Human recombinant soluble ACE2 in severe COVID-19 – The Lancet

Angiotensin changing enzyme 2 (ACE2) is the an extraordinarily out of the ordinary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor and protects extra than one tissues, including the lung, from smash as a regulator of the renin–angiotensin system.

  • Bourgonje AR
  • Abdulle AE
  • Timens W
  • et al.

Angiotensin-changing enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus illness 2019 (COVID-19).

As a result of this fact, ACE2 has change into the level of interest of COVID-19 compare and a plethora of drug construction efforts. Among the many radical compounds under construction is human recombinant soluble ACE2 (hrsACE2 [APN01; Apeiron Biologics, Vienna, Austria]), which has two mechanisms of stir that theoretically ought to be of reduction in COVID-19.

  • Zhang H
  • Penninger JM
  • Li Y
  • Zhong N
  • Slutsky AS

Angiotensin-changing enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and attainable therapeutic goal.

The first entails binding the viral spike protein and thereby neutralising SARS-CoV-2,

  • Monteil V
  • Kwon H
  • Prado P
  • et al.

Inhibition of SARS-CoV-2 infections in engineered human tissues the use of scientific-grade soluble human ACE2.

and the 2nd is minimising smash to extra than one organs, including the lungs, kidneys, and heart, because of unabated renin–angiotensin system hyperactivation and increased angiotensin II concentrations.

  • Kuba Ok
  • Imai Y
  • Rao S
  • et al.

A really most valuable operate of angiotensin changing enzyme 2 (ACE2) in SARS coronavirus-introduced on lung smash.

  • Crackower MA
  • Sarao R
  • Oudit GY
  • et al.

Angiotensin-changing enzyme 2 is an notable regulator of heart operate.

  • Wong DW
  • Oudit GY
  • Reich H
  • et al.

Lack of angiotensin-changing enzyme-2 (Ace2) accelerates diabetic kidney smash.

hrsACE2 has been tested in 89 sufferers, namely in healthy volunteers in segment 1 experiences and in sufferers with acute respiratory harm syndrome (ARDS) in segment 2 scientific experiences, with a elegant safety profile.

  • Haschke M
  • Schuster M
  • Poglitsch M
  • et al.

Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-changing enzyme 2 in healthy human subjects.

  • Khan A
  • Benthin C
  • Zeno B
  • et al.

A pilot scientific trial of recombinant human angiotensin-changing enzyme 2 in acute respiratory harm syndrome.

Furthermore, hrsACE2 can decrease SARS-CoV-2 load by a ingredient of 1000–5000 in in-vitro cell-culture experiments and engineered organoids, instantly demonstrating that ACE2 can successfully neutralise SARS-CoV-2.

  • Monteil V
  • Kwon H
  • Prado P
  • et al.

Inhibition of SARS-CoV-2 infections in engineered human tissues the use of scientific-grade soluble human ACE2.

We describe on this Case Snort the first route of therapy with hrsACE2 of a patient with severe COVID-19.

A 45-year-dilapidated girl used to be admitted to successfully being facility with a 7-day historical past of cough, weak point, myalgia, fever, and dyspnoea, and a 4-day historical past of nausea and diarrhoea. Previous clinical historical past published form 2 diabetes, managed non-pharmacologically by exercise and food regimen, and Grave’s illness for which thyroidectomy had been completed; the patient used to be euthyroid on thyroxin. She had a protracted-established body-mass index and reported elegant exercise tolerance sooner than her display illness. On admission she used to be febrile (38·1°C), mildly hypoxaemic (PaO2 56 mm Hg on room air), and used to be started on oxygen by nasal cannula. A chest x-ray confirmed bilateral patchy consolidations indicative of viral pneumonia (appendix p 6).

Diagnosis of SARS-CoV-2 an infection used to be made by RT-PCR from a nasopharyngeal swab, and therapy with hydroxychloroquine (400 mg twice day to day) and anticoagulation with nadroparin (0·4 mg once day to day) had been started. The next day, the patient’s chest x-ray confirmed increasing bilateral, multifocal, and peripheral ground glass patterns (appendix p 6). Her fractional concentration of oxygen in impressed air (FiO2) used to be 153 mm Hg, and she confirmed signs of exhaustion while on excessive float nasal cannula, with a FiO2 of 70%. We therefore intubated her and archaic a lung retaining ventilatory technique. Preliminary laboratory assessments confirmed mild leukopenia and thrombocytopenia with a profound lymphopenia (0·54 g/L); serum lactate dehydrogenase (636 U/L), ferritin (880 μg/L), C-reactive protein (103 mg/L), and D-dimer (1·3 mg/L) concentrations had been all markedly elevated (appendix p 4).

