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Fever in children with chemotherapy-induced neutropenia

Authors: Nabil M Ahmed, MD, MPH, Patricia M Flynn, MD


Section Editors: Morven S Edwards, MD, David G Poplack, MD
Deputy Editor: Mary M Torchia, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2017. | This topic last updated: Jul 03, 2017.

INTRODUCTION — Infection is a major cause of morbidity and mortality in cancer patients [1]. Fever may be the
first manifestation of a life-threatening infection, particularly during periods of neutropenia. Febrile episodes occur
in approximately one-third of neutropenic episodes in children with chemotherapy-induced neutropenia or after
hematopoietic cell transplantation [2]. The approximate rate of occurrence is 0.76 episodes per every 30 days of
neutropenia.

The demonstration of markedly reduced infection-related morbidity and mortality with the empiric use of broad-
spectrum antibiotics during periods of febrile neutropenia was a major advance in the field of oncology in the
1970s [3,4]. Subsequent studies identified factors associated with a higher risk of bacterial infection and
facilitated a more tailored approach to empiric therapy.

Because of important differences between oncology and hematology patients with neutropenia, fever in the
pediatric cancer patient during periods of therapy-induced neutropenia are reviewed here. The types of infections
and management of fever in the child with other forms of neutropenia are discussed separately. (See "Risk of
infection in children with fever and non-chemotherapy-induced neutropenia" and "Evaluation and management of
fever in children with non-chemotherapy-induced neutropenia".)

Fever in adult cancer patients with neutropenia is discussed separately. (See "Overview of neutropenic fever
syndromes" and "Risk assessment of adults with chemotherapy-induced neutropenia" and "Diagnostic approach
to the adult presenting with neutropenic fever" and "Treatment of neutropenic fever syndromes in adults with
hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and
prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications".)

DEFINITIONS

Neutropenia — Neutropenia is defined as an absolute neutrophil count (ANC) <1500 cells/microL. The ANC is
calculated using the following formula:

● ANC = total white blood cell count (cells/microL) x (percent neutrophils + percent bands) ÷ 100

For purposes of management of the febrile pediatric cancer patient, neutropenia is defined as an ANC <500
cells/microL or an ANC that is expected to decrease to <500 cells/microL during the next 48 hours [5-7].

The relative risk of infection is related to both the degree and duration of neutropenia. An increased risk becomes
apparent at an ANC <1000 cells/microL, is greater at an ANC ≤500 cells/microL and greatest at an ANC ≤100

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cells/microL (profound neutropenia) [2,8]. Patients with neutropenia projected to last for more than seven days
also are at a higher risk of infection than are those with neutropenia of shorter duration [9].

Patients with hematologic malignancies that impair phagocytosis and killing of pathogens also are at increased
risk of infection even if their ANC is normal ("functional neutropenia") [6]. Other factors that predispose to
infection in association with chemotherapy include breakdown of skin and mucosal barriers, such as mucositis
following methotrexate treatment, and altered humoral and cellular immunity [10].

Infections in pediatric cancer patients are more common during periods of chemotherapy-induced neutropenia,
but they also can occur in the absence of neutropenia. For example, 90 percent of pediatric oncology patients
have central venous catheters, which may be a source of infection whether or not the child is neutropenic.
Because children are not always able to convey localized complaints, children with cancer who develop fever
must be evaluated for infections regardless of the ANC.

Fever — Fever generally is defined as a single oral temperature ≥38.3°C (101°F) in neutropenic patients [11]. A
temperature ≥38°C (100.4°F) for longer than one hour or two elevations >38°C (100.4°F) during a 12-hour period
are additional definitions of fever that may be used [6,12].

Oral temperature measurements are preferred, although an axillary temperature is acceptable if the patient is
unable to use an oral thermometer. Generally, no conversion is made between axillary and oral temperatures.
However, more conservative guidelines suggest that adding 0.5°F (0.3°C) to the axillary temperature reading
may be warranted. Electronic thermometers are now available with oral, axillary, and rectal modes that
automatically adjust for the location of the measure such that no manipulation of the displayed temperature is
necessary. Package inserts of electronic thermometers should be read to determine if this feature is available.
Rectal temperature measurement should be avoided in neutropenic patients because of associated risks of
mucosal trauma and bacteremia.

Fever often is the sole sign of occult infection in the neutropenic host [6]. However, this sign may be absent in
some infected patients who instead may be hypothermic, hypotensive, listless, or confused. Thus, infection must
be considered and treated empirically if any signs of clinical deterioration are present in a neutropenic child,
regardless of the recorded temperature. Similarly, infected children who are receiving glucocorticoids may
present with a lower and/or intermittent temperature elevation – or may be afebrile.

Risk category — Patients with fever and neutropenia can be divided into high- and low-risk categories based
upon presenting signs and symptoms, counts, underlying cancer, type of therapy and the anticipated length of
neutropenia, and medical comorbidities [6]. However, there is no currently agreed-upon risk stratification
specifically for children [13,14].

