Risk Prediction in Pediatric Cancer Patients With Fever
Hana Hakim, MD,* Patricia M. Flynn, MD,*†‡ Deo Kumar Srivastava, PhD,§ Katherine M. Knapp, MD,*†
Chenghong Li, PhD,§ James Okuma, MS,§ and Aditya H. Gaur, MD*
Background: To identify predictors for 2 risk measures—“proven inva-
sive bacterial infection or culture-negative sepsis (IBD)” and “clinical
complications (CC)”—in pediatric cancer patients with fever and neutro-
Methods: Records of 390 patients with FN hospitalized over 2 years were
reviewed. For the 332 who met inclusion criteria, one FN episode was
randomly selected. Independent predictors at presentation were analyzed
using multiple regression models. Optimal cut-off risk prediction scores
were determined. These models were validated by bootstrap analysis.
Results: Patients’ median age was 6.0 years; 66% had an underlying
diagnosis of leukemia. Independent predictors of IBD (n ? 56) were
absolute neutrophil count ?100, temperature at presentation ?39.0°C,
“sick” clinical appearance, and underlying diagnosis of acute myeloid
leukemia. A total weighted score ?24 reliably identified patients at low
risk for IBD. Independent predictors of CC (n ? 47) were relapse of
malignancy, non-white race, “sick” clinical appearance, and underlying
diagnosis of acute myeloid leukemia. A total weighted score ?19 predicted
patients at low risk for CC. Of those misclassified as low risk, 11 of 12 with
IBD and 3 of 9 with CC had the outcome within 24 hours of presentation.
Of the remaining patients classified as low-risk for IBD and CC, 99.5% and
97.1%, respectively, remained outcome-free after 24 hours of observation.
Conclusions: This study identifies predictors of infection/complications in
pediatric patients with FN, establishes clinical cut-off scores and highlights
the importance of the initial clinical impression and 24 hours of observa-
tion. These prediction models warrant prospective validation.
Key Words: fever, neutropenia, children, cancer, risk, prediction
(Pediatr Infect Dis J 2010;29: 53–59)
ment with intravenous (IV) broad-spectrum antibiotics in an inpa-
ever and neutropenia (FN) is a common complication in pa-
tients undergoing chemotherapy to treat cancer. Empiric treat-
tient setting is the mainstay of therapy for FN in pediatric
patients.1–3However, this patient population is heterogeneous, and
not all pediatric patients with FN are at the same risk for compli-
cations and bacterial infections. Models of risk prediction for
FN-related morbidity and mortality and risk-based stratification
of care including outpatient and oral antibiotics have been
suggested4–21and are being increasingly used for adults. Risk
prediction can result in tremendous cost saving, better resource
utilization, and improved quality of care.22
The key factor in risk prediction is to consistently and
reliably identify patients “at risk.” Of the several risk prediction
models proposed,23–35few apply to pediatric patients. While many
previous studies focused on derivation datasets using retrospective
study designs, the 2 conducted prospectively,26–28found different
predictor variables, did not establish weighted risk prediction
scores and, unlike the approach now commonly used in adult
patients,23,24had limited focus on clinical complications (CC) as
an outcome measure. Clinical complications evaluated in previous
models did not include adverse events occurring without associ-
ated hemodynamic instability or sepsis syndrome, such as respi-
ratory failure and altered mental status. With the above summa-
rized limitations and needs, as the first step of a planned 3-part
evaluation, we designed a retrospective study to examine candidate
predictor variables for 2 measures of risk for FN: proven invasive
bacterial infection or culture-negative sepsis (IBD) and clinical
complications (CC). The next steps of our planned study will be to
use this information to build prediction models that could be
further optimized and validated prospectively, and as a final step,
to evaluate risk-stratified FN management in a randomized clinical
Study Population and Design
We retrospectively reviewed the records of 390 pediatric
(?22 years) patients with cancer who developed FN in an outpa-
tient setting and were hospitalized for further management at St.
