and result in embolic phenomena
- Transesophageal echo is necessary if transthoracic echo is
negative
• Pericarditis is a rare complication
• Surgery plus amphotericin B is necessary

49
 CNS Candidiasis

• Risk group includes neonates, neutropenic patients, complicated

neurosurgery or VP shunts
• Presentation is generally indolent
• CSF profile includes pleocytosis, increased protein and low glucose
• Can be accompanied by microabscesses, granuloma or vascular
lesions
• Amphotericin + 5 FC is recommended
• Long-term adverse sequelae (including aqueductal stenosis) is
common

50
 Candida Endophthalmitis

• 10-37% of adults with candidemia develop endophthalmitis

• Only one eye is involved in 50%
• Onset may be acute or delayed, and symptoms are indolent
• Small, sharply outlined lesions in the posterior pole are most
common. Lesions may be absent during neutropenia.
• Lesions may disappear or enlarge to rupture into vitreous and
anterior chamber
• Therapy includes systemic amphotericin + 5 FC
- Role of fluconazole is investigational

51
 Acute Disseminated Candidiasis

• Diagnosis is often made postmortem and premortem blood cultures

are positive in <60-70%
- Newer diagnostics (PCR) are specific but several lack optimal
specificity and are experimental
• Clinical presentation consists of persistent fever, sometimes with
evidence of shock and DIC
- Skin lesions include papules with gray necrotic centers
- Myositis may be an accompanying symptom
• Sites of dissemination includes skin, kidneys, lungs, GI tract, liver,
spleen, CNS, eyes, thyroid, joints.
• Therapy includes prompt initiation of amphotericin B, 1 mg/kg/d,
optimally in combination with 5 FC
• Duration of therapy depends on the organs that are involved and
duration of immunosuppression

52
 Chronic Disseminated Candidiasis
Hepatosplenic Candidiasis

• Primarily found in patients who were neutropenic, but rarely diag-

nosed during neutropenia
• Multisystem granulomatous disease
• Syndrome consists of
- New or persistent fever at recovery from neutropenia
- Some patients have abdominal pain or RUQ tenderness
- Elevated alkaline phosphatase
- Leukocytosis
- Bulls eye lesions on ultrasound, CT or MR

53
 Chronic Disseminated Candidiasis
Hepatosplenic Candidiasis

• Imaging lesions are generally not positive during neutropenia

• Diagnosis requires biopsy of lesions
• Biopsy cultures are often negative
• Therapy requires a long course of amphotericin B with 5 FC
- Treatment continues until resolution of lesions or dense
granulation
- Liposomal formulations of amphotericin may be more beneficial
- Continuation therapy with fluconazole

54
 Cryptococcosis: Epidemiology and Ecology

• C. neoformans is the only species known to cause human infection

- Monomorphic yeast, 4-6 um in diameter
• Has a worldwide prevalence
• AIDS has changed the frequency of this infection
- Rare in pediatric AIDS (<1%)
- Incidence in children with cancer is 0.5%
• Infection follows inhalation into lungs
• Exposure to pigeon excreta is the source of human exposure
- Isolated in <1% of soil samples but >50% of pigeon droppings
- Human-to-human transmission not reported
• Major risk groups include patients with cancer, acquired or congeni-
tal immunodeficiency disorders, transplant patients

55
 Cryptococcosis: Pathogenesis

• Following inhalation, a primary pulmonary complex is formed that

either heals or progresses
• The capsule can inhibit phagocytosis
• Cellular defenses are the most important. Patients with altered T
helper numbers or function are most vulnerable.

