Background: Influenza-associated pulmonary aspergillosis (IAPA) is a significant fungal complication in patients with influenza-induced acute-respiratory-distress-syndrome (ARDS). The impact of empirical antifungal treatment on IAPA incidence and outcomes remains unclear.

Methods: In this observational multicenter study (9 treatment centers), we included all consecutive patients admitted to intensive care units (ICUs) with influenza-associated ARDS between September 1, 2016, and March 1, 2025. We compared patients receiving empirical antifungal treatment with those who did not, focusing on 30-day IAPA incidence (primary outcome) and survival (secondary outcome). Propensity score weighting was used to account for baseline characteristic imbalances. IAPA cases were classified based on the Fungal-Infections-in-Adult-Patients-in-ICU (FUNDICU) consensus criteria.

Results: We included 172 patients, 61 (35%) of whom received empirical antifungal therapy (94% posaconazole). IAPA was diagnosed in 24 cases, with a median onset of 2 days after ICU admission. Of these, 20 occurred in the non-treatment group and 4 in the empirical treatment group. The 30-day IAPA incidence was 7.7% in the treatment group and 20.4% in the non-treatment group (p=0.002). The sub-distributional hazard ratio (sHR) for IAPA incidence in the empirical treatment group compared to the non-treatment group was 0.21 (95% CI 0.10-0.92, p=0.045). However, there was no significant difference in 30-day ICU survival.

Conclusion: In ICU patients with influenza ARDS, empirical antifungal treatment was associated with significantly reduced IAPA incidence, but this did not translate into improved survival. Randomized controlled trials are warranted to evaluate the efficacy and safety of patients´ specific empirical antifungal treatment with regard to IAPA incidence and outcomes.