ww.sciencedirect.com

p e d i a t r i c i n f e c t i o u s d i s e a s e x x x ( 2 0 1 4 ) 1e5

Available online at w

ScienceDirect

journal homepage: www.elsevier .com/locate/p id

Original Article

Febrile neutropenia in pediatric cancer patients:Experience from a tertiary health care facilityof Pakistan

Muhammad Matloob Alam a,*, Zehra Fadoo b

a Fellow Pediatric Hematology & Oncology, Department of Paediatrics & Child Health, Aga Khan University Hospital,

Stadium Road, PO Box 3500, Karachi 74800, Pakistanb Consultant Pediatric Oncologist, Diplomate American Board of Pediatrics, Department of Paediatrics & Child

Health, Aga Khan University Hospital, Stadium Road, PO Box 3500, Karachi 74800, Pakistan

a r t i c l e i n f o

Article history:

Received 26 September 2013

Accepted 16 June 2014

Available online xxx

Keywords:

Febrile neutropenia

Prolonged

Pediatric

Adverse outcome

Fungal infection

* Corresponding author. Tel.: þ92 300 280285E-mail addresses: matloob.alam@aku.edu

Please cite this article in press as: Alamtertiary health care facility of Pakistan, P

http://dx.doi.org/10.1016/j.pid.2014.06.0022212-8328/Copyright © 2014, Indian Academ

a b s t r a c t

Aims: Pediatric cancer patients with febrile neutropenia (FN) have an increased risk of

infectious complications and mortality.

Methods: This study was a retrospective analysis of pediatric cancer patients with FN.

Results: Out of 872 episodes of FN, 559 (64.1%) were males and 313 (35.9%) females. The

mean age was 5.32 ± 4.07 years. ALL (67.7%) was the most common diagnosis followed by

AML (12.2%), lymphoma (9.9%) and solid tumors (5.8%). Age < 5 year (Odd Ratio ¼ 1.5; p ¼0.043), AML (OR ¼ 1.8; p ¼ 0.019), patients who received chemotherapy within 2 week of FN

(OR ¼ 1.9; p ¼ 0.007), absolute neutrophil count < 50/cm (OR ¼ 1.5; p < 0.041), platelets count

< 50,000/cm (OR ¼ 1.5; p < 0.027), fungal infection (OR ¼ 15.6; p < 0.001), and pneumonia

were identified as risk factors associated with development of prolonged FN in pediatric

cancer patients. A total of 25 (2.9%) patients required PICU admission and 12 (1.4%) patients

expired. Both variables, PICU admission (9% Vs 2%; OR ¼ 5.4; p < 0.001) and mortality rate

(5.2% Vs 0.8%; OR ¼ 8.1; p < 0.001) were statistically significant in patients with prolonged

FN versus FN respectively.

Conclusion: Prospective studies in large cooperative trials may be beneficial in evaluating

these risk factors further.

Copyright © 2014, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights

reserved.

1. Introduction

There have been major advances in the treatment and out-

comes of childhood cancer over the last few decades.

Improved outcomes have largely been achieved by aggressive

9 (mobile); fax: þ92 021 3, dr.matloobalam@hotma

MM, Fadoo Z, Febrile nediatric Infectious Disea

y of Pediatrics, Infectious

treatment of childhood cancers including systemic antineo-

plastic and radiation therapy that have secondary effects on a

variety of normal cells including hematopoietic elements of

the bone marrow.1 Chemotherapy induced neutropenia is a

common complication which renders children extremely

vulnerable to life threatening infections. Epidemiological

4934292.il.com (M.M. Alam).

eutropenia in pediatric cancer patients: Experience from ase (2014), http://dx.doi.org/10.1016/j.pid.2014.06.002

Disease Chapter. All rights reserved.

p e d i a t r i c i n f e c t i o u s d i s e a s e x x x ( 2 0 1 4 ) 1e52

studies have demonstrated a high incidence of sepsis in pae-

diatrics cancer patients. Rates up to 12.8% and 17.4% in chil-

dren aged 1e9 years and 10e19 years respectively, have been

reported making febrile neutropenia (FN) a worrying and

serious complication in childhood cancer treatment.1,2

In recent years, several studies from developed countries

have evaluated the risk factors for bacteremia or poor out-

comes among patientswith cancer and helped to establish the

current guidelines for the treatment of FN.3e5 However,

despite major advances in understanding, established guide-

lines and recommendations for the treatment of FN, children

remain extremely vulnerable to life threatening infections.

