Non-invasive aspergillosis following COVID-19 exacerbates the severity of SARS-CoV-2 infection.

BACKGROUND: Few large-scale population-based studies have examined the association between COVID-19 and respiratory aspergillosis. Using nationwide data, we investigated whether SARS-CoV-2 infection increases respiratory aspergillosis incidence and whether COVID-19-associated aspergillosis affects COVID-19 severity. We also analyzed public COVID-19 transcriptomic datasets to assess effects on airway structural and immune cells. STUDY DESIGN AND METHODS: From 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, and matched controls. Outcomes were respiratory aspergillosis incidence, including invasive and non-invasive forms, and its association with COVID-19 severity. RESULTS: COVID-19 was associated with increased subsequent respiratory aspergillosis. Diabetes, COPD, and other comorbidities further increased fungal infection incidence among COVID-19 patients. Both invasive and non-invasive aspergillosis were associated with greater COVID-19 severity. Systemic corticosteroid use markedly increased severity and mortality in both forms. Antifungal-related genes and pathways, including CCR6, CXCL9, and CX3CR1, were consistently downregulated after SARS-CoV-2 infection and/or corticosteroid treatment. INTERPRETATION: COVID-19 was associated with increased respiratory aspergillosis incidence, and respiratory aspergillosis was associated with worse COVID-19 outcomes regardless of invasiveness. Further studies should evaluate whether antifungal treatment improves COVID-19 outcomes.