9 days after symptom onset (baseline, day 2 after successfully being facility admission), therapy with hrsACE2 (APN01; 0·4 mg/kg) intravenous infusion for 5 min twice day to day used to be started. This compassionate use therapy used to be initiated after consultations amongst attending physicians, the patient’s family, and external infectious illness and ARDS experts. After administration of the first hrsACE2 dose, the patient modified into afebrile interior hours. Her temperature increased the next day with purulent respiratory secretions, suggesting a bacterial pneumonia, which used to be treated with cefuroxime. A tracheal aspirate therefore grew methicillin-sensitive Staphylococcus aureus (MSSA). Renin–angiotensin system fingerprinting and angiotensin-essentially based mostly markers, as successfully as cytokines and smash biomarkers, had been measured once day to day for the length of the 7-day administration of hrsACE2 and thereafter for a total of 14 days. SARS-CoV-2 viral load and neutralising antibodies had been measured once day to day in plasma. The presence of viral RNA used to be additionally measured in nasopharyngeal swabs and tracheal aspirations (appendix p 2).

Treatment with hrsACE2 used to be continued as planned for 7 days and used to be successfully tolerated with out evident drug-linked aspect-effects. Her scientific route used to be sophisticated by slowly resolving pneumonia with repeated detection of MSSA in tracheal suctions and Enterobacter aerogenes bacteraemia, and her antibiotics had been modified to linezolid and aztreonam. Her scientific condition improved gradually and extubation used to be completed on day 21 after baseline. The patient used to be then transferred to neurological rehabilitation for therapy of severe illness myopathy, which improved after physiotherapy. On day 57, she used to be discharged from the successfully being facility.

After the first injection of hrsACE2 we noticed a marked low cost of angiotensin II (resolve 1A, B; appendix p 4). hrsACE2 administration resulted in a profound lengthen of the ACE2 merchandise angiotensin 1–7 and angiotensin 1–9 (resolve 1B) and their most valuable downstream metabolite angiotensin 1–5 (appendix p 7) precise through your whole commentary length. Normalising the sum of these three renin–angiotensin system peptides to renin exercise resulted in an angiotensin-essentially based mostly marker that used to be linked to soluble plasma ACE2 exercise (resolve 1C), which used to be confirmed by an angiotensin II-to-angiotensin 1–7 conversion assay (resolve 1D); ACE2 exercise remained increased as a lot as 7 days following administration of the final dose of hrsACE2. Additionally, the angiotensin 1–7/angiotensin II and angiotensin 1–5/angiotensin II ratios confirmed a marked skewing towards ACE2-generated peptides (appendix p 7). The sum of all 5 angiotensin metabolites as sure by renin–angiotensin system equilibrium analysis confirmed a trusty correlation with renin concentration, as validated in pooled human plasma spiked with assorted concentrations of renin and hrsACE2, respectively (appendix p 7). We additionally noticed soluble ACE2 display in tracheal fluid precise through the commentary length, showing an lengthen towards day 6 that peaked 36 h following administration of the closing dose of hrsACE2 (resolve 1D); whether or no longer this reflects shedding of endogenous ACE2 or accumulation of hrsACE2, or both, remains to be elucidated.

Figure thumbnail gr1

Figure 1Human recombinant soluble ACE2 pharmacodynamics and drug concentrations

(A) Renin–angiotensin system fingerprinting of angiotensin metabolites in terms of human recombinant soluble ACE2 dosing. Circle sizes and angiotensin values correspond to metabolite concentrations (pmol/L). Black arrows designate the catalysing reactions mediated by the indicated enzymes. (B) Plasma concentrations of varied ACE2 substrates and catalysed merchandise. (C) ACE2 exercise because the sum of ACE2 merchandise and downstream metabolites linked to plasma renin exercise. (D) ACE2 exercise (angiotensin II-to-angiotensin 1–7 catalytic conversion assays) in plasma and tracheal suctions. First dose administered on day 0; crimson triangles display days on which drug used to be administered. ACE2=angiotensin changing enzyme 2. AT1R=angiotensin II form 1 receptor. MAS=G protein coupled receptor Mas. NEP=honest endopeptidase.