This contributes to a significant morbidity and mortality in

pediatric patients with cancer.1,6,7

Mortality associated with FN ranges from 2 to 6% in chil-

dren.8,9 Considering that the overall mortality rate for FN ep-

isodes was 10% a decade ago the current 2e4% rate indicates a

significant improvement in management resulting in a

favorable impact. Nevertheless this mortality rate still re-

mains substantial, warranting further improvement.

The single most important advancement in oncology

supportive care leading to an improved survival has been the

prompt initiation of empirical antibacterial antibiotics when

the neutropenic patient becomes febrile. Before this approach

was instituted in the early 1970s, the mortality rate from

gram-negative infections, approached 80%, but with the

widespread use of effective empirical antibiotics, the overall

mortality rate has significantly declined.10 Recently the In-

fectious Diseases Society of America has published general

guidelines for use of antimicrobial agents in neutropenic pa-

tients with unexplained fever.11

Many studies from developed countries have reported the

importance of prompt management of FN. However, reports

from the developing countries are lacking and no published

reports are available in Pakistan. Thus this study was carried

out to identify the burden of febrile neutropenia and describe

the demographic, clinical feature, laboratory data and man-

agement outcomes of febrile neutropenia in pediatric cancer

patients at tertiary health care center of Pakistan.

2. Material and methods

2.1. Study design and setting

This is a retrospective study analyzing the clinical data of all

children admitted with or who developed febrile neutropenia

in the pediatric oncology unit at the Aga Khan University

Hospital (AKUH) in Karachi, Pakistan from January 2011 to

December 2012.

2.2. Patient population and definition

Patients one month to 15 years of age, who were admitted to

the pediatric oncology ward from January 2011 to December

2012 with diagnosis of febrile neutropenia (FN) were

included. For definition the Fever and Neutropenia Guideline

of Infectious Diseases Society of America (IDSA) were fol-

lowed.12 Fever was defined as a single oral temperature of

>38.3 �C or a temperature of >38.0� sustained over a 1-h

Please cite this article in press as: Alam MM, Fadoo Z, Febriletertiary health care facility of Pakistan, Pediatric Infectious Disea

period on more than one occasion in a 24-h period. Neu-

tropenia was defined as an absolute neutrophil count (ANC)

of less than 500/mm3.

2.3. Data collection

All patients who had diagnosis codes for both neoplastic dis-

ease (International Classification of Diseases, 9th revision,

clinical modification [ICD-9-CM] code 140e239) and febrile

neutropenia, and were 15 years of age or younger were iden-

tified by using health information management system and

included in the analysis. For those patients who had more

than one admission for febrile neutropenia, each admission

was counted as separate case. The primary outcomes of this

analysis were pediatric intensive care unit (PICU) admission

and mortality. Relevant covariates data were collected

including demographic features, type of malignancy, phase of

chemotherapy, clinical features at presentation, duration of

symptoms, presentation location (Emergency department,

clinic, or inpatient ward), initial laboratory findings including

total white blood cell (WBC) count, ANC, and platelet count;

microbiological data, antibiotic(s) used, radiological finding (if

applicable) and outcomes data. All patients were treated as in

patients following the International Pediatric Fever and Neu-

tropenia Guideline.13

2.4. Statistical analysis

The data was analyzed by using SPSS version 20.0 (IBM, Chi-

cago, USA) was used. Summary statistics were used to

describe the cohort. Results were presented as mean and

standard deviation for continuous variables and frequency

and percentage for categorical variables. Data was stratified in

two groups to identify the mortality associated risk factors in

pediatric oncology patients with febrile neutropenia. A p-

value of <0.05 was considered statistically significant.

