PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management

SECTION P  Infections and Cancer

98 Infections in Children With Cancer

Monica I. Ardura and Andrew Y. Koh

Approximately one third of pediatric patients with cancer who have fever
and neutropenia have a clinically or microbiologically proven site of
infection. Table 98.1 summarizes documented infections identified in 3
large clinical trials of empiric antibiotic therapy administered to patients
admitted to the National Cancer Institute for fever during episodes of
neutropenia.1–3
DIAGNOSIS AND MANAGEMENT OF SPECIFIC
CLINICAL SYNDROMES OF INFECTION
Catheter-Associated Bacteremia
Several series evaluating the use of central venous catheters in patients
with cancer confirmed that these devices increase the incidence of
bloodstream infection (BSI), regardless of the level of bone marrow
suppression.4,5 Although gram-positive organisms, particularly coagulase-
negative staphylococci, emerged as the predominant pathogens, almost
any bacteria can be responsible for central line–associated BSI (CLABSI)
bacteremia. Fungi, most often Candida spp., also can cause CLABSI and
are difficult to eradicate without removal of the contaminated device.6,7
Mixed flora bacteremia should prompt an investigation to identify a
causative event (e.g., swimming with the catheter unprotected, dropping
of catheter tubing into bathwater, chewing on catheter tubing by young
children, disconnection of catheter caps or tubing) so that appropriate
education can be provided.
In evaluating children for CLABSI, cultures should be obtained from
all lumens of a multilumen device. Because of the increased risk of
CLABSI, empiric antibiotics may also be warranted in non-neutropenic
patients with central venous catheters who have fever with no localizing

TABLE 98.1  Documented Sites of Infection in Patients with Cancer, Fever, and Neutropenia
Pizzo et al.1 Pizzo et al.2 Freifeld et al.3
Site or Type of Infection No. (%) No. (%) No. (%) Total No. (%)
Bloodstream 81 (43) 109 (27) 20 (17) 210 (29)
Pulmonary 28 (15) 88 (21) 16 (13) 132 (18)
Cutaneous 42 (22) 43 (10) 19 (16) 104 (14)
Head, eyes, ears, nose, throat 11 (6) 69 (17) 28a (23) 108 (15)
Gastrointestinal 4 (2) 35 (9) 30 (25) 69 (10)
Urinary tract 22 (11) 29 (7) NR 51 (7)
Other 2 (1) 38 (9) 7 (6) 47 (7)
a
Includes cases of severe mucositis.
NR, not reported separately.

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findings. The choice of agent used for empiric antibiotic therapy in
children with cancer should have a broad spectrum of activity, and take
into account the severity of illness, associated neutropenia, history of
infection or colonization with multidrug-resistant bacteria, and antimi-
crobial prophylaxis regimens. Vancomycin may not be necessary empiri-
cally unless the patient has evidence of soft tissue infection at the catheter
site or elsewhere, clinical instability, or a history of a resistant gram-
positive pathogen.8–10
Infection of soft tissue at the catheter site can be confined to the
skin immediately surrounding the exit site of a catheter or can involve
deeper soft tissue around the subcutaneously tunneled portion of
the catheter or access port. Localizing findings in a neutropenic child
should be considered evidence of infection, thus mandating hospitaliza-
tion and administration of broad-spectrum antibiotics, including an
antistaphylococcal agent. Induration, erythema, tenderness, or fluctu-
ance along the subcutaneous tunnel tract generally requires removal
of the catheter, debridement of infected tissue, and systemic antibiotic
therapy.
Catheter management (salvage or removal) depends on the pathogen,
the type of catheter, the patient’s clinical manifestations, and complica-
tions. Most episodes of bacterial CLABSI can be successfully treated with
the catheter in place, even when multiple organisms are identified.4,11
Although current guidelines recommend the addition of antibiotic lock
therapy for catheter salvage, data on an additional benefit of antibiotic
or ethanol lock therapy in pediatric oncology patients with CLABSI are
inconclusive, warranting prospective study.12,13 Removal of the catheter
is recommended if the patient has erythema or exudate at the catheter
site (concerning for a catheter pocket or tunnel infection), bacteremia
with certain pathogens, persistence of bacteremia despite 72 hours of
appropriate antimicrobial therapy, or the presence of concomitant
endocarditis, suppurative thrombophlebitis, or metastatic infection.14
Specific organisms require removal of the catheter: Staphylococcus
aureus,11,12 Bacillus spp.,14,15 Mycobacterium spp.,16 Pseudomonas aerugi-
nosa and multidrug-resistant gram-negative bacteria (e.g., Acinetobacter
spp.), and fungi (including Candida spp.)6,7,9,14 Polymicrobial infections
may require removal of the catheter.
Skin Infections
Cutaneous infections are common in immunocompromised patients.
These infections accounted for 22% to 33% of infections in an older
series,17 as well as 16% of infections present at the time of hospitalization
for fever and neutropenia in another study.3 Infections of the skin can be
caused by bacteria, fungi, or viruses.