56
 Cryptococcosis
Diagnosis

• Direct examination of CSF, urine, sputum or pus (digested with 10%

NaOH) can be positive with India ink prep
• Histopathology sections can be stained with mucicarmine to demon-
strate yeast with capsules
• Latex agglutination detection of polysaccharide capsule has a sensi-
tivity >90%
- Suitable only for serum and CS
- Should contain a control for RF, a source of false positives in
CSF
- False positives can occur with Trichosporon beigelii
• Lumbar CSF titers are higher than those of ventricular fluid
• Lysis-centrifugation methodology is most sensitive and rapid
- Cultures may take from 1-21 days (mean 3 days)
• Grows well on Sabouraud agar (without cycloheximide)
• Niger seed agar is effective for urine and sputum samples from AIDS
patients
• Rapid urease test is helpful since >90% of isolates show urease
activity within 15 min

57
 Cryptococcosis
Clinical Manifestations

• Lungs are the site of entry

• Patients with chronic lung disease may have asymptomatic coloniza-
tion.
• Previously normal patients have a self-limited pneumonia, some-
times with cavitations.
• Diffuse miliary disease can rarely occur with disseminated disease.
• Localized nodular infiltrates can occur, which can be confused with
tumor nodules, especially in non-neutropenic cancer patients

58
 Cryptococcosis
Meningoencephalitis

• Most common clinical manifestation and major cause of death

• Can be rapid or indolent
- Indolent cases are characterized by headache, nausea, dizzi-
ness, irritability, impaired cognition, ataxia that progresses to
lassitude, blurred vision and coma. Fever is often low grade.
- Acute cases may deteriorate and die within 2 weeks. These
patients become somnolent and nauseated with headache.
• Nuchal rigidity is rare
• Signs of increased ICP are more common
• Cranial nerve palsy can occur
• Differential diagnosis includes aseptic meningitis or brain tumor
• Lumbar CSF has increased opening pressure. Cryptococcal antigen
- In rapidly progressing cases, the CSF antigen (or India ink) is
positive without other abnormalities

59
 Cryptococcosis
Clinical Manifestations

• Skin lesions are most common around the face and can be pustular
or ulcerative and occur in 10% of patients with cryptococcosis
• Skeletal lesions occur in 5% and may be confined to a single lesion,
most commonly involving the vertebrae.
• Ocular lesions include papilledema, optic atrophy, extraocular motor
palsy.
• It usually can not be detected in the urine, although it frequently is
isolated from urine in patients with disseminated disease.
• Cryptococcus can also be associated with
- Pyelonephritis
- Prostatitis
- Adrenal cortical lesions
- Endocarditis
- Hepatosplenic disease
- GI and GU tract involvement

60
 Cryptococcosis
Treatment

• Standard therapy for meningoencephalitis

- Amphotericin B, 0.5 mg/kg/d for 6 weeks plus
- 5-flucytosine, 100 mg/kg in 4 divided doses for 6 weeks
• Patients with HIV who develop meningitis require maintenance
therapy with fluconazole
• Death can occur in up to 15%. Poor prognosticators include rapid
disease progression, increased ICP at diagnosis, poor CSF re-
sponse.

61
 Aspergillosis
• More than 135 species and 18 varieties exist
- 16 species and 1 variety have been associated with human
disease
# A. fumigatus is most common cause of invasive and
noninvasive disease worldwide
# A. flavus is second, causing disease in immunosuppressed
hosts
# A. niger is usually saprophytic
# A. niger and A fumigatus are common cause of a "fungus
ball"
Aspergillus: Aspergillus is the fungal organism we prefer not to see
in the immunocompromised host, fumigatus and flavus species
are the major ones that are encountered. A. niger is usually a
saprophyte and not associated with significant infection. It is the
one that you see in fungus balls, and that usually is a non-invasive
syndrome.
Invasive forms of aspergillus include both pulmonary and non-
pulmonary manifestations. The non-pulmonary manifestations
include involvement of a variety of different organ systems, but the
most common one is the pulmonary disease and the most com-
mon port of entry is through the upper airway. The disease that
one is most concerned about is the localized and then dissemi-
nated forms of pulmonary aspergillus.
62
 Aspergillosis
Epidemiology and Ecology

• Most species are found in soil, various food products, cotton and
organic debris
• A. fumigatus grows well at temperatures >550C and compost piles
are an excellent media
• Moldy grains are source of Aspergillus spores
• Hospital sources (eg, fireproofing material) have been contaminated
with A. flavus. Also, potted plants, hospital construction.
• Spores can be inhaled or contaminate wound surface
• Invasive disease has been reported in
- 2% of patients undergoing renal transplantation
- 4-17% of patients undergoing liver transplantation
- Aspergillus is the most common fungal pneumonia in organ
transplant patients
- Invasive disease occurs in 5-20% during chemotherapy-induced
granulocytopenia or bone marrow transplantation

