Immune signatures, testing, and management of febrile neutropenia in pediatric cancer patients

ABSTRACT

Introduction

Infectious complications, particularly invasive bacterial and fungal infections, are still a major cause of morbidity in pediatric cancer patients and are associated with significant mortality. Over the last few years, there has been much effort in defining risk groups to tailor antimicrobial therapy, and in establishing pediatric-specific guidelines for antimicrobial strategies.

Areas covered

This review provides a critical overview of defining risk groups for infection, diagnostic work-up, antimicrobial prophylaxis, empirical therapy, and treatment of established infections.

Expert opinion

To date, no generalizable risk prediction model has been established for pediatric cancer patients. There is growing interest in defining the impact of the individual genetic background on infectious complications. New diagnostic tools have been developed over the last few years, but they need to be validated in pediatric cancer patients. International, pediatric-specific guidelines for antimicrobial prophylaxis, empirical therapy, and treatment of established infections have recently been published and will harmonize antimicrobial strategies in the future.

KEYWORDS:

• Infection
• bacteria
• fungi
• child
• cancer
• risk group
• diagnostics
• prophylaxis
• therapy

Article highlights

• Although the mortality of infectious complications in children with hematological malignancy or a solid tumor has decreased over time, bacterial and fungal infections remain a major cause of morbidity.

• Neutropenia is an important risk factor for infectious complications, with the individual risk increasing with lower absolute neutrophil counts and with longer periods of neutropenia.

• Risk prediction rules may help to tailor antimicrobial management, but none of the existing validated risk prediction rules can be applied universally as they also depend on institutional factors.

• Genetic polymorphisms have an impact on the risk and outcome of infections, but large studies validating preliminary results are lacking.

• Biomarkers may help to predict the clinical course of an infectious episode but sufficiently powered studies are needed before results can be translated into daily clinical practice.

• Although blood cultures including antimicrobial resistance testing remain the gold standard, new culture-independent techniques, such as next-generation sequencing (NGS) are promising as they are faster and may increase the yield of positive results.

• Diagnosis of invasive mold infections is difficult and includes imagings and non-culture-based assays such as galactomannan and PCR.

• In contrast to international guidelines that gave a weak recommendation for levofloxacin prophylaxis in children with acute myeloid leukemia (AML) and relapsed acute lymphoblastic leukemia (ALL), the ECIL-8 guideline does not recommend antibacterial prophylaxis in children with cancer. These differences are caused by different strategies for generating clinical practice guidelines (e.g. including/excluding observational studies).

• Mold-active antifungal prophylaxis is indicated in high-risk patients, such as children with AML, relapsed leukemia, hematopoietic cell transplant (HCT) recipients, and subpopulations of children with ALL. The preferred agent for this indication depends on a number of factors, such as concomitant medication, age, and comorbidities.

• Empirical antibacterial therapy is a long-standing standard of care in febrile neutropenic children. In clinically stable patients at low risk for infections with a resistant pathogen, monotherapy with an anti-pseudomonal non-carbapenem β-lactam plus β-lactamase inhibitor combination or a fourth-generation cephalosporin is recommended. In clinically unstable patients, a carbapenem with or without a second Gram-negative active agent, and with or without a glycopeptide should be given, whereas in patients colonized or previously infected with a resistant pathogen, treatment should be adjusted on the basis of the results of prior resistance testing.

• Empirical antifungal therapy using caspofungin or liposomal amphotericin B should be given to febrile patients with an expected absolute neutrophil count (ANC) ≤500/µl for at least 10 days, who do not respond to empirical broad-spectrum antibiotics. Pre-emptive antifungal therapy based on imaging and galactomannan findings could be an alternative strategy.

• In addition to targeted treatment for established fungal infections, reductions in immunosuppression, and surgical management need to be considered.

Declaration of interest

K. Bochennek served as a consultant to EUSA Pharma. T. Lehrnbecher served as a consultant to Basilea, Gilead Sciences, Pfizer, Merck/MSD, Mundipharma, and Roche, and in the speaker’s bureau of Gilead Sciences, Merck/MSD, EUSA Pharma, Pfizer, and Sanofi Pasteur. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.