A review of treatment modalities for Middle East Respiratory Syndrome

Yin Mo, Dale Fisher, Yin Mo, Dale Fisher

Abstract

The Middle East Respiratory Syndrome coronavirus (MERS-CoV) has been a focus of international attention since its identification in 2012. Epidemiologically it is characterized by sporadic community cases, which are amplified by hospital-based outbreaks. Healthcare facilities in 27 countries from most continents have experienced imported cases, with the most significant outbreak involving 186 cases in Korea. The mortality internationally is 36% and guidance for clinical management has yet to be developed. Most facilities and healthcare providers outside of the Middle East receiving patients have no or little experience in the clinical management of MERS. When a case does occur there is likely little time for a critical appraisal of the literature and putative pharmacological options. We identified published literature on the management of both MERS-CoV and the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) through searches of PubMed and WHO and the US CDC websites up to 30 April 2016. A total of 101 publications were retrieved for critical appraisal. Most published literature on therapeutics for MERS are in vitro experiments, animal studies and case reports. Current treatment options for MERS can be categorized as: immunotherapy with virus-specific antibodies in convalescent plasma; polyclonal and monoclonal antibodies produced in vitro or in genetically modified animals; and antiviral agents. The use of any therapeutics in MERS-CoV remains investigational. The therapeutic agents with potential benefits and warranting further investigation include convalescent plasma, interferon-β/ribavirin combination therapy and lopinavir. Corticosteroids, ribavirin monotherapy and mycophenolic acid likely have toxicities that exceed potential benefits.

© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

References

    1. WHO. Middle East Respiratory Syndrome Coronavirus (MERS-CoV): MERS-CoV in Republic Korea at a Glance. .
    1. Zumla A, Chan JF, Azhar EI et al. . Coronaviruses—drug discovery and therapeutic options. Nat Rev Drug Discov 2016; 15: 327–47.
    1. Al Ghamdi M, Alghamdi KM, Ghandoora Y et al. . Treatment outcomes for patients with Middle Eastern Respiratory Syndrome Coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia. BMC Infect Dis 2016; 16: 174.
    1. Song W, Wang Y, Wang N et al. . Identification of residues on human receptor DPP4 critical for MERS-CoV binding and entry. Virology 2014; 471–473: 49–53.
    1. Raj VS, Mou H, Smits SL et al. . Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013; 495: 251–4.
    1. Chan RWY, Chan MCW, Agnihothram S et al. . Tropism of and innate immune responses to the novel human betacoronavirus lineage C virus in human ex vivo respiratory organ cultures. J Virol 2013; 87: 6604–14.
    1. Jie Zhou, Hin Chu, Cun Li et al. . Active replication of Middle East Respiratory Syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis. J Infect Dis 2014; 209: 1331–42.
    1. Eckerle I, Muller M, Kallies S et al. . In-vitro renal epithelial cell infection reveals a viral kidney tropism as a potential mechanism for acute renal failure during Middle East respiratory syndrome (MERS) coronavirus infection. Virol J 2013; 10: 359.
    1. Kindler E, Jonsdottir HR, Muth D et al. . Efficient replication of the novel human betacoronavirus EMC on primary human epithelium highlights its zoonotic potential. MBio 2013; 4: e00611–12.
    1. Zielecki F, Weber M, Eickmann M et al. . Human cell tropism and innate immune system interactions of human respiratory coronavirus EMC compared to those of severe acute respiratory syndrome coronavirus. J Virol 2013; 87: 5300–4.
    1. de Wilde AH, Jochmans D, Posthuma CC et al. . Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother 2014; 58: 4875–84.
    1. Dyall J, Coleman CM, Hart BJ et al. . Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother 2014; 58: 4885–93.
    1. Chan JF, Chan K-H, Kao RY et al. . Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect 2013; 67: 606–16.
    1. Chen F, Chan KH, Jiang Y et al. . In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol 2004; 31: 69–75.
    1. Amoss HL, Chesney AM. A report on the serum treatment of twenty-six cases of epidemic poliomyelitis. J Exp Med 1917; 25: 581–608.
