Fever a nd Neutropenia

in Pediatric Patients
with Ca ncer
Garth Meckler, MD, MSHSa,b,c,*, Susan Lindemulder, MDd,e

KEYWORDS
 Neutropenia  Fever  Pediatric  Oncology  Management

OVERVIEW

The treatment for most pediatric malignancies is based on systemic, aggressive multi-
modality therapy including systemic antineoplastic and radiation therapy. Although
this approach has led to impressive improvements in the cure rates for many pediatric
malignancies, it has secondary effects on a variety of normal cells, including hair, skin,
mucous membranes, and the hematopoietic elements of the bone marrow. The result-
ing bone marrow suppression produces intermittent periods of leukopenia (especially
neutropenia), anemia, and thrombocytopenia of varying severity and duration. The risk
of morbidity and mortality because of serious infection during periods of neutropenia
is greatly increased. Although most pediatric oncology patients are managed by pedi-
atric oncologists at large academic centers, they may live far from the tertiary care
setting and present with fever to local community hospital emergency departments
(EDs) for initial evaluation, management, and stabilization before transfer for further
care. Therefore, it is important for all providers in an emergency medical setting,
regardless of location, to be familiar with the concepts involved in the evaluation
and management of febrile, neutropenic, pediatric cancer patients.

a
Department of Emergency Medicine, Oregon Health & Science University, CDW-EM, 3181 SW
Samuel Jackson Park Road, Portland, OR 97239-3098, USA
b
Department of Pediatrics, Oregon Health & Science University, CDW-EM, 3181 SW Samuel
Jackson Park Road, Portland, OR 97239-3098, USA
c
Section of Pediatric Emergency Medicine, Oregon Health & Science University, CDW-EM, 3181
SW Samuel Jackson Park Road, Portland, OR 97239-3098, USA
d
Department of Pediatrics, Oregon Health & Science University, CDRCP, 3181 SW Sam Jackson
Park Road, Portland, OR 97239-3098, USA
e
Division of Pediatric Hematology/Oncology, Oregon Health & Science University, CDRCP, 3181
SW Sam Jackson Park Road, Portland, OR 97239-3098, USA
* Corresponding author. Department of Emergency Medicine, Oregon Health & Science Univer-
sity, CDW-EM, 3181 SW Samuel Jackson Park Road, Portland OR 97239-3098.
E-mail address: mecklerg@ohsu.edu (G. Meckler).

Emerg Med Clin N Am 27 (2009) 525–544

doi:10.1016/j.emc.2009.04.007 emed.theclinics.com
0733-8627/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
526 Meckler & Lindemulder

DEFINITIONS

Though some variability exists in the definition of fever for the pediatric oncology
patient, it is most often defined as a single oral or equivalent temperature of greater
than 38.3 C (101 F) or two consecutive temperatures greater than 38.0 C (100 F) in
a 12-hour period lasting at least 1 hour.1 Although rectal measurement most accu-
rately reflects core body temperature, the theoretical risk of bacterial translocation
during the procedure of inserting the thermometer into the anus (particularly in the
child with mucositis) is a contraindication, and therefore oral or axillary measurements
are recommended. Neutropenia is defined as an absolute neutrophil count (ANC)
<500/mm3 or <1,000/mm3 with an expected decline.1

PATHOPHYSIOLOGY

To understand the impact of multimodality regimens on infection risk, one must under-
stand the impact these therapies have on the body’s defenses, including innate and
adaptive immunity and the physiologic response to infection. Nonspecific recognition
of an invading pathogen falls in the innate immune system, which includes mucocuta-
neous barriers, phagocytic cells, natural killer cells, nonclonal T and B cells, and the
response networks that regulate these cells. Adaptive immunity includes those
aspects of the immune system that provide a pathogen-specific response including
production of specific antibodies and T-lymphocyte cell-mediated immunity. The
physiologic response to infection involves all of the major organs, but of particular
importance in this setting are the cardiovascular, pulmonary, and endocrine systems,
including stress hormones.

INNATE IMMUNITY

The first line of defense against invasive disease is the mucocutaneous barrier, which
includes specialized cells of the skin and respiratory, gastrointestinal (GI), and genito-
urinary tracts. For example, the GI tract contributes to innate immunity through acid-
producing parietal cells, antimicrobial molecules, and bactericidal fatty acids secreted
in the intestine, as well as secretory IgA, which protects mucosal surfaces.2,3 The
respiratory tract includes ciliated and mucus-producing cells that trap and expel path-
ogens, and surfactant-producing cells that help to opsonize bacteria, viruses, and
fungi.4–6
Pediatric cancers and their treatment compromise the innate immune system in
a variety of ways. Breakdown of the mucocutaneous barrier by local tumor invasion,
surgical removal of the primary or metastatic lesions, radiation therapy, graft-
versus-host disease (GVHD), and mucositis caused by cytotoxic chemotherapy
agents (eg, methotrexate, high-dose cytosine arabinoside, and etoposide) allow inva-
sion of pathogens. Furthermore, most pediatric oncology patients have indwelling
surgical devices (central venous catheter, ventricular drain, chest tube, nasogastric
tube, or urinary catheter) placed during therapy, which may further disrupt the muco-
cutaneous barrier. In addition to indwelling devices, frequent blood draws compro-
mise the epidermal barrier and provide an additional opportunity to introduce
pathogens directly into the bloodstream. Functional compromise by local radiation
therapy to the lung can result in paralysis of the ciliated cells. Even supportive
measures meant to protect the patient can inadvertently disrupt the physiology of
the innate immune system. For example, antacids used to prevent gastritis associated
with high dose steroids can compromise the physiologic barrier by decreasing or
inactivating gastric acid secretion.
 Fever and Neutropenia in Pediatric Patients 527