High-risk — High-risk patients have an increased risk of severe infection. Patients with any of the following
should be considered as high-risk [6]:

● Neutropenia (ANC <500 cells/microL) anticipated to last >7 days. Although the 2010 Infectious Diseases
Society of America (IDSA) guidelines define patients as high-risk if they have profound neutropenia (ANC
≤100 cells/microL) anticipated to last >7 days [6], we have opted to define high-risk as neutropenia (ANC
<500 cells/microL) anticipated to last >7 days. Formal studies to clearly differentiate between patients with
an ANC <500 cells/microL and ANC ≤100 cells/microL are lacking.

● Evidence of hepatic insufficiency (aminotransferase levels >5 times normal values) or renal insufficiency
(creatinine clearance <30 mL/min)

● Comorbid medical problems including, but not limited to:

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• Hemodynamic instability

• Oral or gastrointestinal mucositis that interferes with swallowing or causes diarrhea

• Gastrointestinal symptoms, including abdominal pain, nausea, vomiting, or diarrhea

• New-onset neurologic or mental status changes

• Intravascular catheter infection (especially catheter tunnel infection)

• New pulmonary infiltrate or hypoxemia or underlying chronic lung disease

● Patients with infant acute lymphoblastic leukemia, acute myeloid leukemia, or within 30 days of
hematopoietic cell transplant

The Multiple Association for Supportive Care in Cancer (MASCC) score may be used to formally assess risk of
infection [15]. Patients with MASCC score <21 are at high risk. However, the utility of the MASCC Risk-Index
score in pediatric patients is questionable since it was derived from persons older than 16 years and is
influenced by chronic medical conditions, such as chronic obstructive pulmonary disease, diabetes, and
congestive heart failure that are uncommon in children.

High-risk patients should be admitted to the hospital for empiric antimicrobial therapy (algorithm 1).

Low-risk — Low-risk patients are those with [6]:

● Neutropenia expected to resolve within seven days


● Stable and adequate hepatic and renal function
● No active comorbidities

Carefully selected low-risk patients may be candidates for oral empiric therapy or outpatient treatment.

ETIOLOGY OF FEVER — The rate of documented infection, when a child presents with fever and therapy-
induced neutropenia, ranges between 10 and 40 percent [2,16-19]. No clinical or microbiologic evidence of
infection will be established in the remainder. Bacteremia is the most common form of documented infection
[2,18]. Other sites of infection include the gastrointestinal tract, with oral or intestinal mucositis or diarrhea
caused by organisms such as Clostridium difficile and Salmonella spp; upper and lower respiratory tract; urinary
tract; and skin and soft tissues [1,16,20].

Rates of bacteremia vary greatly (range approximately 20 to 50 percent) depending upon the institution and
underlying malignancy [17,18,21-24].

Both gram-positive and gram-negative organisms are isolated frequently from the blood in febrile neutropenic
children [2,18,25]. The frequency of pathogenic organisms varies from institution to institution. In general, there is
a global shift toward a dominance of gram-positive organisms due to the ubiquitous use of prophylactic
antimicrobials and indwelling venous catheters. The most common gram-positive pathogens are coagulase-
negative staphylococci, viridans streptococci, and Staphylococcus aureus (including methicillin-resistant S.
aureus) [2,18,23]. Aerobic gram-negative bacilli account for approximately one-third to one-half of bacteremic
episodes, with Escherichia coli, Klebsiella spp, Pseudomonas spp, Acinetobacter spp, and Enterobacter spp
among the more common isolates [2,18,23].

Fungi, typically Candida spp, are more likely to be recovered after prolonged courses of broad-spectrum
antibiotics but occasionally may be the primary pathogen [2]. Other potential fungal organisms include
Aspergillus spp, Zygomycetes, and Cryptococcus spp [26,27]. Fusarium spp also have been increasingly
recognized in these hosts [28]. The increasing use of antifungal prophylaxis is likely to shift the distribution of
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fungal isolates away from Candida spp and toward mold infections [29]. This is particularly true in hematopoietic
cell transplant recipients.

The most significant viral etiologies are herpes simplex and varicella-zoster virus [18,30,31]. Respiratory viruses
are also frequently detected in nasopharyngeal aspirates [18,31-35].

EVALUATION — Infection is a major cause of morbidity and mortality in cancer patients. Serious infection may
occur in the absence of fever and/or neutropenia and must be considered in the pediatric cancer patient who is
febrile and neutropenic; febrile but not neutropenic; or neutropenic and afebrile with signs of infection or clinical
deterioration [7].

Prompt initiation of empiric therapy can be life-saving, so rapid (but thorough) evaluation is critical.

History — Important aspects of the history in a child with fever and neutropenia include [6]:

● New site-specific symptoms


● Antimicrobial prophylaxis
● Infection exposures
● History of documented infections or colonization
● Concomitant noninfectious cause of fever (eg, receipt of blood products)
● Underlying comorbid conditions (eg, diabetes, recent surgery)
● Previous chemotherapy, agents used, and the stage of therapy (to anticipate the length of the neutropenic
episode)
● Intravascular catheters or other devices

In a multicenter historic cohort, totally implantable catheters (eg, mediports, portacaths) were associated with
decreased risk of serious bacterial infection compared with tunneled external catheters (odds ratio [OR] 0.53,
95% CI 0.36-0.77) and peripherally inserted catheters (OR 0.41, 95% CI 0.28-0.61) [36]. Totally implantable
catheters were also associated with decreased hospital stay, duration of antibiotics, need for intensive care, and
duration of intensive care.