    1. McGuire LW, Redden WR. The use of convalescent human serum in influenza pneumonia: a preliminary report. Am J Public Health 1918; 8: 741–4.
    1. Mupapa K, Massamba M, Kibadi K et al. . Treatment of ebola hemorrhagic fever with blood transfusions from convalescent patients. J Infect Dis 1999; 179Suppl 1: S18–23.
    1. Cheng Y, Wong R, Soo YO et al. . Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis 2005; 24: 44–6.
    1. WHO. WHO–International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) MERS-CoV Outbreak Readiness Workshop 2013. .
    1. WHO. Blood Regulators Network (BRN) Position Paper on Collection and Use of Convalescent Plasma or Serum as an Element in Middle East Respiratory Syndrome Coronavirus Response. .
    1. Zhao J, Perera RA, Kayali G et al. . Passive immunotherapy with dromedary immune serum in an experimental animal model for Middle East Respiratory Syndrome coronavirus infection. J Virol 2015; 89: 6117–20.
    1. Chan KH, Chan JF, Tse H et al. . Cross-reactive antibodies in convalescent SARS patients' sera against the emerging novel human coronavirus EMC (2012) by both immunofluorescent and neutralizing antibody tests. J Infect 2013; 67: 130–40.
    1. Du L, Kou Z, Ma C et al. . A truncated receptor-binding domain of MERS-CoV spike protein potently inhibits MERS-CoV infection and induces strong neutralizing antibody responses: implication for developing therapeutics and vaccines. PLoS ONE 2013; 8: e81587.
    1. Ohnuma K, Haagmans BL, Hatano R et al. . Inhibition of Middle East Respiratory Syndrome coronavirus infection by anti-CD26 monoclonal antibody. J Virol 2013; 87: 13892–9.
    1. Ying T, Li H, Lu L et al. . Development of human neutralizing monoclonal antibodies for prevention and therapy of MERS-CoV infections. Microbes Infect 2015; 17: 142–8.
    1. Sakamoto S, Tanaka H, Morimoto S. Towards the prophylactic and therapeutic use of human neutralizing monoclonal antibodies for Middle East respiratory syndrome coronavirus (MERS-CoV). Ann Transl Med 2015; 3: 35.
    1. Luke T, Wu H, Zhao J et al. . Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo. Sci Transl Med 2016; 8: 326ra21.
    1. Pascal KE, Coleman CM, Mujica AO et al. . Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection. PNAS 2015; 112: 8738–43.
    1. Du L, Zhao G, Yang Y et al. . A conformation-dependent neutralizing monoclonal antibody specifically targeting receptor-binding domain in MERS-CoV spike protein. J Virol 2014; 88: 7045–53.
    1. Li Y, Wan Y, Liu P et al. . A humanized neutralizing antibody against MERS-CoV targeting the receptor-binding domain of the spike protein. Cell Res 2015; 25: 1237–49.
    1. Yu X, Zhang S, Jiang L et al. . Structural basis for the neutralization of MERS-CoV by a human monoclonal antibody MERS-27. Scientific Reports 2015; 5: 13133.
    1. Mou H, Raj VS, van Kuppeveld FJ et al. . The receptor binding domain of the new Middle East Respiratory Syndrome coronavirus maps to a 231-residue region in the spike protein that efficiently elicits neutralizing antibodies. J Virol 2013; 87: 9379–83.
    1. Tang XC, Agnihothram SS, Jiao Y et al. . Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution. Proc Natl Acad Sci USA 2014; 111: E2018–26.
    1. Ying T, Du L, Ju TW et al. . Exceptionally potent neutralization of Middle East Respiratory Syndrome coronavirus by human monoclonal antibodies. J Virol 2014; 88: 7796–805.
