Poor control of viral replication in the lung as major driver of early respiratory failure in ventilated patients with COVID-19

The contribution of active SARS-CoV-2 viral replication to respiratory failure in severe COVID-19 remains unclear. We prospectively analysed bronchoalveolar lavage (BAL) samples from 159 critically ill COVID-19 patients requiring invasive mechanical ventilation (IMV) for SARS-CoV-2 RNA load, replication-competent virus and host immune gene expression. Viral RNA was detected in 84.3% of patients and 60% were positive for replication-competent virus. Viral culture positivity showed the strongest association with shorter time from symptom onset to IMV initiation. Despite robust type I/III interferon expression, immune effector responses were impaired, and only CXCL10 and PDL1 gene expression were associated with early respiratory failure. These findings underscore uncontrolled viral replication as a key driver of early respiratory failure in critically ill COVID-19 patients.