The next line of defense in the innate immune system includes phagocytic cells such
as neutrophils, circulating monocytes, and tissue macrophages. These cells phagocy-
tose and destroy pathogens through oxidative and nonoxidative mechanisms and
help regulate the immune response through the release of cytokines. Chemotherapy
has quantitative and qualitative effects on these cells. Cytotoxic agents decrease
the number of circulating neutrophils and monocytes. Infectious risk increases directly
with the following: (1) severity of neutropenia (ANC < 100 cells/mm3 imposes a greater
risk than ANC < 500 cells/mm3), (2) rate of ANC decline (rapidly falling rate imposes
a greater risk than chronic neutropenia or aplastic anemia), and (3) duration of neutro-
penia.7 In addition to quantitative changes associated with therapy, functional
changes in the phagocytic cells occur as well. Neutrophils from patients with leukemia
or lymphoma can have impaired chemoattractant responsiveness, bactericidal killing,
and superoxide production.8–11 In addition, concomitant corticosteroid treatment
reduces oxidative and nonoxidative killing mechanisms of host cells.12–14 The result
of these quantitative and functional impairments of the phagocytic cells is an inability
of the immune system to adequately respond to invading bacterial and fungal
pathogens.

ADAPTIVE IMMUNITY

The adaptive immune system is composed of B and T cell populations responsible

for regulating the humoral and cell-mediated host response. This arm of the immune
system is also impaired quantitatively and qualitatively by malignancy and its treat-
ment. Decreases in antibody producing B cells and plasma cells over the course
of therapy result in defective immunoglobulin synthesis and hypogammaglobuline-
mia. This results in an increased susceptibility to infection with bacterial, fungal,
and viral organisms. The encapsulated bacteria Streptococcus pneumoniae, Haemo-
philus influenzae type B, and Neisseria meningitidis are bacterial organisms that can
cause overwhelming infection in patients with an impaired immunity. Some thera-
peutic regimens target T cells preferentially, impairing the cellular immune response
and increasing the risk for fungal, viral, or intracellularly replicating bacterial infection.
T-cell function is also impaired by corticosteroids, radiation, and by receiving T-cell-
depleted stem cell sources for bone marrow transplant. Some patients may have
prolonged deficits in T-cell function.15,16
Other organ systems affected by cancer or its treatment further contribute to
impaired host defenses. For example, splenectomy may be part of the treatment
plan for some malignancies. The spleen functions to filter the blood, produce anti-
bodies, remove damaged cells from circulation, and opsonize circulating organisms.
Physical or functional asplenia increases the risk for fulminant sepsis because of
encapsulated bacteria. Another example is neurologic impairment caused by treat-
ment or disease, which can increase the risk for aspiration pneumonia. Mechanical
obstruction of hollow organs by tumor, including bowel, bronchi, or ureters, can
lead to colonization and postobstructive infection. Finally, nutritional deficiency is
common among children undergoing chemotherapy and can adversely impact
immune function in a multitude of ways.

PHYSIOLOGIC COMPENSATION TO INFECTION

In addition to impacting the immune system directly and indirectly, malignancy and its
treatment can impair the host’s physiologic response to overwhelming infection.
Chemotherapy and radiation can injure the lung, leading to restrictive lung disease
and impaired gas exchange, which can worsen hypoxia and respiratory failure in
528 Meckler & Lindemulder

the setting of pneumonia. Cardiac dysfunction caused by agents such as doxorubicin

can impair the ability of the heart to meet the increased output seen in sepsis and can
contribute to decompensation and shock. Cranial irradiation may induce permanent
pituitary dysfunction resulting in an inadequate stress hormone response to sepsis,
further exacerbating physiologic decompensation.