63
 Aspergillosis
Epidemiology and Ecology

• Risk factors for infection following BMT

- Age greater than 30 years
- HLA match and presence of GVHD
- Conditioning regimen - T cell depletion, steroids
- Duration of neutropenia
• CGD patients are vulnerable to Aspergillus
• HIV patients can also develop aspergillosis

64
 Aspergillosis
Pathogenesis

• Usual portal of entry is the respiratory tract. Less common are GI

tract and traumatized skin
• Initial control is by the pulmonary macrophages
• Some conidia can be carried by macrophages to the RE system and
can be associated with dissemination
• Corticosteroids are a major risk factor for infection
• Neutropenia or neutrophil dysfunction contribute
• Fungus ball is a large mycelial mass growing in cavities in the upper
lobe of the lungs or sinuses. Fungus balls are not associated
with invasive disease

65
 Aspergillosis
Pathogenesis and Pathology

• Invasive aspergillosis is characterized by hyphal invasion of blood

- Infection spreads hematogenously as well as by contiguity.
- In patients with CGD, vascular invasion is not apparent but a
massive inflammatory response is evident

66
 Aspergillosis
Laboratory Diagnosis

• Morphology of A. fumigatus and A. niger is distinct enough so that

positive identification can be made on histological appearance
• Aspergillus grows well on conventional media
- Sabouraud's and malt extract with antibiotics are used
- Cycloheximide should be avoided

67
 Aspergillosis
Clinical Manifestations

• Allergy to Aspergillus antigen causes allergic bronchopulmonary

aspergillosis
• Saprophytic colonization of air spaces
- Otomycosis
- Fungus ball of paranasal sinus
- Endobronchial colonization
- Fungus ball of the lung

68
 Aspergillosis
Clinical Manifestations

• Keratitis or endophthalmitis can occur from trauma or surgery.

• Otomycosis is colonization of the external auditory canal
- Greenish-black or fuzzy growth on cerumen
- Can become invasive in severely compromised hosts

69
 Aspergillosis
Clinical Manifestations

• Fungus balls of the paranasal sinus or lung represents saprophytic

colonization without invasion
- Maxillary sinus is most common but other sinuses can be
involved
- The fungus ball itself can contribute to obstruction but not bony
erosion
- In the lung, a fungus ball usually occurs in a preexisting cavity.
Hemoptysis is a complication

70
 Aspergillosis
Clinical Manifestations

• Invasive Pulmonary Aspergillosis

- Symptoms can be subacute to acute, nearly always with fever
- Cough, pleuritic pain and hemoptysis in neutropenic patients
- Can be more indolent in CGD, and fever may be absent
• In immunosuppressed hosts, radiograph shows single or multiple
round or infarct-like lesions, sometimes with cavitation or
hemorrhage
- CT is more sensitive
- Infection follows or co-exists with a bacterial (Pseudomonas) or
viral (CMV) infection
• Invasive Pulmonary Aspergillosis
- Vascular invasion causes infarction of distal tissues
- Pulmonary infection crosses contiguous tissues - through the
diaphragm into the stomach or liver; into the pericardium, heart
or SVC
- Hematogenous infection occurs in a third of cases
- Cavitation, sometimes associated with neutrophil recovery, can
sometimes be accompanied by massive hemoptysis

71
 Aspergillosis
Clinical Manifestations

• Invasive Sinus Infection

- May be acute or chronic
- Acute infection is associated with fever and may be accompa-
nied by symptoms of sinusitis or rhinitis, lesions over the nose
or sinus area, necrotic lesions of the turbinates or hard palate
- Can spread to contiguous tissues including orbit or brain
- Most frequently associated with prolonged neutropenia
- Sensitivity of repeated nasal cultures is 50%

