Indian J Pediatr
DOI 10.1007/s12098-012-0901-y
SYMPOSIUM ON PGIMER MANAGEMENT PROTOCOLS ON ONCOLOGICAL EMERGENCIES
Febrile Neutropenia: Outline of Management
Sapna Oberoi & Renu Suthar & Deepak Bansal & R. K. Marwaha
Received: 9 March 2012 / Accepted: 18 September 2012
# Dr. K C Chaudhuri Foundation 2012
Abstract Febrile neutropenia is a common emergency en-
countered in children receiving chemotherapy for a malignan-
cy. Left untreated, it can lead to serious morbidity and
mortality. Febrile neutropenia is suspected in any patient on
chemotherapy who presents with fever. Prompt evaluation and
management by the primary contact pediatrician is essential
for a successful outcome. A detailed history and physical
examination is warranted to identify source of infection, al-
though two thirds of them may not have localizing symptoms
or signs. Risk stratification is valuable in categorizing the
severity and guiding therapy. Initial stabilization, prompt ini-
tiation of appropriate antibiotics and adequate supportive care
are the cornerstone of treatment. Knowledge of the locally
prevailing bacteriological profile and antimicrobial suscepti-
bility data is crucial for each hospital/unit to frame and peri-
odically modify guidelines for the choice of antimicrobials.
Delay in initiating antimicrobials significantly worsens the
outcome. Education of the family as well as the members of
the treating unit is important in this regard. Pro-active steps
must be taken to reduce incidence of hospital acquired sepsis.
Diagnosis and management in relevance to the emergency
room is reviewed and institutional practice is shared.
Keywords Absolute neutrophil count . Acute lymphoblastic
leukemia . ALL . Cancer . Culture . Growth-factors
Introduction
Febrile neutropenia is the most common emergency encoun-
tered in children on treatment for a malignancy and remains
S. Oberoi : R. Suthar : D. Bansal (*) : R. K. Marwaha
Hematology-Oncology unit, Department of Pediatrics,
Advanced Pediatric Center, Post Graduate Institute of Medical
Education and Research, Chandigarh 160012, India
e-mail: deepakritu@yahoo.com
a significant cause of morbidity and mortality. It commonly
occurs in children diagnosed to have acute leukemia, lym-
phoma, solid tumor or aplastic anemia [1]. It may result
from the underlying malignancy per se or typically due
to the effect of chemotherapy. Fever may be the sole
manifestation of a serious infection in neutropenic chil-
dren as other signs of systemic inflammation might be
attenuated. Therefore, all children with febrile neutrope-
nia should undergo a systematic evaluation, including a
history and physical examination, appropriate diagnostic
tests, and prompt initiation of empirical antimicrobial
therapy.
Definitions
Febrile neutropenia A single oral temperature of ≥38.3 °C
(101 °F) or a temperature of ≥38.0 °C (100.4 °F) for ≥1 h,
with an absolute neutrophil count [Absolute neutrophil count
(ANC) 0 mature granulocytes + neutrophil band or stab cells]
of <500/mm3, or an ANC that is expected to decrease to <500
cells/mm3 during the next 48 h [2].
Profound neutropenia ANC<100 cells/mm3
Prolonged neutropenia Neutropenia lasting >7 d
Evaluation
History
A relevant history should include the following points:
& Fever onset, duration and severity
& Associated localizing symptoms: Ear, nose, throat, res-
piratory, gastrointestinal tract, musculoskeletal and uri-
nary system
 Indian J Pediatr