ETIOLOGY

The epidemiology of neutropenic infection varies with the geographic location of the
treatment center.17–23 Only 10% to 30% of neutropenic fevers yield a microbiologic
diagnosis.17–27 When a source is identified, 85% to 90% of the pathogens are either
gram-positive or gram-negative bacteria. The most common causes of neutropenic
fever in children are listed in Table 1. Although this section describes the microbiology
of neutropenic fever, it should be emphasized that noninfectious causes of fever,
including response to chemotherapeutic agents such as cytosine arabinoside, are
diagnoses of exclusion.
Gram-negative and anaerobic infections often originate from GI flora, whereas skin
and respiratory flora contribute to gram-positive infections. Gram-positive organisms
predominate and are often related to indwelling central catheters and mucositis from
aggressive chemotherapy; however, gram-negative infections are nearly as common
and must be considered in the ill-appearing patient. Antibiotic resistance, including
methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant
Enterococcus, are also important when considering empiric antibiotic coverage.
Acute viral infections of concern in this population include respiratory and GI viruses

Table 1
Potential infectious etiologies in febrile neutropenic children

Bacterial
Gram-Positive Gram-Negative Viral Fungal Other
Staphylococcus Escherichia coli Herpes simplex Candida spp Pneumocystis
spp jiroveci
Streptococcus Pseudomonas Varicella-zoster Aspergillus spp Protozoa
spp aeruginosa
Enterococcus Klebsiella spp, Respiratory Zygomycetes Chemotherapy-
spp syncytial virus related fever
Corynebacterium Enterobacter Influenza A Fusarium spp
spp spp and B
Bacillus spp Anaerobes Parainfluenza Scedosporium
spp
Clostridium spp Adenovirus Cryptococcus
neoformans
Rotavirus
Enterovirus
Cytomegalovirus
Epstein-Barr
Human herpes
virus 6
BK virus
JC virus
 Fever and Neutropenia in Pediatric Patients 529

often acquired from others in daycare or school settings or from siblings, in addition to
nosocomial infection. Varicella, influenza, respiratory syncytial virus (RSV) and adeno-
virus carry high morbidity and mortality in neutropenic patients. Bone marrow trans-
plant recipients are also at risk for acute infection or reactivation of latent infection
with the herpes family viruses (cytomegalovirus, Epstein-Barr virus, herpes simplex
virus [HSV]), and the polyomaviruses (John Cunningham or JC and BK).28,29 Given
ubiquitous colonization with Pneumocystis jiroveci, this intracellular organism can
become an opportunistic pathogen causing significant mortality. Most patients
receiving immunosuppressive therapy are empirically placed on Pneumocystis
prophylaxis for the duration of therapy.30–32 Fungal pathogens are a less common
cause of clinical disease, but are more likely in patients with prolonged neutropenia
(>10 days), relapsed disease, prolonged or high-dose steroids, and in the setting of
chronic immunosuppression after bone marrow transplant.33 Protozoan infections
are uncommon among children in the United States but must be considered in any
immunocompromised host.

RISK FACTORS

Several attempts have been made to stratify risk for serious infection and complica-
tions in the febrile neutropenic patient.34–40 A number of factors conferring high risk
of infection have been identified. Aggressive surveillance and empiric treatment of
these patients with broad-spectrum intravenous antibiotics has lead to a decrease
in gram-negative sepsis-related mortality from 80% several decades ago to its current
level of 1% to 3%.26,27 In addition to the ANC and duration of neutropenia, several
factors seem to confer an increased risk for failure of first line empiric therapy, life-
threatening infection, or death. Some of these factors are nonspecific clinical signs
universally recognized as harbingers of serious infection: (1) pneumonitis, (2) severe
mucositis, (3) signs of compensated or decompensated shock, (4) dehydration, (5)
hypotension, (6) respiratory distress or compromise, and (7) failure of a major organ
system. Mucosal ulceration, vomiting, and diarrhea increase the risk of infection
through disruption of the mucocutaneous barrier as previously described.
Additional factors that confer higher risk of infection include relapsed leukemia
because of circulating cancer cells that have impaired immune function and
decreased bone marrow capacity to produce normal numbers of functional cells.
Poorly controlled solid malignancies associated with alterations in cytokine, chemo-
kine, and other protein production may impair regulation of immune response even
in the face of normal neutrophil counts. Treatment with high-dose cytarabine is asso-
ciated with increased susceptibility to infection and mortality from Streptococcus vir-
idans and fungal infection because of prolonged neutropenia. Age less than 1 year has
also been implicated as an independent risk factor, possibly the result of develop-
mental immaturity of innate immunity, use of diapers, which leads to increased expo-
sure of skin to urine and stool, and inability to communicate symptoms or localize pain
to caregivers and medical staff. Additional laboratory markers associated with high
risk of infection include C-reactive protein (CRP) greater than 90 mg/L, platelet count
less than 50,000, and absolute monocyte count less than 100. Additional serum
markers under investigation include a range of cytokines.
Inpatient management of high-risk patients using broad-spectrum antibiotics has
decreased overall mortality among pediatric cancer patients. However, this manage-
ment scheme is associated with disruption of family life, prolonged hospital admis-
sions, high medical costs, nosocomial complications, and increasing resistance to
antibiotics. As a result, interest has recently turned toward identifying low-risk criteria
530 Meckler & Lindemulder