72

Aspergillosis
Clinical Manifestations
• CNS is most common site for disseminated disease
- Can consist of single or multiple lesions
• Cutaneous lesions can occur at sites of trauma or catheter insertion.
- Can also be consequence of disseminated infection
• Endocarditis can be a consequence of cardiac surgery or can occur
with iv drug use
- Cardiac lesions can also occur with disseminated infection
• GI involvement can include an ulcerative esophagitis or lesions in
the stomach, small and large intestine. A Budd-Chiari syndrome has
been described in association with Aspergillus.
• Osteomyelitis of the ribs and vertebrae can occur
- Direct extension from lung lesions
- As part of hematogenous infection
Fungus balls. In the lungs of patients they generally don’t represent
invasive disease, but they can be seen in other sites as well. One
can see evidence of fungus balls in the sinuses as well.
Hemoptysis is something that can occur. A saprophytic form of
fungus balls can occur as an isolated lesion. Some have advo-
cated surgical removal of those lesions prior to the administration
of chemotherapy.
Surgery doesn’t, however, play a role in invasive aspergillus. It is
interesting to note that early on the symptoms can be subjective
and vaguely associated with fever. Cough and pleuritic pain sug-
gests the presence of aspergillus pneumonia.
In immunosuppressed hosts the chest radiograph can sometimes
show anything from single to multiple round lesions. These can
sometimes look like tumor nodules, but they can undergo evolution
rather rapidly as well because hemorrhage can occur into them. A
plain chest x-ray may be negative for aspergillus but the CT scan
may reveal sites of infection.
Invasive aspergillus is really an angioinvasive disease, and vascu-
lar invasion is what leads to an infarction of tissues and the pulmo-
nary infection really follows the tissue, so that you can see an
extension of this disease contiguously through the lung planes
through the diaphragm and into the liver and spleen and all the way
down to the kidneys. Hematogenous spread can occur although
positive blood cultures often don’t. And one can see cavitation of
lesions at times of recovery of neutrophils.
The syndrome of rhinocerebral disease or invasive sinus infection
is as important with aspergillus as it is with Mucor. This can be
both acute and chronic. Acute infection is associated with fever
and can be associated with a bit of an eschar around the anterior
nares, which can spread rapidly through the cribriform plate into
the brain. This is a very severe infection and in order to treat this,
surgical therapy in tandem with systemic amphotericin or other
antifungal agents is essential.
The central nervous system is the most common site of dissemi-
nated disease and can consist of both single as well as multiple
lesions, and one can see cutaneous lesions. These can be part of
a systemic syndrome or can be secondary to local inoculation.
Local inoculation from environmental sources, particularly around
catheter sites can be associated with aspergillus.
The treatment is with a combination of amphotericin, sometimes in
association with surgery. Itraconazole has been employed. The
problem with itraconazole is that it is imperfectly absorbed in this
patient population. It is not adequate first-line therapy.
Surgery has been used to extricate both central nervous system as
well as sinus infections. Its role in pulmonary disease is largely
restricted to the solitary cavitary lesions in which hemoptysis is a
risk factor, but it really doesn’t make a difference on indications
throughout the basic disease because the extension of the dis-
ease is simply too much.
73
 Aspergillosis
Treatment

• Drug of choice is amphotericin B at 1-1.5 mg/kg/d

- Little data exist regarding combination regimens
- Liposomal preparations are being explored
- Itraconazole has been used for continuation therapy

74
 Aspergillosis
Treatment

• Surgery is used to extirpate CNS and sinus lesions

• Role for pulmonary lesions is limited to
- Solitary cavitary lesion refractory to medical therapy
- Hemoptysis from a solitary cavity
- Contiguous invasion of esophagus, ribs or pericardium
• Leukocyte transfusions have been employed in CGD

75
 Mucormycosis

• The causative agents are members of the Zygomycetes (class) and

Mucorales (order)
- The agents responsible for most invasive infection include:
Rhizopus, Absidia, Mucor and Cunninghamella
# Other members of this order also cause infection, including:
Saksenaea, Apophysomyces, Syncephalastrum,
Cokeromyces, although not necessarily invasive disease

