Download PDF
Drug Res (Stuttg) 2020; 70(07): 291-297
DOI: 10.1055/a-1170-4395
Opinion Paper

Interferons in the Therapy of Severe Coronavirus Infections: A Critical Analysis and Recollection of a Forgotten Therapeutic Regimen with Interferon Beta

Josef Brzoska
1   Linical Europe GmbH, Frankfurt, Germany
*   Last affiliations prior to retirement
,
Harald von Eick
2   CTI Clinical Trial and Consulting Services Europe GmbH, Ulm, Germany
*   Last affiliations prior to retirement
,
Manfred Hündgen
3   Rentschler Biotechnologie GmbH, Laupheim, Germany
*   Last affiliations prior to retirement
› Author Affiliations
› Further Information
Also available at
   Permissions and Reprints

Abstract

The pharmacological and immunological properties of interferons, especially those of interferon beta, and the corresponding treatment strategies are described, and the results of studies with different interferons in coronavirus infections are analysed. Furthermore, the data obtained with high-dosed native interferon beta in life-threatening acute viral diseases as well as the results of clinical pilot studies with high-dosed recombinant interferon beta-1a are provided because they serve as the rationale for the proposed therapeutic regimen to be applied in acute viral infections. This regimen differs from those approved for treatment of multiple sclerosis and consists of interferon beta-1a administered as a 24 hour intravenous infusion at a daily dose of up to 90 µg for 3–5 consecutive days. Since under this regimen transient severe side effects can occur, it is analysed which patients are suitable for this kind of treatment in general and if patients with severe coronavirus infections could also be treated accordingly.

Key words

antiviral drugs - cytokines - drug research - human pharmacology - infectious diseases - immunopharmacology - SARS - MERS - COVID-19 - SARS-CoV-2