Bacteria.  Bacterial skin infections usually are caused by staphylococci
or streptococci. In immunocompromised patients, both gram-positive
and gram-negative bacteria, including enteric organisms and Pseudomo-
nas, can be isolated either from the blood or from material obtained from
fine-needle aspiration of the area of cellulitis.18 P. aeruginosa infection
classically is associated with the severe necrotic skin lesion ecthyma
gangrenosum (Fig. 98.1), although invasive infections with other gram-
negative organisms, staphylococci, mycobacteria, and fungi can cause
ecthyma gangrenosum. Empiric therapy for suspected bacterial cellulitis
should provide broad-spectrum coverage. Every effort should be made
to establish a microbiologic diagnosis; new skin lesions should be exam-
ined using biopsy and culture.
Fungi.  Fungal pathogens including Candida, Aspergillus, Fusarium,
Scedosporium, and agents of mucormycosis can cause cutaneous lesions
either as isolated, primary infections or as manifestations of disseminated
infection.19 Routine blood and fungal blood cultures and tissue histologic
examination and culture should be obtained. Black, rapidly progressing,
necrotic eschars should prompt immediate evaluation for fungal infec-
tion. Tender, erythematous skin nodules or pustules can develop during
candidemia; examination can aid diagnosis while awaiting culture results.
Superficial cultures of suggestive skin lesions may not provide adequate
material for diagnosis of fungal infections; biopsy generally is more
useful. A cutaneous fungal infection resulting from Aspergillus or other
molds often is a manifestation of hematogenous spread or local angio-
invasive infection, requiring surgical debridement in addition to pro-
longed antifungal therapy.
Viruses.  Cutaneous viral infections can result from either primary
infection or viral reactivation. Herpes simplex virus (HSV) and
Infections in Children With Cancer 98
FIGURE 98.1  Ecthyma gangrenosum in an 8-year-old boy with newly diagnosed
acute lymphocytic leukemia, fever, and bacteremia caused by Pseudomonas
aeruginosa.
varicella-zoster virus (VZV) can cause painful or pruritic vesicular
lesions that can become secondarily infected. The diagnosis is confirmed
by unroofing a fresh vesicle, scraping the base of the lesion, and testing
the sample by direct fluorescent antibody or polymerase chain reaction
(PCR) for HSV and VZV. Differentiation is important because VZV
infection requires higher doses of acyclovir (10 mg/kg/dose or 500 mg/
m2/dose every 8 hours) than does HSV infection. Acyclovir prophy-
laxis has demonstrated benefit in preventing reactivation in HSV- and
VZV-seropositive recipients of allogeneic hematopoietic cell transplan-
tation (HCT) and in patients receiving induction therapy for acute
leukemia.9,20–22
Patients with cancer who develop primary varicella, especially patients
who are actively receiving chemotherapy, are at increased risk of serious
disseminated disease, including giant cell pneumonia, encephalitis,
hepatitis, and purpura fulminans. Rates of dissemination and subsequent
mortality (estimated as 7% to 20% in untreated patients23) have been
reduced by rapid initiation of intravenous acyclovir therapy.24 Although
recurrent disease in the form of herpes zoster is rarely associated with
severe complications when VZV infection remains localized to the skin,
dissemination occurs in up to 25% of patients with immunocompro-
mising conditions.25 Severe abdominal pain, back pain, or evidence of
inappropriate antidiuretic hormone secretion can herald multisystem
involvement, indicating an urgent need to initiate intravenous acyclovir
therapy.26
Scabies.  A severe variant of scabies (caused by Sarcoptes scabiei),
called Norwegian or crusted scabies, occurs in immunodeficient patients,
especially patients with leukemia or lymphoma, and is characterized
by the presence of 103 to 106 viable mites, resulting in widespread,
hyperkeratotic, crusted lesions. This form of scabies is highly contagious
and also can be recalcitrant to standard topical scabicidal therapy. Oral
ivermectin is highly effective for treating both routine scabies and
Norwegian scabies after a single administration, although additional
treatment often is given.27,28
Pulmonary Infections
The lungs are the most common sites of localized infection in patients
with neutropenia, and pulmonary infection in this population produces
a wide variety of symptoms, signs, and radiographic appearances. Table
98.2 summarizes causative agents suggested by radiographic findings.
Localized Infiltrates
Acute localized infiltrates at the onset of fever in a patient with cancer,
with or without neutropenia, are most often caused by bacterial

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 PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION P  Infections and Cancer

TABLE 98.2  Causes of Pulmonary Processes in Patients with Cancer as Suggested by Radiographic Abnormality
Radiographic Manifestation Infectious Cause Noninfectious Process
Focal consolidation (lobar or Bacteria (routine and nosocomial pathogens) Pulmonary hemorrhage
segmental) Legionella Pulmonary infarction
Oral flora (aspiration and postobstructive) Atelectasis
Mycobacterium tuberculosis Radiation pneumonitis
Fungi (Cryptococcus, Histoplasma, Coccidioides) Drug-related pneumonitis
Tumor
Diffuse interstitial infiltrate Viruses Pulmonary edema
Pneumocystis jirovecii Adult respiratory distress syndrome
Mycobacteria, including miliary tuberculosis Drug-related pneumonitis
Disseminated fungi (Cryptococcus, Histoplasma, Coccidioides) Radiation pneumonitis
Mycoplasma Lymphangitic metastasis
Chlamydophila Lymphocytic interstitial
pneumonitis (HIV)
Nodular infiltrate (with or without Molds: Aspergillus, Mucor, Fusarium Tumor
cavitation) Bacteria (especially Staphylococcus aureus, Pseudomonas,
Klebsiella, anaerobic bacteria), Nocardia
Mycobacteria, including M. tuberculosis
Viruses (e.g., CMV, HSV, VZV, EBV, RSV)
CMV, cytomegalovirus; EBV, Epstein-Bar virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; RSV, respiratory syncytial virus; VZV, varicella-zoster virus.

