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As the death toll from the COVID-19 pandemic caused by SARS-CoV-2 continues to mount globally, scientists, healthcare agencies, and pharmaceutical companies are trying hard to find a “cure” and devise treatment strategies to reduce mortality. “Repurposing” existing drugs to fight COVID-19 remains an important strategy. Since respiratory failure remains one of the leading causes of death in COVID-19 patients, in this commentary, we have critically discussed the potential benefit of neutrophil elastase inhibitors (NEIs) in patients hospitalised with severe COVID-19. Around one in three COVID-19 patients admitted to a hospital develop systemic inflammatory conditions such as cytokine release syndrome (CRS) [1] and acute respiratory distress syndrome (ARDS) [2]. Since lymphocytopenia is often reported in severe COVID-19 patients, it suggests that systemic inflammatory complications, associated with disease severity and mortality, are likely to be mediated by leukocytes other than T cells [3]. The drop in lymphocyte count is accompanied by an increase in neutrophil count and a decrease in monocytes, eosinophils, and basophils [4, 5], indicating that, together with lymphocytopenia, increased neutrophil count and neutrophil-to-lymphocyte ratio may be important predictors of disease severity in COVID-19 patients [5]. A recent case study supported this hypothesis [6]. The patient’s deterioration on day 12 of illness was preceded by an elevation in his neutrophil count on day 11, while lymphocytes and monocytes remained low [6]. Given that there is often a short window between the time of hospital admission and development of ARDS in severe cases [3, 6], a rapid prophylactic therapy is warranted to effectively prevent complications and death. Neutrophils play a pivotal role in the development of ARDS through the production of toxic mediators including reactive oxygen species and proteases, especially elastase [7]. Furthermore, neutrophils can produce interleukin 6 (IL-6) in response to viral infections, in particular single-stranded RNA viruses such as SARS-CoV-2 via a Toll-like receptor 8 (TLR8)-mediated mechanism [8]. These cells are also important sources of soluble IL6 receptors (IL-6R) in the lungs and may contribute to pathogenic IL-6R trans-signaling in chronic respiratory diseases [9]. The importance of this kind of signaling for the development of CRS has been demonstrated in chimeric antigen receptor T cell (CART)-treated lymphoma patients [10]. These studies suggest that increased neutrophil count can contribute to CRS and lung damage in patients with ARDS. Additionally, elastase secreted by these cells is one of the key proteolytic enzymes shown to activate the spike (S) protein of coronaviruses and shift the viral entry to a low pHindependent route [11]. We advocate the use of NEIs such as sivelestat to alleviate neutrophil-induced damage in high-risk COVID-19 patients. Initiation of sivelestat will serve two strategic purposes; first, it will mitigate the damaging effect of neutrophil elastase on the lung connective tissue, and second, it will limit the virus spreading capabilities by preventing S protein proteolytic activation (Fig. 1). Sivelestat is approved in Japan and the Republic of Korea for the treatment of acute lung injury and ARDS. Although existing clinical data is somewhat conflicting, the severity of lung injury remains an important predictor for treatment outcomes in such patients [12, 13]. Clinical

Neutrophil Elastase Inhibitors: A potential prophylactic treatment option for SARS-CoV-2-induced respiratory complications?