COVID-19 Associated Pulmonary Aspergillosis: Systematic Review and Patient-Level Meta-Analysis

Kariyawasam, R. M.; Dingle, T. C.; Kula, B. E.; Sligl, W. I.; Schwartz, I. S.

Rationale Pulmonary aspergillosis may complicate COVID-19 and contribute to excess mortality in intensive care unit (ICU) patients. The incidence is unclear because of discordant definitions across studies. Objective We sought to review the incidence, diagnosis, treatment, and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA), and compare research definitions. Methods We systematically reviewed the literature for ICU cohort studies and case series including [≥]3 patients with CAPA. We calculated pooled incidence. Patients with sufficient clinical details were reclassified according to 4 standardized definitions (Verweij, White, Koehler, and Bassetti). Measurements Correlations between definitions were assessed with Spearmans rank test. Associations between antifungals and outcome were assessed with Fishers Exact test. Main Results 38 studies (35 cohort studies and 3 case series) were included. Among 3,297 COVID-19 patients in ICU cohort studies, 313 were diagnosed with CAPA (pooled incidence 9.5%). 197 patients had patient-level data allowing reclassification. Definitions had limited correlation with one another ({rho}=0.330 to 0.621, p<0.001). 38.6% of patients reported to have CAPA did not fulfill any research definitions. Patients were diagnosed after a median of 9 days (interquartile range 5-14) in ICUs. Tracheobronchitis occured in 5.3% of patients examined with bronchoscopy. The mortality rate (50.0%) was high, irrespective of antifungal use (p=0.28); this remained true even when the analysis was restricted to patients meeting standardized definitions for CAPA. Conclusions The reported incidence of CAPA is exaggerated by use of non-standard definitions. Further research should focus on identifying patients likely to benefit from antifungals.