& Phase of chemotherapy (intensive vs. non intensive)
& Duration since the last chemotherapy
& Recent hospitalization and antibiotics received, if any
Examination
Vitals (temperature, heart rate, respiratory rate, capillary refill
time, blood pressure, saturation) should be checked in every
patient of suspected febrile neutropenia who walks in to the
emergency room. The patient may appear well despite being
in a state of hemodynamic compromise. A detailed physical
examination focusing on possible sites of infection must be
undertaken. Sites that deserve attention and are commonly
overlooked include oral cavity, ear, sinuses, skin, nails, peria-
nal area, intravascular catheter insertion site and the site of
bone marrow aspiration. The potential causes of infection in
patients with febrile neutropenia are listed in Table 1.
Indicators in history and examination can provide valuable
clues to the etiology of fever. For e.g., a child with respiratory
distress and hypoxemia with bilateral diffuse infiltrates on
chest radiograph may have infection with Pneumocystis jir-
oveci or respiratory syncytial virus. Fungal infection should be
suspected in the presence of skin lesions (necrotic eschars,
nodules or target lesions), sinusitis, orbital cellulitis or pleu-
ritic pain. Fever, headache, seizures, encephalopathy or focal
deficits may occur due to encephalitis, encephalomyelitis,
bacterial meningitis or brain abscess. Cytomegalovirus, Vari-
cella zoster virus, Epstein-Barr virus, mumps and Human
herpesvirus-6 are the common viruses responsible for enceph-
alitis. Brain abscess typically results from invasive infections
due to aerobic and anaerobic bacteria or fungi.
1. Complete blood count, including differential leukocyte
count and ANC
2. Serum electrolytes, urea and creatinine
3. Blood culture: Obtain as early as possible and always
before the administration of antibiotics. Two sets of blood
cultures from separate venipuncture sites should ideally
be drawn. In the presence of a central venous catheter, a
blood culture should be obtained from each lumen of the
catheter and another from a peripheral vein.
4. Chest radiograph: In patients with respiratory symptoms
and signs
5. Cultures from any other site, as clinically relevant. This
includes stool, urine, cerebrospinal fluid, skin, respira-
tory secretions or pus.
Second line investigations. These are dictated by the
clinical course:
1. Serum Galactomannan test, CT scan of chest/paranasal
sinuses may be indicated in patients with suspected
fungal infection.
2. Bronchoalveolar lavage: If pneumonia is non-resolving/
non-responding.
3. Skin biopsy, from skin nodules, if any.
Risk Stratification
Assessment of risk is crucial in determining the appropriate
choice of antimicrobials, the route of administration (intra-
venous vs. oral), setting (inpatient vs. outpatient) and dura-
tion. The patients can be classified as low or high risk [2, 3].
Low Risk Patients

Patients at low risk of a serious infection include children

Investigations
who fulfill the following criteria [2, 4]:
First line investigations to be performed in every case & Clinically stable and ‘well’ looking
include: & Temperature <39 °C