2.5. Ethical approval

The study was approved by the Ethical Review Board (ERB) of

Aga Khan University, Karachi.

3. Results

The total number of admissions in the pediatric oncology unit

during the study period was 2516 and a total admission with

febrile neutropenia was 918 (36.5%). Forty-six cases were

excluded from the study because of noncompliance and/or

missing data. Out of 872 available febrile neutropenic patients

for analysis, 737 (84.5%) had febrile neutropenia of less than 5

days versus 135 (15.5%) patients with prolonged febrile neu-

tropenia (FN > 5 days). Febrile neutropenia and PFN admission

rate among all pediatric oncology patients was 34.7% and 5.3%

respectively.

Demographic features, clinical characteristics of the pa-

tients and their hospitalizations are presented in Table 1. The

mean age of the study population was 5.32 (±SD 4.07) years.

There were 559 (64.1%) males and 313 (35.9%) females, with

male: female ratio 1:1.8. The emergency room was the most

neutropenia in pediatric cancer patients: Experience from ase (2014), http://dx.doi.org/10.1016/j.pid.2014.06.002

Table 1 e Baseline characteristics of the study patients(n ¼ 872).

Characteristics Number (%)

Gender Male 559 (64.1%)

Female 313 (35.9%)

Age <5 year 506 (58.1%)

>5year 366 (41.9%)

Cancer type ALL 590 (67.7%)

AML 105 (12.2%)

Lymphoma 86 (9.9%)

Sarcomas 51 (5.8%)

CNS tumors 11(1.3%)

Others 28 (3.2%)

Presenting complaints Fever 715 (81.9%)

Poor appetite 598 (68.6%)

Vomiting 163 (18.7%)

Cough 139 (15.9%)

Mucositis 124 (14.2%)

Diarrhea 98 (11.2%)

Urinary complaints 26 (2.9%)

Rash 10 (1.1%)

Source of fever BSI 58 (6.6%)

Bacterial infection 48 (5.5%)

Fungal infection 10 (1.1%)

URTI 192 (22%)

Pneumonia 23 (2.6%)

Fungal Pneumonia 8 (0.9%)

Infectious Diarrhea 16 (1.8%)

UTI 11 (1.3%)

Cause Unknown 564 (64.7%)

Presentation location: Emergency Department 719 (82.4%)

Received chemotherapy within the preceding

2 weeks

656 (75.2%)

ANC 250e500/cm 254 (29.1%)

50e250/cm 279 (31.9%)

<50/cm 339 (38.9%)

Hemoglobin <9 g/dl 538 (61.7%)

Platelets count 50,000e150,000/cm 508 (58.3%)

<50,000/cm 364 (41.7%)

PICU Admission 25 (2.9%)

Died 12 (1.4%)

Abbreviations: ALL: Acute Lymphoblastic Leukemia, AML: Acute

Myeloid Leukemia, CNS, BSI: Blood Stream Infection, URTI: Upper

Respiratory Tract Infection, UTI: Urinary Tract Infection, ANC:

Absolute Neutrophil Count, PICU: Pediatric Intensive Care Unit.

p e d i a t r i c i n f e c t i o u s d i s e a s e x x x ( 2 0 1 4 ) 1e5 3

common presenting location accounting for 719 (82.4%) of

hospitalizations. Acute lymphoblastic leukemia (ALL) was the

most common malignancy accounting for 590 (67.7%) of all

admissions followed by Acute Myeloid Leukemia (n ¼ 105;

12.2%), lymphoma (n ¼ 86; 9.9%) and sarcomas (n ¼ 51; 5.8%).

Pyrexia (n ¼ 715; 81.9%) alone was the commonest presenting

complaint followed by poor oral intake (68.6%), vomiting

(18.7%), cough (15.9%), mucositis (14.2%), diarrhea, urinary

complaints and rash (Table 1).