Physical examination — A careful physical examination should be performed with particular attention paid to
those sites most commonly infected, including [6]:

● Abnormal vital signs, particularly tachycardia (even without hypotension)


● Skin, especially folds, areas surrounding nail beds, central venous line exit sites and subcutaneous tunnel, if
present, and sites of bone marrow aspiration and lumbar puncture
● Sinuses
● Oropharynx, with attention to the gingiva
● Lungs
● Abdomen
● Perineum, particularly the perianal and labial regions

Mild erythema or tenderness should not be ignored because signs of inflammation in the neutropenic patient may
be subtle. Repeated physical examinations are essential. Visual signs of inflammation may become evident only
when neutrophil counts are recovering.

Laboratory tests and imaging — The laboratory evaluation for the child with fever and neutropenia should
include (at minimum) [6]:

● Complete blood count with differential and platelet count

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● Electrolytes, creatinine, and blood urea nitrogen


● Liver transaminases and total bilirubin
● Blood cultures
● Cultures, molecular diagnostic assays, and/or imaging of other sites of suspected infection as clinically
indicated (described below)

Additional tests suggested by the National Institute for Health and Care Excellence (NICE) include C-reactive
protein (CRP), lactate, and urinalysis in children <5 years [7]. CRP has been used in risk categorization
strategies in several pediatric studies.

Treatment should be initiated as soon as possible after cultures are obtained and should not be delayed while
waiting for results or performing additional studies.

Blood cultures should be obtained without delay. Blood cultures should be taken from each lumen of the central
line when such access is available [14,37]. Opinions vary as to whether blood should be cultured from peripheral
sites, as well [38-40]. The rationale for culturing blood from both peripheral and central sites is to differentiate a
catheter-related infection from a bacteremia from another source and to guide decisions about whether to retain
or remove a catheter [41]. A catheter-related bloodstream infection can be diagnosed if the colony count of
microbes in blood obtained via the catheter hub is at least threefold greater than that obtained from the
peripheral blood or if the culture obtained via the catheter hub becomes positive at least two hours before the
peripheral blood when using a continuous read system. However, treatment recommendations for central
catheter-related infections and for bacteremias from other sources are similar, and many institutions do not
recommend the routine culturing of blood from peripheral sites in addition to central sites even though peripheral
cultures are necessary to confirm a diagnosis of catheter-related bloodstream infection.

Obtaining more than one blood culture is helpful in the interpretation of blood culture results. If coagulase-
negative staphylococci are isolated from two or more blood cultures, true bacteremia is more likely than
contamination of the specimen, which may be reflected by a single positive blood culture. When obtaining blood
from a central venous catheter, the importance of sampling all lumens is supported by studies in which 32 to 43
percent of positive cultures from double lumen catheters were positive from only one of multiple lumens [38,42].

If the child remains febrile after initiation of empiric antibiotic therapy, daily blood cultures should be obtained for
the next two days, after which blood cultures should be repeated when there is a change in clinical status [6,43].
Blood cultures also should be repeated if fever recurs following initial defervescence in response to empiric
antibiotic therapy.

In addition to the blood, it may be useful to culture urine in febrile, neutropenic girls, or young children who may
not complain of urinary tract symptoms. In one study, urinary tract infections accounted for 11 percent of all
documented infections in febrile neutropenic patients, and 76 percent of those occurred in girls [1]. In another
small study, UTI occurred in 5 of 58 febrile neutropenia episodes [44].

Additional studies should be obtained only as clinically indicated. Examples include:

● Respiratory virus molecular analysis or culture of nasopharyngeal wash or swab if respiratory signs and
symptoms are present [35].

● Chest radiographs in children with respiratory signs and symptoms [14,45,46]. A chest radiogram that is
negative for infiltrates should be interpreted with caution because infiltrates might appear with a delay or
only when neutrophil counts are recovering.

● Abdominal imaging (radiographs or computed tomography) and/or ultrasonography in children with


abdominal signs and symptoms, particularly abdominal pain.
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● Lumbar puncture for altered mental status or meningeal signs; platelet transfusion may be necessary before
lumbar puncture in patients with thrombocytopenia.

● C. difficile toxin assay should be performed in patients with diarrhea. Although usually of limited value, stool
culture, stool for viral particles, ova, parasites, and viral cultures should be considered if the clinical
presentation is suggestive of infection.

● Culture and Gram stain of drainage from any site with drainage.

● Aspiration and/or biopsy in children with skin and soft tissue lesions to be sent for microbial staining, culture,
histology, and cytology [20].