Table 1 Potential causes of infection in patients with febrile neutropenia

System Cause of infection

Eyes Conjunctivitis, orbital cellulitis

Ear, nose, throat Otitis media, sinusitis, tonsillitis, pharyngitis, oral candidiasis
Teeth Dental caries/abscess
Chest Pneumonia
Abdomen Diarrhea, dysentery, neutropenic enterocolitis, pseudomembranous colitis
Perineum Perianal candidiasis, perianal abscess
Skin Cellulitis, abscess, nodular or target lesions suggestive of fungal infections, varicella rash, purpura fulminans
CNS Meningitis, meningoencephalitis, cavernous sinus thrombosis
Urinary tract Urinary tract infection
Intravascular catheters Exit site infection, tunnel infection
Indian J Pediatr
& Non-intensive phase of chemotherapy, e.g., maintenance
phase of chemotherapy
& Malignancy in remission
& Lack of any focus of infection e.g., pneumonia, abscess,
sinusitis or diarrhea etc.
& Lack of medical co-morbidities
& ANC≥100/mm3 and likely to rise within the next 7 d.
& Absolute monocyte count >100/mm3
& Not fulfilling any criteria for the high risk category
If a close follow-up can be ensured, such episodes can
often be managed with oral antibiotics [5]. The choice
includes cefixime, amoxicillin-clavulanate or levofloxacin
[2]. If there is a doubt regarding the clinical condition or
reliability of follow-up, the patient should be admitted and
administered intravenous antibiotics, as in the high risk
group.
High-Risk Patients
Any of the following indicators categorize a patient as
‘high-risk’ [2, 4]:
& Recent intensive chemotherapy
& Profound neutropenia (ANC<100 cells/mm3), anticipat-
ed to extend for >7 d. It is typically observed during or
following the intensive phases of therapy, e.g., induc-
tion, consolidation or intensification blocks of chemo-
therapy in patients with acute lymphoblastic leukemia
& Any focus of infection, e.g., cellulitis, abscess, pneumo-
nia, diarrhea, etc.
& Evidence of hypotension, respiratory distress or
hypoxemia
& Mucositis interfering with oral intake or resulting in
diarrhea
Management
‘High-risk’ patients are to be hospitalized and adminis-
tered broad-spectrum intravenous antibiotics (Fig. 1).
Knowledge of the locally prevailing bacteriological pro-
file and antimicrobial susceptibility data is crucial for
the choice of antimicrobials. Each hospital/unit must
review the prevalance of common pathogens and their
antimicrobial susceptibility data periodically to frame
and modify the choice of antimicrobials in their setting.
Majority of infections in febrile neutropenia are caused
by gram negative organisms e.g., Pseudomonas aerugi-
nosa, E. coli, Klebsiella pneumonia and Acinetobacter
species [5, 6]. Staphylococcus aureus, coagulase nega-
tive Staphylococcus and Enterococcus are the common
gram positive organisms [6–8]. Fungal infections with
Candida, Aspergillus or Mucor are usually encountered
in patients with prolonged febrile neutropenia who are
receiving broad spectrum antibiotics [1, 2].
Antibiotics
It is important that patients are administered the first dose of
antibiotics without any delay. The patients in the authors
unit who are receiving intensive blocks of chemotherapy are
instructed to reside in the vicinity of the hospital, so that
antibiotics can be started promptly at the onset of fever.
Delay in initiating antimicrobials significantly increases
the morbidity and mortality. Education of the family as well
as the members of the treating unit is important in this
regard. Care-takers are advised not to administer paraceta-
mol at home as it may mask fever and can lead to delay in
seeking medical care.
& Anti-pseudomonal β-lactam agents: Monotherapy with
anti-pseudomonal β-lactam agents such as anti-
pseudomonas penicillin (piperacillin-tazobactum), anti-
pseudomonal cephalosporin (cefoperazone-sulbactum) or
carbepenems (meropenem or imipenem-cilastatin) or
cefepime is recommended as first line by Infectious Dis-
ease Society of America [2]. However, no significant
differences in treatment failure, including antibiotic mod-
ification, infection-related mortality, or adverse events
were observed while comparing anti-pseudomonas peni-
cillin±aminoglycoside regimen with carbapenem mono-
therapy in a recent metaanalysis [9]. Hence, carbapenems
can be reserved as second line antibiotics to prevent the
emergence of drug resistant organisms. Cefoperazone-
sulbactum along with Amikacin are the current first line
choice in authors unit. Therapy is switched to second line
drugs: Vancomycin and Carbepenems (meropenem or
imipenem-cilastatin) after 48–72 h, if fever is unrelenting
and there is no improvement in the clinical condition.
Colistin is reserved as a third line drug.
& In a hemodynamically unstable patient, an adequate
coverage for drug-resistant gram-negative and gram-
positive organisms, as well as for anaerobes should be
given. Hence, second line antibiotics should be admin-
istered upfront. A combination of an anti-pseudomonal
carbapenem, such as imipenem or meropenem, as well
as addition of an aminoglycoside, together with vanco-
mycin (three antibiotics) provides this cover [2].
& Specific gram positive cover is not a standard part of
initial empiric antibiotic therapy [2]. It should be added
in initial therapy, if patient has evidence of any of the
following:
– Hemodynamic instability
– Severe sepsis
– Radiographically confirmed pneumonia
– Clinically suspected catheter related infection
 Indian J Pediatr

Fever (>38.3OC) and neutropenia (Absolute neutrophil count <500/mm3)

LOW RISK HIGH RISK

Non intensive phase of chemotherapy Intensive phase of chemotherapy

Clinically stable with no co-morbidity Clinically unstable patient
No focus of infection Any medical co-morbidity
Absolute neutrophil count ≥100/mm3 Any focus of infection
Anticipated neutropenia <7 d Absolute neutrophil count <100/mm3
Anticipated neutropenia >7d

INITIAL STABILIZATION and INVESTIGATIONS

Take care of airway, breathing and

INPATIENT IV ANTIBIOTICS circulation
OUT PATIENT ANTIBIOTICS
Gastrointestinal intolerance Obtain CBC, blood culture, electrolytes
Good oral intake Concern for compliance or Chest X-Ray and other cultures if indicated
Assured follow-up follow-up

