Defining COVID-19-associated pulmonary aspergillosis: systematic review and meta-analysis

Abstract

Background: Pulmonary aspergillosis may complicate coronavirus disease 2019 (COVID-19) and contribute to excess mortality in intensive care unit (ICU) patients. The disease is poorly understood, in part due to discordant definitions across studies.

Objectives: We sought to review the prevalence, diagnosis, treatment, and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA) and compare research definitions.

Data sources: PubMed, Embase, Web of Science, and MedRxiv were searched from inception to October 12, 2021.

Study eligibility criteria: ICU cohort studies and CAPA case series including ≥3 patients were included.

Participants: Adult patients in ICUs with COVID-19.

Interventions: Patients were reclassified according to four research definitions. We assessed risk of bias with an adaptation of the Joanna Briggs Institute cohort checklist tool for systematic reviews.

Methods: We calculated CAPA prevalence using the Freeman-Tukey random effects method. Correlations between definitions were assessed with Spearman's rank test. Associations between antifungals and outcome were assessed with random effects meta-analysis.

Results: Fifty-one studies were included. Among 3297 COVID-19 patients in ICU cohort studies, 313 were diagnosed with CAPA (prevalence 10%; 95% CI 8%-13%). Two hundred seventy-seven patients had patient-level data allowing reclassification. Definitions had limited correlation with one another (ρ = 0.268-0.447; p < 0.001), with the exception of Koehler and Verweij (ρ = 0.893; p < 0.001); 33.9% of patients reported to have CAPA did not fulfill any research definitions. Patients were diagnosed after a median of 8 days (interquartile range 5-14) in ICUs. Tracheobronchitis occurred in 3% of patients examined with bronchoscopy. The mortality rate was high (59.2%). Applying CAPA research definitions did not strengthen the association between mould-active antifungals and survival.

Conclusions: The reported prevalence of CAPA is significant but may be exaggerated by nonstandard definitions.

Keywords: Aspergillus; CAPA; Fungal infection; ICU; Mycosis; SARS-CoV-2; Secondary infection.