that may allow for less aggressive management strategies in the outpatient setting.
Comparison of low-risk models is difficult because of variable methodology and
outcomes, but some of the proposed low-risk factors include a temperature less
than 39 C, monocyte counts of 1000/mm3 or more, lack of medical comorbidity or
radiographic evidence of pneumonia, outpatient status at time of febrile episode,
anticipated short duration of neutropenia (<7 days), and malignancy other than acute
myelogenous leukemia. Research into laboratory markers of risk (CRP, interleukin
(IL)-6, IL-8, tumor necrosis factor-a, interferon-g, and others) and host genetic char-
acteristics associated with infection risk are ongoing. A number of studies in Europe
and South America have demonstrated the safe treatment of select low-risk popula-
tions with oral antibiotic therapy.25,38–46 Although preliminary data suggests that
outpatient management of carefully selected patients may be safe and effective,
these management strategies are not yet standard-of-care and should not be used
outside of the setting of a clinical trial.

ASSESSMENT AND EVALUATION

Ideally, a member of the primary oncology team will notify staff at the emergency
facility that a febrile, potentially neutropenic, pediatric oncology patient needs emer-
gent evaluation. This provides an opportunity to record information about the patient’s
age, diagnosis, and recent therapy, in addition to pertinent past medical history, espe-
cially related to infection. This conversation also provides an opportunity to discuss
specific plans for assessment and management. Important considerations in the
history, physical examination, and evaluation of the febrile oncology patient are further
reviewed later in this article.

History
The history should include a thorough review of symptoms and exposures to try to
identify a potential source of infection. It is important to remember that a neutropenic
patient has a decreased response to inflammation, so clues regarding a potential
source of infection may be subtle. Routine questions on history should include the
height and duration of fever, associated chills or shaking, orthostatic symptoms, myal-
gias, and associated symptoms such as headache, cough, rhinorrhea, shortness of
breath, chest pain, ear pain, sore throat, abdominal pain, vomiting, diarrhea, pain
with urination, and skin lesions. Potential exposures at home or at school should be
sought. Oral intake and urine and stool output should be ascertained. Symptoms of
particular importance in this population include pain with stools that could indicate
perirectal cellulitis or abscess, symptoms of mucositis (extent and location, degree
of pain and interventions, active sloughing of mucosa), signs of infection (redness,
swelling, or tenderness) around a central venous line or other hardware, and changes
in surgical wounds that often demonstrate delayed healing because of chemotherapy
and may provide a portal for infection.
A careful review of medications with attention to recent chemotherapeutic agents,
(inpatient, intravenous [IV], oral, intrathecal) prophylactic antibiotics and colony-stim-
ulating factors should be documented. Patients and their families should be ques-
tioned carefully about adherence to prophylaxis regimens. For example, were any
doses accidentally forgotten, does the child routinely spit out the medications and
is it redosed, does the child vomit regularly after medication administration, is it
possible that a teenager could ‘‘cheek’’ or throw away the medicine? It is also impor-
tant to check that medication dosage is appropriate for the child’s weight, which may
change with therapy (eg, weight gain associated with steroid therapy). Finally, a review
 Fever and Neutropenia in Pediatric Patients 531

of past febrile episodes, surveillance culture results, and immunization status

including influenza vaccination should be sought.

Vital Signs
All patients should have a full set of vital signs recorded and frequently reassessed
during their ED visit. Temperature, respiratory rate, heart rate, blood pressure, pulse
oximetry, and weight are essential to record for all oncologic patients with fever and
suspected neutropenia. Abnormal vital signs may be the only sign of impending life-
threatening infection in the otherwise well-appearing child. Tachypnea or mild hypoxia
may represent pneumonitis or an evolving consolidation. Tachycardia out of propor-
tion to fever, crying, anxiety, or pain should be considered compensated shock,
particularly when persistent. Weight recorded in the ED can be compared with a recent
clinic weight to aid in assessing the degree of dehydration from poor oral intake or fluid
losses from vomiting or diarrhea.

