Risk and prognostic patterns of viral-associated invasive pulmonary aspergillosis: impact of corticosteroid and antibiotic exposure in non-neutropenic hosts.

Background: Invasive pulmonary aspergillosis (IPA), which is traditionally linked to immunocompromised states, has been increasingly observed in non-neutropenic patients with severe viral pneumonias, especially those caused by the 2009 novel influenza A (H1N1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The influence of corticosteroid and antibiotic exposure on IPA risk and outcomes in this population remains poorly defined. This study aimed to investigate the impact of corticosteroid and antibiotic exposure on the risk and outcomes of IPA in non-neutropenic patients with viral pneumonias. Methods: A retrospective study was conducted for 234 non-neutropenic adults with laboratory-confirmed H1N1, coronavirus disease 2019 (COVID-19), or co-infection. The clinical, laboratory, and therapeutic data were examined for associations with IPA incidence and mortality. Restricted cubic spline models were employed to assess the non-linear dose-response relationships. Survival differences were evaluated using Kaplan-Meier (KM) curves. Results: IPA occurred in 152 patients (65.00%), with the highest incidence in co-infection (89.00%), followed by H1N1 (67.00%) and COVID-19 (42.00%). IPA was associated to higher corticosteroid and antibiotic exposure, diabetes, chronic lung disease, and intensive care unit (ICU) admission. Co-infection correlated to greater drug exposure, higher Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, and increased mortality (36.80% vs. 6.30-9.70%). Both therapies presented with U-shaped or inverted U-shaped associations with IPA risk and mortality, peaking at 5-15 days of treatment and corticosteroid doses of >600 mg. Chronic obstructive pulmonary disease (COPD) and hypoalbuminemia further increased susceptibility and worsened outcomes. The KM curves revealed the steepest survival decline in co-infected patients. Conclusions: Both corticosteroid and antibiotic exposures are independently associated to increased risk and mortality of IPA, in a non-linear, dose-dependent manner. These findings emphasize the importance of judicious therapeutic use and early risk stratification to mitigate IPA burden.