OVERVIEW OF TREATMENT — The cornerstone of therapy for the febrile, neutropenic patient is prompt
initiation of empiric broad-spectrum antibiotics. Administration of antibiotic therapy more than 60 minutes after
presentation has been associated with increased adverse outcomes and length of stay [47,48]. In an
observational study in pediatric cancer patients, receipt of antibiotics within 60 minutes of presentation was
associated with decreased rates of ICU consultation or admission among [49]. A prospective study in adult
cancer patients also demonstrated increased 28-day mortality when antibiotics were administered between 31
and 60 minutes after presentation than when they were administered within 30 minutes (18 versus 3 percent)
[50].

General guidelines have been published for the use of empiric antibiotics during episodes of fever and
neutropenia, including those published by the Infectious Diseases Society of America (IDSA), most recently
updated in 2010, the International Pediatric Fever and Neutropenia Guideline Panel (2017), and the National
Institute for Health and Care Excellence (NICE) (2012) [6,7,14].

Empiric antimicrobial therapy — The 2010 IDSA and 2017 International Pediatric Fever and Neutropenia
Guideline Panel guidelines provide suggestions for empiric antibiotics in neutropenic patients with cancer
(algorithm 1) [6,14]. However, they are only meant to be guidelines, and treatment must be individualized for
each patient (eg, those at risk for infections with resistant organisms) and known patterns of bacterial
susceptibility in the institution.

The guidelines emphasize that, when choosing empiric therapy, each practitioner should consider [6,14,51]:

● Whether the child is at high or low risk of infection (see 'Risk category' above)

● Drug allergies of the patient, if any

● Presence of organ dysfunction, particularly renal and hepatic

● The particular chemotherapeutic regimen and when it was administered: for example, an association exists
between viridans streptococcal infection and high-dose cytarabine therapy [52,53]

● Whether the patient was receiving prophylactic antimicrobials

● Previous colonization with resistant bacteria (eg, methicillin-resistant S. aureus [MRSA]; vancomycin-
resistant enterococcus; extended-spectrum beta-lactamase producing organism, including Klebsiella
pneumoniae carbapenemase)

Bacterial infections in neutropenic cancer patients may be caused by either gram-positive or gram-negative
organisms, and thus, empiric antibiotic therapy must be effective against a broad spectrum of potential
pathogens (see 'Etiology of fever' above). For patients in whom a site of infection is defined, therapy can be

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adjusted from broad-spectrum to the most appropriate treatment for the particular infection once the patient has
become afebrile [6].

Initial therapy

Suggested regimens — Initial therapy with a broad-spectrum antipseudomonal beta-lactam (eg, cefepime
or ceftazidime), a carbapenem (eg, meropenem), or piperacillin-tazobactam is recommended for uncomplicated
episodes of fever in neutropenic patients [6,7,14]. Randomized controlled trials and systematic reviews have
demonstrated that empiric monotherapy with these agents is as efficacious as combination therapy but with
fewer adverse events [54-59].

Recommended agents include:

● Cefepime – 50 mg/kg intravenously (IV) every 8 hours up to a maximum of 2 g per dose; adjust dose for
renal dysfunction; OR

● Ceftazidime – 50 mg/kg IV every 8 hours up to a maximum of 2 g per dose; adjust dose for renal
dysfunction; OR

● Meropenem – For children ≥3 months of age: 20 mg/kg IV every 8 hours up to a maximum of 1 g per dose
for non-central nervous system infections and 40 mg/kg IV every 8 hours up to a maximum of 2 g/dose for
central nervous system infections; adjust dose for renal dysfunction; OR

● Piperacillin-tazobactam – For infants and children <30 kg: 100 mg/kg of piperacillin component IV every 6 to
8 hours; for children ≥30 kg: 3 g of piperacillin component IV every 6 hours; the maximum daily dose of the
piperacillin component is 16 g/day; the dose must be adjusted for renal dysfunction; this regimen aims to
optimize drug levels for organisms that may have higher minimum inhibitory concentrations (MICs) than in
the past [60]

If a carbapenem is to be used, meropenem is preferred because of the risk of seizures with imipenem-cilastatin.

Additional antimicrobials may be added to the initial regimen based on the clinical presentation, suspected
antimicrobial resistance, or for management of complications. As an example, if abdominal symptoms are
present, particularly abdominal pain or blood per rectum, metronidazole should be added if the initial combination
does not adequately cover anaerobic organisms [5,6]. Likewise, if infection with MRSA is suspected, the addition
of vancomycin may be beneficial.

Vancomycin — Vancomycin is not routinely recommended in the initial empiric regimen for patients with
fever and neutropenia [6,7]. It should be reserved for children with clear indications for additional gram-positive
coverage.

Although up to two-thirds of bacterial isolates from blood in febrile neutropenic cancer patients are gram-positive
cocci, frequently coagulase-negative staphylococci resistant to extended-spectrum penicillins or third-generation
cephalosporins, the morbidity and mortality have not differed in patients treated with or without vancomycin in the
initial antibiotic regimen [61-64]. Infections with alpha-hemolytic streptococci may be an exception to this
observation [65].

The use of vancomycin as part of empiric therapy of febrile neutropenia is discouraged to decrease colonization
or infection with vancomycin-resistant enterococci (VRE). Many institutions have implemented guidelines for the
use of vancomycin recommended by the Hospital Infection Control Practices Advisory Committee of the Centers
for Disease Control and Prevention (CDC) [66]. These restrictions include using vancomycin in febrile
neutropenic patients only when there is a strong suspicion of infection with a gram-positive organism.