Concurrent with reduced angiotensin II concentrations we detected a marked low cost in the inflammatory cytokine interleukin (IL)-6 and chemokine IL-8 (resolve 2A; appendix p 4), both of which play an extraordinarily out of the ordinary operate in lung smash and cytokine storm.

  • Zhang X
  • Tan Y
  • Ling Y
  • et al.

Viral and host elements linked to the scientific of COVID-19.

Furthermore, concentrations of soluble developed glycosylation close product-specific receptor, a marker for lung epithelial smash linked to better mortality in ARDS,

  • Jabaudon M
  • Blondonnet R
  • Pereira B
  • et al.

Plasma sRAGE is independently linked to increased mortality in ARDS: a meta-analysis of particular person patient files.

and the irritation marker ferritin, had been markedly lowered following hrsACE2 administration (resolve 2A). Serum concentrations of the inflammatory marker tumour necrosis ingredient α and the lung harm biomarker serum surfactant protein D confirmed an preliminary lengthen followed by a marked decrease.

  • Lopez-Cano C
  • Lecube A
  • Garcia-Ramirez M
  • et al.

Serum surfactant protein D as a biomarker for measuring lung involvement in chubby sufferers with form 2 diabetes.

A the same lengthen nonetheless delayed decrease (probably due to bacterial complications) had been illustrious for C-reactive protein and for the endothelial smash marker angiopoietin 2 concentrations (resolve 2B; appendix p 4). As a result of this fact, hrsACE2 therapy used to be linked to a marked decrease in concentrations of severe cytokines implicated in COVID-19 pathology, and hrsACE2 remains catalytically energetic in the scenario of severe COVID-19.

Figure thumbnail gr2

Figure 2Inflammatory, endothelial, and alveolar biomarkers

(A) Plasma concentrations of IL-6, IL-8, sRAGE, and ferritin. (B) Plasma concentrations of C-reactive protein, TNFα, surfactant protein D, and angiopoietin-2. Crimson triangles display days on which drug used to be administered. IL=interleukin. sRAGE=soluble developed glycation close product receptor. TNFα=tumour necrosis ingredient.

SARS-CoV-2 used to be detectable in the plasma 2 days sooner than administration (day −2, 32 000 copies per mL) and on the first day of administration (day 0, 2500 copies per mL; resolve 3A). 1 day later, plasma viraemia had lowered to a extremely low stage (270 copies per mL) and thereafter remained undetectable for the length of day to day testing, till the close of the commentary length when viral RT-PCR plasma testing used to be stopped. In tracheal aspirates, SARS-CoV-2-specific RT-PCR published an lengthen of the measured viral RNA interior 2 days of beginning hrsACE2 therapy, followed by quick clearance till the close of the therapy length (resolve 3B; appendix p 4).

hrsACE2 binds to the spike glycoprotein of SARS-CoV-2 at an affinity calculated to be roughly 1·2 nM,

  • Walls AC
  • Park YJ
  • Tortorici MA
  • Wall A
  • McGuire AT
  • Veesler D

Structure, operate, and antigenicity of the SARS-CoV-2 spike glycoprotein.

an affinity equivalent to excessive affinity antibody binding. Because hrsACE2 would now not comprise an Fc put of living to instantly hyperlink to the immune system, assessing whether or no longer hrsACE2 therapy for 1 week would possibly possibly possibly intervene with the formation of antibodies towards the virus used to be an extraordinarily out of the ordinary. As a result of this fact, we assessed plasma neutralising anti-SARS-CoV-2 antibodies, which had been first detected 7 days after symptom onset and reached a plateau 5 days later (resolve 3A)—at a the same timepoint as beforehand reported.

  • Okba NMA
  • Muller MA
  • Li W
  • et al.

