Indirect comparison of prevalence, risk factors, and mortality in COVID 19 versus influenza associated pulmonary aspergillosis in critically ill adults

Invasive pulmonary aspergillosis is a severe complication of viral pneumonia in critically ill patients. COVID-19–associated pulmonary aspergillosis (CAPA) and influenza-associated pulmonary aspergillosis (IAPA) are increasingly recognized as significant contributors to morbidity and mortality in intensive care units (ICUs). However, no study has systematically compared their prevalence, risk factor profiles, and attributable mortality within a single evidence synthesis. We therefore undertook an indirect comparative meta-analysis, in which CAPA and IAPA estimates were pooled separately and then contrasted indirectly, rather than compared head-to-head within the same patients. We searched PubMed/MEDLINE, Embase, Cochrane Library, Scopus, and Web of Science from inception to March 31, 2025. Eligible studies were observational cohort or case-control studies reporting on CAPA or IAPA in adult ICU patients. Pooled prevalence estimates were calculated using the Freeman–Tukey double arcsine transformation with DerSimonian–Laird random-effects models. Risk factors and attributable mortality were pooled as odds ratios (ORs) with 95% confidence intervals (CIs). All-cause mortality was the only mortality outcome analysed and is referred to as such throughout. CAPA and IAPA were not compared at the individual-patient level; instead, separately pooled estimates were contrasted indirectly using tests for subgroup differences, and 95% prediction intervals, together with the between-study variance τ², were derived for all pooled estimates. The study was registered with PROSPERO (CRD420261365038) and reported in accordance with the PRISMA 2020 and MOOSE guidelines. A total of 89 studies (68 CAPA, 21 IAPA) encompassing 19,482 critically ill patients were included. The pooled prevalence of CAPA in ICU patients was 10.2% (95% CI 8.1–12.6%; I² = 87%; τ² = 0.004; 95% prediction interval 3.7–19.6%), compared with 19.4% (95% CI 14.8–24.6%; I² = 83%; τ² = 0.004; 95% prediction interval 10.2–30.8%) for IAPA ( p < 0.001). Pooled all-cause mortality was 51.2% (95% CI 44.8–57.5%; 95% prediction interval 31.3–70.9%) for CAPA and 51.8% (95% CI 43.1–60.4%; 95% prediction interval 36.6–66.9%) for IAPA ( p = 0.92). Attributable mortality ORs were 2.65 (2.04–3.45) for CAPA and 2.44 (1.75–3.40) for IAPA ( p = 0.68). The separately pooled prevalence of IAPA was nearly two-fold higher than that of CAPA in ICU patients, yet both conditions were associated with all-cause mortality exceeding 50%. These findings underscore the need for routine fungal surveillance protocols in patients with severe influenza and COVID-19. Because the comparison between CAPA and IAPA was indirect and based on observational studies, the reported associations should be interpreted as hypothesis-generating rather than causal.