Atypical response to bacterial co-infection and persistent neutrophilic broncho-alveolar inflammation distinguish critical COVID-19 from influenza.

Neutrophils are recognized as important circulating effector cells in the pathophysiology of severe coronavirus disease 2019 (COVID-19). However, their role within the inflamed lungs is incompletely understood. Here, we collected broncho-alveolar lavage (BAL) fluids and parallel blood samples of critically ill COVID-19 patients requiring invasive mechanical ventilation and compared BAL fluid parameters with those of mechanically ventilated influenza patients, as a non-COVID-19 viral pneumonia cohort. Compared to influenza, BAL fluids of COVID-19 patients contained increased numbers of hyperactivated degranulating neutrophils and elevated concentrations of the cytokines IL-1β, IL-1RA, IL-17A, TNF-α and G-CSF, the chemokines CCL7, CXCL1, CXCL8, CXCL11 and CXCL12α, and the protease inhibitors elafin, secretory leukocyte protease inhibitor (SLPI) and tissue inhibitor of metalloproteinases 1 (TIMP-1). In contrast, α-1 antitrypsin levels and net proteolytic activity were comparable in COVID-19 and influenza BAL fluids. During antibiotics treatment for bacterial co-infections, increased BAL fluid levels of several activating and chemotactic factors for monocytes, lymphocytes and NK cells were detected in COVID-19 patients whereas concentrations tended to decrease in influenza patients, highlighting the persistent immunological response to co-infections in COVID-19. Finally, the high proteolytic activity in COVID-19 lungs suggests considering protease inhibitors as a treatment option.