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The 2010 guidelines from the IDSA recommend that vancomycin be reserved for the following clinical scenarios
[6]:

● Hypotension or other signs of cardiopulmonary deterioration


● Radiographically documented pneumonia
● Clinically suspected central venous line site infection (eg, chills or rigors with infusion through the catheter
and cellulitis around the catheter entry or exit site)
● Skin or soft tissue infection at any site [20]
● Known colonization with MRSA, penicillin- and cephalosporin-resistant Streptococcus pneumoniae
● When a blood culture has been reported to be growing gram-positive bacteria and identification and
susceptibility testing are pending

Additional indications for vancomycin may include:

● Substantial mucositis
● Prophylaxis with quinolones during afebrile neutropenia
● Previous history of infection with penicillin-resistant streptococci
● Recent intensive chemotherapy associated with a high risk for infection with such organisms (eg, alpha-
hemolytic streptococcal infection following high-dose cytarabine) [18]

If vancomycin is added to the empiric regimen for one of the above indications and susceptible bacteria are not
recovered from the patient within two to three days, vancomycin should be discontinued [6]. Vancomycin can be
associated with nephrotoxicity; kidney function should be strictly monitored. Vancomycin levels are warranted for
patients with renal dysfunction.

Aminoglycosides — Aminoglycosides are not recommended for initial therapy for febrile neutropenic
cancer patients. However, they may be added to the initial regimen in the presence of complications (eg,
hypotension and pneumonia) or if there is a suspicion of antimicrobial resistance [6].

Once the patient is stable and the susceptibilities are known, the aminoglycoside may be discontinued.
Aminoglycoside monotherapy should not be used either as empiric coverage or treatment because of the rapid
development of resistance. Aminoglycosides are associated with oto- and nephrotoxicity and drug levels and
kidney function should be strictly monitored [67].

Initial oral therapy for low-risk patients — Although it has not been well-studied in children, the
combination of ciprofloxacin and amoxicillin-clavulanate is an option for combination therapy for low-risk patients
who are candidates for oral empiric therapy [6,68-70]. In two randomized trials, the rate of treatment failure and
duration of fever, neutropenia, and antimicrobial therapy were similar in patients treated with oral
ciprofloxacin/amoxicillin-clavulanate versus intravenous ceftriaxone or cefepime [68,70].

Modifications of initial therapy — After initiation of the initial antimicrobial regimen, patients should be
monitored closely. Modification of the regimen may be warranted based upon a variety of clinical scenarios,
including (algorithm 2) [6,7]:

● Change in clinical status or vital signs


● Isolation of a blood-borne organism
● Documented clinical or microbiologic infection
● Development of signs or symptoms of a localized infection
● Persistent fever for more than four days (algorithm 3)
● Recurrent fever after initial defervescence

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Antifungal therapy — Fungi are not often isolated as the initial cause of fever and neutropenia but are often in
the differential diagnosis of persistent or recurrent fever. Clinically occult fungal infection must be considered in
children with persistent fever (ie, ≥4 days) and neutropenia despite empiric antibacterial therapy [14,71].
Additional risks for invasive fungal infection include acute myeloid leukemia, relapsed acute leukemia, high-risk
acute lymphoblastic leukemia, prolonged neutropenia (>10 days), highly myelosuppressive chemotherapy, high-
dose glucocorticoids (usually defined as prednisone ≥20 mg per day, or >2 mg/kg per day for patients weighing
<10 kg) for ≥14 days (or equivalent [72]), and allogeneic hematopoietic cell transplant recipients [14,29,71,73-
77]. A variety of fungi can cause infection in cancer patients, and early diagnosis can be difficult.

The 2010 IDSA guidelines and the 2017 International Pediatric Fever and Neutropenia Guidelines (IPFNG)
indicate that the addition of empiric antifungal therapy may be warranted for high-risk patients who have
persistent fever after four to seven days of broad-spectrum antibiotics and no identified source of fever [6,14].
Routine use of empiric antifungal therapy is not recommended for low-risk patients. Before initiating antifungal
therapy, suggested evaluations include abdominal imaging, computed tomography (CT) of the chest, CT of the
sinuses (in patients with localizing signs or symptoms), and biopsy of any suspicious lesions [6,14]. The 2017
IPFNG suggest that galactomannan should not be used to guide initiation of empiric antifungal therapy because
of its poor positive predictive value and inability to exclude non-Aspergillus molds [14,78]. Although beta-D
glucan is widely used in adult cancer patients, it is not recommended in children because its diagnostic accuracy
has not been demonstrated in this population [14,78-80].

Empiric antifungal therapy is usually continued until resolution of neutropenia in the absence of evidence of
invasive fungal infection [77]. However, there is little evidence to guide this decision.

Antifungal therapy is supported by a randomized, placebo-controlled trial in which empiric intravenous


administration of amphotericin B early in the course of febrile neutropenia was effective in the control of clinically
occult fungal invasion and in the prevention of fungal superinfections [9].

