Incidence and Mortality of COVID-19 Associated Invasive Fungal Infections Among Critically-Ill Intubated Patients: A Multicenter Retrospective Cohort Analysis

Background: Previous research suggests a potential association between COVID-19 invasive fungal infections and high mortality among intubated patients. However, most of the current evidence derives from small case series conducted during the first waves of the COVID-19 pandemic and are geographically restricted, limiting their interpretability of incidence and effect on mortality. We examined incidence and mortality between COVID-19 and invasive fungal infections using a multicenter COVID-19 database. Methods: Using the National COVID Cohort Collaborative (N3C), we conducted a retrospective analysis of patients 18 years or older intubated for SARS-CoV-2 from 76 medical centers in the United States. The primary outcomes were the incidence of COVID-19 associated invasive fungal infections (CAIFI) and all-cause mortality at 90-days. To assess all-cause mortality, we fitted Cox proportional hazard models after adjusting for confounders via inverse probability weighting. Further, we controlled for immortal time bias using the exposure variable as time-varying in survival models. Findings: Out of the 4,449,472 patients with COVID-19 diagnosed during the study period, 67,511 (1ꞏ5%) met our cohort definition. The incidence of CAIFI was 2ꞏ6% (n=1,760/67,511). CAIFI caused by Aspergillus (49ꞏ1%; n=865/1,760) and Candida (39ꞏ1%; n=688/1,760) were the most common. Following inverse probability weighting, CAIFI associated to Aspergillus [HR: 2ꞏ0; 95% CI: 1ꞏ8-2ꞏ2], Candida [HR: 1ꞏ7; 95% CI: 1ꞏ5-1ꞏ9], Cryptococcus [HR: 1ꞏ6; 95% CI: 1ꞏ2-2ꞏ1] and Mucorales [HR: 1ꞏ4; 95% CI: 1ꞏ0-2ꞏ0] were associated with increased mortality. Interpretation: CAIFI is relatively common and associated with higher 90-day all-cause mortality among intubated patients. Clinicians should maintain a high degree of suspicion.Funding Information: Mayne Pharma Inc. and National Institutes of Health.Declaration of Interests: JCZM, AMR, AEM, BP declare no conflict of interests. AS and PBM received funding from Washington University Institute of Clinical and Translational Sciences grant from the National Center for Advancing Translational Sciences of the National Institutes of Health [UL1 TR002345]. AS has received funding Mayne Pharma Inc for this study and has received funding from Astellas and Scynexis in the past.Ethics Approval Statement: The authors received a data user agreement authorization to analyze the data. The DUR request was RP-287159 and National COVID Cohort Collaborative granted permission.