Abstract
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 bronchoalveolar 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 patients with influenza, as a non–COVID-19 viral pneumonia cohort. Compared with those of patients with influenza, BAL fluids of patients with COVID-19 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, and tissue inhibitor of metalloproteinases 1. In contrast, α-1 antitrypsin levels and net proteolytic activity were comparable in COVID-19 and influenza BAL fluids. During antibiotic treatment for bacterial coinfections, increased BAL fluid levels of several activating and chemotactic factors for monocytes, lymphocytes, and NK cells were detected in patients with COVID-19 whereas concentrations tended to decrease in patients with influenza, highlighting the persistent immunological response to coinfections in COVID-19. Finally, the high proteolytic activity in COVID-19 lungs suggests considering protease inhibitors as a treatment option.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (COVID-19) continue to pose a major threat to global health and the global economy, with more than 267 million confirmed cases and more than 5.27 million deaths as of December 2021 [1]
The absolute neutrophil count in the bronchoalveolar lavage (BAL) fluid was significantly increased in COVID-19 compared with influenza patients (Figure 1H)
It is well established that an atypical cytokine storm drives the systemic inflammation in severe COVID-19 [3, 4, 12, 29, 30], which is confirmed by our results
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (COVID-19) continue to pose a major threat to global health and the global economy, with more than 267 million confirmed cases and more than 5.27 million deaths as of December 2021 [1]. Up to 20% of patients develop severe acute respiratory distress syndrome (ARDS), requiring intensive care [2]. The systemic hyperinflammatory response in severe COVID-19 is associated with dysregulation of the immune system and is characterized by an atypical cytokine storm, lymphopenia, and increased neutrophil counts in blood [3,4,5]. Growing consensus exists that neutrophils are key effector cells in severe COVID-19. Within the bronchoalveolar space, increased neutrophil counts with a heterogeneous phenotype are seen, but most information is available from single-cell transcriptomics studies whereas information on protein levels is limited [17,18,19]. The effect on the inflammatory response of bacterial or fungal coinfection(s) in mechanically ventilated COVID-19 patients requires further investigation. Ventilator-associated lower respiratory tract infections are significantly more prevalent in COVID-19 compared with influenza patients or ventilated patients without viral infections [20] and are associated with a longer duration of ventilation, hospitalization in intensive care units (ICUs), and mortality [21, 22]
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