76
 Mucormycosis
Mucor does just about everything that aspergillus can do only more
Epidemiology and Ecology so because it is more recalcitrant to intervention. The agents of
Mucor responsible for invasive disease include Rhizopus, Absidia,
Mucor and Cunninghamella. There are other members of this
family that can also be associated with significant disease, particu-
larly in the upper airway and around the sinuses. The syndrome
with Mucor looks like aspergillus but is even more recalcitrant to
treatment and that is the rhinocerebral syndrome with again exten-
sion through the ethmoid sinuses through the cribriform plate, and
• Distribution is worldwide. Organisms found in decaying vegetables,
into the brain.
compost piles, soil, old bread
• Nosocomial infections can occur (e.g., Elastoplast) but is less
common than with Aspergillus
• Major risk factors for infection include diabetes, malignancy, organ
transplantation, chronic liver or kidney disease, burns or other
disruptions of physical defense barriers

77
 Mucormycosis
Pathogenesis and Pathology
• Portal of entry is respiratory, GI or skin
• Diabetic ketoacidosis predisposes to progressive nasal and cerebral
mucormycosis
• Neutropenia, or altered phagocytic function (e.g., steroids) contrib-
ute.
• Hallmark is vascular invasion by hyphae leading to thrombosis and
infarction. Thrombosis may occur in large as well as small vessels.
• Spread can be contiguous or hematogenous
Pneumonia can occur with Cryptococcus and can be rapidly pro-
gressive, can be associated with both cavitation and can, on rare
occasions, be associated with exsanguinating hemoptysis. These
are very serious infections. Treatment of cranial, facial
mucormycosis is a combination of both surgical debridement as
well as antifungal therapy.
Less common fungi can cause notable infection in this patient
population, depending upon the region that one is in. This includes
Trichosporon which is a yeast that is commonly associated with
white piedra, but it can be associated with fungemia and dissemi-
nated infection. A fact that is interesting to note and important to
note is that it shares cross reactivity with cryptococcal antigens, so
cryptococcal antigen positivity doesn’t always mean Cryptococcus.
It could be Trichosporon. It responds poorly to amphotericin B.
Fusarium, which is a plant pathogen, can cause disseminated
infection usually beginning on the skin or muscles and associated
with fungemia.
Pseudallescharia boydii mimics aspergillus and Mucor in its ap-
pearance and profile and it is important to think about and diag-
nose because it tends to be resistant to amphotericin, but is sensi-
tive to miconazole. Bipolaris as well as Penicillium marneffei can
cause serious infection both in cancer as well as HIV patients.
Bone marrow and in solid organ transplant patients. If one looks at
the patient population undergoing bone marrow transplantation,
one can begin to categorize the likelihood of infection based upon
where one is in the course of post-transplant. Early on bacterial
infections during the neutropenic phase are very similar to what
one sees in the neutropenic cancer patient who wasn’t receiving
bone marrow transplantation. And similarly, fungal infections can
occur in the same manner. What is different in this patient popula-
tion is the time of onset on various viral infections. With herpes
simplex appearing early, Cytomegalovirus occurring generally
between 30 and 60 days post-transplant and Varicella zoster
generally after that, more particularly after about 100 days.
So if one looks at the evaluation of the patient undergoing bone
marrow transplantation, the pretreatment evaluation largely centers
on screens for those organisms that are likely to cause problems,
including Cytomegalovirus, the Epstein-Barr virus, herpes sim-
plex, hepatitis. One looks for evidence of any kind of organ involve-
ment and of course for the presence of ova and parasites. Here
particularly, Strongyloides, in the presence of immunosuppressive
therapy, can be associated with a hyperinfection syndrome that
includes polymicrobial bacteremia as well as pneumonic infiltrates.
During the early period, that is before the engraftment transplanta-
tion, the patterns of infection are largely that related to fever and
neutropenia. And the other infections that one thinks about are
herpetic gingivostomatitis; Largely this is a reactivation infection
and generally prevented by the use of prophylactic acyclovir. The
fungal infections are very similar to those that occur in the setting
of fever and neutropenia.
Hemorrhagic cystitis can occur in this patient population. Here,
one thinks about particularly adenovirus as well as
cytomegalovirus. During the new period following transplantation,
78
 Mucormycosis which is during the early engraftment phase, Pneumonitides can
occur, and there is a difference depending upon whether the
patient has undergone allogeneic versus autologous bone marrow
Laboratory Diagnosis transplantation. In the setting of allogeneic bone marrow trans-
plantation, the syndrome of interstitial pneumonia largely associ-
ated with CMV as well as graft versus host disease is manifest.
And when it occurs it carries with it a very high degree of morbidity
and mortality.

