Antifungal prophylaxis among critically ill COVID-19 patients: a meta-analysis and systematic review

BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) affects a significant proportion of patients admitted to the ICU and is associated with increased mortality, underscoring the need for effective prophylaxis. While observational studies suggest a benefit from antifungal prophylaxis, its efficacy remains unconfirmed by randomized trials, and its impact on clinical outcomes is unclear. METHODS: We conducted a systematic review and meta-analysis (PROSPERO: CRD42023462988) of nine ICU-based studies, comparing antifungal prophylaxis (primarily inhaled amphotericin B or systemic posaconazole) with standard care. The primary outcome was CAPA incidence; secondary outcomes included mortality, time to CAPA onset, and ICU length of stay. Risk of bias was assessed using ROBINS-I, with publication bias evaluated via Egger’s test and funnel plot symmetry. Subgroup and sensitivity analyses were performed to assess heterogeneity and robustness. RESULTS: Among 1,321 patients included, antifungal prophylaxis significantly reduced CAPA incidence (RR 0.21, 95% CI 0.14–0.33; p < 0.001) and CAPA risk (OR 0.22, 95% CI 0.12–0.40; p < 0.001). Inhaled amphotericin B demonstrated consistent benefit (RR 0.18, 95% CI 0.06–0.52; p = 0.001), whereas systemic posaconazole showed variable results. No significant effects were observed on mortality (RR 1.05; p = 0.69), time to CAPA onset (MD −0.33 days; p = 0.73), or ICU stay duration (MD 1.59 days; p = 0.34). Efficacy was most evident in retrospective cohorts and among patients receiving invasive mechanical ventilation. Sensitivity analyses excluding high-bias studies confirmed the findings. CONCLUSION: This meta-analysis suggests a potential role for antifungal prophylaxis, especially topical amphotericin B, in reducing the risk of CAPA among critically ill COVID-19 patients, albeit survival or ICU stay was unaffected. The favorable profile of topical amphotericin B necessitates direct comparison with systemic azoles in future trials. Prospective, randomized studies are imperative to validate these findings for universal application, refine prophylactic regimens for broader populations, and assess long-term clinical and economic impacts.