Excessive acute respiratory syndrome coronavirus 2-specific antibody responses in coronavirus illness 2019 sufferers.

Furthermore, hrsACE2 infusions did now not intervene with the technology of anti-viral IgA and IgG antibodies in the patient’s plasma (appendix p 4). Thus, intravenous therapy with hrsACE2 has no obvious compose on anti-SARS-CoV-2 seroconversion.

ACE2 is the an extraordinarily out of the ordinary cell surface receptor for SARS-CoV-2.

  • Zhou P
  • Yang XL
  • Wang XG
  • et al.

A pneumonia outbreak linked to a fresh coronavirus of probable bat foundation.

We have beforehand confirmed that ACE2 counterbalances the outcomes of angiotensin II and thereby protects the heart, kidney, and importantly the lung via its enzymatic exercise in the renin–angiotensin system.

  • Crackower MA
  • Sarao R
  • Oudit GY
  • et al.

Angiotensin-changing enzyme 2 is an notable regulator of heart operate.

  • Wong DW
  • Oudit GY
  • Reich H
  • et al.

Lack of angiotensin-changing enzyme-2 (Ace2) accelerates diabetic kidney smash.

  • Imai Y
  • Kuba Ok
  • Rao S
  • et al.

Angiotensin-changing enzyme 2 protects from severe acute lung failure.

Furthermore, we confirmed that ACE2 is the an extraordinarily out of the ordinary SARS-CoV receptor in vivo,

  • Kuba Ok
  • Imai Y
  • Rao S
  • et al.

A really most valuable operate of angiotensin changing enzyme 2 (ACE2) in SARS coronavirus-introduced on lung smash.

explaining why SARS-CoV and now SARS-CoV-2 modified into highly pathogenic viruses, with ACE2 being the receptor for both viruses, and downregulation of ACE2 via virus binding resulting in loss of renin–angiotensin system tissue homoeostasis.

  • Imai Y
  • Kuba Ok
  • Rao S
  • et al.

Angiotensin-changing enzyme 2 protects from severe acute lung failure.

These outcomes present a molecular clarification as to why SARS-CoV and SARS-CoV-2 infections cause severe and continually lethal lung failure. Furthermore, genetic inactivation of ACE2 causes severe lung smash in influenza A H5N1-challenged and H7N9-challenged mice, while administration of soluble ACE2 protects from lethal avian influenza A H5N1 infections.

  • Zou Z
  • Yan Y
  • Shu Y
  • et al.

Angiotensin-changing enzyme 2 protects from lethal avian influenza A H5N1 infections.

  • Yang P
  • Gu H
  • Zhao Z
  • et al.

Angiotensin-changing enzyme 2 (ACE2) mediates influenza H7N9 virus-introduced on acute lung smash.

Angiotensin II plasma concentrations are increased in acute lung smash,

  • Imai Y
  • Kuba Ok
  • Rao S
  • et al.

Angiotensin-changing enzyme 2 protects from severe acute lung failure.

predict fatal outcomes in sufferers infected with H7N9,

  • Huang F
  • Guo J
  • Zou Z
  • et al.

Angiotensin II plasma ranges are linked to illness severity and predict fatal outcomes in H7N9-infected sufferers.

and, importantly, are additionally linked to severity of COVID-19.

  • Liu Y
  • Yang Y
  • Zhang C
  • et al.

Medical and biochemical indexes from 2019-nCoV infected sufferers linked to viral loads and lung smash.

ACE2 converts angiotensin II into angiotensin 1–7, which acts via its G protein coupled receptor Mas receptor to counterbalance induction of the renin–angiotensin system. Angiotensin II can pressure cardiac illness, hypertension, fibrotic adjustments in the lung and liver, diabetic nephropathy, irritation, blood vessel constriction, and lung smash, all of that are worsened in ACE2 mutant mice and would possibly possibly be alleviated in experimental mouse objects the use of hrsACE2.

  • Gheblawi M
  • Wang Ok
  • Viveiros A
  • et al.

Angiotensin-changing enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the invention of ACE2.

Angiotensin II infusion in sufferers has additionally been linked to increased thrombotic occasions and induction of the proinflammatory cytokine IL-6.

  • Senchenkova EY
  • Russell J
  • Almeida-Paula LD
  • Harding JW
  • Granger DN

Angiotensin II-mediated microvascular thrombosis.