pathogens. Because both community-acquired and healthcare-associated
pathogens can be responsible for pneumonia in neutropenic patients,
initial antibiotic therapy should provide coverage for organisms such
as Streptococcus pneumoniae and Haemophilus influenzae, as well as
Pseudomonas spp. and other gram-negative bacteria. Legionella also
is considered in febrile, immunocompromised patients with patchy
infiltrates. Legionella can colonize air conditioning equipment and
showerheads and can be spread by aerosolization of contaminated water.
Antigen testing of urine is sensitive and specific for L. pneumophila,
serogroup 1. Patients with pulmonary metastases of cancers also can
have an increased risk for postobstructive pneumonia resulting from
mouth flora, including anaerobic bacteria. The antibiotic regimens used
for empiric therapy for fever without localizing findings in a patient
with neutropenia (e.g., fourth-generation cephalosporin, extended-
spectrum penicillin, or carbapenem) are appropriate for initial man-
agement of pneumonia. In some cases, the addition of a macrolide or
fluoroquinolone for possible Mycoplasma or Legionella infections is
warranted. In children with clinical or imaging findings consistent
with possible community-associated Staphylococcus aureus pneumonia,
vancomycin or clindamycin should be added to the beta-lactam therapy.
Viruses, such as influenza and parainfluenza viruses, respiratory
syncytial virus, and adenovirus, also can cause localized infiltrates
in immunocompromised children, although a diffuse process is more
common. In one study, respiratory viruses were detected in 52% of 50
episodes of fever in neutropenic children with negative bacterial cultures,
though ascribing a causal role in the clinical illness is challenging.29
Consideration of a viral infection can lead to specific therapy (e.g.,
as in influenza), but it does not obviate the need for broad-spectrum
antibiotic therapy in a patient with neutropenia, fever, and a pulmonary
infiltrate.
A patient with localized infiltrates who fails to respond to broad-
spectrum antibiotics has broad differential diagnostic possibilities.
Guidelines recommend bronchoalveolar lavage (BAL) fluid sampling
in patients with fever, neutropenia, and an infiltrate of uncertain
origin.9 Infection resulting from fungi, Nocardia, mycobacteria (includ-
ing Mycobacteria tuberculosis),30 or antibiotic-resistant, healthcare-
associated bacteria can manifest with localized infiltrates. Endemic fungi,
Histoplasma, Cryptococcus, and Coccidioides also can cause localized
pneumonitis in selected geographic regions and, in compromised hosts,
can also be associated with extrapulmonary infection. The presence
of Candida in upper respiratory tract or tracheal secretions, even in
patients with pulmonary infiltrates, correlates poorly with causation
because of the high frequency of colonization of the oral cavity and
tracheobronchial tree. Blood culture results that are positive for Candida
or typical retinal lesions of endophthalmitis are associated with dis-
seminated infection, which can include pneumonia. In the absence
of these findings, definitive diagnosis usually requires histopathologic
confirmation.
The fungal pathogens of most concern in the patient with neutropenia
include Aspergillus, Fusarium, agents of mucormycosis, Scedosporium,
and Trichosporon because these organisms cause rapidly progressive,
extensively destructive infection. Unlikely to be identified at the onset
of neutropenia and fever, the finding of a progressive or new infiltrate,
accompanied by fever, nonproductive cough or hemoptysis, and pleuritic
chest pain, in a persistently neutropenic patient during broad-spectrum
antibiotic therapy suggests the diagnosis of invasive fungal pneumonia
(most frequently with Aspergillus). Computed tomography (CT) may
reveal multiple pulmonary nodules (sometimes with cavitation) that are
not readily apparent on routine chest radiographs.31 The classic histo-
pathologic findings in aspergillosis are invasion of the blood vessels with
thrombosis and resulting infarction and hemorrhage. Whereas recovery
of Aspergillus from the respiratory tract of patients without neutropenia
can represent colonization, isolation of this organism in the setting of
prolonged neutropenia and pulmonary infiltrate is highly predictive of
invasive disease,32 and is sufficient evidence for initiation of antifungal
therapy. In biopsy-proven Aspergillus pneumonia, BAL has a recovery rate
of only 50%, and transbronchial biopsy has a recovery rate of only 20%.