Physical Examination
Every patient evaluated for fever and neutropenia requires a thorough examination to
attempt to identify a source of infection. This requires full exposure of the skin and all
patients should be placed in a gown, despite the temptation to spare the child or family
another invasive examination with an unfamiliar provider. A ‘‘look, listen, feel’’
approach as taught in basic life support is often helpful to establish a quick assess-
ment of illness severity—visual assessment of the patient’s color, muscle tone, degree
of activity, respiratory pattern, and mental status (note interactions with caregivers,
environment, and examiner); listening for grunting, stridor, or wheezing; and feeling
for skin temperature, pulses, and capillary refill. This rapid assessment will help clas-
sify the patient in respiratory distress or failure and define whether the patient’s
presentation is compensated or decompensated.
The practitioner may then turn to a systematic head-to-toe examination. The head-
ears–eyes-nose-throat (HEENT) examination should specifically note the presence
and extent of mucositis (few discrete ulcers vs extensive involvement with sloughing)
and the moisture of the mucous membranes. The mouth, nose, sinuses, and palate
should also be carefully examined; white plaques may indicate yeast infection such
as Candida and black plaques may indicate fungal infection such as Aspergillus or
Mucor. The lungs should be carefully auscultated for signs of consolidation, though
tachypnea may be the only sign of respiratory infection in the severely neutropenic
child. The chest wall and central venous catheter site should be inspected for
erythema, warmth, tenderness, or fluctuance. The abdomen should be examined
carefully for tenderness that might indicate pancreatitis (especially following recent
asparaginase chemotherapy), liver enlargement, gallbladder inflammation, or diffuse
right lower quadrant pain potentially signaling typhlitis. As noted earlier, pulses and
capillary refill should be assessed, remembering that warm shock presents with
bounding pulses and brisk capillary refill, whereas cold shock is associated with
cool, mottled extremities and sluggish capillary refill. Any surgical site, including cath-
eters, ventriculoperitoneal shunts, biopsy sites, resection sites, and orthopedic inci-
sions should be examined for signs of superficial or deep infection. In addition, the
perirectal area should be visually inspected for erythema and the perianal area
palpated for evidence of abscess. Digital rectal examination is contraindicated as it
may result in further translocation of bacteria.
Primary varicella and zoster infections deserve special mention with regard to phys-
ical examination in the neutropenic population. The rash associated with these
diseases is often altered in children undergoing therapy and may initially appear as
532 Meckler & Lindemulder

papules in small numbers rather than the expected multiple vesicular lesions. Occa-
sionally zoster reactivation will present only as pain and hypoesthesia without rash
(zoster sine herpete). These patients should be considered extremely infectious as
they are much more likely to have disseminated disease and should be placed in
airborne and contact isolation until the diagnosis is ruled out or the disease resolves
completely.

Laboratory Tests
The initial laboratory evaluation of the febrile pediatric oncology patient should include
a complete blood count with manual differential to determine whether the patient is
neutropenic, and blood cultures should be performed on samples from all central
venous catheters. Peripheral blood cultures are no longer indicated because they
have been proven to provide limited additional information when the central blood
culture is of adequate volume. Additional laboratory studies are not routinely useful
and should be directed by the clinical picture (Table 2).
In some institutions, radiographs of the chest (CXR) are routinely included in the
initial evaluation of all febrile neutropenic patients, regardless of symptomatology.
Evidence suggests that a CXR may not be as useful as a screening test. The incidence
of pneumonia on CXR in febrile neutropenic patients has been found to be 3% to 6%,

Table 2
Additional laboratory tests for consideration in the initial evaluation

Test
Complete metabolic panel
Lipase
Urinanalysis and urine culture
Nasal wash for rapid viral evaluation
Chest radiograph (2 views)
Throat culture and rapid Streptococcus test
Abdominal imaging (radiograph,
ultrasound, CT scans)
Skin swabs for viral or bacterial culture
Indications
Concern for metabolic abnormality due to
nephrotoxic drugs
Excessive fluid losses (vomiting, diarrhea)
TPN–dependence
History of liver dysfunction
Examination findings consistent with
pancreatitis
Recent therapy with asparaginase
Urinary frequency, urgency, dysuria
Exposure to influenza A, B
Exposure to RSV
Consistent clinical picture
Hypoxia
Unexplained tachypnea
Concerning symptoms
Physical examination findings (rales, wheeze)
Pain and exudate on examination
Exposure to group A Streptococcus
Clinical picture consistent with group A
Streptococcus
Focal tenderness on examination
Concern for typhlitis
Concern for surgical abdomen
Vesicular lesions consistent with VZV and HSV
Erythema or exudate at the site of hardware
or surgical incision

Abbreviations: TPN, total parenteral nutrition; VZV, varicella zoster virus.

 Fever and Neutropenia in Pediatric Patients 533

with almost all cases being associated with clinical signs and symptoms.47–50
Because there is no national consensus, the decision regarding when to obtain
a CXR on febrile neutropenic pediatric patients should be based on institutional
standards.

MANAGEMENT

All management should be performed in telephone consultation with the primary pedi-
atric oncology team when possible. The care of critically ill patients should include
early contact with an intensivist and arrangements for prompt transfer to definitive
care after initial resuscitation and attempted stabilization. The general ED manage-
ment of the neutropenic patient is depicted in Fig. 1. The goal for all oncology patients
should be rapid triage, medical evaluation, and identification of neutropenic fever,
leading to early administration of empiric antibiotics (discussed separately in a later
section), careful observation and reassessment of vital signs, and transfer to the
appropriate ward or intensive care unit. All pediatric oncology patients presenting to

Fig. 1. General approach to the febrile pediatric oncology patient. CBC, complete blood
count; PICU, pediatric intensive care unit.
534 Meckler & Lindemulder

the ED with fever should initially be placed on monitors. Management of the airway,
breathing, and circulation should be the first priority.
Definitions of sepsis, severe sepsis, and decompensated shock are listed in
Table 3.9 The detailed management of sepsis is beyond the scope of this chapter;
however, a number of excellent reviews of sepsis, including the importance of early
goal-directed therapy have been recently published.51–55

