Publication date: Jul 04, 2025

Background: A limited number of large-scale population-based studies regarding the causality between COVID-19 and respiratory aspergillosis exist. Herein, using nationwide data, we investigated whether SARS-CoV-2 infection increases incidence of respiratory aspergillosis and impact of COVID-19-associated aspergillosis on severity of COVID-19. Further, to assess the biological impact of SARS-CoV-2 infection on airway structural and immune cells, we analyzed publicly available COVID-19 transcriptomic datasets. Study Design and Methods: Utilizing a nationwide cohort of 8.5 million clinical registries, we included over 550,000 patients diagnosed with COVID-19 between October 8, 2020, and December 31, 2021, along with control-matched group. The primary outcomes were aspergillosis incidence, including both invasive and non-invasive forms, and its impact on the severity of COVID-19. Results: COVID-19 was closely associated with increased incidence of subsequent respiratory aspergillosis. Comorbidities, including diabetes and COPD, increased the incidence of fungal infections in COVID-19 patients. Regarding severity of COVID-19, both invasive and non-invasive aspergillosis exacerbated the severity of the disease. Particularly, systemic corticosteroids had an overwhelming impact on the increased severity and mortality in both forms of aspergillosis. Notably, antifungal-related genes and pathways, including CCR6, CXCL9, and CX3CR1, were consistently downregulated following SARS-CoV-2 infection and/or corticosteroid treatment. Interpretation: Our findings indicate that COVID-19 increases the incidence of respiratory aspergillosis. Moreover, respiratory aspergillosis, irrespective of its clinical invasiveness, significantly exacerbates the severity of COVID-19. Well-designed studies on the therapeutic potential of antifungal agents to improve the outcomes of COVID-19 are warranted.

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