Jude Children’s Research Hospital (St. Jude), Memphis, TN from
January 1, 2004 to December 31, 2005. Data for patients who had
already received a stem cell transplant or developed FN during
hospitalization for other reasons were excluded from analysis. We
developed a list of candidate variables (Table, Supplemental Dig-
ital Content 1, http://links.lww.com/INF/A314) on the basis of
variables identified by previous risk-prediction studies23,24,26–29
and by this retrospective medical record review. These included:
demographics; underlying cancer; relapse; granulocyte-colony
stimulating factor (G-CSF) use; steroid use within the past 14
days; duration of neutropenia; presence of indwelling central
venous catheter (CVC); time since last chemotherapy; antifungal
therapy for probable or proven fungal infection within the past 6
months; colonization by methicillin-resistant Staphylococcus au-
reus (MRSA), vancomycin-resistant Enterococcus (VRE), or
Pseudomonas aeruginosa within the past 4 weeks; prophylactic or
treatment antibiotics; vital signs; and laboratory tests. Blood cul-
Accepted for publication October 1, 2009.
From the *Department of Infectious Diseases, St. Jude Children’s Research
Hospital, Memphis, TN; Departments of †Pediatrics and ‡Preventive Med-
icine, University of Tennessee Health Science Center, Memphis, TN; and
§Department of Biostatistics, St. Jude Children’s Research Hospital, Mem-
Supported by a National Institutes of Health grant (CA21765) and the American
Lebanese Syrian Associated Charities (ALSAC).
Presented as a poster at the 45th Annual Meeting of Infectious Diseases Society
of America (IDSA), San Diego, CA, October 2007. Another part was presented
as a poster at the 48th Annual Interscience Conference on Antimicrobial Agents
and Chemotherapy (ICAAC)/45th Annual Infectious Diseases Society of
America (IDSA) Meeting, Washington, DC, October 2008.
The authors report no conflicts of interest.
Address for correspondence: Hana Hakim, MD, Department of Infectious Diseases,
Mail Stop 600, St. Jude Children’s Research Hospital, 262 Danny Thomas
Place, Memphis, TN 38105-3678. E-mail: Hana.Hakim@stjude.org.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions
of this article on the journal’s Web site (www.pidj.com).
Copyright © 2009 by Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 29, Number 1, January 2010
www.pidj.com | 53
and healthcare professionals’ preferences. J Clin Oncol. 2004;22:3922–
21. Vidal L, Paul M, Ben dor I, et al. Oral versus intravenous antibiotic treatment
for febrile neutropenia in cancer patients: a systematic review and meta-
analysis of randomized trials. J Antimicrob Chemother. 2004;54:29–37.
22. Kern WV. Risk assessment and treatment of low-risk patients with febrile
neutropenia. Clin Infect Dis. 2006;42:533–540.
23. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Asso-
ciation for Supportive Care in Cancer risk index: a multinational scoring
system for identifying low-risk febrile neutropenic cancer patients. J Clin
24. Talcott JA, Siegel RD, Finberg R, et al. Risk assessment in cancer patients
with fever and neutropenia: a prospective, two-center validation of a
prediction rule. J Clin Oncol. 1992;10:316–322.
25. Talcott JA, Whalen A, Clark J, et al. Home antibiotic therapy for low-risk
cancer patients with fever and neutropenia: a pilot study of 30 patients
based on a validated prediction rule. J Clin Oncol. 1994;12:107–114.
26. Santolaya ME, Alvarez AM, Aviles CL, et al. Prospective evaluation of a
model of prediction of invasive bacterial infection risk among children with
cancer, fever, and neutropenia. Clin Infect Dis. 2002;35:678–683.
