El-Shimy, Ismail Amr

Hadi, Muhammad Abdul

Mohamed, Mahmoud M A

English

University of Birmingham Research Portal

  University of BirminghamNeutrophil Elastase InhibitorsMohamed, Mahmoud M A; El-Shimy, Ismail Amr; Hadi, Muhammad AbdulDOI:10.1186/s13054-020-03023-0License:Creative Commons: Attribution (CC BY)Document VersionPublisher's PDF, also known as Version of recordCitation for published version (Harvard):Mohamed, MMA, El-Shimy, IA & Hadi, MA 2020, 'Neutrophil Elastase Inhibitors: A potential prophylactictreatment option for SARS-CoV-2-induced respiratory complications?', Critical care (London, England), vol. 24,no. 1, 311. https://doi.org/10.1186/s13054-020-03023-0Link to publication on Research at Birmingham portalGeneral rightsUnless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or thecopyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposespermitted by law.•	Users may freely distribute the URL that is used to identify this publication.•	Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of privatestudy or non-commercial research.•	User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?)•	Users may not further distribute the material nor use it for the purposes of commercial gain.Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document.When citing, please reference the published version.Take down policyWhile the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has beenuploaded in error or has been deemed to be commercially or otherwise sensitive.If you believe that this is the case for this document, please contact UBIRA@lists.bham.ac.uk providing details and we will remove access tothe work immediately and investigate.Download date: 28. Jun. 2022EDITORIAL Open AccessNeutrophil Elastase Inhibitors: A potentialprophylactic treatment option for SARS-CoV-2-induced respiratory complications?Mahmoud M. A. Mohamed1†, Ismail Amr El-Shimy2,3† and Muhammad Abdul Hadi4*As the death toll from the COVID-19 pandemic caused bySARS-CoV-2 continues to mount globally, scientists,healthcare agencies, and pharmaceutical companies are try-ing hard to find a “cure” and devise treatment strategies toreduce mortality. “Repurposing” existing drugs to fightCOVID-19 remains an important strategy. Since respiratoryfailure remains one of the leading causes of death inCOVID-19 patients, in this commentary, we have criticallydiscussed the potential benefit of neutrophil elastase inhibi-tors (NEIs) in patients hospitalised with severe COVID-19.Around one in three COVID-19 patients admitted to ahospital develop systemic inflammatory conditions suchas cytokine release syndrome (CRS) [1] and acute re-spiratory distress syndrome (ARDS) [2]. Since lymphocy-topenia is often reported in severe COVID-19 patients,it suggests that systemic inflammatory complications, as-sociated with disease severity and mortality, are likely tobe mediated by leukocytes other than T cells [3]. Thedrop in lymphocyte count is accompanied by an increasein neutrophil count and a decrease in monocytes, eosin-ophils, and basophils [4, 5], indicating that, together withlymphocytopenia, increased neutrophil count andneutrophil-to-lymphocyte ratio may be important pre-dictors of disease severity in COVID-19 patients [5]. Arecent case study supported this hypothesis [6]. The pa-tient’s deterioration on day 12 of illness was preceded byan elevation in his neutrophil count on day 11, whilelymphocytes and monocytes remained low [6]. Giventhat there is often a short window between the time ofhospital admission and development of ARDS in severecases [3, 6], a rapid prophylactic therapy is warranted toeffectively prevent complications and death.Neutrophils play a pivotal role in the development ofARDS through