Open lung biopsy may be required.33,34 Aspergillus galactomannan testing
on blood and BAL specimens can facilitate the diagnosis of invasive pul-
monary aspergillosis in patients with hematologic diseases, with overall
sensitivity and specificity for proven invasive aspergillosis of 71% and
89%, respectively.35–39 Thus, a positive galactomannan assay coupled with
a consistent CT appearance can suggest probable invasive aspergillosis in
a neutropenic patient with cancer or a history of HCT40; a positive culture
result of a specimen obtained from a normally sterile site remains the gold
standard for proven infection. Other non–culture-based assays, including
β-D-glucan and fungal PCR, show promise as adjuncts to diagnosis, but
they remain investigational in pediatrics.40a
Voriconazole is considered the drug of choice for primary treatment
of invasive aspergillosis based on the findings of an international, ran-
domized, open-label trial demonstrating that voriconazole conferred a
significant benefit of survival and overall therapeutic response compared
with patients treated with amphotericin.41–43 Liposomal amphotericin
can be considered as alternative or salvage therapy.44 The echinocandin
agent caspofungin initially was approved for use in patients with refrac-
tory aspergillosis. A prospective study enrolling 90 patients with invasive
aspergillosis who were refractory to (86%) or intolerant of amphotericin
B, liposomal amphotericin B, or triazoles (14%) and who were treated

588
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with caspofungin showed a favorable response to caspofungin therapy
in 45% of patients (50% with pulmonary aspergillosis and 23% with
disseminated aspergillosis).45 Although successful use of caspofungin as
first-line monotherapy for invasive aspergillosis has been reported,46,47 no
randomized controlled trials comparing efficacy with other antifungal
agents have been conducted. Finally, given few adverse effects and a
theoretical lack of antagonism, combination therapy with voriconazole
and an echinocandin for invasive aspergillosis can be considered.48–50
Results of a randomized, double-blind, placebo-controlled trial in adults
with hematologic malignant diseases and after HCT who had suspected
or documented invasive aspergillosis demonstrated improved survival
rates in patients who received combination therapy with voriconazole
and an echinocandin compared with patients who received voriconazole
monotherapy.51 Other fungal pathogens, such as Histoplasma capsulatum,
Coccidioides immitis, and Cryptococcus neoformans, can also cause focal
infiltrates in patients with neutropenia who are receiving corticosteroid
therapy or with epidemiologic exposures.52
Diffuse or Interstitial Infiltrates
Diffuse or interstitial infiltrates can represent a nonbacterial process,
although both gram-positive and gram-negative bacteria can cause inter-
stitial pneumonitis. In children not receiving antimicrobial prophylaxis,
Pneumocystis jirovecii is the organism most often identified in the setting
of diffuse, interstitial infiltrates. Historically, in children with leukemia
during maintenance chemotherapy who did not receive prophylaxis,
incidence rates of Pneumocystis pneumonia (PCP) were 2% to 22%.53 The
incidence of PCP in patients with cancer has been reduced substantially
with the standard use of prophylactic trimethoprim-sulfamethoxazole
(TMP-SMX). Nonetheless, P. jirovecii should be considered in children
receiving corticosteroid therapy or in children with significant cell-
mediated immune deficiency who have fever, nonproductive cough,
tachypnea, and hypoxemia. In a review of oncology patients with con-
firmed PCP, 70% of patients became symptomatic while corticosteroid
dosages were being tapered.54 The chest radiograph in PCP typically
reveals bilateral perihilar interstitial, or alveolar, infiltrates that spread
to involve all lobes (Fig. 98.2), but virtually any radiographic pattern
can occur. The diagnosis is established by microscopic findings of either
cysts or trophozoites on smears of respiratory tract secretions obtained
by sputum induction, BAL, or open lung biopsy. Because Pneumocystis
cannot be cultured, and the sensitivity of microscopy is lower in patients
who do not have human immunodeficiency virus (HIV) infection, addi-
tional assays have been applied, including Pneumocystis PCR and β-D-
glucan assays, to improve diagnostic yield. Pneumocystis PCR performed
on BAL or sputum specimens from non-HIV immunocompromised
patients compared with conventional microscopy methods in one study
FIGURE 98.2  Chest radiograph showing bilateral interstitial and alveolar infiltrates
in a child with acute lymphocytic leukemia and Pneumocystis pneumonia.