Despite the potential benefits of empiric amphotericin B therapy, its use is limited by substantial toxicity,
particularly nephrotoxicity. Potentially less toxic alternatives include lipid formulations of amphotericin B
(liposomal amphotericin, amphotericin B complex, or amphotericin B colloidal dispersion), echinocandins (eg,
caspofungin or micafungin), and triazole derivatives (eg, voriconazole). The IDSA guidelines indicate that there is
insufficient information to suggest a preferred first-line antifungal agent [6]. Lipid formulations of amphotericin B
often are used in children. The 2017 International Pediatric Fever and Neutropenia Guidelines recommend either
liposomal amphotericin B or caspofungin [14]. However, if lipid formulations of amphotericin B are not available,
amphotericin B deoxycholate is acceptable. In children receiving antifungal prophylaxis with an amphotericin B
formulation, an antifungal from a different class should be used as empiric therapy.

Pooled analysis of four randomized trials [81-84] found lipid formulations of amphotericin B to have similar rates
of breakthrough fungal infections, but less nephrotoxicity and infusion-related toxicity (liposomal formulations)
than conventional amphotericin B [85].

Caspofungin is approved by the US Food and Drug Administration (FDA) for the treatment of fever and
neutropenia in children ≥3 months. However, data regarding its safety and efficacy in children with fever and
neutropenia are limited. A multicenter randomized trial comparing caspofungin with liposomal amphotericin B in
82 children with persistent fever and neutropenia found that the two agents had similar response rates and
adverse effects, including infusion-related toxicity and nephrotoxicity [86]. However, the trial was not powered to
detect statistically significant differences. Further study is indicated.

Voriconazole is another antifungal agent that has been insufficiently studied in children with fever and
neutropenia. A systematic review of two trials comparing voriconazole with amphotericin B found liposomal
amphotericin B to be more effective than voriconazole [87].
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Duration of therapy — The duration of empiric antibiotic therapy depends upon the clinical circumstances of the
individual patient. The traditional endpoint has been negative blood cultures for at least 48 hours, resolution of
fever for at least 24 hours, and resolution of neutropenia (ie, absolute neutrophil count [ANC] >500 cells/microL)
[6,14,88]. However, investigators have studied risk factors for the development of serious infection in an effort to
reduce the length of time of hospitalization (if any) and the length of therapy in children and adolescents with low
risk for significant complications [16,18,89-91].

Patients with prolonged neutropenia (ie, more than seven days) generally are considered at relatively high risk
for both bacterial and fungal infections. However, retrospective review of 33 children with prolonged neutropenia
from one institution demonstrated that such patients can be discharged safely before resolution of the
neutropenia if they appeared well, were afebrile for at least 24 hours, had sterile blood cultures, had any local
infection under control, and showed evidence of bone marrow recovery [21,90]. Bone marrow recovery was
defined as any sustained increase in platelet count and ANC or absolute phagocyte count (APC = ANC +
absolute monocyte count). These investigators also showed that patients with either transient or prolonged
neutropenia could be discharged safely from the hospital with antibiotics discontinued when they met the above
criteria [90,91]. Similar criteria are used to guide decisions on the appropriate duration of therapy at other
institutions [11].

Data from a small retrospective study suggest that patients who are afebrile for at least 24 hours, are in good
clinical condition, have been treated with intravenous antibiotics for a minimum of 72 hours, and have no
identified infectious source can be discharged from the hospital without antibiotics before evidence of marrow
recovery [92]. The 2017 International Pediatric Fever and Neutropenia Guidelines suggest that this is a
reasonable approach for patients with low-risk fever and neutropenia [14].

Colony stimulating factors

Prophylactic use — Most children treated for cancer in the United States are treated on research protocols,
and many of the intensive chemotherapy regimens incorporate the use of granulocyte-colony stimulating factor
(G-CSF) immediately after courses of chemotherapy. Potential benefits of prophylactic G-CSF or granulocyte-
monocyte colony stimulating factor (GM-CSF) include a reduction in the duration of neutropenia and, in theory,
the risk of infection. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-
induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic
cell transplantation".)

Although most pediatric studies have demonstrated that prophylactic use of G-CSF reduces the duration of
neutropenia, conclusions about its impact on rates of febrile neutropenia, days of fever, days of intravenous
antibiotic use, rates of documented infection, and lengths of hospital stay have conflicted [93-97]. The conflicting
results may reflect differences in the myelosuppressive intensity of the various chemotherapy regimens, one of
many variables among the different studies. In a meta-analysis of 16 randomized, controlled trials of the
prophylactic use of CSFs in children, CSFs were associated with a 20 percent reduction in febrile neutropenia
and an approximately two-day decrease in hospitalization duration, but no difference in parenteral IV antibiotic
therapy or infection-related mortality rate [98].

The 2010 IDSA guidelines for neutropenic patients indicate that prophylactic use of CSFs may be warranted for
patients in whom the anticipated risk of fever and neutropenia is ≥20 percent [6].