27. Santolaya ME, Alvarez AM, Becker A, et al. Prospective, multicenter
evaluation of risk factors associated with invasive bacterial infection in
children with cancer, neutropenia, and fever. J Clin Oncol. 2001;19:3415–
28. Klaassen RJ, Goodman TR, Pham B, et al. “Low-risk” prediction rule for
pediatric oncology patients presenting with fever and neutropenia. J Clin
29. Rackoff WR, Gonin R, Robinson C, et al. Predicting the risk of bacteremia
in childen with fever and neutropenia. J Clin Oncol. 1996;14:919–924.
30. Lucas KG, Brown AE, Armstrong D, et al. The identification of febrile,
neutropenic children with neoplastic disease at low risk for bacteremia and
complications of sepsis. Cancer. 1996;77:791–798.
31. Alexander SW, Wade KC, Hibberd PL, et al. Evaluation of risk prediction
criteria for episodes of febrile neutropenia in children with cancer. J Pediatr
Hematol Oncol. 2002;24:38–42.
32. Paganini HR, Aguirre C, Puppa G, et al. A prospective, multicentric scoring
system to predict mortality in febrile neutropenic children with cancer.
33. Ammann RA, Hirt A, Luthy AR, et al. Identification of children presenting
with fever in chemotherapy-induced neutropenia at low risk for severe
bacterial infection. Med Pediatr Oncol. 2003;41:436–443.
34. Rondinelli PI, Ribeiro Kde C, de Camargo B. A proposed score for
predicting severe infection complications in children with chemotherapy-
induced febrile neutropenia. J Pediatr Hematol Oncol. 2006;28:665–670.
35. Wicki S, Keisker A, Aebi C, et al. Risk prediction of fever in neutropenia
in children with cancer: a step towards individually tailored supportive
therapy? Pediatr Blood Cancer. 2008;51:778–783.
36. Perkins NJ, Schisterman EF. The inconsistency of “optimal” cutpoints
obtained using two criteria based on the receiver operating characteristic
curve. Am J Epidemiol. 2006;163:670–675.
37. Efron B, Chong G. A leisurely look at the bootstrap, the jackknife, and
cross-validation. Am Stat. 1983;37:36–48.
38. Danai PA, Moss M, Mannino DM, et al. The epidemiology of sepsis in
patients with malignancy. Chest. 2006;129:1432–1440.
39. Metzger ML, Castellino SM, Hudson MM, et al. Effect of race on the
outcome of pediatric patients with Hodgkin’s lymphoma. J Clin Oncol.
40. Fleischhack G, Kambeck I, Cipic D, et al. Procalcitonin in paediatric cancer
patients: its diagnostic relevance is superior to that of C-reactive protein,
interleukin 6, interleukin 8, soluble interleukin 2 receptor and soluble
tumour necrosis factor receptor II. Br J Haematol. 2000;111:1093–1102.
41. Lehrnbecher T, Venzon D, de Haas M, et al. Assessment of measuring
circulating levels of interleukin-6, interleukin-8, C-reactive protein, soluble
Fc gamma receptor type III, and mannose-binding protein in febrile chil-
dren with cancer and neutropenia. Clin Infect Dis. 1999;29:414–419.
42. Secmeer G, Devrim I, Kara A, et al. Role of procalcitonin and CRP in
differentiating a stable from a deteriorating clinical course in pediatric
febrile neutropenia. J Pediatr Hematol Oncol. 2007;29:107–111.
43. Stryjewski GR, Nylen ES, Bell MJ, et al. Interleukin-6, interleukin-8, and
a rapid and sensitive assay for calcitonin precursors for the determination of
bacterial sepsis in febrile neutropenic children. Pediatr Crit Care Med.
44. Santolaya ME, Alvarez AM, Aviles CL, et al. Predictors of severe sepsis
not clinically apparent during the first twenty-four hours of hospitalization
in children with cancer, neutropenia, and fever: a prospective, multicenter
trial. Pediatr Infect Dis J. 2008;27:538–543.
The Pediatric Infectious Disease Journal • Volume 29, Number 1, January 2010Infection and Cancer
© 2009 Lippincott Williams & Wilkins
www.pidj.com | 59