The cause of febrile neutropenia was identified in only 308

(35.3%) patients, with URTI in (n ¼ 192; 22%), BSI in (n ¼ 58;

6.6%), pneumonia (n ¼ 31; 3.5%), infectious diarrheas (n ¼ 16;

1.8%) and UTI (n¼ 11; 1.3%). More than 50% of the patients had

hemoglobin counts less than 10 g/dl, absolute neutrophil

count (ANC) less than 50/cm, and platelet counts less than

50,000/cm.

Analysis was performed for the identification of risk fac-

tors for development of PFN in pediatric oncology patients and

Please cite this article in press as: Alam MM, Fadoo Z, Febrile ntertiary health care facility of Pakistan, Pediatric Infectious Disea

Crude OR and confidence interval (CI) was calculated (Table 2).

Age less than 5 year (OR ¼ 1.5; p ¼ 0.043), AML (OR ¼ 1.8; p ¼0.019), patients who received chemotherapy within 2 week of

FN (OR ¼ 1.9; p ¼ 0.007), severe neutropenia ANC < 50/cm

(OR ¼ 1.5; p < 0.041), platelets count < 50,000/cm (OR ¼ 1.5;

p < 0.027), fungal infection (OR ¼ 15.6; p < 0.001), and pneu-

monia were found as risk factors associated with develop-

ment of PFN in pediatric cancer patients with FN.

A total of 25 (2.9%) patients required PICU admission and

overall 12 (1.4%) patients expired. Both variables, PICU

admission (9% Vs 2%; OR ¼ 5.4; p < 0.001) and mortality rate

(5.2% Vs 0.8%; OR ¼ 8.1; p < 0.001) were statistically significant

in patients with prolonged FN versus FN respectively.

4. Discussion

A number of studies from developed countries have evaluated

the risk factors for bacteremia or poor outcomes and there has

been increasing interest in stratifying patients with febrile

neutropenia into risk categories to establish the current

guidelines for the treatment of febrile neutropenia.8,12,14,15

The current study used a single institution experience from

a developing country to identify the risk factors and outcomes

for development of prolonged FN in pediatric cancer patients.

In many studies, age group has emerged as a significant

independent risk factor for both longer length of stay and

death.8 Although infancy has been cited as a high risk pedi-

atric age group, most studies have very few infants and young

children to evaluate this relationship.16e19 In the current

study, the risk of PFN was higher in children younger than 5

years to those older than 5 years (57% vs. 66%; OR 1.5;

p ¼ 0.043). It is possible that there are differences in the pri-

mary cancer type, pharmacokinetics of chemotherapy

received and its tolerance among the two age groups.

One of the criteria established in the management of

febrile neutropenia is the absolute neutrophil count at pre-

sentation,with ANC<200/cmbeing associatedwith a high risk

of infection and bacterial sepsis.20 In more recent studies, the

value of the absolute monocyte count has been shown to

correlate highly with the duration and outcome of febrile

neutropenic episodes.16,21,22 While larger American and Eu-

ropean centers push toward identifying the individual com-

ponents of the white cell count that contribute to the duration

of febrile neutropenic episodes such as the absolutemonocyte

count. However in developing countries, clinicians often have

to work without these laboratory indicators. Investigating the

relationship between the total WBC coupled with other clin-

ical parameters may prove useful to predict the duration and

outcome of febrile neutropenia. Out data showed that severe

myelosuppression i.e., severe neutropenia and severe

thrombocytopenia were also associated with the prolongation

of febrile neutropenic episodes. This is consistent with studies

that have identified that patients with more severe neu-

tropenia and thrombocytopenia have a higher risk for pro-

longed febrile neutropenia and adverse event.8,23 This

relationship serves as an important prognostic factor in

management of febrile neutropenic episodes.

For the evaluation of risk by cancer type, ALL was used as

the reference category. It should be noted that an odds ratio of

eutropenia in pediatric cancer patients: Experience from ase (2014), http://dx.doi.org/10.1016/j.pid.2014.06.002

Table 2 e Risk factors and outcome for prolonged febrile neutropenia (n ¼ 872).