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Infections in Children With Cancer 98
showed sensitivity of 87% and specificity of 92% for PCP, with a negative
predictive value of 100%.55 A positive serum (1,3)-β-D glucan assay may
be an early indicator of PCP and has been used clinically in children with
malignant diseases; the assay has positive and negative predictive values
of 61% to 64% and 98% to 99%, respectively.56–58 In non-neutropenic
patients with diffuse infiltrates who are unable to undergo BAL or
biopsy, an empiric course of TMP-SMX can be considered.59 Definitive
therapy for PCP is TMP-SMX, 15 to 20 mg/kg/day divided into every 6
hour doses for 21 days. Patients with severe PCP who have an absolute
contraindication to TMP-SMX therapy should receive pentamidine
intravenously. Prednisone usually is given to patients with moderate or
severe PCP concomitantly with antibiotic therapy. Other therapies found
to be effective for PCP in HIV-infected patients include pentamidine,
trimetrexate, atovaquone, and clindamycin plus primaquine. Recurrence
of PCP or breakthrough infection is unusual in children with cancer
receiving TMP-SMX prophylaxis, but it is reported in HIV-infected
children.60
Viral infections also can cause pneumonia with diffuse or interstitial
infiltrates. Whereas the common respiratory tract viruses cause more
severe disease in immunocompromised patients, the most serious cases
are caused by cytomegalovirus (CMV). CMV pneumonitis has been seen
most often in patients receiving allogeneic bone marrow transplants,
within the first 3 months after transplantation. Clinical presentation
includes fever and rapidly progressive diffuse pulmonary infiltrates,
often requiring ventilatory assistance. Risk factors for CMV pneumonitis
include the presence of pretransplant CMV seronegativity in the donor
and seropositivity in the, receipt of total body irradiation as part of the
pretransplant regimen, and development of graft-versus-host disease.61
The definitive diagnosis of CMV lower respiratory tract disease requires
identification of viral cytopathic effect on lung tissue obtained by biopsy.
Historically, CMV pneumonitis had a mortality rate of more than
80%. Antiviral treatment with ganciclovir or foscarnet has improved
outcomes, with overall survival rates of 50% to 70%. The added benefit
of pooled or CMV-specific intravenous immunoglobulin is less clear.62–64
Standard practice in many transplant centers now includes preemptive
strategies including surveillance testing (quantitative CMV DNA or
RNA PCR tests) and preemptive therapy with intravenous ganciclovir
for patients who have CMV isolated from any site during the early post-
HCT period.21,65
Other herpesviruses, particularly VZV and HSV, can cause diffuse
pneumonitis in patients with cancer. Respiratory syncytial virus also can
cause severe lower respiratory tract disease with a high mortality rate,
notably in patients undergoing therapy for acute myelogenous leukemia
or after HCT.66,67 Parainfluenza virus, influenza virus (including H1N1),
human metapneumovirus, adenovirus, and human herpesvirus 6 can
cause interstitial pneumonitis in pediatric patients with cancer.68,69
Respiratory virus detection before HCT, even of rhinovirus alone, has
been associated with lower survival rates at day 100.70
Infections of the Ears and Sinuses
Patients who have been hospitalized or who are receiving chemotherapy
may have altered microbial flora. In addition to the usual bacterial
pathogens responsible for otitis media (S. pneumoniae, H. influenzae,
Moraxella catarrhalis), nosocomial pathogens (such as gram-negative
organisms) must be considered. In the neutropenic child, ear infections
can be accompanied by pain, with minimal erythema of the tympanic
membrane and canal. Malignant otitis externa resulting from invasive
infection of the auditory canal with P. aeruginosa (and occasionally
invasive fungi) occurs more commonly in patients with diabetes mellitus
or patients receiving corticosteroids, but it also is seen in patients receiv-
ing chemotherapy and requires aggressive debridement and intravenous
antimicrobial therapy.
Although mastoiditis is an uncommon infection in pediatric patients
with cancer, those children with anatomic abnormalities of the middle
ear and children with prolonged neutropenia are at increased risk. Fungi
(particularly Aspergillus) can cause mastoiditis in neutropenic patients.
Surgical debridement usually is required for cure.71
The paranasal sinuses also can become infected with typical patho-
gens or the altered bacterial flora in hospitalized patients. Sinusitis was
found more commonly in children with hematologic malignant diseases
than in those with solid tumors in one series, and 41% of 91 children
589
 PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION P  Infections and Cancer
with acute lymphoblastic leukemia had abnormal sinus radiographs at
the time of induction chemotherapy.72 Children with tumors involv-
ing the sinuses (e.g., nasopharyngeal carcinoma, Burkitt lymphoma,
rhabdomyosarcoma) are at particular risk for recurrent or chronic
sinusitis; distinguishing between progressive or necrotizing tumor and
infection is challenging. Sinus radiography and CT are helpful tools
in the diagnosis. Broad-spectrum antibiotics, including an agent with
activity against anaerobic organisms, are necessary for treatment of
sinusitis in neutropenic patients. If symptoms do not improve within 48
to 72 hours of empiric antibiotic therapy, aspiration or biopsy should be
performed.
Patients who remain neutropenic for more than 7 days are at increased
risk of fungal infection, including sinusitis. In a series of fungal sinusitis in
children, facial pain or headache, fever, facial swelling (which developed
in 50% of patients), and abnormal findings on sinus radiographs were
the most common manifestations.72 In a 10-year retrospective analysis
of invasive fungal sinusitis, Aspergillus flavus accounted for >50% of
cases, and periorbital swelling (41% of patients) was the most common
presenting symptom.73 Other fungal pathogens include Mucor, Fusarium,
Scedosporium, Rhizopus, among others. A small, blackened eschar within
the nose or sinus can be the first manifestation, with rapid progression,
significant tissue invasion, necrosis secondary to vascular thrombosis,
and ultimate extension into the orbits or brain. Obtaining biopsy mate-
rial for histopathologic examination and culture is necessary to establish
the diagnosis definitively. Management of rhinocerebral fungal infection
requires aggressive surgical debridement and longterm therapy with vori-
conazole for Aspergillus sinusitis and amphotericin B and posaconazole
considerations for zygomycosis.