Interventional use — Significant benefits from initiating CSFs in the midst of febrile neutropenia have not
been firmly established. In a randomized study of 186 episodes of febrile neutropenia in pediatric cancer
patients, a small but statistically significant reduction in the length of hospital stay (five versus seven days) and
days of intravenous antibiotic use (five versus six days) was observed with administration of G-CSF compared
with placebo [99]. In another randomized trial in 66 patients with chemotherapy-induced febrile neutropenia (59
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with acute lymphoblastic leukemia), those treated with G-CSF had shorter median time to resolution of
neutropenia (4 versus 13 days), but no significant differences in duration of fever or antibiotic treatment, addition
of antifungal therapy, or incidence of shock [100]. Comparable, modest results were obtained in a study
evaluating the effect of the addition of GM-CSF during episodes of fever and neutropenia [101].

Whether high-risk patients (see 'High-risk' above) and/or those with predicted prolonged courses of neutropenia
(ie, more than 7 days) might benefit from the use of G-CSF remains unanswered. Nonetheless, interventional G-
CSF may be warranted for children with complicated episodes of fever and neutropenia [102-104].

Outpatient management — Outpatient management of fever and neutropenia with intravenous or oral
antibiotics may be an option for carefully selected low-risk patients if daily follow-up is ensured [6,14]. Several
studies using strict eligibility criteria suggest that outpatient treatment may be safe and appropriate for children at
low risk of serious infection [105-108].

In a retrospective study, hypotension, requirement for fluid resuscitation, and a diagnosis of leukemia or
lymphoma correlated with an increased probability of bacteremia and persistent fever and ANC <100
cells/microL after 48 hours of empiric therapy were associated with a high risk of complications [16]. Based upon
these observations, the investigators suggested that children who initially present without signs of sepsis and
who are afebrile and have an ANC >100 cells/microL after 48 hours of empiric therapy could be considered for
early hospital discharge, with continuation of outpatient antibiotics [16].

Another retrospective review of 33 children with prolonged neutropenia demonstrated that such patients can be
discharged safely before resolution of the neutropenia if they appeared well, were afebrile for at least 24 hours,
had sterile blood cultures, had any local infection under control, and showed evidence of bone marrow recovery
[90]. Bone marrow recovery was defined as any sustained increase in platelet count and ANC or absolute
phagocyte count (APC = ANC + absolute monocyte count).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries
and regions around the world are provided separately. (See "Society guideline links: Neutropenic fever in
children with cancer".)

SUMMARY AND RECOMMENDATIONS

● Infection is a major cause of morbidity and mortality in cancer patients. Fever may be the first manifestation
of a life-threatening infection, particularly during periods of neutropenia. (See 'Introduction' above.)

● Neutropenia, for the purpose of management of the febrile pediatric cancer patient, is defined as an absolute
neutrophil count (ANC) of <500 cells/microL or an ANC that is expected to decrease to <500 cells/microL
during the next 48 hours. In neutropenic patients, fever is defined as a single oral temperature ≥38.3°C
(101°F), a temperature ≥38°C (100.4°F) for longer than one hour, or two elevations >38°C (100.4°F) during
a 12-hour period. (See 'Definitions' above.)

● Patients with fever and neutropenia can be categorized as high- or low-risk for severe infection based upon
presenting signs and symptoms, ANC, underlying cancer, type of therapy, and medical comorbidities. High-
risk is defined by neutropenia (ANC <500 cells/microL) anticipated to last >7 days; hepatic or renal
insufficiency; or comorbid medical problems. Low-risk is defined by neutropenia expected to resolve within 7
days; stable and adequate hepatic and renal function; and no active comorbidities. (See 'Risk category'
above.)

● Between 10 and 40 percent of children with fever and chemotherapy-induced neutropenia have a
documented infection. Bloodstream infections are the most common and may be caused by gram-positive
organisms, gram-negative organisms, or fungi. (See 'Etiology of fever' above.)

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● Infection is a major cause of morbidity and mortality in cancer patients. Serious infection may occur in the
absence of fever and/or neutropenia and must be considered in the pediatric cancer patient who is febrile
and neutropenic; febrile but not neutropenic; or neutropenic and afebrile with signs of infection or clinical
deterioration. Prompt initiation (ie, as soon as possible, but definitively within 60 minutes of presentation) of
empiric therapy can be life-saving, so rapid (but thorough) evaluation is critical. (See 'Evaluation' above.)

● Important aspects of the history include new site-specific symptoms, antimicrobial prophylaxis, infection
exposures, recent infections or colonizations, underlying comorbid conditions, and noninfectious causes of
fever (eg, receipt of blood products). (See 'History' above.)

● Areas of particular interest on the physical examination include the skin (especially skin folds, nail beds,
central line sites, and sites of recent procedures such as bone marrow aspiration or lumbar puncture);
sinuses; oropharynx, including the gums; lungs; abdomen; and perineum. Mild erythema or tenderness may
be important clues to infection. The physical examination must be repeated at least daily after initiation of
empiric antimicrobial therapy. (See 'Physical examination' above.)

