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.

Fig. 1

PRISMA flowchart.

Fig. 2

Venn diagram illustrating number of patients meeting each COVID-19–associated pulmonary aspergillosis (CAPA) classification, among 277 patients with individual-level data. Ninety-four patients (33.9%) did not meet criteria for any of the definitions for CAPA: 75 (27.1%) were classified as not meeting criteria for CAPA for all four definitions, and another 19 (6.9%) did not meet CAPA criteria for any of the Verweij, White, and Koehler definitions and were unclassifiable by Bassetti criteria because of lack of reported radiographic details.

Fig. 3

Forest plot of reported prevalence of COVID-19–associated pulmonary aspergillosis in (a) intensive care unit (ICU) cohort studies and (b) among only those ICU patients receiving invasive mechanical ventilation.

Fig. 4

Summary forest plots for prevalence of COVID-19–associated pulmonary aspergillosis in cohort studies with individual patient-level data permitting reclassification, as reported and upon reclassification per four published research definitions.

Fig. 5

Summary forest plots for antifungal treatment and survival amongst patients with COVID-19–associated pulmonary aspergillosis as reported (a) and when reclassified according to Verweij (b), White (c), and Koehler (d). Analysis of patients who met classification by Bassetti could not be performed because an insufficient number of studies met the minimum criteria for meta-analysis.

Supplementary Figure 1

Prevalence of COVID-19-associated pulmonary aspergillosis in cohort studies with patient-level data (a) as reported and when reclassified according to Verweij (b), White (c) Koehler - proven/probable classifications only (d) Koehler - any classifications and (e) Bassetti.