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.