Variables Febrile neutropenian ¼ 737 (%)

Prolonged febrile neutropenian ¼ 135 (%)

Crude OR (CI)a p-value

Gender

Male 464 (63%) 95 (70%) 1.4 (0.94e2.08) 0.099

Femaleb 273 (37%) 40 (30%)

Age

<5 year 417 (57%) 89 (66%) 1.5 (1.01e2.18) 0.043

>5 yearb 320 (43%) 46 (34%)

Cancer type

ALLb 508 (69%) 82 (61%)

1.8 (1.11e3.06)

1.6 (0.93e2.89)

0.019

0.086

AML 81 (11%) 24 (18%)

Lymphoma 68 (9%) 18 (13%)

Received chemotherapy within the

preceding 2 weeks

542 (77%) 114 (84%) 1.9 (1.19e3.19) 0.007

ANC (<50/cm) 276 (38%) 63 (47%) 1.5 (1.02e2.12) 0.041

Platelets count (<50,000/cm) 296 (40%) 68 (50%) 1.5 (1.05e2.18) 0.027

Hemoglobin <9 g/dl 445 (60%) 93 (69%) 1.4 (0.98e2.15) 0.061

Bacterial infection 36 (5%) 12 (9%) 1.9 (0.96e3.75) 0.060

Fungal infection 5 (0.7%) 13 (13%) 15.6 (5.46e44.54) <0.001Pneumonia 14 (1%) 9 (7%) 3.7 (1.56e8.71) 0.004

Outcome variables

PICU Admission 13 (2%) 12 (9%) 5.4 (2.42e12.18) <0.001Expired 5 (0.8%) 7 (5%) 8.1 (2.51e25.61) <0.001

Abbreviations: OR: Odd Ratio, CI: 95% Confidence Interval, ALL: Acute Lymphoblastic Leukemia, AML: Acute Myeloid Leukemia, ANC: Absolute

Neutrophil Count, PICU: Pediatric Intensive Care Unit.

Note: For each variable of risk factor, not having the specific risk was used as the reference group.

All statistically significant values (p values < 0.05) presented in bold.a The odds ratio reflects the risk of prolonged febrile neutropenia as compared to febrile neutropenia for each variable.b This is the reference group for the categorical predictor variable.

p e d i a t r i c i n f e c t i o u s d i s e a s e x x x ( 2 0 1 4 ) 1e54

less than 1 for any of the cancer types in this analysis in-

dicates a lower risk of the outcome as compared to ALL. In

comparison to ALL, a diagnosis of AML was associated with

two-fold increased risk of prolonged FN and adverse outcome.

A similar study reported three-fold of longer length of stay as

well as death in AML patients as compare to ALL.8 A diagnosis

of lymphoma and osteosarcoma/Ewing's sarcoma or rhabdo-

myosarcoma was associated with a significant reduction in

risk of composite adverse outcome. This is consistent with

studies in adult populations that have identified the diagnosis

of solid tumors as a low risk factor.4 Similarly, pediatric

studies have identified leukemia or relapse of leukemia as

high risk factors for FN and bacterial infection.9,24

Additionally, the complication diagnoses (i.e., sepsis or

bacteremia, pneumonia and fungal infection) were signifi-

cantly associated with the prolongation of febrile neutropenia

in our study. A diagnosis of sepsis or bacteremia conferred a

1.9-fold increase in the risk (5% vs. 9%), although the p value

(p ¼ 0.06) was not significant. This may be because of early

recognition and prompt initiation of antibiotic. However,

despite the widespread use and availability of broad spectrum

antibiotics, bacteremia/sepsis remains the most important

independent prognostic marker for poor outcome and/or

mortality. Pneumonia was associated with an increased risk

of PFN and poor outcomes in our study, as shown in another

studywith three-fold and eight-fold increase in the risk of PFN

and death respectively.8 Fungal infections were also associ-

ated with an increased risk of PFN similar to three-fold and

five-fold increase in the risk of PFN and death reported.8

A recently published study25 also reported that composite

adverse event outcomes in FN occurred in 11.1% of admissions

Please cite this article in press as: Alam MM, Fadoo Z, Febriletertiary health care facility of Pakistan, Pediatric Infectious Disea

