Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza
Seppe Cambier, Mieke Metzemaekers, Ana Carolina de Carvalho, Amber Nooyens, Cato Jacobs, Lore Vanderbeke, Bert Malengier-Devlies, Mieke Gouwy, Elisabeth Heylen, Philippe Meersseman, Greet Hermans, Els Wauters, Alexander Wilmer, the CONTAGIOUS Consortium, Dominique Schols, Patrick Matthys, Ghislain Opdenakker, Rafael Elias Marques, Joost Wauters, Jennifer Vandooren, Paul Proost
Seppe Cambier, Mieke Metzemaekers, Ana Carolina de Carvalho, Amber Nooyens, Cato Jacobs, Lore Vanderbeke, Bert Malengier-Devlies, Mieke Gouwy, Elisabeth Heylen, Philippe Meersseman, Greet Hermans, Els Wauters, Alexander Wilmer, the CONTAGIOUS Consortium, Dominique Schols, Patrick Matthys, Ghislain Opdenakker, Rafael Elias Marques, Joost Wauters, Jennifer Vandooren, Paul Proost
View: Text | PDF
Research Article COVID-19 Immunology

Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza

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.

Authors

Seppe Cambier, Mieke Metzemaekers, Ana Carolina de Carvalho, Amber Nooyens, Cato Jacobs, Lore Vanderbeke, Bert Malengier-Devlies, Mieke Gouwy, Elisabeth Heylen, Philippe Meersseman, Greet Hermans, Els Wauters, Alexander Wilmer, the CONTAGIOUS Consortium, Dominique Schols, Patrick Matthys, Ghislain Opdenakker, Rafael Elias Marques, Joost Wauters, Jennifer Vandooren, Paul Proost

×

Figure 6

Quantification of protease activity and protease and protease inhibitor levels in BAL fluid from patients with severe COVID-19 or influenza.

Options: View larger image (or click on image) Download as PowerPoint
Quantification of protease activity and protease and protease inhibitor ...
ELISA was used to determine concentrations of (A) TIMP-1, (B) TIMP-1/MMP-9 complexes, (C) SLPI, (D) elafin, and (E) α-1 antitrypsin (serpin A1) in BAL fluid samples from COVID-19 patients (n = 31) and influenza patients (n = 14). (F) Total gelatinolytic activity, as determined in a kinetic assay measuring degradation of a fluorogenic gelatin substrate; (G) total MMP proteolytic activity, as determined measuring degradation of a fluorogenic omni MMP substrate; (H) total elastinolytic activity, as determined measuring degradation of a fluorogenic elastin substrate; and (I) neutrophil elastase levels (quantified by ELISA) were measured within the BAL fluid samples. (J–L) Correlation between chemokine/cytokine levels, proteolytic activity, and protease inhibitors measured in the BAL fluid of COVID-19 patients. Data are shown as box-and-whisker plots (box: median with interquartile range, whiskers: full data distribution), with each dot representing an individual patient sample. The dashed lines indicate the lower detection limits. Unfilled symbols indicate values above the upper detection limit. Data were statistically analyzed by a linear mixed model with correction for multiple samples per patient using a random intercept model. Correlation analysis was performed calculating a repeated measures correlation coefficient and plotted utilizing a simple linear regression line. P values are shown above brackets.