Fragments of alpha-1-antitrypsin in patients with severe COVID-19 and bacterial pulmonary sepsis

We read with great interest the recent article by Zerimech et al. proposing a protease-antiprotease imbalance as a key pathophysiological mechanism in the progression of COVID-19 to severe ARDS (acute respiratory distress syndrome) [1]. In this correspondence, we would like to offer new evidence relating to this finding by providing the concentrations of two C-terminal protease cleavage products of alpha-1-antitrypsin (AAT) in plasma. A deficiency in alpha-1-antitrypsin, a protease inhibitor and acute-phase protein with anti-inflammatory properties, has been proposed to play a role in the pathogenesis of COVID-19. A first association was observed by Vianello et al. who found regions in Italy with higher incidence of hereditary AAT deficiency to be affected more severely by the pandemic [2]. Aside from its anti-inflammatory effects, AAT also has antiviral properties. It has been shown that AAT inhibits the transmembrane protease serine subtype 2 (TMPRSS2), which is necessary for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter the cell [3]. In patients with COVID-19, the ratio of proinflammatory IL-6 and AAT was able to predict disease severity andmortality [4]. Similarly to chronic lung disease [5], an antiprotease–protease imbalance has been proposed to contribute to disease severity in patients with COVID-19 by Zerimech et al. [1]. The study found higher peak values of neutrophil elastase (NE) and matrix metalloprotease-12 (MMP-12) in patients who died from severe COVID-19. A variety of enzymes and pathophysiological conditions has been identified that are associated with the formation of C-terminal peptides of AAT (CAAPs) including NE and MMP-12. Some CAAPs have also been proposed to serve as putative biomarkers for a variety of diseases. Analysis of sepsis patients demonstrate that certain CAAPs are significantly increased in blood during systemic inflammation compared to healthy individuals [6]. To the best of our knowledge, there is hitherto no evidence for the formation of CAAPs during viral infections. However, a recent proteomic study comparing mild and severe patients with COVID-19 found different concentrations of AAT peptides in the urine, indicating a distinct AAT cleavage pattern during host response to viral infection [7]. To clarify the role of CAAPs during severe COVID-19, we have analyzed plasma concentrations of two AAT fragments, C-36 (cleavage product of i.a. NE) and C-42 (cleaved i.a. by MMP-12), using our newly developed LC/MS-MS method [6]. Patients samples were obtained from a subgroup of an ongoing single-center prospective cohort study on days three (T1) and seven (T2) after onset of severe disease in patients with severe COVID-19 (n=10) and compared with patients with bacterial sepsis of pulmonary origin (n=10) and healthy controls (n=10) [8]. All three cohorts showed no significant differences in sex (all cohorts 30% female) and age (median healthy: 65 y, sepsis: 63 y, COVID-19: 61.5 y). Patients had a similar disease Arite Bigalke and Charles Neu (first authors) as well as Michael Kiehntopf and Sina Coldewey (senior authors) contributed equally to this work.