the production of toxic mediators includ-ing reactive oxygen species and proteases, especiallyelastase [7]. Furthermore, neutrophils can produce inter-leukin 6 (IL-6) in response to viral infections, in particu-lar single-stranded RNA viruses such as SARS-CoV-2via a Toll-like receptor 8 (TLR8)-mediated mechanism[8]. These cells are also important sources of soluble IL-6 receptors (IL-6R) in the lungs and may contribute topathogenic IL-6R trans-signaling in chronic respiratorydiseases [9]. The importance of this kind of signaling forthe development of CRS has been demonstrated inchimeric antigen receptor T cell (CART)-treated lymph-oma patients [10]. These studies suggest that increasedneutrophil count can contribute to CRS and lung dam-age in patients with ARDS. Additionally, elastase se-creted by these cells is one of the key proteolyticenzymes shown to activate the spike (S) protein of coro-naviruses and shift the viral entry to a low pH-independent route [11].We advocate the use of NEIs such as sivelestat to alle-viate neutrophil-induced damage in high-risk COVID-19patients. Initiation of sivelestat will serve two strategicpurposes; first, it will mitigate the damaging effect ofneutrophil elastase on the lung connective tissue, andsecond, it will limit the virus spreading capabilities bypreventing S protein proteolytic activation (Fig. 1). Sive-lestat is approved in Japan and the Republic of Korea forthe treatment of acute lung injury and ARDS. Althoughexisting clinical data is somewhat conflicting, the sever-ity of lung injury remains an important predictor fortreatment outcomes in such patients [12, 13]. Clinical© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.* Correspondence: m.a.hadi@bham.ac.uk†Mahmoud M. A. Mohamed and Ismail Amr El-Shimy contributed equally tothis work.4School of Pharmacy, College of Medical and Dental Sciences, University ofBirmingham, Edgbaston, Birmingham B15 2TT, UKFull list of author information is available at the end of the articleMohamed et al. Critical Care          (2020) 24:311 https://doi.org/10.1186/s13054-020-03023-0trials that reported positive outcomes of sivelestat treatmentin patients with ARDS and ALI had recruited patients mainlywith lung injury score (LIS) < 2.5. On the other hand, trialsreporting negative outcomes particularly the STRIVE studyhad recruited patients mainly with LIS > 2.5 [12, 13] empha-sizing the critical importance of an early intervention withsivelestat. Notably, patients enrolled in the STRIVE studywere more heterogeneous than the other trials and includedmore cases with non-pulmonary organ failures, conditionsthat are not relevant to COVID-19 patients [12, 13]. Further-more, post hoc analysis of patient subgroups from theSTRIVE study with mean LIS < 2.5 and those with systemicinflammatory response syndrome revealed a positive out-come of sivelestat on mortality rate and ventilator-free days[12, 13]. More importantly, the STRIVE study failed to iden-tify any evidence of drug-related toxicity and did not offerany plausible explanation for the increase in long-term mor-tality in sivelestat-treated groups [12].Although current evidence to support the use of NEIsin ARDS induced by COVID-19 is lacking, wehypothesize that early administration of these drugs topatients with lymphocytopenia and LIS < 2.5 may be ofsignificant value to prevent disease progression. Futureclinical trials should be designed to evaluate the effect-iveness of sivelestat in COVID-19 patients admitted tohospital with high risk of respiratory failure.AcknowledgementsNot applicableAuthors’ contributionsMMAM, IAE, and MAH conceived the idea. MMAM and IAE wrote the initialdraft. MAH critically reviewed the paper. All authors have read the finalversion and agreed to submit for publication in the journal.FundingNo funding was obtained from any governmental and non-governmentalsource in the preparation of this manuscript.Availability of data and materialsNot applicableEthics approval and consent to participateNot applicableConsent for publicationNot applicableCompeting interestsNone declared.Author details1Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1,10117 Berlin, Germany. 