Invasive Fungal Infections in Pediatric and Young Adult Patients with Hematologic Malignancies or after Hematopoietic Stem Cell Transplant

Introduction

Invasive fungal infections (IFI) cause significant morbidity and mortality in children and young adults with hematologic malignancies and those after hematopoietic stem cell transplant (HSCT). IFI is difficult to diagnose, and data on changes in incidence over time are limited. The incidence of IFI will likely change over time as chemotherapy regimens and antifungal prophylaxis utilization change. To address this knowledge gap, we sought to characterize the number and type of IFI cases across two sites from 2013 to 2021. We also investigated the utilization of antifungal prophylaxis and the clinical outcomes of patients.

Methods

IFI was defined as microbiologic or pathologic identification of fungal elements or a fungal organism from a sterile site or bronchioalveolar lavage. Patients were eligible for inclusion if they were between the ages 0 to 26 years with an underlying diagnosis of acute lymphoblastic leukemia/lymphoma (ALL/Lly), acute myeloid leukemia (AML) or those with a history of hematopoietic stem cell transplant (HSCT) for any reason who had received cancer-directed therapy or immune suppression at either Lucile Packard Children's Hospital (LPCH) or Children's Hospital of Orange County (CHOC) within one year of diagnosis of IFI. IRB approval was obtained at both sites. Potential patients were identified by a search of the electronic health record for prespecified ICD9/10 codes. Cases were then manually reviewed for inclusion. Patients with a history of multiple fungal infections were included. Data on demographics, clinical history, IFI presentation and treatment, antifungal prophylaxis and vital status 6 months after diagnosis of IFI were abstracted and entered into a secure Redcap database.

We used Pearson correlation coefficient to assess for the association between year and number of IFI cases. Univariate and multivariate Cox proportional hazard analyses were used to assess the association between type of infection and demographic factors with vital status 6 months after first IFI.

Results

Between 2013 and 2021, we identified a total 81 cases of IFI in 70 patients with hematologic malignancies or after HSCT at LPCH and CHOC. Mean age at diagnosis of first IFI was 13, 61% of patients had a diagnosis of ALL/Lly, 30% of patients had AML, and 29% of patients were overweight or obese. The number of cases of IFI increased significantly over time, from 2 cases in 2013 to 13 cases in 2021 (Pearson correlation 0.82, p<0.01). The most common organism identified was candida species (41% of infections), followed by mucorales (21%), aspergillus (19%), and other (19%). Overall survival (OS) at 6 months after first IFI was 75.7%, and there was no significant difference based on utilization of antifungal prophylaxis. Mortality at 6 months was 46.2% for aspergillus, 33.3% for mucorales, and 13.8% for candida infections. In the patients that did die, fungal infection accounted for 70% of the cause of deaths. In univariate analyses, higher body mass index (BMI) and aspergillus infections were significantly associated with increased risk for all-cause mortality (hazard ratio 1.05 per 1-unit increase in BMI, p 0.04; hazard ratio 4.11, p 0.03, respectively). In multivariate analyses, only BMI was associated with a significantly increased risk of death at 6 months (hazard ratio 1.09, p 0.02).

Conclusions

This retrospective study aimed to characterize IFI in pediatric and young adult patients over 8 years across two centers. The number of cases of IFI significantly increased over time. This could be due to increased intensity of chemotherapy regimens, changes in fungal resistance patterns, or improvements in diagnostic testing. Elevated BMI was the only patient demographic associated with increased risk of mortality 6 months after first IFI diagnosis. While obesity is associated with inferior outcomes in patients with acute leukemia, it has not previously been reported to increase the risk of death after IFI. Surprisingly, aspergillus infection, but not mucorales infection, was associated with increased all-cause mortality. It is possible that patients with mucorales infection had more modifications to their chemotherapy regimen which allowed for improved short term outcomes but may impact longer term survival. This study highlights the need for further research to characterize the change in incidence and epidemiology of IFI over time.

Huynh:Servier: Research Funding.