ABSTRACT
Rationale Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterised by an IL-6 driven cytokinemia, associated with a rapidly developing acute respiratory distress syndrome (ARDS). A blunted AAT response to IL-6 in SARS-CoV-2 has been associated with increased morbidity and mortality. One of the main functions of IL-6 is regulation of acute-phase proteins such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the proteaseanti- protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS). In addition, we investigated the effect of anti-IL-6 therapy on anti-protease defence. Methods Levels and activity of AAT and neutrophil elastase (NE) were measured in plasma (n=20), airway tissue (n=8) and tracheal secretions (n=13) of people with severe SARS-CoV-2 infection. AAT and IL-6 levels were also evaluated over time in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab (n=30). Results AAT plasma levels doubled in severe SARS-CoV-2 ARDS patients (329g/L +/- 08 g/L as compared to baseline levels 174g/L +/- 011 g/L, P<0001). In lung parenchyma AAT levels were increased. Despite no increase in neutrophils, an increased percentage of neutrophils involved in NET formation were observed in the alveoli. A protease-anti-protease imbalance was detected in tracheal aspirates (TA). NE was active and AAT inactivated, reflecting cleavage and complexation with NE. The major airway anti-protease, secretory leukoprotease inhibitor (SLPI) was decreased in SARS-CoV-2-infected lungs and cleaved in TAs. Induction of AAT in SARS-CoV-2 infection occurred mainly through IL-6 signalling. Tocilizumab (IL-6 receptor antagonist) down-regulated AAT during infection (13g/L+/-0225 from 2469 g/L+/-0197, P<00001) while IL-6 remained elevated (NS=0.0998) as reflected by the IL-6/AAT ratio (P=0046). Conclusion 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 not only as a pro-inflammatory cytokine but as an anti-inflammatory regulator. In conclusion 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.