  • Han Y
  • Runge MS
  • Brasier AR

Angiotensin II induces interleukin-6 transcription in vascular tender muscle cells through pleiotropic activation of nuclear ingredient-kappa B transcription elements.

Our compassionate use in a patient with COVID-19 now shows that hrsACE2 is extremely energetic in cleaving angiotensin II into angiotensin 1–7, as successfully as cleaving angiotensin I into angiotensin 1–9, beginning with the first infusion, and that hrsACE2 remains energetic precise through the route of the 7-day therapy.

After halt of the therapy, angiotensin II concentrations returned interior 48 h to concentrations sooner than therapy, in accordance to previous files on the half-lifestyles of hrsACE2 in humans.

  • Haschke M
  • Schuster M
  • Poglitsch M
  • et al.

Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-changing enzyme 2 in healthy human subjects.

Notably, angiotensin 1–7 concentrations remained elevated for as a lot as 7 days after hrsACE2 therapy used to be stopped, suggesting long-term beneficial effects. When put next with baseline, markedly increased soluble ACE2 exercise used to be detected in plasma as a lot as 7 days after dosing used to be stopped, which used to be paralleled by sustained elevation of the ACE2-dependent renin–angiotensin system markers. Whether low concentrations of hrsACE2 are ample to crimson meat up angiotensin 1–7 concentrations for a chronic time or whether or no longer therapy introduced on endogenous enzyme exercise that would possibly possibly epic for these effects needs further analysis. Of display, a 2nd patient with severe COVID-19 signs bought two doses of compassionate therapy with hrsACE2 for 1 day; on the choice hand, due to quick term 1-day therapy, we did now not encompass the patient on this Case Snort. Importantly, infusion of hrsACE2 on this patient used to be linked to a quick and markedly reduced serum angiotensin II concentration, successfully increasing angiotensin 1–7 concentration and alternative renin–angiotensin system markers for as a lot as 5 days. Thus, hrsACE2 maintains its tissue retaining enzymatic exercise to diminish angiotensin II concentrations in sufferers with COVID-19. Notably, our compassionate use therapy used to be started at a unhurried stage of the illness in which inflammatory parameters had been elevated and respiratory operate had already markedly deteriorated. A segment 2/3 watch of hrsACE2 is currently ongoing and involves sufferers with COVID-19 at earlier stages of the illness (pre-intubation).

Plenty of efforts are underway to block SARS-CoV-2 an infection, with approaches including blocking off viral entry—as an illustration, fusin or transmembrane protease serine 2 inhibitors; soluble ACE2 or antibodies, peptides, or exiguous molecules that mimic ACE2 binding to the viral spike protein; and inhibiting the viral proteases and viral RNA-dependent RNA polymerase (eg, remdesivir). Furthermore, vaccines namely concentrated on the spike–ACE2 interplay are in construction.

  • Corey BL
  • Mascola JR
  • Fauci AS
  • Collins FS

A strategic intention to COVID-19 vaccine R&D.

As a result of this fact, ACE2 is on the core of COVID-19 compare and drug construction. Providing first files on the compose of blocking off the viral spike glycoprotein in sufferers with COVID-19 is of paramount importance. Here, we now comprise supplied files on soluble ACE2 therapy in a patient with SARS-CoV-2 an infection.

Acknowledging the obstacles of our watch, the tips display that the virus disappeared impulsively from the serum; and, albeit at a later time after hrsACE2 (APN01) therapy, from the nasal cavity and lung. Whether this decrease in viral load reflects the compose of hrsACE2 therapy or the pure historical past of the illness remains speculative. Importantly, hrsACE2 therapy did now not intervene with the technology of neutralising antibodies. The equivalent used to be considered for the patient receiving hrsACE2 for 1 day—impulsively undetectable serum viraemia and technology of anti-viral IgG and IgA antibodies (files no longer confirmed). Pondering that SARS-CoV-2 can instantly infect blood vessels, as sure in our experimental organoid model

  • Monteil V
  • Kwon H
  • Prado P
  • et al.