Gastrointestinal Tract Infections
Underlying diseases and the cytotoxic and radiation regimens used in
therapy predispose pediatric patients with cancer to alterations of the
gastrointestinal mucosa that lead to local infections and portals of entry
for resident microorganisms.
Mucositis and Esophagitis
Mucositis can range in severity from isolated, small oral ulcers to exten-
sive mucosal sloughing of the oral cavity and more distal gastrointestinal
tract. A recognizable complication of mucositis is necrotizing or marginal
gingivitis, characterized by a periapical line of erythema and tenderness.
Because this condition presumably results from anaerobic infection,
empiric antibiotic therapy should include an effective agent (e.g.,
clindamycin, metronidazole, piperacillin-tazobactam, or meropenem).
In addition, children who have had prolonged hospitalization or have
received broad-spectrum antibiotics can have oral colonization with
gram-negative organisms or fungi. Chemotherapy-induced mucositis
also can become superinfected with Candida, Aspergillus,74 or HSV.
A Gram stain of scrapings (swab or tongue depressor) may identify
yeast or hyphae, and immunofluorescent stain, PCR, or culture may
confirm HSV infection. Mild Candida infection may respond to topical
treatment with clotrimazole troches, but fluconazole, voriconazole,75
caspofungin,76–78 or amphotericin B usually is given because stomatitis
can lead to locally invasive or disseminated fungal infection, or both.
Oral or intravenous acyclovir is given for HSV stomatitis. Because 70%
to 80% of children with a past history of HSV infection have reactivation
during induction chemotherapy for leukemia or after HCT, oral acyclovir
is given prophylactically during the high-risk period of leukopenia.79
Septicemia caused by α-hemolytic streptococci can complicate muco-
sitis and has high rates of shock and central nervous system (CNS)
infection. Penicillin nonsusceptibility as high as 75% is reported in
such cases.80
Although the differential diagnosis of substernal burning chest pain
and odynophagia includes both infectious and noninfectious causes of
esophagitis, establishing a specific cause can be difficult. Neither barium
swallow nor endoscopic visualization reliably distinguishes among
Candida, HSV, and noninfectious causes (e.g., mucositis secondary
to chemotherapy or radiation). In one study, 21 of 22 patients with
cancer who had a clinical and microbiologic diagnosis of oral candidiasis
also had endoscopic and microbiologic findings diagnostic of candidal
esophagitis, a finding suggesting that oropharyngeal candidiasis can
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represent a reliable marker for esophageal candidiasis in patients with
cancer.81 Definitive diagnosis, however, requires endoscopically per-
formed biopsy and culture. When biopsy is considered too risky (e.g.,
a patient with a platelet count of <50,000/mm3), a sequential approach
can begin with empiric azole therapy (for Candida esophagitis), and
if there is a lack of clinical improvement within 48 hours, change to
amphotericin or caspofungin. Failure to improve within 48 hours of
amphotericin or caspofungin makes Candida spp a less likely cause
of esophagitis, and endoscopic biopsy should be reconsidered. If a
biopsy cannot be performed, an empirical trial of acyclovir for pre-
sumptive HSV esophagitis could be considered. In the patient without
neutropenia, infectious causes of esophagitis are uncommon; symp-
tomatic treatment with antacids or histamine-blocking agents can be
appropriate.
Intra-Abdominal Infections
The epidemiology of infectious diarrhea in children with fever and
neutropenia is not well described. Infectious causes are broad, but
most common viruses, including norovirus, enterovirus, adenovirus,
and rotavirus, are responsible. More severe or protracted illness and
prolonged viral shedding are expected in immunocompromised patients,
especially in HCT recipients.82 CMV also can cause severe colitis in
HCT recipients and in patients receiving anti-CD52 monoclonal
antibody therapy; case reports also describe CMV-associated colitis in
patients receiving systemic chemotherapy for hematologic malignant
diseases and lymphomas.83,84 A history of travel, food consumption,
water exposure (water park, well water), and animal exposure should
be sought in children with fever and acute diarrhea. Fever and bloody
diarrhea make the possibility of bacterial enteritis more likely, and
stool samples should be tested by culture or PCR. Evaluation for
parasitic infections (e.g., enzyme immunoassays for Giardia and Cryp-
tosporidium, stool ova and parasite testing) is determined by exposure
history.
