Poor control of pulmonary viral replication in COVID-19 patients with early respiratory failure

BACKGROUND: Severe respiratory failure is the leading cause of intensive care unit (ICU) admission and mortality in critically ill COVID-19 patients. However, whether active viral replication persists in the lower respiratory tract of these patients and contributes to lung injury remains unclear. METHODS: We conducted a prospective cohort study of 159 critically ill COVID-19 patients requiring invasive mechanical ventilation (IMV). A bronchoalveolar lavage (BAL) sample was collected within 24 h of intubation. SARS-CoV-2 RNA load (N1, N2, E, and subgenomic E) and the expression of 18 host immune-related genes were assessed. A replication-competent virus was detected using a Vero cell culture assay by inoculating cells with BAL samples and monitoring cytopathic effects. SARS-CoV-2 replication was confirmed by RT-qPCR. Association of virological and immunological factors with time from symptom onset to IMV initiation was evaluated using multivariable linear regression. RESULTS: SARS-CoV-2 RNA was detected in 84.3% of BAL samples, and 71.7% were positive for subgenomic E RNA. Replication-competent virus was confirmed in 60% of the samples. High RNA levels and SARS-CoV-2 culture positivity were independently associated with shorter time from symptom onset to IMV initiation, with culture positivity showing the strongest association. Gene expression profiling revealed a marked suppression of innate immune effectors, despite robust expression of type I and type III interferons. CXCL10 and PDL1 were the only genes independently associated with shorter time from symptom onset to IMV initiation. CONCLUSIONS: At the time of IMV initiation, patients with early respiratory failure showed high levels of SARS-CoV-2 RNA and evidence of active viral replication in the lower respiratory tract. This group represents a distinct virological phenotype that could benefit from therapeutic interventions targeting pulmonary viral replication. REGISTRATION: Sub-study of the CIBERESUCICOVID project (NCT04457505).