Inhibition of SARS-CoV-2 infections in engineered human tissues the use of scientific-grade soluble human ACE2.

and put up-mortem examinations,

  • Ackermann M
  • Verleden SE
  • Kuehnel M
  • et al.

Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.

intravenous shipping of hrsACE2 would possibly possibly possibly comprise an extraordinarily out of the ordinary compose on blocking off the systemic spread of the virus from the lung to other organs.

Contributors

AZ and JMP designed the watch and wrote the manuscript. MP did the renin–angiotensin system analyses, created the figures, and assisted with writing the manuscript. WH, TS, MT, AG, EP, DH, HL, CW, and SN mute files. JHA, KS, and AB did the virological analyses and assisted with writing the manuscript. DH assured quality and regulatory compliance. EP-S, AM, NM, HZ, and ASS contributed to files interpretation and revised the manuscript. All authors mentioned the outcomes, commented on the manuscript, and accredited the closing version of the manuscript.

Declaration of pursuits

JMP is a founder and shareholder of Apeiron Biologics. ASS is a advisor to Apeiron Biologics. All other authors expose no competing pursuits.

Acknowledgments

We thank the patient and her family for taking part on this compare. We thank Thomas Penz and Alexandra Popa from CeMM Study Center for Molecular Capsules of the Austrian Academy of Sciences, Vienna, Austria, for aid with sequencing the virus stress archaic in the neutralisation assay. We thank Jutta Hutecek from the Center for Virology, Medical College of Vienna, for radiant technical assistance (neutralisation assays). We thank the pharmacy division and Denise Kogler for compounding and GCP toughen. We thank Apeiron Biologics for offering hrsACE2 for this compassionate use. The Case Snort used to be supported by Canada 150 Chair and Canada Institutes for Heath Study (CIHR) grants to JMP [VR3-17652] and to ASS (137772) and HZ (FDN143285). AB and JMP are supported by the von Zastrow Foundation, the Vienna Science and Technology Fund (WWTF) COVID-19 Quickly Response Call, and an EU COVID-19 IMI grant. This work is additionally supported by the CIHR (grant number OV3–170344 and SBC-171482). JMP has bought funding from the Modern Medicines Initiative 2 Joint Venture (JU) under grant agreement number 101005026. The JU receives toughen from the European Union’s Horizon 2020 compare and innovation programme and the European Federation of Pharmaceutical Industries and Associations. No funding sources had any operate in the writing of the manuscript or the resolution to put up. The corresponding writer had elephantine score admission to to the whole files in the watch and had closing duty for the resolution to put up for publication.

Supplementary Cloth

References

  1. 1.
    • Bourgonje AR
    • Abdulle AE
    • Timens W
    • et al.

    Angiotensin-changing enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus illness 2019 (COVID-19).

    J Pathol. 2020; 251: 228-248

  2. 2.
    • Zhang H
    • Penninger JM
    • Li Y
    • Zhong N
    • Slutsky AS

    Angiotensin-changing enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and attainable therapeutic goal.

    Intensive Care Med. 2020; 46: 586-590

  3. 3.
    • Monteil V
    • Kwon H
    • Prado P
    • et al.

    Inhibition of SARS-CoV-2 infections in engineered human tissues the use of scientific-grade soluble human ACE2.

    Cell. 2020; 181: 905-913

  4. 4.
    • Kuba Ok
    • Imai Y
    • Rao S
    • et al.

    A really most valuable operate of angiotensin changing enzyme 2 (ACE2) in SARS coronavirus-introduced on lung smash.

    Nat Med. 2005; 11: 875-879

  5. 5.
    • Crackower MA
    • Sarao R
    • Oudit GY
    • et al.

    Angiotensin-changing enzyme 2 is an notable regulator of heart operate.

    Nature. 2002; 417: 822-828

  6. 6.
    • Wong DW
    • Oudit GY
    • Reich H
    • et al.

    Lack of angiotensin-changing enzyme-2 (Ace2) accelerates diabetic kidney smash.

    Am J Pathol. 2007; 171: 438-451

  7. 7.
    • Haschke M
    • Schuster M
    • Poglitsch M
    • et al.

    Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-changing enzyme 2 in healthy human subjects.

    Clin Pharmacokinet. 2013; 52: 783-792

  8. 8.
    • Khan A
    • Benthin C
    • Zeno B
    • et al.