Clostridium difficile Infection.  Pseudomembranous or antibiotic-
associated colitis can follow antibiotic administration for empiric therapy
in febrile neutropenic patients. Many patients become colonized with
Clostridium difficile during hospitalization and can have prolonged
shedding.85 The incidence of C. difficile infection in hospitalized chil-
dren is 15-fold greater in children with cancer compared with children
without cancer.86–88 Symptoms of C. difficile disease range from mild
abdominal pain to severe bloody colitis. Diarrheal stool samples should
be tested for C. difficile toxin whenever diarrhea or abdominal pain
develops in a patient with neutropenia. Metronidazole is the drug of
choice for the initial episode of mild to moderate infection, and oral
vancomycin is given for more severe infections.89 Children with malig-
nant diseases have a higher risk for recurrent disease.90 Treatment of first
recurrence usually is with the same regimen as for the initial episode,
but additional recurrences generally are treated with oral vancomycin
therapy using a tapered regimen.89 A trial of adding rifampicin to
metronidazole therapy did not show a trend toward better efficacy.91
Nitazoxanide92,93 and teicoplanin94 are potential alternatives to traditional
therapy.
Typhlitis.  The immunosuppressed patient with cancer is at increased
risk of intra-abdominal infections because of invasion or obstruction
of the bowel by tumor, extension of mucosal ulcerations, or slough-
ing secondary to chemotherapy. Typhlitis, or neutropenic cecitis, is a
necrotizing process involving the cecum and terminal ileum that is seen
almost exclusively in patients with cancer who have profound neutrope-
nia (most often associated with treatment of acute myeloid leukemia).95
Additional risk factors identified in children include the presence of
mucositis, HCT, and receipt of chemotherapy in the preceding 2 weeks.96
Typhlitis manifests with nausea, vomiting, diarrhea, and abdominal pain
localized to the right lower quadrant (mimicking appendicitis) that can
become generalized and usually is accompanied by fever and systemic
symptoms. Because of neutropenia, many patients with peritonitis lack
classic signs.97 Concomitant bacteremia or fungemia can occur. Plain
radiographs are nonspecifically abnormal unless free air or intramural
pneumatosis is noted. Abdominal ultrasound examination or CT can
better demonstrate cecal wall thickening, pericecal edema, fat stranding,
and intramural pneumatosis of the cecum. Histopathologic examination
of the bowel reveals infiltration of the bowel wall with bacteria, usually

gram-negative bacilli (especially Pseudomonas), with little or no sur-
rounding inflammation, and progression to necrosis in some areas. In a
review of 24 cases of typhlitis over 30 years, bacteremia was documented
in 8 of 24 children, and thickening of the bowel wall was present on CT
scans in 17 of 20 patients studied.81 Most patients with typhlitis respond
to medical management, including complete bowel rest, parenteral nutri-
tion, broad-spectrum antibiotic therapy, and recovery from effects of
cancer therapies, including resolution of neutropenia.98 No controlled
trials have evaluated optimal antibiotic therapy for typhlitis; empiric
therapy should include agents active against enteric gram-negative
bacteria and Pseudomonas, enterococci, and anaerobes. In patients with
protracted fever despite broad-spectrum antibiotics, the addition of an
antifungal agent is prudent. Surgical resection of necrotic bowel can be
necessary when perforation, abscess formation, uncontrolled bleeding,
or necrosis occurs.99 In adults with neutropenic enterocolitis, mortality
rates can exceed 50%.100
Clostridium septicum Infection.  Although uncommon, a catastrophic
complication of typhlitis consists of spontaneous peritonitis and septi-
cemia caused by Clostridium septicum. Neutrophil dysfunction and bowel
ischemia are factors associated with increased risk and severity with
C. septicum infection.101 Peritonitis classically manifests fulminantly with
rapidly progressive abdominal wall myonecrosis, crepitance, hemolysis,
and shock; fever can be absent. C. septicum can be part of the natural
flora of the gastrointestinal tract, is more aerotolerant than Clostridium
perfringens, and can grow in viable, non-necrotic tissue. More than 80%
of patients with C. septicum septicemia have an underlying malignant
disease.102,103 The steps in pathogenesis are thought to be loss of mucosal
integrity secondary to malignant disease or chemotherapy, microbial
invasion of the bowel wall, and rapid proliferation in the setting of
immunosuppression or granulocytopenia.104 Additionally, C. septicum
produces an α toxin that may play some role in the severity of infec-
tion. Antibiotics with anticlostridial activity must be initiated urgently if
C. septicum infection is suspected.
Hepatosplenic candidiasis.  Hepatosplenic candidiasis (also referred to
as chronic disseminated candidiasis) is an invasive form of candidiasis
that occurs in patients with cancer, especially patients with prolonged
neutropenia. Clinical clues are persistent fever during neutropenia that
is unresponsive to broad-spectrum antibiotics and, sometimes, right
upper quadrant abdominal pain or tenderness and an elevated serum
alkaline phosphatase level. Hepatosplenic candidiasis can occur despite
antifungal therapy. Most often, multiple cultures from blood, urine,
and other sites are sterile. Typical hepatic “bull’s eye” lesions noted on
ultrasonography or hypodense lesions can be seen as the neutrophil
count begins to recover. Magnetic resonance imaging may be the most
sensitive study. Before recovery of the inflammatory response, hepatic
lesions can be missed by all imaging techniques available. The detection
of Candida enolase antigen and d-arabinitol and mannan antibodies
in serum has been used as an additional tool for diagnosing invasive
candidiasis.105–107 Confirmation of the diagnosis can require liver biopsy.