with in-hospital mortality occurring in 0.7%, PICU admission

occurring in 4.7%, and fluid resuscitation � 40ml/kg occurring

in 10.1%. In our series, total of 25 (2.9%) patients required PICU

admission and overall 12 (1.4%) patients expired. Both

outcome variables were statistically significant regarding

PICU admission (9% Vs 2%; OR ¼ 5.4; p < 0.001) and mortality

rate (5.2% Vs 0.8%; OR ¼ 8.1; p < 0.001) in patients with PFN

versus FN respectively. Overall the mortality rate in pediatric

studies of febrile neutropenia have ranged from 0.7% to

3.9%.9,16,21,22

Limitations of this study include those inherent to its sin-

gle center, retrospective design. We were not able to assess all

the variables and were limited by the completeness of docu-

mentation by treating physician. Additionally, we did not

collect physiologic data (heart rate and blood pressure), which

may have enhanced our understanding of the poor outcome.

Finally, we did not attempt to account for baseline level of

illness, existing comorbidities, or for sources of infection other

than bacteremia and fungal infection.

Our study indicates that a younger age, diagnosis of AML,

severe neutropenia (ANC < 50/cm), severe thrombocytopenia

(platelets < 50,000/cm), fungal infection and pneumonia

should be considered as a high risk factors associated with

development of prolonged febrile neutropenia in pediatric

cancer patients. The identification of risk factors for poor

outcomes may help in devising protocols and updating

guidelines for providing targeted therapy based on risk criteria

and hematopoietic growth factor support thus help to reduce

the cost of cancer care as well as improve the overall out-

comes in children with cancer. Prospective studies of pro-

longed febrile neutropenia among children enrolled in large

neutropenia in pediatric cancer patients: Experience from ase (2014), http://dx.doi.org/10.1016/j.pid.2014.06.002

p e d i a t r i c i n f e c t i o u s d i s e a s e x x x ( 2 0 1 4 ) 1e5 5

cooperative trials may be beneficial in evaluating these risk

factors further.

Conflicts of interest

All authors have none to declare.

r e f e r e n c e s

1. Ellis M. Febrile neutropenia evolving strategies. Ann NY AcadSci. 2008;1138:329e350.

2. Hallahan AR, Shaw PJ, Rowell G, O'Connell A, Schell D, Gillis J.Improved outcome of children with malignance admitted to apediatric intensive care unit. Crit Care Med.2000;28:3718e3721.

3. Pizzo PA. Management of fever in patients with cancer andtreatment-induced neutropenia. N Engl J Med.1993;328(18):1323e1332.

4. Hughes WT, Armstrong D, Bodey GP, et al. 2002 guidelines forthe use of antimicrobial agents in neutropenic patients withcancer. Clin Infect Dis. 2002;34:730e751.

5. Ozer H, Armitage JO, Bennett CL, et al. Update ofrecommendations for the use of hematopoieticcolony-stimulating factors: evidence-based, clinicalpractice guidelinesdAmerican Society of Clinical OncologyGrowth and Factors Expert Panel. J Clin Oncol.2000;18:3558e3585.

6. Meckler G, Lindemulder S. Fever and neutropenia in pediatricpatients with cancer. Emerg Med Clin North Am.2009;27(3):525e544.

7. Walsh TJ, Roilides E, Groll AH, Gonzalez C, Pizzo P. Infectiouscomplications in pediatric cancer patients. In: Pizzo PA,Poplack DG, eds. Principles & Practice of Pediatric Oncology. 5thed. Philadelphia, PA: Lippincott Williams & Wilkens;2005:1269e1275.

8. Basu SK, Fernandez ID, Fisher SG, Asselin BL, Lyman GH.Length of stay and mortality associated with febrileneutropenia among children with cancer. J Clin Oncol.2005;23(31):7958e7966.