    A pilot scientific trial of recombinant human angiotensin-changing enzyme 2 in acute respiratory harm syndrome.

    Crit Care. 2017; 21: 234

  9. 9.
    • Zhang X
    • Tan Y
    • Ling Y
    • et al.

    Viral and host elements linked to the scientific of COVID-19.

    Nature. 2020; 583: 437-440

  10. 10.
    • Jabaudon M
    • Blondonnet R
    • Pereira B
    • et al.

    Plasma sRAGE is independently linked to increased mortality in ARDS: a meta-analysis of particular person patient files.

    Intensive Care Med. 2018; 44: 1388-1399

  11. 11.
    • Lopez-Cano C
    • Lecube A
    • Garcia-Ramirez M
    • et al.

    Serum surfactant protein D as a biomarker for measuring lung involvement in chubby sufferers with form 2 diabetes.

    J Clin Endocrinol Metab. 2017; 102: 4109-4116

  12. 12.
    • Walls AC
    • Park YJ
    • Tortorici MA
    • Wall A
    • McGuire AT
    • Veesler D

    Structure, operate, and antigenicity of the SARS-CoV-2 spike glycoprotein.

    Cell. 2020; 181 (): 281

  13. 13.
    • Okba NMA
    • Muller MA
    • Li W
    • et al.

    Excessive acute respiratory syndrome coronavirus 2-specific antibody responses in coronavirus illness 2019 sufferers.

    Emerg Infect Dis. 2020; 26: 1478-1488

  14. 14.
    • Zhou P
    • Yang XL
    • Wang XG
    • et al.

    A pneumonia outbreak linked to a fresh coronavirus of probable bat foundation.

    Nature. 2020; 579: 270-273

  15. 15.
    • Imai Y
    • Kuba Ok
    • Rao S
    • et al.

    Angiotensin-changing enzyme 2 protects from severe acute lung failure.

    Nature. 2005; 436: 112-116

  16. 16.
    • Zou Z
    • Yan Y
    • Shu Y
    • et al.

    Angiotensin-changing enzyme 2 protects from lethal avian influenza A H5N1 infections.

    Nat Commun. 2014; 53594

  17. 17.
    • Yang P
    • Gu H
    • Zhao Z
    • et al.

    Angiotensin-changing enzyme 2 (ACE2) mediates influenza H7N9 virus-introduced on acute lung smash.

    Sci Obtain. 2014; 47027

  18. 18.
    • Huang F
    • Guo J
    • Zou Z
    • et al.

    Angiotensin II plasma ranges are linked to illness severity and predict fatal outcomes in H7N9-infected sufferers.

    Nat Commun. 2014; 53595

  19. 19.
    • Liu Y
    • Yang Y
    • Zhang C
    • et al.

    Medical and biochemical indexes from 2019-nCoV infected sufferers linked to viral loads and lung smash.

    Sci China Life Sci. 2020; 63: 364-374

  20. 20.
    • Gheblawi M
    • Wang Ok
    • Viveiros A
    • et al.

    Angiotensin-changing enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the invention of ACE2.

    Circ Res. 2020; 126: 1456-1474

  21. 21.
    • Senchenkova EY
    • Russell J
    • Almeida-Paula LD
    • Harding JW
    • Granger DN

    Angiotensin II-mediated microvascular thrombosis.

    Hypertension. 2010; 56: 1089-1095

  22. 22.
    • Han Y
    • Runge MS
    • Brasier AR

    Angiotensin II induces interleukin-6 transcription in vascular tender muscle cells through pleiotropic activation of nuclear ingredient-kappa B transcription elements.

    Circ Res. 1999; 84: 695-703

  23. 23.
    • Corey BL
    • Mascola JR
    • Fauci AS
    • Collins FS

    A strategic intention to COVID-19 vaccine R&D.

    Science. 2020; 368: 948-950

  24. 24.
    • Ackermann M
    • Verleden SE
    • Kuehnel M
    • et al.

    Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.

    N Engl J Med. 2020; 383: 120-128

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Printed: September 24, 2020

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DOI: https://doi.org/10.1016/S2213-2600(20)30418-5

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© 2020 Elsevier Ltd. All rights reserved.

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