Treatment usually requires a prolonged course of antifungal therapy.108
Amphotericin B lipid complex has been shown to be effective in the
treatment of hepatosplenic candidiasis.109 Fluconazole has been used as
salvage therapy in patients in whom amphotericin B treatment failed
or who had serious amphotericin B–related toxicities, or as step-down
oral therapy in improved patients.31,52,110,111 Treatment failures with
fluconazole in this setting, however, have been reported. Determining
the appropriate end point of antifungal therapy is challenging, often
depending on resolution or calcification of visualized lesions; antifungal
therapy should be continued through periods of chemotherapy-induced
immunosuppression.
Perianal Cellulitis
Although, in general, children have fewer chemotherapy-related perirectal
lesions than do adults, children are prone to develop mucositis involving
the rectal mucosa. These lesions provide a focus for local cellulitis or
abscess, usually involving enteric gram-negative facultative and anaerobic
organisms. Multiple organisms, most commonly anaerobes, are identi-
fied in most cases in which surgical drainage or needle aspiration is per-
formed.112 Most patients can be treated effectively with antibiotics alone.
Appropriate choices include piperacillin-tazobactam, meropenem, or a
fourth-generation cephalosporin, in combination with metronidazole.
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Infections in Children With Cancer 98
Central Nervous System Infections
Infections of the CNS occur infrequently in children undergoing chemo-
therapy for cancer. These infections must be considered in children who
have had a neurosurgical procedure. Placement of an intraventricular
shunt poses an additional risk of infection; 25% of children experience
a related CNS infection, but death is rare.113 Indolent infections are most
common with organisms of low pathogenicity, such as Staphylococcus
epidermidis and Propionibacterium acnes; many shunt-associated infec-
tions can be resolved without removing the device. Because of the vague
nature of associated symptoms, any child with a CNS device who has
fever and no localizing findings should have cerebrospinal fluid sampled
for cell count, chemical evaluation, and culture.
Although meningitis in patients with cancer is uncommon (one study
noted that less than 0.9% of febrile neutropenic episodes in pediatric
patients with cancer were caused by CNS infections114), but it is associ-
ated with significant mortality and morbidity rates.115 Patients with fever
and a change in mental status should be evaluated, diagnostic tests should
be performed, and empiric therapy should be initiated promptly. Some
studies have reported meningeal signs only in a minority of neutropenic
patients or in patients who have had neurosurgical manipulation who
develop meningitis116–118; thus the absence of meningeal signs does not
exclude the diagnosis of meningitis. In a retrospective review of 40
cases of bacterial or fungal meningitis in pediatric patients with cancer,
most patients (65%) had had recent neurosurgical procedures, a CNS
device placed, or a cerebrospinal fluid leak, and one third of patients had
neutropenia.115 Fever and altered mental status were the most consistent
signs; meningismus was notably less frequent in neutropenic patients.
S. aureus and S. pneumoniae were the most common pathogens. Of the
5 patients with fatal outcomes, all were neutropenic at presentation.
Candidal meningitis in children with cancer is rare but has high mortality
rates.119 Similarly, although the incidence of CNS Aspergillus infection
is low, the mortality rate approaches 100%. A retrospective review of
81 adults with definite or probable CNS aspergillosis who were treated
with voriconazole showed complete or partial response in approximately
one third, as well as improved survival rates in patients who underwent
therapeutic neurosurgical procedures.120 In published data in children,
CNS aspergillosis commonly manifested as brain abscesses, and as
in adults, surgical management was associated independently with
improved survival rates.121,122
Cystitis
Hemorrhagic cystitis, manifesting as bladder pain and significant gross
hematuria, has been reported in bone marrow transplant recipients.
Adenovirus (particularly type 11), CMV, and polyomavirus (BK virus)
are causative agents. PCR detection of viruses is possible in both urine
and blood.123 Older age, receipt of HCT, and detection of BK virus were
associated with risk of hemorrhagic cystitis and greater disease severity
in children.124 Although case reports documenting successful treatment
of adenovirus and polyomavirus hemorrhagic cystitis with intravenous
ribavirin, vidarabine, cidofovir, and ganciclovir have been reported,
case-controlled randomized studies have not been performed to confirm
benefit.125–128
Osteoarticular Infections
Bone and joint infections occurring in patients with cancer also are
relatively rare. Children with soft tissue or bone tumors are at risk of
infectious complications related to surgical tissue trauma or to destruc-
tion by the tumor. It can be difficult to distinguish osteomyelitis from
tumor or the effects of local radiation. Any organism that can lead to
bacteremia or fungemia (e.g., Aspergillus spp.,129) can cause osteomyelitis
or arthritis. Diagnosis and treatment can be particularly complex in
children who have had limb-sparing procedures involving bone and joint
prostheses and whose longterm stability of the prosthesis is of concern.
Serial imaging studies can suggest infection, but biopsy and culture
of the involved bone are necessary for definitive diagnosis. Longterm
antimicrobial therapy is mandatory when infection occurs, and revision
of the prosthesis often is required for cure.130
All references are available online at www.expertconsult.com.
591
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592.e1
 PART II  Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION P  Infections and Cancer
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