EMPIRIC BROAD-SPECTRUM ANTIBIOTICS

Specific antibiotic choices should be guided by local microbiology, susceptibilities,

and individual patient risk factors and therefore will vary by institution. The general
principle guiding empiric treatment, however, remains the selection of antimicrobial
agents with a broad spectrum of activity against gram-negative and gram-positive
organisms likely to cause disease in this patient population.
Early protocols used combination therapy, typically a b-lactam antibiotic (third or
fourth generation cephalosporin) plus an aminoglycoside.56–59 More recently, mono-
therapy using broad-spectrum b-lactam antibiotics with antipseudomonal activity
have been shown to be as effective as combination therapy. Common monotherapy
choices include cephalosporins (ceftazidime, cefepime) or carbapenems (imipenem,
meropenem).60–70 Individual choices must take into account institutional patterns of
antibiotic resistance that vary widely.1
Although broad-spectrum monotherapy may suffice for most stable neutropenic
patients, additional coverage should be considered for specific conditions or risk
factors. Patients who have received high-dose cytarabine, for example, are at
increased risk for alpha hemolytic Streptococcus infection, which is associated with
significant resistance to antibiotics.71 Vancomycin should be added to the traditional

Table 3
Sepsis and related terminology

Systemic inflammatory response syndrome T > 38.5 or <36.0 C

(SIRS) Tachycardia > 2 SD for age or bradycardia
if < 1 y
RR > 2 SD for age
WBC above or below age norms (not related
to chemotherapy)
Sepsis SIRS in presence of proven or suspected
infection
Severe sepsis Sepsis 1 cardiovascular dysfunction (see next
row), respiratory distress syndrome, or R2
organ dysfunctions (neurologic, renal,
hepatic, hematologic)
Septic shock Sepsis 1 cardiovascular dysfunction
(hypotension, vasopressor dependence,
acidosis, elevated lactate, oliguria, delayed
capillary refill, core to peripheral
temperature gap > 3 C)

Abbreviations: RR, relative risk; SD, standard deviation; SIRS, systemic inflammatory response
syndrome; T, temperature; WBC, white blood cell.
Data from Goldstein B, Giroir B, Randolph A. International Consensus Conference on Pediatric
Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ
dysfunction in pediatrics. Pediatr Crit Care Med 2005;6(1):2–8.
 Fever and Neutropenia in Pediatric Patients 535

broad-spectrum therapy of these patients. Vancomycin should also be considered for

patients with signs of central venous catheter infection including surrounding cellulitis
or tenderness and for patients with a known history or exposure to MRSA. When there
is clinical suspicion of typhlitis or an intra-abdominal catastrophe, empiric coverage
should be broadened to include better anaerobic activity—triple therapy with metro-
nidazole, a third or fourth generation cephalosporin, and vancomycin is commonly
used in this setting.

ANTIVIRALS

As discussed earlier, viral infections are common in pediatric oncology patients and
are associated with significant morbidity and mortality in this population. The avail-
ability of rapid detection for many viruses (including influenza, RSV, and adenovirus)
can lead to the early diagnosis and should be considered when symptoms are sugges-
tive of viral disease. Although empiric use of antiviral agents is not standard-of-care in
the ED, a number of antiviral drugs are available, and the select use of these medica-
tions should be considered in consultation with an oncologist and infectious disease
specialist. Treatment for influenza, RSV, and adenovirus are briefly discussed later.
Despite the recommendations of the Centers for Disease Control and Prevention
(CDC) for annual influenza vaccination in healthy children older than 6 months and
evidence that trivalent vaccine may be effective in cancer patients, vaccination rates
for influenza remain low.72 Furthermore, there may be reduced immunogenicity of
vaccination in children undergoing treatment for hematologic malignancy. When
symptoms and local epidemiology suggest clinical infection with influenza, rapid
antigen testing can confirm infection. Two classes of drugs with activity against influ-
enza are available and approved for use in children. The adamantanes (amantadine
and rimantadine) target the M2 ion channel protein found only on influenza A and
are approved for children older than 12 months. Though relatively safe, recent wide-
spread resistance to this class of drugs limits their efficacy, particularly among
H3N2 strains, and their use should only be considered after consultation with infec-
tious disease experts. Two neuraminidase inhibitors are available for use in chil-
dren—oseltamivir is available in liquid preparation and has been approved for use in
children older than 12 months , and zanamivir, administered as an inhalation powder,
is approved for use in children older than 7 years. Both drugs are active against influ-
enza A and B, although oseltamivir has a relatively decreased efficacy against influ-
enza B. Both drugs have been shown to decrease the duration of fever and
symptoms in otherwise healthy children and may decrease progression to lower-tract
disease in adult bone marrow transplant patients.73–77 Data from widespread use of
these drugs in Japan have led to recent concerns regarding the emerging resistance
to oseltamivir and serious side effects. A total of 71 deaths have been reported in
Japan between 2001 and 2007, including 18 sudden deaths in children younger
than 10 years and five deaths related to neuropsychiatric disturbances in teenagers.
The mechanism of sudden death is not fully understood but is believed to be related
to the central suppressive effects of the drug leading to centrally mediated cardiopul-
monary arrest.78–80 This has prompted the Food and Drug Administration to issue
a black box warning regarding potential behavioral effects, particularly in adolescents.
Zanamivir inhalation may precipitate bronchospasm in children with underlying reac-
tive airway disease, and caution should be exercised in this population. Both drugs are
effective for prophylaxis in cases of known exposure to influenza in the high-risk,
unvaccinated oncology patient. Because of the potential adverse effects associated
536 Meckler & Lindemulder

