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).