• Histologically mucor can be recognized by their broad (7-15 um)

hyphae and lack of regular septations. Unlike the regular dichoto-
mous branching of Aspergillus.
• Mucorales grow rapidly on most mycological media (without
cycloheximide)

79
 Mucormycosis
Clinical Manifestations

• Rhinocerebral syndrome is most common in uncontrolled diabetics

or patients with cancer.
• Infection is acute and rapidly progressive.
• Extension from ethmoid sinus to the orbit is frequent, resulting in
loss of ocular movement, proptosis and involvement of CN III, IV
and V.
• Extension to dura and brain with embolization of distal brain tissue
may occur.
• Pneumonia is accompanied by fever and rapidly progresses
• Infiltrates progress rapidly with apparent cavitation
• Hemoptysis can occur, and may be massive
• Infection of the bronchus or trachea can occur independently of
pneumonitis
• Cutaneous mucormycosis occurs at sites of trauma, iv sites or
post-op sites
- Skin lesions are generally single, begin as erythematous,
indurated cellulitis but develop central black necrosis
• GI lesions arise in 7% - the stomach is most common followed by
the colon. GI lesions can serve as a nidus for dissemination
• CNS involvement can be by direct extension or hematogenous
spread
- Local extension is mostly from ethmoid sinus
- Hematogenous disease is mostly from a pulmonary focus
• Cardiac mucormycosis is rare, but endocardial vegetations have
been described

80
 Mucormycosis
Treatment

• Craniofacial mucormycosis without extension to the brain or carotid

artery can respond to surgical debridement, control of the underlying
disease and amphotericin B
• Treatment of pulmonary disease or disseminated infection in com-
promised hosts is very disappointing, even with higher doses of
amphotericin or liposomal preparations

81
 Less Common Pathogens

• Trichosporon beigelii, a yeast that causes white piedra, can cause

fungemia and disseminated disease
- Shares cross reactivity with Cryptococcal antigen
- Responds poorly to amphotericin
• Fusarium, a plant pathogen, can cause disseminated infection in
immunocompromised hosts
- Generally begins with skin lesion or invasion through
impaired integument with dissemination

82
 Less Common Pathogens

• Pseudallescheria boydii mimics Aspergillus in its appearance and

clinical manifestations. Notable for its resistance to amphotericin B.
It is sensitive to miconazole.
• Bipolaris, Wangiella and Exserohilum are agents of
Phaeohyphomycosis. Can cause cutaneous, pulmonary, CNS and
disseminated infections
• Penicillium marneffei presents with disseminated infection in cancer
and AIDS patients. Histopathologic lesions resemble histoplasmosis

83
 Special Considerations in Bone
Marrow Transplant Patients

• Pretreatment evaluation
- Serology for CMV, EBV, HSV, Hepatitis B, Serology, RPR, HIV
- Chemistries including hepatic enzymes, renal function, CBC
- Stool for ova and parasites
- PPD
- Chest radiograph