9. Santolaya ME, Alvarez AM, Becker A, et al. Prospective,multicenter evaluation of risk factors associated withinvasive bacterial infection in children with cancer,neutropenia, and fever. J Clin Oncol. 2001;19(14):3415e3421.

10. Campbell M, Salgado C, Quintana J, et al. Mejorı�a en elprono�stico de la leucemia linfobl�astica aguda en nin~os de unpaı�s en desarrollo: resultados del protocolo nacional chilenoPINDA 87. Rev Chil Pediatr. 1999;70:405e414.

11. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practiceguideline for the use of antimicrobial agents in neutropenic

Please cite this article in press as: Alam MM, Fadoo Z, Febrile ntertiary health care facility of Pakistan, Pediatric Infectious Disea

patients with cancer. Update by the Infectious DiseasesSociety of America Clin Infect Dis. 2010;52:427e431.

12. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practiceguideline for the use of antimicrobial agents in neutropenicpatients with cancer: 2010 update by the Infectious DiseasesSociety of America. Clin Infect Dis. 2011;52(4):427e431.

13. Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for themanagement of fever and neutropenia in children withcancer and/or undergoing hematopoietic stem-celltransplantation. J Clin Oncol. 2012;30(35):4427e4438.

14. Mendes AV, Sapolnik R, Mendonca N. New guidelines for theclinical management of febrile neutropenia and sepsis inpediatric oncology patients. J Pediatr (Rio J). 2007;83(2 suppll):S54eS63.

15. Phillips B, Selwood K, Lane SM, et al. Variation in policies forthe management of febrile neutropenia in United KingdomChildren's Cancer Study Group centres. Arch Dis Child.2007;92(6):495e498.

16. Baorto EP, Aquino VM, Mullen CA, Buchanan GR, DeBaun MR.Clinical parameters associated with low bacteremia risk in1100 pediatric oncology patients with fever and neutropenia.Cancer. 2001;92(4):909e913.

17. Aquino VM, Herrera L, Sandler ES, Buchanan GR. Feasibility oforal ciprofloxacin for the outpatient management of febrileneutropenia in selected children with cancer. Cancer.2000;88(7):1710e1714.

18. Jones GR, Konsler GK, Dunaway RP, Pusek SN. Infection riskfactors in febrile, neutropenic children and adolescents.Pediatr Hematol Oncol. 1996;13(3):217e229.

19. Mustafa MM, Aquino VM, Pappo A, Tkaczewski I,Buchanan GR. A pilot study of outpatient management offebrile neutropenic children with cancer at low risk ofbacteremia. J Pediatr. 1996;128(6):847e849.

20. Acquino VM, Tkaczewski I, Buchanan GR. Early discharge oflow risk febrile neutropenic children and adolescents withcancer. Clin Infect Dis. 1997;25:74e78.

21. Klaassen RJ, Goodman TR, Pham B, Doyle JJ. “Low-risk”prediction rule for pediatric oncology patients presentingwith fever and neutropenia. J Clin Oncol. 2000;18(5):1012e1019.

22. Rackoff WR, Gonin R, Robinson C, Kreissman SG, Breitfeld PB.Predicting the risk of bacteremia in children with fever andneutropenia. J Clin Oncol. 1996;14(3):919e924.

23. Timothy M, Bodkyn C. The outcome of febrile neutropenicepisodes in paediatric oncology at the Wendy FitzwilliamPaediatric Hospital. West Indian Med J. 2011;60(2):153e157.

24. Lucas KG, Brown AE, Armstrong D, Chapman D, Heller G. Theidentification of febrile, neutropenic children with neoplasticdisease at low risk for bacteremia and complications ofsepsis. Cancer. 1996;77(4):791e798.

25. Fletcher M, Hodgkiss H, Zhang S, et al. Prompt administrationof antibiotics is associated with improved outcomes in febrileneutropenia in children with cancer. Pediatr Blood Cancer.2013;60(8):1299e1306.

eutropenia in pediatric cancer patients: Experience from ase (2014), http://dx.doi.org/10.1016/j.pid.2014.06.002