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.
ABSTRACT
Rationale: It has been suggested that individuals with ZZ alpha-1 antitrypsin deficiency (AATD) might suffer from more severe and prolonged pulmonary exacerbations compared to their MM counterparts due to the loss of immunomodulatory AAT protein. During the COVID-19 pandemic it was advised that individuals with ZZ AATD should, where practicable, cocoon to avoid contracting COVID-19. Methods: A survey of ZZ AATD individuals attending the Irish National Centre for Expertise for AATD was conducted 1 year into the COVID-19 pandemic. It evaluated the effects of cocooning on patient-reported exacerbation frequency during the 1-year COVID-19 period versus the 2 years prior to COVID-19. 184 individuals were contacted by phone, mail, or email. Results: 114 (62%) individuals successfully completed the survey. 73 (64%) cocooned during the pandemic, with men (39) and women (34) almost equally likely to cocoon. Those who cocooned tended to have a lower baseline FEV1 (% predicted). Women who cocooned had a mean FEV1 of 73.5% compared to a mean of 97.5% for women who did not cocoon. Men who cocooned had a mean FEV1 of 52.8% compared to a mean of 78.9% for men who did not cocoon. Men benefited from lower rates of exacerbation due to cocooning. They suffered an average of 0.92 exacerbations during the cocooning period versus 1.56 exacerbations per year prior to the pandemic (P = 0.0298). Women, regardless of cocooning status and non-cocooning men also demonstrated a trend towards fewer exacerbations but these were not statistically significant. In terms of hospitalisations, there were no differences observed between men or women based on cocooning status. This was likely due to the low rate of hospital admissions during the 3-year period. 14 (12%) of 114 respondents contracted COVID-19, 7 (50%) of whom were hospitalised. There was a single fatality from COVID-19. Conclusion: Further work needs to be done to establish the effects of risk reduction behaviours such as cocooning on exacerbation frequency and which groups may benefit most from this strategy. Our survey suggests that men with more advanced respiratory disease were most likely to benefit from a cocooning strategy and this may be applicable to non-COVID threats in the future.