Immunosuppression is associated with loss of airway microbiome resilience in severe COVID-19

Background The role of the lower airway microbiome in COVID-19-associated mortality remains poorly understood despite evidence implicating secondary pathogens and non-airway commensals. The influence of prior immunosuppression on the lower airway microbiome and its contribution to mortality in mechanically ventilated patients has been largely unexplored. Given that host-microbiome interactions are dynamic, we assessed longitudinal patterns in the respiratory microbiome associated with mortality and immunosuppression status. Results We conducted longitudinal forecasting, differential abundance, and comparative network analyses of metatranscriptomic data from 604 upper and lower airway samples collected from 243 mechanically ventilated COVID-19 patients to profile key microbial factors associated with immunosuppression and clinical outcome. SARS-CoV-2 was enriched over time in immunosuppressed patients and in both immunosuppressed and immunocompetent patients who died, highlighting the need for aggressive viral infection control early in the disease course. Using longitudinal forecasting and differential abundance analyses, we observed a progressive increase in opportunistic pathogens, such as Staphylococcus aureus and Escherichia coli , among the taxa most predictive of mortality. Concurrently, immunosuppressed individuals exhibited a significant decrease in typical airway commensals alongside a restructuring and marked destabilization of the microbial community compared with their immunocompetent counterparts. Conclusions These findings indicate that loss of airway microbiome stability in immunosuppressed patients constitutes an independent factor contributing to increased susceptibility to opportunistic pathogens and poor clinical outcomes.