with antiviral therapy, careful consideration of risks and benefits should be made
before use of these antiviral agents.
Infection with RSV can also result in serious disease in the pediatric oncology
patient, particularly after T-cell-depleted bone marrow transplant. As with influenza,
rapid testing for RSV is now available, and treatment options for severe disease
include the antiviral agent ribavarin and human monoclonal antibody to RSV, palivizu-
mab.81–85 A recent Cochrane review of ribavirin found from 12 clinical trials, all in
infants younger than 6 months and in which confidence intervals from pooled data
were wide, that ribavirin may decrease mortality, respiratory deterioration, and length
of hospital stay.86 Controlled trials in older and immunocompromised children are
lacking, and the use of this medication and palivizumab should be made in consulta-
tion with infectious disease experts.
Adenoviral infection is associated with high mortality rates in bone marrow trans-
plant recipients. No specific treatment strategies have been tested in controlled trials,
though antiviral therapy with cidofovir, ribavirin, and vidarabine have been reported
with variable efficacy.87–90

ANTIFUNGALS

Empiric antifungal therapy is rarely indicated in the ED unless there is specific

evidence of fungal infection on the initial evaluation. Risk factors for invasive fungal
disease include prolonged neutropenia (>10 days), relapsed leukemic disease or pro-
longed neutropenic fever despite antibiotic therapy (>5 days). Until recently, the treat-
ment of fungal disease was associated with significant morbidity. Amphotericin B, the
primary option for antifungal treatment in the past, was well known for adverse side
effects including fever, chills, rigors, nausea, vomiting, and nephrotoxicity. Newer lipo-
somal preparations of amphotericin (AmBisome, Abelcet, and Amphotec) are associ-
ated with fewer side effects. These newer antifungals can be used as initial empiric
therapy or treatment for proven mycoses in patients receiving concomitant nephro-
toxic agents, those with previous renal impairment, or in patients with an anticipated
lengthy course likely to be limited by nephrotoxicity.91–95 Additional antifungal classes
have recently shown promise for treating fungal disease with differing side-effect
profiles. The azole class of antifungals include topical preparations (clotrimazole, mi-
conazole, and ketoconazole) and parental formulations (itraconazole, fluconazole,
voriconazole, and posaconazole). The azole group has activity against yeast and
the newest approved agent, voriconazole, is considered the drug of choice for treat-
ment of invasive aspergillosis.96–99 Significant drug interactions and hepatotoxicity are
the main limitation of the azoles. Ketoconazole is no longer used in this population
because of its high risk of hepatotoxicity. The echinocandin class of antifungals
includes caspofungin, micafungin, and anidulafungin, which have activity against
azole-resistant Candida species and Aspergillus. The echinocandins are attractive
agents in this population because they are well-tolerated and have fewer drug interac-
tions.100–103

ADDITIONAL MANAGEMENT CONSIDERATIONS

Colony-Stimulating Factor
Many children will be receiving a colony-stimulating factor, such as granulocyte
colony-stimulating factor, as part of the therapeutic regimen. Recent guidelines
recommend that a colony-stimulating factor be given if the chemotherapy regimen
is anticipated to result in rates of febrile neutropenia greater than or equal to
20%.104,105 In a meta-analysis, colony-stimulating factors were shown to reduce the
 Fever and Neutropenia in Pediatric Patients 537

rate of febrile neutropenia, decrease the length of hospitalization for febrile neutrope-
nia, reduce the documented infection rate, and reduce amphotericin use; however,
they have not been shown to reduce overall infection-related mortality. If a patient is
not already on colony-stimulating factors, there is no information that the addition of
these medications is of benefit, and they should not be initiated in the ED.106

