Abstract
SummaryBackgroundInterleukin-6 (IL-6) is elevated in SARS-CoV-2 infection. IL-6 regulates acute-phase proteins, such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the protease-anti-protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS) compared to non-SARS-CoV-2 ARDS (nsARDS) and the effects of tocilizumab (IL-6 receptor antagonist) on anti-protease defence in SARS-CoV-2 infection.MethodsLevels and activity of AAT and neutrophil elastase (NE) were measured in plasma, airway tissue and tracheal secretions (TA) of people with SARS-CoV-2 ARDS or nsARDS. AAT and IL-6 levels were evaluated in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab.FindingsAAT plasma levels doubled in SARS-CoV-2 ARDS. In lung parenchyma AAT levels were increased, as was the percentage of neutrophils involved in NET formation. A protease-anti-protease imbalance was detected in TA with active NE and no active AAT. The airway anti-protease, secretory leukoprotease inhibitor was decreased in SARS-CoV-2-infected lungs and cleaved in TA. In nsARDS, plasma AAT levels were elevated but TA samples had less AAT cleavage, with no detectable active NE in most samplesInduction of AAT in ARDS occurred mainly through IL-6. Tocilizumab down-regulated AAT during SARS-CoV-2 infection.InterpretationThere is a protease-anti-protease imbalance in the airways of SARS-CoV-2-ARDS patients. This imbalance is a target for anti-protease therapy.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a major global health risk with few therapies available to modify its clinical www.thelancet.com Vol 77 Month March, 2022Research in contextEvidence before this studySevere acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection is characterised by an IL-6 driven cytokinemia, associated with a rapidly developing acute respiratory distress syndrome (ARDS)
This study shows that the alpha-1 antitrypsin (AAT) response to SARS-CoV-2 infection is compartmentalized with an appropriate increase in plasma and alveoli but an inadequate response in airways
We investigated the effect of IL-6 on beta-galactoside alpha-2-6 sialyltransferase[1] (ST6GAL1) expression as this mediates AAT sialylation during acute inflammation, promoting increased binding of AAT to interleukin (IL)-8 and neutrophil activating peptide (NAP)-2, thereby regulating neutrophil chemotaxis.[9]
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a major global health risk with few therapies available to modify its clinical www.thelancet.com Vol 77 Month March, 2022Research in contextEvidence before this studySevere acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection is characterised by an IL-6 driven cytokinemia, associated with a rapidly developing acute respiratory distress syndrome (ARDS). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a major global health risk with few therapies available to modify its clinical www.thelancet.com Vol 77 Month March, 2022. This study shows that the AAT response to SARS-CoV-2 infection is compartmentalized with an appropriate increase in plasma and alveoli but an inadequate response in airways. This underlines a significant, but potentially treatable, protease-antiprotease imbalance in SARS-CoV-2 ARDS as well as highlighting IL-6’s importance in SARS-CoV-2 pathology as a pro-inflammatory cytokine but as an anti-inflammatory regulator. There is unopposed NE activity in the airways of people with SARS-CoV-2 ARDS, which could be amenable to AAT therapy. Our data suggest caution in the use of IL-6 blocking therapies in SARS-CoV-2-infected individuals
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