Fever accompanying neutropenia (or febrile neutropenia [FN]) is a common complication of chemotherapy or hematopoietic stem-cell transplantation among children and adolescents with cancer; it also represents the most frequent potentially lethal complication of chemotherapy for these young patients1; however, pediatric FN risk prediction can be a challenge. FN can be a symptom of life-threatening infection or sepsis; traditional management has therefore involved open-ended hospital admissions and intravenous (IV) antibiotic administration.2 No risk-stratification tool has been validated or widely adopted for clinical use specifically with children, but management recommendations have been published based on the available research literature. A 2013 study indicates that time to antibiotic administration is an important measure of quality of care for these children.3 The availability of polymerase chain reaction (PCR)-based diagnostic tests for identifying microbial infections allows rational treatment planning, and recent evidence-based reviews of research data are helping to strengthen and cohere our understanding of pediatric chemotherapy-associated FN. Although its safety has not yet been established in clinical trials, the early outpatient management of low-risk FN with oral or IV antibiotics is emerging in the research literature as a potential alternative to traditional prolonged inpatient IV-only antibiotic therapy.1,4
Risk stratification tools and management guidelines have been released for adults with chemotherapy-associated FN. Children, on the other hand, are not simply “little adults”, and it should not be assumed that FN and its treatment are easily extrapolated from adult studies to pediatric practice, emphasized Lillian Sung, MD, PhD, hematologist/oncologist at The Hospital for Sick Children in Toronto, Ontario, Canada.5
“The immune system matures throughout the pediatric age range,” Dr. Sung and her colleagues noted, in their article published in the European Journal of Cancer.5 They explained that children and adults have significant differences in immunity and the capacity for postchemotherapy immune system recovery, leaving children at particular risk for developing FN.5
In addition, children with cancer “receive much more intensive treatment with a curative intent compared with adults,” they wrote.5 “Even when focusing on the same cancer type, treatment intensity and both incidence and severity of treatment-related complications are higher in treatment protocols designed for children as compared to adults. Therefore, it is not surprising that regimens used to treat children with cancer are more likely to result in FN.”
Together, the differences between adults and children represent a distinct epidemiology of chemotherapy-associated infections and FN, reported Dr. Sung and colleagues.5
Research also suggests that empiric antibiotic therapies for FN, such as when infectious agents are identified and matched to appropriate treatment, are more successful in children than in adults, with shorter intervals to the abatement of fever, lower rates of infection-related mortality, and better overall survival.2,5
A 2013 study published in Pediatric Blood Cancer reported that longer time to antibiotic administration, and admission to a pediatric intensive care unit (ICU) within 24 hours of presentation, are two important risk factors for FN-associated adverse outcomes.3 Of 1,628 children diagnosed with FN at the Children’s Medical Center in Dallas, TX, between 2001 and 2009, 4.7% were admitted to the pediatric ICU.3 Time to antibiotic administration—but not length of hospitalization—correlated significantly with adverse events (odds ratio [OR], 1.29; 95% CI: 1.02-1.64). Pediatric inpatient FN mortality rates were low (0.7%).3
Outpatient management of FN cases that are deemed to be low risk with oral or IV antibiotics might well be effective in children with cancer, but clinical trials have not yet established the safety of this approach as an alternative to traditional inpatient IV antibiotic therapy.1 Furthermore, risk stratification for children with cancer and FN remains a significant empirical challenge; while prediction tools for adverse outcomes are under development, no risk stratification system has yet been validated or widely adopted for clinical use with children.4-7 The popular Multinational Association for Supportive Care in Cancer [MASCC] risk index, for example, is not used with children.5,8
A 2012 systematic review and meta-analysis of data from nine newly published validation studies of the efficacy of proposed risk stratification rules among children with cancer and FN, found geographic variation in the predictive ability of the rules—suggesting that local validation will be necessary before widespread clinical adoption is possible.6