Transfusions
Transfusions of either packed red blood cells (PRBCs) or platelets may need to be initi-
ated in the ED as clinically indicated by critical values or evidence of bleeding. It is
important to remember that all transfusions need to be irradiated and leukodepleted
to avoid sensitization. If the evaluating facility cannot provide these blood products,
transfusion should be delayed in the otherwise stable patient. Guidelines for PRBCs
and platelet transfusion vary between centers, but general recommendations
regarding indication, dose, and expected response for platelet transfusions are
provided in the following paragraphs.107
The guidelines for transfusion of PRBCs depend on the clinical scenario in which the
patient presents to the ED. In a stable, asymptomatic child presenting with fever and
neutropenia, in whom recovery is expected soon, transfusion is not indicated until
hemoglobin levels decrease to less than 7 g/dL. Patients presenting with alterations
of normal vital signs such as tachycardia, tachypnea or hypotension that are otherwise
stable should be transfused for hemoglobin levels less than 8 g/dL. Clinical scenarios
that require transfusion at higher hemoglobin levels between 8 and 10 g/dL include
oxygen requirement because of pulmonary or cardiac morbidity, thrombocytopenia
with history of prior significant hemorrhage, procedure that is anticipated to be asso-
ciated with blood loss, and fatigue. Fatigue may negatively impact the quality of life
and is typically seen in adolescent patients who require a higher resting hemoglobin
when compared with younger patients. The expected response to PRBC transfusion
is approximately 2 g/dL for each 10 mL/kg transfused. The transfusion amount should
be calculated based on the goal hemoglobin and should be administered by giving
each 10 mL/kg over 4 hours.
Guidelines for transfusion of platelets, much like PRBCs, vary with the clinical
scenario in the ED. General considerations are summarized in Table 4. When dosing
platelets, one random donor equivalent unit per 10 kg should raise the platelet count
between 50 and 100/ mm3 and can be infused over 30 to 60 minutes. Before the initi-
ation of any transfusion, the practitioner should consult previous medical records and

Table 4
General guidelines for platelet transfusion

Clinical Context Suggested Platelet Level (cells/mm3)

Asymptomatic patient >10
Minor bleeding (epistaxis, mucosal bleeding) >20
Major bleeding (hemoptysis, GI or CNS bleed, >100
hemorrhagic cystitis)
CNS tumor >50
Diagnostic LP >10–20
Surgical procedure >50–100

Abbreviations: CNS, central nervous system; LP, lumbar puncture.

538 Meckler & Lindemulder

ask the patient’s caregiver if there is any history of a transfusion reaction requiring pre-
medication before infusion of the blood product.

Pituitary Dysfunction
Some patients may develop pituitary dysfunction as a result of neurosurgery or cranial
radiation. Most of these patients are routinely monitored for pituitary dysfunction or are
aware of their condition and the primary oncology team should provide advanced noti-
fication of this special consideration at the time of the initial referral. All patients with
panhypopituitary dysfunction should receive prompt stress-dose hydrocortisone to
avoid further complications. Though dosing based on body surface area can be dis-
cussed with an endocrinologist, a safe rule-of-thumb is to administer 25 mg IV/intra-
muscular for patients in the first 2 years of life, 50 mg for toddlers and school aged
children, and 100 mg for adolescents. Stress-dose steroids can be life-saving, have
few side effects, will not interfere with the oncology treatment regimen, and should
be administered without delay. Adrenal insufficiency should also be considered in
patients receiving prolonged steroid therapy (some phases of acute lymphoblastic
leukemia treatment, GVHD prophylaxis, treatment after bone marrow transplantation,
or to control edema related to radiation effects).

Observation Period
In the bacteremic patient, administration of antibiotics may precipitate decompensa-
tion or sepsis syndrome through lysis of bacteria and release of bacterial cell wall
products, such as lipopolysaccharides. In addition, allergic reactions or idiopathic
reactions to transfused blood products may compromise patient stability. Because
of these risks, it is important to observe and monitor these patients for a period of
time during and after antibiotic administration or transfusion, with reassessment of
vital signs before transfer from the ED to the hospital ward. Unstable patients should
be resuscitated and transferred as soon as possible to an intensive care unit.

SUMMARY

The approach to the treatment of the febrile neutropenic pediatric patient has evolved
considerably as high- and low-risk criteria have been defined and broad-spectrum
antibiotics developed. Although individual evaluation and management strategies
should be based on local epidemiology, microbial resistance patterns, and institu-
tional practice standards, the general approach to these patients is the same. Critically
ill or septic neutropenic patients should undergo resuscitation according to advanced
life support guidelines, cultures should be obtained, and broad-spectrum antibiotics
should be administered. Stable patients with a recognizable source of infection should
have appropriate cultures obtained and source-specific antibiotics administered. Chil-
dren with fever, neutropenia, and no obvious source of infection are typically managed
as inpatients with broad-spectrum monotherapy antibiotics, pending results of blood
cultures. In some institutions, stable patients with no obvious source of infection and
an ANC that is expected to recover quickly may be managed as outpatients following
administration of a long-acting broad-spectrum parenteral antibiotic with close outpa-
tient follow-up and surveillance of cultures. In all cases, the management of these
patients will ideally be conducted with good communication between ED physicians
and pediatric oncologists.
 Fever and Neutropenia in Pediatric Patients 539

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