    1. Jiang L, Wang N, Zuo T et al. . Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein. Sci Transl Med 2014; 6: 234ra59.
    1. Johnson RF, Bagci U, Keith L et al. . 3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012. Virology 2016; 490: 49–58.
    1. Corti D, Zhao J, Pedotti M et al. . Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus. Proc Natl Acad Sci USA 2015; 112: 10473–8.
    1. Corti D, Passini N, Lanzavecchia A et al. . Rapid generation of a human monoclonal antibody to combat Middle East respiratory syndrome. J Infect Public Health 2016; 9: 231–5.
    1. Arabi YM, Arifi AA, Balkhy HH et al. . Clinical course and outcomes of critically ill patients with Middle East Respiratory Syndrome coronavirus infection. Ann Intern Med 2014; 160: 389–97.
    1. Kapoor M, Pringle K, Kumar A et al. . Clinical and laboratory findings of the first imported case of Middle East Respiratory Syndrome coronavirus to the United States. Clin Infect Dis 2014; 59: 1511–8.
    1. Arabi Y, Balkhy H, Hajeer AH et al. . Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus 2015; 4: 709.
    1. Yaseen M Arabi. Anti-MERS-COV Convalescent Plasma Therapy NCT02190799. .
    1. Modjarrad K. Treatment strategies for Middle East respiratory syndrome coronavirus. J Virus Erad 2016; 2: 1–4.
    1. Yeh KM, Chiueh TS, Siu LK et al. . Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital. J Antimicrob Chemother 2005; 56: 919–22.
    1. Wu W, Wang JF, Liu PM et al. . Clinical features of 96 patients with severe acute respiratory syndrome from a hospital outbreak. Zhonghua Nei Ke Za Zhi 2003; 42: 453–7.
    1. Li ZZ, Shen KL, Wei XM et al. . Clinical analysis of pediatric SARS cases in Beijing. Zhonghua Er Ke Za Zhi 2003; 41: 574–7.
    1. Soo YO, Cheng Y, Wong R et al. . Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect 2004; 10: 676–8.
    1. Ho JC, Wu AY, Lam B et al. . Pentaglobin in steroid-resistant severe acute respiratory syndrome. Int J Tuberc Lung Dis 2004; 8: 1173–9.
    1. Hung IF, To KK, Lee CK et al. . Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis 2011; 52: 447–56.
    1. Hung IN, To KW, Lee C et al. . Hyperimmune intravenous immunoglobulin treatment: a multi-centre double-blind randomized controlled trial for patients with severe A(H1N1) infection. Chest 2013; 144: 464–73.
    1. Mair-Jenkins J, Saavedra-Campos M, Baillie JK et al. . The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis 2015; 211: 80–90.
    1. Weingartl H, Czub M, Czub S et al. . Immunization with modified vaccinia virus Ankara-based recombinant vaccine against severe acute respiratory syndrome is associated with enhanced hepatitis in ferrets. J Virol 2004; 78: 12672–6.
    1. Clay C, Donart N, Fomukong N et al. . Primary Severe Acute Respiratory Syndrome coronavirus infection limits replication but not lung inflammation upon homologous rechallenge. J Virol 2012; 86: 84234–44.
    1. Public Health England. Treatment of MERS-CoV: Information for Clinicians. Clinical Decision Making Support for Treatment of MERS-CoV Patients v3.0 2015. .
    1. Müller MA, Meyer B, Corman VM et al. . Presence of Middle East respiratory syndrome coronavirus antibodies in Saudi Arabia: a nationwide, cross-sectional, serological study. Lancet Infect Dis 2015; 15: 559–64.
    1. Gierer S, Hofmann-Winkler H, Albuali WH et al. . Lack of MERS coronavirus neutralizing antibodies in humans, eastern province, Saudi Arabia. Emerging Infect Dis 2013; 19: 2034–6.
    1. Aburizaiza AS, Mattes FM, Azhar EI et al. . Investigation of anti-Middle East respiratory syndrome antibodies in blood donors and slaughterhouse workers in Jeddah and Makkah, Saudi Arabia, fall 2012. J Infect Dis 2014; 209: 243–6.
