Invasive Fungal Disease in Pediatric Heart Transplant Recipients
Authors: Liversedge Matthew , Wang Jeffrey , Boustany Mickael , Sharova Anna , Downes Kevin J , Otto William 
Published: October 2024

Abstract

Background
The epidemiology of IFD following pediatric heart transplantation (pHT) is poorly characterized. We sought to evaluate use of antifungal prophylaxis and describe the epidemiology of IFD in pHT at two large children’s hospitals.

Methods
We performed a retrospective cohort study of pediatric and young adult (≤21 years) patients undergoing heart transplantation at Cincinnati Children’s Hospital Medical Center (CCHMC) and Children’s Hospital of Philadelphia (CHOP) between 2012 and 2021. We recorded demographic, clinical, medication, and laboratory data for pHT patients through 12 months post-transplant. We identified use of topical (oral nystatin) and systemic antifungal prophylaxes in the peri-transplant period (7 days prior through 14 days following transplant) and analyzed if certain transplant variables were associated with the administration of systemic antifungals during this period using rank sum and chi squared tests. Applying published definitions, we quantified the incidence of proven and probable IFD and explored the characteristics of these cases.

Results
A total of 201 patients underwent heart transplant at CCHMC and CHOP. The majority were male (60.2%), White (66.7%), and not Hispanic or Latino (88.1%). Median age at time of transplant was 7.4 years (IQR 0.9-14.2).
During the peri-transplant period, 143 (71.1%) patients received oral nystatin and 37 (18.4%) received systemic antifungal prophylaxis, not including PJP prophylaxis. 41 individuals (20.4%) were not on any antifungal prophylaxis throughout this period. Delayed chest closure was significantly associated with the administration of systemic antifungals (p&lt;0.001) while several other variables (age, hospital, immunosuppression medication, ECMO/LVAD pre-transplant) were not.
In total, 8 patients (4%) developed proven (n=5) or probable (n=3) IFD. In our cohort, the incidence rate of proven/probable IFD in the first year post-transplant was 44.8 per 1000 patient-years. The characteristics of these cases are shown in Table 1. Time from pHT to IFD ranged from 11 days to 196 days (median time = 25.5 days). All cases of proven IFD occurred within 28 days of transplant. In three cases of proven/probable IFD, patients were receiving a systemic antifungal or PJP prophylaxis in the seven days prior to IFD onset. Two cases met the definition of probable IFD but the infections resolved without directed therapies.
Four patients with proven IFD died within 1 year following transplant, although in only 3 cases was IFD a contributing factor. The one-year all-cause mortality rate among pHT patients with proven/probable IFD (50%) was higher than that in pHT patients without IFD (10.3%; Fisher’s exact p=0.008).

Conclusion
Over a 10-year period at CCHMC and CHOP, 4% of pHT patients developed proven or probable IFD within one-year post-transplant. All proven IFD cases occurred within a month of transplant while probable cases occurred more than 100 days post-transplant. Delayed chest closure was significantly associated with the administration of systemic antifungal prophylaxis. Patients with proven IFD had poor outcomes despite receipt of appropriate antifungal treatment. Given the low incidence of IFD at these two centers, we were unable to evaluate risk factors for IFD in this population and so larger studies would be needed.