2Integrative Research Institute (IRI) for Life Sciences,Humboldt University Berlin, Philippstrasse 13, 10115 Berlin, Germany.3Institute of Pathology, Charité - Universitätsmedizin Berlin, Charitéplatz 1,10117 Berlin, Germany. 4School of Pharmacy, College of Medical and DentalSciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.Received: 13 May 2020 Accepted: 25 May 2020References1. Zhang C, Wu Z, Li J-W, Zhao H, Wang GQ. The cytokine release syndrome(CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonisttocilizumab may be the key to reduce the mortality. Int J AntimicrobAgents. 2020. https://doi.org/10.1016/j.ijantimicag.2020.105954.2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patientsinfected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.3. Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al. COVID-19 infection:the perspectives on immune responses. Cell Death Differ. 2020. https://doi.org/10.1038/s41418-020-0530-3.4. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation ofimmune response in patients with COVID-19 in Wuhan, China. Clin InfectDis. 2020. https://doi.org/10.1093/cid/ciaa248.5. Zhang B, Zhou X, Zhu C, Feng F, Qiu Y, Feng J, et al. Immune phenotypingbased on neutrophil-to-lymphocyte ratio and IgG predicts disease severityand outcome for patients with COVID-19. medRxiv. 2020. https://doi.org/10.1101/2020.03.12.20035048.6. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findingsof COVID-19 associated with acute respiratory distress syndrome. LancetRespir Med. 2020;8:420–2.7. Donnelly SC, MacGregor I, Zamani A, Gordon MW, Robertson CE, SteedmanDJ, et al. Plasma elastase levels and the development of the adultrespiratory distress syndrome. Am J Respir Crit Care Med. 1995;151:1428–33.8. Zimmermann M, Arruda-Silva F, Bianchetto-Aguilera F, Finotti G, Calzetti F,Scapini P, et al. IFNα enhances the production of IL-6 by human neutrophilsactivated via TLR8. Sci Rep. 2016;6:19674. https://doi.org/10.1038/srep19674.9. Farahi N, Paige E, Balla J, Prudence E, Ferreira RC, Southwood M, et al.Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronicobstructive pulmonary disease and asthma. Hum Mol Genet. 2017;26:1584–96.10. Li C, Zhang C, Chen X, Zhang Y, Chen J, Kang L, et al. Relative depletion ofsoluble interleukin 6 receptors abolished the development of cytokinerelease syndrome after CART19/22 and lenalidomide treatment forlymphoma. Blood. 2019;134(Supplement 1):5313.11. Belouzard S, Madu I, Whittaker GR. Elastase-mediated activation of thesevere acute respiratory syndrome coronavirus spike protein at discrete siteswithin the S2 domain. J Biol Chem. 2010;285:22758–63.12. Zeiher BG, Artigas A, Vincent JL, Dmitrienko A, Jackson K, Thompson BT,et al. Neutrophil elastase inhibition in acute lung injury: results of the STRIVEstudy. Crit Care Med. 2004;32:1695–702.13. Aikawa N, Kawasaki Y. Clinical utility of the neutrophil elastase inhibitorsivelestat for the treatment of acute respiratory distress syndrome. Ther ClinRisk Manag. 2014;10:621–9.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Fig. 1 Mechanism of action of neutrophil elastase inhibitors in COVID-19. indicates block. ARDS acute respiratory distress syndromeMohamed et al. Critical Care          (2020) 24:311 Page 2 of 2