    1. Lau SK, Lau CC, Chan KH et al. . Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment. J Gen Virol 2013; 94: 2679–90.
    1. Josset L, Menachery VD, Gralinski LE et al. . Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. mBio 2013; 4: e00165–13.
    1. Haagmans BL, Kuiken T, Martina BE et al. . Pegylated interferon-αprotects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat Med 2004; 10: 290–3.
    1. Sainz B Jr, Mossel EC, Peters CJ et al. . Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV). Virology 2004; 329: 11–7.
    1. Barnard DL, Day CW, Bailey K et al. . Evaluation of immunomodulators, interferons and known in vitro SARS-coV inhibitors for inhibition of SARS-coV replication in BALB/c mice. Antivir Chem Chemother 2006; 17: 275–84.
    1. Cervantes-Barragan L, Zust R, Weber F et al. . Control of coronavirus infection through plasmacytoid dendritic-cell- derived type I interferon. Blood 2007; 109: 1131–7.
    1. Ströher U, DiCaro A, Li Y et al. . Severe acute respiratory syndrome-related coronavirus is inhibited by interferon-α. J Infect Dis 2004; 189: 1164–7.
    1. Hensley LE, Fritz EA, Jahrling PB et al. . Interferon-β 1a and SARS coronavirus replication. Emerging Infect Dis 2004; 10: 317–9.
    1. Cinatl J, Morgenstern B, Bauer G et al. . Treatment of SARS with human interferons. Lancet 2003; 362: 293–4.
    1. de Wilde AH, Raj VS, Oudshoorn D et al. . MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment. J Gen Virol 2013; 94: 1749–60.
    1. Haagmans BL, Osterhaus AD. Coronaviruses and their therapy. Antiviral Res 2006; 71: 397–403.
    1. Scagnolari C, Vicenzi E, Bellomi F et al. . Increased sensitivity of SARS-coronavirus to a combination of human type I and type II interferons. Antivir Ther 2004; 9: 1003–11.
    1. Falzarano D, de Wit E, Martellaro C et al. . Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. Sci Rep 2013; 3: 1686.
    1. Zheng Y, Wang QY. Bioinformatics analysis on molecular mechanism of ribavirin and interferon-α in treating MERS-CoV. Zhonghua Liu Xing Bing Xue Za Zhi 2016; 37: 291–3.
    1. Falzarano D, de Wit E, Rasmussen AL et al. . Interferon-α2b and ribavirin treatment improve outcome in MERS-CoV-infected rhesus macaques. Nature Med 2013; 19: 1313–7.
    1. Chan JF, Yao Y, Yeung ML et al. . Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis 2015; 212: 1904–13.
    1. Loutfy MR, Blatt LM, Siminovitch KA et al. . Interferon alfacon-1 plus corticosteroids in Severe Acute Respiratory Syndrome: a preliminary study. JAMA 2003; 290: 3222–8.
    1. Faure E, Poissy J, Goffard A et al. . Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside? PLoS ONE 2014; 9: e88716.
    1. Spanakis N, Tsiodras S, Haagmans BL et al. . Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. Int J Antimicrob Agents 2014; 44: 528–32.
    1. Khalid M, Al Rabiah F, Khan B et al. . Ribavirin and interferon (IFN)-alpha-2b as primary and preventive treatment for Middle East respiratory syndrome coronavirus (MERS-CoV): a preliminary report of two cases. Antivir Ther 2015; 20: 87–91.
    1. Kim UJ, Won EJ, Kee SJ et al. . Combination therapy with lopinavir/ritonavir, ribavirin and interferon-alpha for Middle East respiratory syndrome: a case report. Antivir Ther 2015: 10.3851/IMP300210.3851/IMP3002.