84
Special Considerations in Bone Marrow Transplant
Patients
• Early Period (Before Engraftment)
- Fever and neutropenia may occur, which is similar to cancer
patients
- Herpetic Gingivostomatitis caused by reactivation
- Fungal infections - similar to those in fever/neutropenia
- Hemorrhagic cystitis (adenovirus, CMV, Papovavirus, HSV,
bacteria, chemotherapy, GVH
• Middle Post-transplant Period (Early Engraftment)
- Pneumonitis - due to infectious and non-infectious causes
# Infections - especially CMV.
# Other Important pathogens include RSV, adenovirus, PIV,
Influenza, PCP
- Noninfectious causes Include alveolar hemorrhage, radia-
tion/drug damage, edema, vascular disease
• Late Post-transplant Period
- Bacteremias due to encapsulated organisms (especially S.
pneumoniae)
- Varicella-Zoster infections occur in 25-40% and can become
disseminated
- Hepatitis - due to both infectious and noninfectious causes
Other pathogens that can occur in this setting include the common
respiratory viruses, and there have been in bone marrow transplant
settings particular outbreaks and significant morbidity associated
with these respiratory viruses. Once again, always important to
take into account that non-infectious complications can occur,
including alveolar hemorrhage that is putatively non-infectious.
During the late period the patient who has undergone bone marrow
transplantation, after about say 100 days, bacterial infections can
occur especially due to the encapsulated organisms of which Strep
pneumoniae dominating the situation, and Varicella zoster reacti-
vation becoming important at this point in time.
With regard to those patients who have undergone solid organ
transplantation, here too one can break them down according to
early, middle and late. They include bacterial infections, fungal
infections, and virus infections, and they are differentially distrib-
uted according to where one is in the period post-transplant and
according to the type of transplantation which has been done.
Patients who have renal transplant are most susceptible to septi-
cemia and pyelonephritis, and patients who have undergone liver
transplants are most responsible to various enteric organisms, as
well as to ascending cholangitis. Those who have undergone
intestinal transplantation as you might imagine are most suscepti-
ble to bacterial infections, especially with GI flora.
The bacterial and fungal infections in patients undergoing heart,
cardiac transplantation are notable. Indeed, infections occur
commonly in this patient population 20% to 40% of the time.
Respiratory tract disease is the most important single organ.
Mediastinitis can occur, and both staph and gram negatives can be
the offending organisms. For the patients undergoing heart-lung
transplants, pneumonitis is the most common site of an infection,
especially with gram negative organisms.
85
 Special Considerations in
Solid-organ Transplant Patients
• Important risk factors include
- Site of the transplant (and risk for site-specific infections)
- Underlying disease and its predisposition to infection (eg, CF)
- Status of underlying disease and degree of malnutrition
- Age and age-specific pathogens (RSV in children vs
Cryptococcus in adults)
# Primary vs reactivation infections
- Acquisition of infection from the donor organ (e.g., CMV, EBV,
Toxoplasma, Hepatitis B, C, HIV)
- Intraoperative course (especially ischemia, duration)
- Post-transplant immunosuppression - use of steroids vs
cyclosporine, tacrolimus (FK 506)
- Prolonged use of catheters
- Nosocomial exposures and infection
With regard to viral infections in patients undergoing solid organ
transplantation, Cytomegalovirus tops the list. It is typically ac-
quired from donor organs; therefore, screening becomes important
in the setting of the symptoms and can be manifest between one to
three months following the transplantation. Symptoms can include
fever, as well as hematological abnormalities. Infection can be
disseminated with visceral involvement. Culture and histological
findings are important as well as antigen detection techniques to
assess the risk for infection.
Other viral organisms that occur in solid organ transplantations,
including the Epstein-Barr virus. This can have a broad range of
activities from nonspecific to lymphoproliferative disorders. A
lymphoproliferative syndrome associated with EBV can occur and
treatment for that is actually donor lymphocytes.
Adenovirus is an important infection both in solid organ as well as
allogeneic and autologous bone marrow transplantation. It occurs
often as well in patients undergoing liver transplantation and has a
high degree of morbidity.
86
 Special Considerations in
Solid-organ Transplant Patients

Early Period (0-1 Middle Period (1-6 Late Period (> 6

Month) Month) Months)

Bacterial Infectious Viral Infections Viral infections

Grim negatives CMV (especially EBV
Pseudomonas seronegative recipient VZV
(especially CF) from + donor Community-acquired
Gram positives EBV Bacteria
Fungal Infections VZV Pseudomonas (CF)
Viral infections P. carinii pneumonia Gram negatives
HSV Toxoplasmosis (espe- (small bowel trans-
Respiratory cially heart) plant)
Bacteria Fungal
Pseudomonas (CF) Aspergillus (lung with
Gram negatives (small chronic rejection
bowel tx)

87
 Special Considerations in
Solid-organ Transplant Patients

• Bacterial and Fungal Infections

- Renal Transplants: Septicemia and Pyelonephritis is
common. Pneumonia occurs in 10-25%
- Liver Transplants: Enteric organism account for 50%. Ascend-
ing cholangitis is a common infection
- Intestine: Bacterial infections appear to be common
• Bacterial and Fungal Infections
- Heart Transplants: Infections account for 20% of acute and 40%
of late deaths.
- Respiratory tract is most common site
- Mediastinitis can be a problem
- Staph and gram negatives are problematic
• Heart-Lung Transplants
- Pneumonia is most common site of infection, especially with
gram negatives. Can be difficult to distinguish from rejection.
- Particular problem with CF patients