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

  University of BirminghamNeutrophil Elastase InhibitorsMohamed, Mahmoud M A; El-Shimy, Ismail Amr; Hadi, Muhammad AbdulDOI:10.1186/s13054-020-03023-0License:Creative Commons: Attribution (CC BY)Document VersionPublisher's PDF, also known as Version of recordCitation for published version (Harvard):Mohamed, MMA, El-Shimy, IA & Hadi, MA 2020, 'Neutrophil Elastase Inhibitors: A potential prophylactictreatment option for SARS-CoV-2-induced respiratory complications?', Critical care (London, England), vol. 24,no. 1, 311. https://doi.org/10.1186/s13054-020-03023-0Link to publication on Research at Birmingham portalGeneral rightsUnless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or thecopyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposespermitted by law.•	Users may freely distribute the URL that is used to identify this publication.•	Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of privatestudy or non-commercial research.•	User may use extracts from the document in line with the concept of ‘fair dealing’ under the Copyright, Designs and Patents Act 1988 (?)•	Users may not further distribute the material nor use it for the purposes of commercial gain.Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document.When citing, please reference the published version.Take down policyWhile the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has beenuploaded in error or has been deemed to be commercially or otherwise sensitive.If you believe that this is the case for this document, please contact UBIRA@lists.bham.ac.uk providing details and we will remove access tothe work immediately and investigate.Download date: 11. May. 2021EDITORIAL Open AccessNeutrophil Elastase Inhibitors: A potentialprophylactic treatment option for SARS-CoV-2-induced respiratory complications?Mahmoud M. A. Mohamed1†, Ismail Amr El-Shimy2,3† and Muhammad Abdul Hadi4*As the death toll from the COVID-19 pandemic caused bySARS-CoV-2 continues to mount globally, scientists,healthcare agencies, and pharmaceutical companies are try-ing hard to find a “cure” and devise treatment strategies toreduce mortality. “Repurposing” existing drugs to fightCOVID-19 remains an important strategy. Since respiratoryfailure remains one of the leading causes of death inCOVID-19 patients, in this commentary, we have criticallydiscussed the potential benefit of neutrophil elastase inhibi-tors (NEIs) in patients hospitalised with severe COVID-19.Around one in three COVID-19 patients admitted to ahospital develop systemic inflammatory conditions suchas cytokine release syndrome (CRS) [1] and acute re-spiratory distress syndrome (ARDS) [2]. Since lymphocy-topenia is often reported in severe COVID-19 patients,it suggests that systemic inflammatory complications, as-sociated with disease severity and mortality, are likely tobe mediated by leukocytes other than T cells [3]. Thedrop in lymphocyte count is accompanied by an increasein neutrophil count and a decrease in monocytes, eosin-ophils, and basophils [4, 5], indicating that, together withlymphocytopenia, increased neutrophil count andneutrophil-to-lymphocyte ratio may be important pre-dictors of disease severity in COVID-19 patients [5]. Arecent case study supported this hypothesis [6]. The pa-tient’s deterioration on day 12 of illness was preceded byan elevation in his neutrophil count on day 11, whilelymphocytes and monocytes remained low [6]. Giventhat there is often a short window between the time ofhospital admission and development of ARDS in severecases [3, 6], a rapid prophylactic therapy is warranted toeffectively prevent complications and death.Neutrophils play a pivotal role in the development ofARDS through the production of toxic mediators includ-ing reactive oxygen species and proteases, especiallyelastase [7]. Furthermore, neutrophils can produce inter-leukin 6 (IL-6) in response to viral infections, in particu-lar single-stranded RNA viruses such as SARS-CoV-2via a Toll-like receptor 8 (TLR8)-mediated mechanism[8]. These cells are also important sources of soluble IL-6 receptors (IL-6R) in the lungs and may contribute topathogenic IL-6R trans-signaling in chronic respiratorydiseases [9]. The importance of this kind of signaling forthe development of CRS has been demonstrated inchimeric antigen receptor T cell (CART)-treated lymph-oma patients [10]. These studies suggest that increasedneutrophil count can contribute to CRS and lung dam-age in patients with ARDS. Additionally, elastase se-creted by these cells is one of the key proteolyticenzymes shown to activate the spike (S) protein of coro-naviruses and shift the viral entry to a low pH-independent route [11].We advocate the use of NEIs such as sivelestat to alle-viate neutrophil-induced damage in high-risk COVID-19patients. Initiation of sivelestat will serve two strategicpurposes; first, it will mitigate the damaging effect ofneutrophil elastase on the lung connective tissue, andsecond, it will limit the virus spreading capabilities bypreventing S protein proteolytic activation (Fig. 1). Sive-lestat is approved in Japan and the Republic of Korea forthe treatment of acute lung injury and ARDS. Althoughexisting clinical data is somewhat conflicting, the sever-ity of lung injury remains an important predictor fortreatment outcomes in such patients [12, 13]. Clinical© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.