● The laboratory/imaging evaluation of the child with fever and neutropenia should include (at minimum) (see
'Laboratory tests and imaging' above):

• Complete blood count (CBC) with differential and platelet count

• Electrolytes, creatinine, and blood urea nitrogen

• Liver transaminases and total bilirubin

• Blood cultures

• Cultures, molecular diagnostic assays, and/or imaging of other sites of suspected infection as clinically
indicated; treatment should not be delayed while awaiting results

● The 2010 Infectious Disease Society of America (IDSA) guidelines for antimicrobial agents in neutropenic
patients with cancer provide suggestions for initial empiric antibiotic selection (algorithm 1), modification of
the empiric regimen during days two to four of therapy (algorithm 2), and management of high-risk patients
with fever for more than four days (algorithm 3). (See 'Overview of treatment' above.)

● Monotherapy with a broad-spectrum antipseudomonal beta-lactam (eg, cefepime, ceftazidime), a


carbapenem (eg, meropenem), or piperacillin-tazobactam is recommended for uncomplicated episodes of
fever in neutropenic patients. Vancomycin should be reserved for children with clear indications for gram-
positive coverage. (See 'Empiric antimicrobial therapy' above.)

● Empiric antifungal therapy may be warranted for high-risk patients who have persistent fever after four to
seven days of broad-spectrum antibiotics and no identified source of fever. (See 'Antifungal therapy' above.)

● The duration of empiric antibiotic therapy depends upon the clinical circumstances of the individual patient.
Resolution of neutropenia is the traditional endpoint. Outpatient management of fever and neutropenia with
intravenous or oral antibiotics may be an option for carefully selected low-risk patients if daily follow-up is
ensured. (See 'Duration of therapy' above and 'Outpatient management' above.)

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Topic 6051 Version 43.0

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GRAPHICS

Initial management of fever and neutropenia

ANC: absolute neutrophil count; C. difficile: Clostridium difficile.


* Fever in a neutropenic patient is defined as a single temperature >38.3°C (101°F) or a sustained temperature
>38.0°C (100.4°F) for >1 hour.
¶ The authors consider patients with an ANC <500 cells/microL for >7 days to be at high risk for serious
complications. It should be noted that in the Infectious Diseases Society of America guidelines, patients with an
absolute neutrophil count ≤100 cells/microL for >7 days are considered to be at high risk for serious
complications.
Δ Although ceftazidime monotherapy has been used for many years, we typically recommend using an
alternative. Refer to the UpToDate topic review for details.

Adapted with permission from: Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical Practice Guideline for the Use of
Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of
America. Clin Infect Dis 2011; 52:e56. Copyright © 2011 Oxford University Press. Available at:
www.idsociety.org.

Graphic 60657 Version 18.0

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Reassessment of the patient with neutropenic fever after two to four days of
empiric therapy

ANC: absolute neutrophil count; CT: computed tomography; IV: intravenous; MRI: magnetic resonance imaging.
* We consider patients to be high-risk if they have either of the following characteristics: neutropenia (ANC <500
cells/microL following cytotoxic chemotherapy) anticipated to last >7 days OR significant comorbid conditions. It
should be noted that in the Infectious Diseases Society of America guidelines, an ANC ≤100 cells/microL is used as
the cutoff for high-risk neutropenia.
Δ Fever in a neutropenic patient is defined as a single temperature >38.3°C (101°F) or a sustained temperature
>38.0°C (100.4°F) for >1 hour.

Adapted with permission from: Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical Practice Guideline for the Use of
Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of
America. Clin Infect Dis 2011; 52:e56. Copyright © 2011 Oxford University Press. Available at: www.idsociety.org.

Graphic 74452 Version 14.0

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Reassessment of the high-risk patient with persistent neutropenic fever


after four days of empiric therapy

ANC: absolute neutrophil count; CT: computed tomography; MRI: magnetic resonance imaging.
* We consider patients to be high-risk if they have either of the following characteristics: neutropenia (ANC
<500 cells/microL following cytotoxic chemotherapy) anticipated to last >7 days OR significant comorbid
conditions. It should be noted that in the Infectious Diseases Society of America guidelines, an ANC ≤100
cells/microL is used as the cutoff for high-risk neutropenia.
Δ Fever in a neutropenic patient is defined as a single temperature >38.3°C (101°F) or a sustained temperature
>38.0°C (100.4°F) for >1 hour.
◊ Limited data to support recommendation.

Adapted with permission from: Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical Practice Guideline for the Use
of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of
America. Clin Infect Dis 2011; 52(4):e56-93. Copyright © 2011 Oxford University Press. Available at:
http://www.idsociety.org.

Graphic 53163 Version 14.0

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Contributor Disclosures
Nabil M Ahmed, MD, MPH Consultant/Advisory Boards: Adaptimmune (T cell therapies). Patent Holder: Cell
Medica (T cell therapies). Patricia M Flynn, MD Consultant/Advisory Boards: Merck [Febrile neutropenia
(Posaconazole)]. Morven S Edwards, MD Grant/Research/Clinical Trial Support: Pfizer Inc. [Group B
Streptococcus]. David G Poplack, MD Nothing to disclose Mary M Torchia, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.

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