Although their clinical impacts on outcomes has not yet been established, the development of PCR tests for bacterial, viral, and fungal RNA or DNA from blood samples should reduce the number of FN cases for which the responsible infectious agent remains unknown, which should allow for better-targeted, more accurate antimicrobial therapy plans.1,9
Guidelines developed by Dr. Sung and colleagues and published in the Journal of Clinical Oncology in December 2012 outline recommendations for the management of FN in children with cancer or who are undergoing hematopoietic stem cell transplantation, based on systematic reviews of the published literature.10 The authors were quick to note that “implementation will require adaptation to the local context,” and that there were varying levels of evidence for the recommendations.10
The guideline’s strong recommendations included obtaining blood cultures at the onset of FN from all lumens of central venous catheters and chest radiography only in symptomatic patients.10 The authors also identified antipseudomonal β-lactam or carbapenem empiric monotherapies for children with high-risk FN, and that the addition of a second Gram-negative agent or glycopeptide be reserved for clinically unstable patients or when there is a likelihood of drug-resistant infection.10
Consistent with safety concerns just noted, step-down or outpatient treatment for low-risk FN was a “weak” recommendation in the guidelines.10
- The guidelines also offered strong recommendations for ongoing management of FN for bacterial or viral infections:
- If children are clinically stable, do not modify initial empiric regimen based only on a persisting fever;
- If a child responds to initial empiric therapy, “discontinue double coverage for Gram-negative infections or glycopeptides (if initiated) after 24 to 72 hours if there is no specific microbiologic indication to continue combination therapy”; and
- Discontinuation of empiric antibiotic agents when blood cultures are negative for 48 hours or for patients who have had no fever for 24 hours or longer, and for whom marrow has recovered.10
Research gaps identified by the task force included validation of a high-risk stratification tool for children with FN, identification of the best type and frequency of blood culturing and patient re-evaluation (eg, daily clinic visit vs phone calls), determination of optimal durations for antibiotic treatments in cases of high-risk FN without bone marrow recovery, the clinical value of β-D-glucan testing and routine sinus imaging in children age 2 years or younger with high-risk infectious FN, and optimal assessments and treatment strategies for viral infection-associated pediatric FN.10
Of course, children are not the decision-makers when it comes to treatment options; parents or guardians are—and one small survey conducted at the Hospital for Sick Children in Toronto, Ontario, found that just over one-half of parents and guardians (51.6%) preferred hospital-based IV treatment for pediatric FN.2,5 As research findings accumulate, clinicians will be better able to ensure that such decisions are well informed and evidence-based.
- Ammann RA, Tissing WJE, Phillips B. Rationalizing the approach to children with fever in neutropenia. Curr Opin Infect Dis. 2012;25(3):258-265.
- Diorio C, Martino J, Boydell KM, et al. Parental perspectives on inpatient versus outpatient management of pediatric febrile neutropenia. J Ped Oncol Nursing. 2011;28(6):3355-3362.
- Fletcher M, Hodgkiss H, Zhang S, et al. Prompt administration of antibiotics is associated with improved outcomes in febrile neutropenia in children with cancer. Pediatr Blood Cancer. 2013;60(8):1299-1306.
- Ammann RA, Bodmer N, Hirt A, et al. Predicting adverse events in children with fever and chemotherapy-induced neutropenia: the prospective multicenter SPOG 2003 FN study. J Clin Oncol. 2010;28(12):2008-2014.
- Sung L, Phillips R, Lehrnbecher T. Time for pediatric febrile neutropenia guidelines: children are not little adults. Eur J Cancer. 2011;47(6):811-813.
- Phillips RS, Lehrnbecher T, Alexander S, Sung L. Updated systematic review and meta-analysis of the performance of risk prediction rules in children and young people with febrile neutropenia. PLoS One. 2012;7(5):e38300.
- Teuffel O, Amir E, Alibhai SMH, et al. Cost-effectiveness of outpatient management for febrile neutropenia in children with cancer. Pediatrics. 2011;127(2):e279-e286.
- Klastersky J, Paesmans M. The Multinational Association for Supportive Care in Cancer (MASCC) risk index score: 10 years of use for identifying low-risk febrile neutropenic cancer patients. Support Care Cancer. 2013;21(5):1487-1495.
- Santolaya ME, Farfan MJ, De La Maza V, et al. Diagnosis of bacteremia in febrile neutropenic episodes in children with cancer: microbiologic and molecular approach. Pediatr Infect Dis J. 2011;30(11):957-960.
- Lehrnbecher T, Phillips R, Alexander S, et al. Guidelines for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol. 2012;30(35):4427-4438.