    1. Malik A, El Masry KM, Ravi M et al. . Middle East Respiratory Syndrome Coronavirus during pregnancy, Abu Dhabi, United Arab Emirates, 2013. Emerg Infect Dis 2016; 22: 515–7.
    1. Khalid M, Khan B, Al Rabiah F et al. . Middle Eastern Respiratory Syndrome Corona Virus (MERS CoV): case reports from a tertiary care hospital in Saudi Arabia. Ann Saudi Med 2014; 34: 396–400.
    1. Omrani AS, Saad MM, Baig K et al. . Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis 2014; 4: 1090–5.
    1. Shalhoub S, Farahat F, Al-Jiffri A et al. . IFN-α2a or IFN-β1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother 2015; 70: 2129–32.
    1. Al-Tawfiq JA, Momattin H, Dib J et al. . Ribavirin and interferon therapy in patient infected with the Middle East respiratory syndrome coronavirus: an observational study. Int J Infect Dis 2014; 20: 42–6.
    1. Khalid I, Alraddadi BM, Dairi Y et al. . Acute management and long-term survival among subjects with severe Middle East Respiratory Syndrome coronavirus pneumonia and ARDS. Respir Care 2016; 61: 3340–8.
    1. WHO. Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Fact Sheet No. 401 June 2015. .
    1. Djukanović R, Harrison T, Johnston SL et al. . The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. a randomized trial. Am J Resp Crit Care Med 2014; 190: 145–54.
    1. Wu CY, Jan JT, Ma SH et al. . Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc Natl Acad Sci USA 2004; 101: 10012–7.
    1. Lopez Aspiroz E, Santos Buelga D, Cabrera Figueroa S et al. . Population pharmacokinetics of lopinavir/ritonavir (Kaletra) in HIV-infected patients. Ther Drug Monit 2011; 33: 573–82.
    1. Chu C, Cheng V, Hung I et al. . Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004; 59: 252–6.
    1. Chan KS, Lai ST, Chu CM et al. . Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J 2003; 9: 399–406.
    1. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Medicine 2006; 3: e343.
    1. Snell NJ. Ribavirin—current status of a broad spectrum antiviral agent. Expert Opin Pharmacother 2001; 2: 1317–24.
    1. Crotty S, Maag D, Arnold JJ et al. . The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med 2000; 6: 1375–9.
    1. Morgenstern B, Michaelis M, Baer PC et al. . Ribavirin and interferon-beta synergistically inhibit SARS-associated coronavirus replication in animal and human cell lines. Biochem Biophys Res Commun 2005; 326: 905–8.
    1. Tan EL, Ooi EE, Lin CY et al. . Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs. Emerg Infect Dis 2004; 10: 581–6.
    1. Cinatl J, Morgenstern B, Bauer G et al. . Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003; 361: 2045–6.
    1. Health Canada. Clinical Information – Management of Severe Acute Respiratory Syndrome (SARS) in Adults: Interim Guidance for Health Care Providers. .
    1. US Army Medical Research Institute of Infectious Diseases, personal communication. Severe Acute Respiratory Syndrome (SARS) and Coronavirus Testing, MMWR 2003. .
    1. Barnard DL, Day CW, Bailey K et al. . Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin. Antiviral Res 2006; 71: 53–63.
    1. Zhao Z, Zhang F, Xu M et al. . Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China. J Med Microbiol 2003; 52: 715–20.
    1. Sung J, Wu A, Joynt G et al. . Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak. Thorax 2004; 59: 414–20.
    1. Knowles SR, Phillips EJ, Dresser L et al. . Common adverse events associated with the use of ribavirin for severe acute respiratory syndrome in Canada. Clin Infect Dis 2003; 37: 1139–42.
    1. Booth CM, Matukas LM, Tomlinson GA et al. . Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 2003; 289: 2801–9.
    1. Wong WM, Ho JC, Ooi GC et al. . Temporal patterns of hepatic dysfunction and disease severity in patients with SARS. JAMA 2003; 290: 2663–5.