* Correspondence: m.a.hadi@bham.ac.uk†Mahmoud M. A. Mohamed and Ismail Amr El-Shimy contributed equally tothis work.4School of Pharmacy, College of Medical and Dental Sciences, University ofBirmingham, Edgbaston, Birmingham B15 2TT, UKFull list of author information is available at the end of the articleMohamed et al. Critical Care          (2020) 24:311 https://doi.org/10.1186/s13054-020-03023-0trials that reported positive outcomes of sivelestat treatmentin patients with ARDS and ALI had recruited patients mainlywith lung injury score (LIS) < 2.5. On the other hand, trialsreporting negative outcomes particularly the STRIVE studyhad recruited patients mainly with LIS > 2.5 [12, 13] empha-sizing the critical importance of an early intervention withsivelestat. Notably, patients enrolled in the STRIVE studywere more heterogeneous than the other trials and includedmore cases with non-pulmonary organ failures, conditionsthat are not relevant to COVID-19 patients [12, 13]. Further-more, post hoc analysis of patient subgroups from theSTRIVE study with mean LIS < 2.5 and those with systemicinflammatory response syndrome revealed a positive out-come of sivelestat on mortality rate and ventilator-free days[12, 13]. More importantly, the STRIVE study failed to iden-tify any evidence of drug-related toxicity and did not offerany plausible explanation for the increase in long-term mor-tality in sivelestat-treated groups [12].Although current evidence to support the use of NEIsin ARDS induced by COVID-19 is lacking, wehypothesize that early administration of these drugs topatients with lymphocytopenia and LIS < 2.5 may be ofsignificant value to prevent disease progression. Futureclinical trials should be designed to evaluate the effect-iveness of sivelestat in COVID-19 patients admitted tohospital with high risk of respiratory failure.AcknowledgementsNot applicableAuthors’ contributionsMMAM, IAE, and MAH conceived the idea. MMAM and IAE wrote the initialdraft. MAH critically reviewed the paper. All authors have read the finalversion and agreed to submit for publication in the journal.FundingNo funding was obtained from any governmental and non-governmentalsource in the preparation of this manuscript.Availability of data and materialsNot applicableEthics approval and consent to participateNot applicableConsent for publicationNot applicableCompeting interestsNone declared.Author details1Department of Radiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1,10117 Berlin, Germany. 2Integrative Research Institute (IRI) for Life Sciences,Humboldt University Berlin, Philippstrasse 13, 10115 Berlin, Germany.3Institute of Pathology, Charité - Universitätsmedizin Berlin, Charitéplatz 1,10117 Berlin, Germany. 4School of Pharmacy, College of Medical and DentalSciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.Received: 13 May 2020 Accepted: 25 May 2020References1. Zhang C, Wu Z, Li J-W, Zhao H, Wang GQ. The cytokine release syndrome(CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonisttocilizumab may be the key to reduce the mortality. Int J AntimicrobAgents. 2020. https://doi.org/10.1016/j.ijantimicag.2020.105954.2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patientsinfected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.3. Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al. COVID-19 infection:the perspectives on immune responses. Cell Death Differ. 2020. https://doi.org/10.1038/s41418-020-0530-3.4. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation ofimmune response in patients with COVID-19 in Wuhan, China. Clin InfectDis. 2020. https://doi.org/10.1093/cid/ciaa248.5. Zhang B, Zhou X, Zhu C, Feng F, Qiu Y, Feng J, et al. Immune phenotypingbased on neutrophil-to-lymphocyte ratio and IgG predicts disease severityand outcome for patients with COVID-19. medRxiv. 2020. https://doi.org/10.1101/2020.03.12.20035048.6. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findingsof COVID-19 associated with acute respiratory distress syndrome. LancetRespir Med. 2020;8:420–2.7. Donnelly SC, MacGregor I, Zamani A, Gordon MW, Robertson CE, SteedmanDJ, et al. Plasma elastase levels and the development of the adultrespiratory distress syndrome. Am J Respir Crit Care Med. 1995;151:1428–33.8. Zimmermann M, Arruda-Silva F, Bianchetto-Aguilera F, Finotti G, Calzetti F,Scapini P, et al. IFNα enhances the production of IL-6 by human neutrophilsactivated via TLR8. Sci Rep. 2016;6:19674. https://doi.org/10.1038/srep19674.9. Farahi N, Paige E, Balla J, Prudence E, Ferreira RC, Southwood M, et al.Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronicobstructive pulmonary disease and asthma. Hum Mol Genet. 2017;26:1584–96.10. Li C, Zhang C, Chen X, Zhang Y, Chen J, Kang L, et al. Relative depletion ofsoluble interleukin 6 receptors abolished the development of cytokinerelease syndrome after CART19/22 and lenalidomide treatment forlymphoma. Blood. 2019;134(Supplement 1):5313.11. Belouzard S, Madu I, Whittaker GR. Elastase-mediated activation of thesevere acute respiratory syndrome coronavirus spike protein at discrete siteswithin the S2 domain. J Biol Chem. 2010;285:22758–63.12. Zeiher BG, Artigas A, Vincent JL, Dmitrienko A, Jackson K, Thompson BT,et al. Neutrophil elastase inhibition in acute lung injury: results of the STRIVEstudy. Crit Care Med. 2004;32:1695–702.13. Aikawa N, Kawasaki Y. Clinical utility of the neutrophil elastase inhibitorsivelestat for the treatment of acute respiratory distress syndrome. Ther ClinRisk Manag. 2014;10:621–9.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Fig. 1 Mechanism of action of neutrophil elastase inhibitors in COVID-19. indicates block. ARDS acute respiratory distress syndromeMohamed et al. Critical Care          (2020) 24:311 Page 2 of 2

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

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