DISCUSSION
To date, the majority of investigations of IMI in children have focused on infections resulting from a specific organism, such as invasive aspergillosis, or on very high-risk groups, such as HSCT recipients. Despite substantial evidence supporting the use of antifungal prophylaxis with mold activity in at-risk pediatric cancer populations, few studies have assessed the impact of appropriate prophylaxis on IMI incidence outside of a clinical trial, and none have detailed risk-adapted strategies for guidelines implementation and the subsequent impact on rates of IMI. In this 15-year single-institution study, the overall incidence of IMI in children treated for hematopoietic malignancy with chemotherapy alone was 4.6%, ranging from a low of 1.7% for a diagnosis of lymphoma to a high of 6.4% for a diagnosis of AML. This rate approximates the frequency of IMI previously reported in U.S.- and European-based childhood cancer centers.10,11
Our results suggest a higher risk for IMI in children with Hispanic ethnicity. Factors contributing to the higher rates of IMI observed in Hispanics are likely multifactorial. A higher than expected incidence of infections with Histoplasma, Coccidioides , and Blastomycesspecies has been observed in persons of African, Native American, and Asian descent,12suggesting a role for genetic predisposition.13Further investigation to elucidate the genetic and environmental factors that underlie the excess IMI risk observed among Hispanic children is needed.
We also demonstrate clinical benefit to implementation of a standardized approach to antifungal prophylaxis in high risk childhood cancer populations, evidenced by risk reduction for proven/probable IMI after algorithm implementation. Our results validate and extend findings from a prior, smaller single-institution study that also reported a reduction in IMI incidence after applying risk-adapted IMI prophylaxis in children with leukemia.14Antifungal prophylaxis is routinely prescribed to prevent IMI in children with AML, who are at high risk of infection due to prolonged periods of profound neutropenia induced by intensive chemotherapy. By broadening prophylaxis to include anti-mold coverage, we observed a reduction in the incidence of IMI in patients with AML treated at TCH by 60%. Some adult studies have observed an increase in Mucor spp. infections with use of broadened, anti-mold prophylaxis.15,16Although it is difficult to assess the effect of broadening prophylaxis in a sample of this size, we did observe an increase in RhizopusIMI post-implementation, one of the species in the Mucorales order. Of the proven IMI cases, Rhizopus or Mucor spp. were isolated in five out of 40 cases from 2006-2015 (13%), vs. four out of 13 cases between 2016-2020 (31%). Overall, concurrent to eliminating IMIs related to Aspergillus , we saw an increase in IMIs due toRhizopus , Fusarium , andTrichosporon 17 that did not impact overall survival, but that did correspond with a higher rate of admission to the intensive care unit after 2016, and, for those who died, a higher rate of active fungal disease at time of death. Proven or probable IMI had a substantial impact on survival: only 27% of children with AML and 67% of children with ALL and concurrent IMI survived, compared with current average U.S. survival rates that approach 70% and 90%, for AML and ALL respectively.18,19
The Children’s Oncology Group recommends primary antifungal prophylaxis for children receiving HSCT as well as for patients with AML or myelodysplastic syndrome, with moderate evidence also suggesting benefit to primary prophylaxis for children with anticipated neutropenia greater than 7 days duration.20As noted above, a recent systematic review produced consensus guidelines for systemic antifungal prophylaxis in children with cancer and who are treated with HSCT that extends these recommendations to include mold-active antifungal prophylaxis for children treated for AML, and consideration of mold-active antifungal prophylaxis in children with newly diagnosed or relapsed ALL who are at high risk for fungal infection.8 Though our antifungal prophylaxis algorithm (Figure 1 ) was developed prior to the publication of these consensus guidelines, the algorithm largely adheres to the guideline principles. Specifically, according to our algorithm, antifungal prophylaxis with agents that have anti-mold activity is initiated for all patients diagnosed with AML, relapsed ALL or AML, and initiated during all phases of ALL therapy when inpatient admission through count recovery is recommended. Children with lymphoma are not prescribed antifungal prophylaxis. In addition, the TCH algorithm suggests appropriate anti-mold coverage to minimize potential interactions with chemotherapy agents routinely employed in subsets of ALL and AML, and considers variable absorption and pharmacokinetics of voriconazole and posaconazole in children.21 Exceptions to the published guidelines include our use of antifungal agents that are not mold-active (e.g. fluconazole) for specific moderate risk populations, such as during intensive treatment courses for children with Down syndrome associated ALL, infant ALL, and T cell ALL, as well as during periods of hyperglycemia for patients who develop steroid-induced diabetes during treatment. Importantly, the algorithm is a ‘living’ document, modified as treatment protocols are retired or initiated, as changes are made to the hospital formulary, or as new categories of risk are identified.
Limitations to our study include the anticipated constraints of a retrospective chart review, and the study restriction to a single institution. The relative rarity of this outcome precluded our ability to assess associations and outcomes for individual mold species. We also had insufficient data available to compare antimicrobial resistance patterns in isolated molds pre and post-algorithm implementation. Last, while our antifungal prophylaxis algorithm is evidence-based and largely aligned with current consensus guidelines, adaptations were made in consideration of prevalent fungal pathogens at our institution, additional populations perceived as high risk, and clinical practice preferences for intravenous vs. oral antimicrobials depending on inpatient or outpatient status. These adaptations should be considered when assessing the generalizability of our approach.
As noted by Lehrnbecher et al., the practical application of clinical guidelines requires an appreciation of local IFD epidemiology and the appropriate engagement and education of key stakeholders.8 Here, we describe an approach for the clinical application of evidence-based recommendations to provide antifungal prophylaxis in children with hematologic malignancies that is informed by host and treatment factors, local IMI epidemiology, and input from a multidisciplinary team. Further, we demonstrate a reduction in IMI incidence as clinical evidence of the efficacy of our approach. Ongoing efforts include continued prospective monitoring of fungal species isolated from at-risk populations to assess susceptibility patterns, outcomes, and the need for further algorithm modifications.
Acknowledgements: The study team would like to thank the patients and families who contributed data to this research. This work was supported by a St. Baldrick’s Foundation Consortium Grant to Karen R. Rabin (Reducing Ethnic Disparities in Acute Leukemia), and by an American Society of Hematology Minority Medical Student Award to Ashley Ikwuezunma (mentors Michael E. Scheurer and Maria M. Gramatges).
Data Sharing: De-identified data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.