    1. Markland W, McQuaid TJ, Jain J et al. . Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon. Antimicrobial Agents Chemother 2000; 44: 859–66.
    1. Allison A, Eugui E. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev 1993; 136: 5–28.
    1. Hart BJ, Dyall J, Postnikova E et al. . Interferon-β and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J Gen Virol 2014; 95: 571–7.
    1. Cheng KW, Cheng SC, Chen WY et al. . Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res 2015; 115: 9–16.
    1. Luban J, Bossolt KL, Franke EK et al. . Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell 1993; 73: 1067–78.
    1. Watashi K, Ishii N, Hijikata M et al. . Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell 2005; 19: 111–22.
    1. Yang F, Robotham JM, Nelson HB et al. . Cyclophilin A is an essential cofactor for hepatitis C virus infection and the principal mediator of cyclosporine resistance in vitro. J Virol 2008; 82: 5269–78.
    1. Paeshuyse J, Kaul A, De Clercq E et al. . The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology 2006; 43: 761–70.
    1. de Wilde AH, Zevenhoven-Dobbe JC, van der Meer Y et al. . Cyclosporin A inhibits the replication of diverse coronaviruses. J Gen Virol 2011; 92: 2542–8.
    1. Ooi EE, Chew JSW, Loh JP et al. . In vitro inhibition of human influenza A virus replication by chloroquine. Virology J 2006; 3: 39.
    1. Keyaerts E, Vijgen L, Maes P et al. . In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun 2004; 323: 264–8.
    1. Vincent MJ, Bergeron E, Benjannet S et al. . Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology J 2005; 2: 69.
    1. Paton NI, Lee L, Xu Y et al. . Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. Lancet Infect Dis 2011; 11: 677–83.
    1. Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antivir Res 2014; 110: 94–103.
    1. Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health 2016; 9: 227–30.
    1. Belardo G, La Frazia S, Cenciarelli O et al. . Nitazoxanide, a novel potential anti-influenza drug, acting in synergism with neuraminidase inhibitors. In: Abstracts of the Forty-ninth Annual Meeting of the Infectious Diseases Society of America, Boston, MA, 2011 Abstract 1181 Infectious Diseases Society of America, Arlington, VA, USA.
    1. Cao J, Forrest JC, Zhang X. A screen of the NIH Clinical Collection small molecule library identifies potential anti-coronavirus drugs. Antiviral Res 2015; 114: 1–10.
    1. Haffizulla J, Hartman A, Hoppers M et al. . Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis 2014; 14: 609–18.
    1. Rossignol JF, Samudrala S, Hoppers M et al. . A randomized, double-blind, placebo controlled study of nitazoxanide in adults and adolescents with acute uncomplicated influenza. In: Oral presentation of the Forty-ninth Annual Meeting of the Infectious Diseases Society of America, Boston, MA, 2011 Infectious Diseases Society of America, Arlington, VA, USA.
    1. Zhou N, Pan T, Zhang J et al. . Glycopeptide antibiotics potently inhibit cathepsin L in the late endosome/lysosome and block the entry of Ebola virus, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). J Biol Chem 2016; 291: 9218–32.
    1. Shirato K, Kawase M, Matsuyama S. Middle East Respiratory Syndrome Coronavirus infection mediated by the transmembrane serine protease TMPRSS2. J Virology 2013; 87: 12552–61.
    1. Lu L, Liu Q, Zhu Y et al. . Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor. Nat Commun 2014; 5: 3067.
    1. Channappanavar R, Lu L, Xia S et al. . Protective effect of intranasal regimens containing peptidic Middle East Respiratory Syndrome Coronavirus fusion inhibitor against MERS-CoV infection. J Infect Dis 2015; 212: 1894–903.
    1. Zhou Y, Lu K, Pfefferle S et al. . A single asparagine-linked glycosylation site of the Severe Acute Respiratory Syndrome coronavirus spike glycoprotein facilitates inhibition by mannose-binding lectin through multiple mechanisms. J Virology 2010; 84: 8753–64.