88
 Special Considerations in Solid-organ
Transplant Patients

• Viral Infections
- CMV is most common
- Typically acquired from donor organ reactivation refection; tends
to be less severe
- Symptoms manifest at 1-3 months and include fever,
hematologic abnormalities
- Can include disseminated infection with visceral involvement
- Culture and histological findings can be important in diagnosis
- EBV can have a broad range of disease from nonspecific to
lymphoproliferation and lymphoma. Incidence of EBV
lymphoproliferation may be 20% by 7 years after liver transplan-
tation - however, this may become altered with
immunosuppressive regimen.
- Adenovirus follows 10% of liver transplants (nonspecific to GI
symptoms, cystitis or necrotizing hepatitis/pneumonitis)

89
 Infection Prevention Strategies
Prophylaxis. It is going to be recommended that Trimethoprim
sulfa be restricted to Pneumocystis prophylaxis. They are not
being employed for broad bacterial prophylaxis. Empirical therapy
should be avoided and absolutely avoided for heparin solutions to
try to prevent bacterial infections.

Fluconazole can be used and employed successfully in patients

• Antibiotic Prophylaxis undergoing bone marrow transplantations, but the data is re-
stricted to employing it in other settings. An antibacterial regimen
- Oral nonabsorbable antibiotics is initiated around the time of the transplantation, and particularly
ganciclovir for CMV and trimethoprim sulfa for Pneumocystis.
- Selective decontamination
# Trimethoprim-sulfamethoxazole
# Quinolones
# Antifungal prophylaxis
- Antiviral prophylaxis
- Antiparasitic prophylaxis
• IDSA recommendations
- Trimethoprim/sulfa: Indicated for P. carinii prophylaxis
- Quinolones: Not recommended for routine prophylaxis because
of increasing resistance
- Vancomycin strongly discouraged
- Fluconazole - may have some efficacy in bone marrow
transplant patients - but not recommended for routine use

90
 Prophylaxis after Solid
Organ Transplant
Pittsburgh Children's Regimen

Regi- Kidney Liver Heart Lung Intestine

men

Peri- Cefazolin Amp+ Cefazolin Clinda+ Amp+

opera- Cefo Ceftaz cefo
tive

CMV Ganc Ganc Ganc Ganc Ganc

MG

P. ca- T/S T/S T/S T/S T/S

rinii

91
 Prevention Strategies

• Strategies for Improving Host Defenses

- Cytokines and Immunomodulating agents
- Active and Passive Immunization
# Immunoglobulins
# Monoclonal antibodies
- Combination Therapy

92
 Biologicals in the Clinic

• Hematopoietic cytokines - Colony Stimulating Factors (GM, G,

M-CSF and SCF)
• Interleukins (IL-1, I L-2, IL-3, IL-6, IL-11, IL-12)
• Tumor necrosis factor
• Immunization (active and passive)

93
ASCO Clinical Practice Guidelines for Colony Stim-
ulating Factors

• Colony Stimulating Factors are recommended to

- Reduce likelihood of febrile neutropenia when expected inci-
dence is >40%
- After episode of fever and neutropenia in prior cycle when the
intent is to not reduce dose-intensity.
- After high-dose therapy with autologous bone marrow
• Not clearly recommended
- At the onset of fever and neutropenia unless high likelihood for
septic complications
- Use in AML should be with caution
- CSFs should not be used concurrently with chemotherapy or
radiation, or to support increasing close intensity

94
 Is There a Value to Cell
Replacement Therapy?

• Neutrophil transfusions
- Impact on children with CGD
- Lack of impact on patients with neutropenia

95
 Biologicals: Indications

• Who should receive biologicals

- Not for low-risk patients
- Appropriate for high-risk patients when there is a potential for
benefit based on ASCO guidelines
- Role as an adjunct to the management of fever and neutropenia
is not established
- Role for documented infections is not yet established

96
97