Cefexime, or Defervescence INPATIENT IV ANTIBIOTICS

Amoxicillin/clavulanate, or
Levofloxacillin
If fever persists >48 h
hospitalize & start IV antibiotics
Continue IV or oral
antibiotic till ANC is rising
and ≥500/mm3
As per locally prevailing bacteriological
profile and antimicrobial susceptibility data
Cefoperazone/sulbactum or
Piperacillin/tazobactum ± Amikacin
Vancomycin + Carbapenem if
hemodynamically unstable

Adjust antimicrobials based on clinical

course, counts, radiology & cultures

Fig. 1 Initial management of patient with febrile neutropenia

– Skin or soft tissue infection
– Known colonization with methicillin-resistant Staphy-
lococcus aureus (MRSA), Vancomycin-resistant En-
terococcus (VRE), or Penicillin-resistant Streptococcus
– Severe mucositis, if fluoroquinolone prophylaxis
has been given and ceftazidime is employed as
empirical therapy
& Empirical or presumptive anti-malarial therapy is not
recommended [10].
General Considerations and Supportive Care
& Pro-active steps must be taken to reduce incidence of
hospital acquired sepsis, an increasingly common and
challenging complication in hospitalized patients.
– Frequent hand washing is often not practical in busy
units. However, the use of alcohol based hand rub in
between patients must be ensured by each medical
and nursing personnel.
– Use of IV fluids, central lines, foley’s catheter etc. must
be restricted, if possible. Administration of IV fluids
for minor reasons should be avoided. Nasogastric
feeding should be encouraged in patients with anorexia
or mucositis.
– Rectal enemas, suppositories, and rectal examinations
are contraindicated in neutropenic patients [2, 11]
& Patients with severe sepsis and septic shock should
be managed as per the survival sepsis guidelines
[12]. Non-invasive intermittent positive pressure
ventilation should be attempted in case of acute
respiratory failure, before restoring to mechanical
Indian J Pediatr
ventilation, except in those with severe hemodynam-
ic compromise [13, 14].
& Hemoglobin<8 g/dl is generally an indication for blood
transfusion in a stable patient.
& Indication for platelet transfusion: These vary with the
clinical condition of the patient. In a stable patient with-
out any co-morbidities and bleeds, prophylactic trans-
fusions are recommended at a count below 10×109/
mm3. Few studies have suggested that this threshold
can be further lowered to 5×109/mm3 [1, 15, 16]. Trans-
fusion threshold of 20×109/mm3and 100×109/mm3 is
recommended in patients with minor (mucosal, epistax-
is) and major bleeds (hemoptysis, GI or CNS bleed),
respectively [1]. The practice may often be varied in
different units, depending on physician preferences and
extent of availability of blood products.
& Growth factors: Administration of G-CSF has no role in
the management of children with uncomplicated febrile
neutropenia [12]. However, they might be useful in
reducing the duration of neutropenia and length of hos-
pital stay in children with complicated febrile neutrope-
nia (pneumonia, hypotension, invasive fungal infection
or multi organ dysfunction) [17, 18].
Subsequent Management
It depends upon response to initial antibiotics, clinical status
of the patient, culture results and ANC. The patient should
be transferred under the care of a Pediatric Oncologist at this
point.
& Patient who is without a focus of infection, afebrile
within 2–3 d after first line antibiotics, along with a
rising ANC, with negative cultures, may be discharged
after 24–48 h or may be shifted to oral antibiotics, till
ANC exceeds 500/cumm.
& In case of documented infections, including soft tissue
infection, pneumonia, or bacteremia, appropriate anti-
biotics should be given for 10–14 d.
& Persistent fever beyond 3 d, despite antibiotic therapy
should prompt a thorough search for source of infection:
– Relevant investigations include repeat blood/urine
cultures, stool for clostridium difficile, fungus and
atypical organisms in case of diarrhea, and CT scan
of chest/sinuses
– Antibacterials should be upgraded in high risk
patients with persistent fever after 48–72 h, or ear-
lier in case of any hemodynamic instability.
– Empirical antifungal therapy (Amphotericin) and
investigations for invasive fungal infections should
be considered for patients with persistent or recurrent
fever after 4–7 d of antibiotics and whose overall
duration of neutropenia is expected to exceed 7 d.
Conflict of Interest None.
Role of Funding Source None.
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