    1. Ip WK, Chan KH, Law HK et al. . Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. J Infect Dis 2005; 191: 1697–704.
    1. So LK, Lau AC, Yam LY et al. . Development of a standard treatment protocol for severe acute respiratory syndrome. Lancet 2003; 361: 1615–7.
    1. Wang JT, Sheng WH, Fang CT et al. . Clinical manifestations, laboratory findings, and treatment outcomes of SARS patients. Emerg Infect Dis 2004; 10: 818–24.
    1. Wu W, Wang J, Liu P et al. . A hospital outbreak of severe acute respiratory syndrome in Guangzhou, China. Chin Med J (Engl) 2003; 116: 811–8.
    1. Gomersall CD, Joynt GM, Lam P et al. . Short-term outcome of critically ill patients with severe acute respiratory syndrome. Intensive Care Med 2004; 30: 381–7.
    1. Ho JC, Ooi GC, Mok TY et al. . High-dose pulse versus nonpulse corticosteroid regimens in severe acute respiratory syndrome. Am J Respir Crit Care Med 2003; 168: 1449–56.
    1. Peiris JSM, Lai ST, Poon LLM et al. . Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 2003; 361: 1319–25.
    1. Ooi CG, Khong PL, Ho JC et al. . Severe acute respiratory syndrome: radiographic evaluation and clinical outcome measures. Radiology 2003; 229: 2500–6.
    1. Jones BM, Esk MA, Peiris JSM et al. . Prolonged disturbances of in vitro cytokine production in patients with severe acute respiratory syndrome (SARS) treated with ribavirin and steroids. Clin Exp Immunol 2004; 135: 467–73.
    1. Zhang X, Alekseev K, Jung K et al. . Cytokine responses in porcine respiratory coronavirus-infected pigs treated with corticosteroids as a model for severe acute respiratory syndrome. J Virol 2008; 82: 4420–8.
    1. Lee N, Allen Chan KC, Hui DS et al. . Effects of early corticosteroid treatment on plasma SARS-associated coronavirus RNA concentrations in adult patients. J Clin Virol 2004; 31: 304–9.
    1. Kim SH, Hong SB, Yun SC et al. . Corticosteroid treatment in critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scores. Am J Respir Crit Care Med 2011; 183: 1207–14.
    1. The WHO MERS-CoV Research Group. State of knowledge and data gaps of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in humans. PLoS Curr 2013; 12: 5.
    1. Ruan SY, Lin HH, Huang CT et al. . Exploring the heterogeneity of effects of corticosteroids on acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care 2014; 18: R63.
    1. Griffith JF, Antonio GE, Kumta SM et al. . Osteonecrosis of hip and knee in patients with severe acute respiratory syndrome treated with steroids. Radiology 2005; 235: 168–75.
    1. Hong N, Du XK. Avascular necrosis of bone in severe acute respiratory syndrome. Clin Radiol 2004; 59: 602–8.
    1. Lee DT, Wing YK, Leung HC et al. . Factors associated with psychosis among patients with severe acute respiratory syndrome: a case–control study. Clin Infect Dis 2004; 39: 1247–9.
    1. Wang H, Ding Y, Li X et al. . Fatal aspergillosis in a patient with SARS who was treated with corticosteroids. N Engl J Med 2003; 349: 507–8.
    1. Hui DS, Memish ZA, Zumla A. Severe acute respiratory syndrome vs. the Middle East respiratory syndrome. Curr Opin Pulm Med 2014; 20: 233–41.
    1. Chong YP, Song JY, Seo YB et al. . Antiviral treatment guidelines for Middle East Respiratory Syndrome. Infect Chemother 2015; 47: 212–2.
    1. Peiris JSM, Chu CM, Cheng VCC et al. . Clinical progression and viral load in a community outbreak of coronavirus- associated SARS pneumonia: a prospective study. Lancet 2003; 361: 1767–2.

Source: PubMed

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