Publication History

Received: 24 March 2020

Accepted: 29 April 2020

Article published online:
22 May 2020

© Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 World Health Organization. WHO characterizes COVID-19 as a pandemic. Rolling updates on coronavirus disease (COVID-19) 11 March. 2020 https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen
    PubMedGoogle Scholar
  • 2 Chen N, Zhou M, Dong X. et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395: 507-513
    CrossrefPubMedGoogle Scholar
  • 3 Guan WJ, Ni ZY, Hu Y. et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; DOI: 10.1056/NEJMoa2002032.
    CrossrefPubMedGoogle Scholar
  • 4 Mahase E. Coronavirus: covid-19 has killed more people than SARS and MERS combined, despite lower case fatality rate. BMJ 2020; 368: m641
    PubMedGoogle Scholar
  • 5 Zumla A, Chan JF, Azhar EI. et al. Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov 2016; 15: 327-347
    CrossrefPubMedGoogle Scholar
  • 6 Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov 2020; DOI: doi.org/10.1038/d41573-020-00016-0.
    CrossrefPubMedGoogle Scholar
  • 7 World Health Organization. WHO R&D Blueprint: Informal consultation on prioritization of candidate therapeutic agents for use in novel coronavirus 2019 infection. Geneva, Switzerland, 24 January. 2020. https://apps.who.int/iris/handle/10665/330680
    CrossrefGoogle Scholar
  • 8 Baron S, Coppenhaver DH, Dianzani F et al. Introduction to the interferon system. In: Baron S, Coppenhaver DH, Dianzani F, Fleischmann Jr WR, Hughes TK, Klimpel GR, Niesel DW, Stanton GJ, Tyring SK, Eds. Interferon: Principles and Medical Applications. Galveston, TX: The University of Texas Medical Branch at Galveston Department of Microbiology; 1992: 1–15
  • 9 Cheng VCC, Lau SKP, Woo PCY. et al. Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection. Clin Microbiol Rev 2007; 20: 660-694
    CrossrefPubMedGoogle Scholar
  • 10 Kindler E, Thiel V, Weber F. Interaction of SARS and MERS coronaviruses with the antiviral interferon response. Adv Virus Res 2016; 96: 219-243
    CrossrefPubMedGoogle Scholar
  • 11 Trinchieri G. Type I interferon: Friend or foe?. J Exp Med 2010; 207: 2053-2063
    CrossrefPubMedGoogle Scholar
  • 12 Totura AL, Baric RS. SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon. Curr Opin Virol 2012; 2: 264-275
    CrossrefPubMedGoogle Scholar
  • 13 Brzoska J, Obert HJ. Interferon gamma: ein janusköpfiger Mediator bei Entzündungen. Drug Res 1987; 37: 1410-1416
    PubMedGoogle Scholar
  • 14 Brzoska J, Obert HJ. Immunomodulating effects of interferons: conclusions for therapy. In: Gross G, Jablonska S, Pfister H, Stegner HE, Eds. Genital Papillomavirus Infections. Berlin, Heidelberg: Springer; 1990: 379–391
  • 15 Lazear HM, Schoggins JW, Diamond MS. Shared and distinct functions of type I and type III interferons. Immunity 2019; 50: 907-923
    CrossrefPubMedGoogle Scholar
  • 16 Hündgen M, von Eick H. Interferone. Grundlagen und Anwendung in Klinik und Praxis. Med Monatsschr Pharm 1991; 14: 164-173
    PubMedGoogle Scholar
  • 17 Friedman RM. Clinical uses of interferons. Br J Clin Pharmacol 2007; 65: 158-162
    PubMedGoogle Scholar
  • 18 Antonelli G, Scagnolari C, Moschella F. et al. Twenty-five years of type I interferon-based treatment: a critical analysis of its therapeutic use. Cytokine Growth Factor Rev 2015; 26: 121-131
    CrossrefPubMedGoogle Scholar
  • 19 Li SF, Gong MJ, Zhao FR. et al. Type I interferons: distinct biological activities and current applications for viral infection. Cell Physiol Biochem 2018; 51: 2377-2396
    CrossrefPubMedGoogle Scholar
  • 20 Stewart WE. The Interferon System. Wien, New York: Springer; 1981
    Google Scholar
  • 21 Brzoska J. Interferon gamma in cinical use: review of indications. In: Hollenberg CP, Sahm H, Eds. Therpeutics, Diagnostics, New Vaccines, Interferon Treatment and Plasma Proteins (BIOTEC 4). Stuttgart, Jena, New York: Gustav Fischer; 1992: 109–115
  • 22 Obert HJ, Pöhlau D. Beta-Interferon. Schwerpunkt Multiple Sklerose. Berlin, Heidelberg, New York: Springer; 2000
    Google Scholar
  • 23 Borden EC, Sen GC, Uze G. et al. Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov 2007; 6: 975-990
    CrossrefPubMedGoogle Scholar
  • 24 Bracarda S, Eggermont AM, Samuelsson J. Redefining the role of interferon in the treatment of malignant diseases. Eur J Cancer 2010; 46: 284-297
    CrossrefPubMedGoogle Scholar
  • 25 Ni L, Lu J. Interferon gamma in cancer immunotherapy. Cancer Med 2018; 7: 4509-4516
    CrossrefPubMedGoogle Scholar
  • 26 Aricò E, Castiello L, Capone I. et al. Type I interferons and cancer: an evolving story demanding novel clinical applications. Cancers 2019; 11: 1943
    CrossrefPubMedGoogle Scholar
  • 27 Bocci V. Pharmacokinetics of interferons and routes of administration. In: Baron S, Coppenhaver DH, Dianzani F, Fleischmann Jr WR, Hughes TK, Klimpel GR, Niesel DW, Stanton GJ, Tyring SK, Eds. Interferon: principles and Medical Applications. Galveston, TX: The University of Texas Medical Branch at Galveston Department of Microbiology; 1992: 417–425
  • 28 Mühl H, Pfeilschifter J. Anti-inflammatory properties of pro-inflammatory interferon-γ. Int Immunopharmacol 2003; 3: 1247-1255
    CrossrefPubMedGoogle Scholar
  • 29 Hündgen M. Pharmakologie der Interferone -alpha, -beta und -gamma. In: Schmoll HJ, Schöpf E, Eds. Lokale und systemische Tumortherapie mit Interferonen (Aktuelle Immunologie 5). München, Bern, Wien, San Francisco: W Zuckschwerdt; 1988: 5–16
  • 30 Hündgen M, von Eick H. Pharmakologie von Interferonen (IFN-α, IFN-β, IFN-γ). In: Orfanos CE, Garbe C, Eds. Das maligne Melanom der Haut. München, Bern, Wien, San Francisco: W Zuckschwerdt; 1990: 243–247
  • 31 Fierlbeck G, Schiebel U, Bruchelt G. et al. Pharmacokinetic and immunological investigations in patients treated with recombinant interferon beta. J Interferon Res 1990; 10 (Suppl. 01) 126(Abstract)
    PubMedGoogle Scholar
  • 32 Fierlbeck G, d'Hoedt B, Stroebel W. et al. Intraläsionale Therapie von Melanommetastasen mit rekombinantem Interferon-β. Hautarzt 1992; 43: 16-21
    PubMedGoogle Scholar
  • 33 Fierlbeck G, Ulmer A, Schreiner T. et al. Pharmacodynamics of recombinant IFN-β during long-term treatment of malignant melanoma. J Interferon Cytokine Res 1996; 16: 777-781
    CrossrefPubMedGoogle Scholar
  • 34 Foster GR. Review article: pegylated interferons: chemical and clinical differences. Aliment Pharmacol Ther 2004; 20: 825-830
    CrossrefPubMedGoogle Scholar
  • 35 Cocco E, Marrosu MG. Profile of PEGylated interferon beta in the treatment of relapsing-remitting multiple sclerosis. Ther Clin Risk Manag 2015; 11: 759-766
    PubMedGoogle Scholar
  • 36 Brzoska J. Topische Interferonpräparationen bei dermatologischen Erkrankungen. In: Gross G, Bröcker EB, Eds. Interferon-Therapie in der Dermatologie (Aktuelle Immunologie 11). München, Bern, Wien, San Francisco: W Zuckschwerdt; 1994: 1–9
  • 37 Cinatl J, Morgenstern B, Bauer G. et al. Treatment of SARS with human interferons. Lancet 2003; 362: 293-294
    CrossrefPubMedGoogle Scholar
  • 38 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
    PubMedGoogle Scholar
  • 39 Haagmans BL, Kuiken T, Martina BE. et al. Pegylated interferon-α protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat Med 2004; 10: 290-293
    CrossrefPubMedGoogle Scholar
  • 40 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: 1003-1011
    PubMedGoogle Scholar
  • 41 Spiegel M, Pichlmair A, Mühlberger E. et al. The antiviral effect of interferon-beta against SARS-coronavirus is not mediated by MxA protein. J Clin Virol 2004; 30: 211-213
    CrossrefPubMedGoogle Scholar
  • 42 Zheng B, He ML, Wong KL. et al. Potent inhibition of SARS-associated coronavirus (SCoV) infection and replication by type I interferons (IFN-α/β) but not by type II interferon (IFN-γ). J Interferon Cytokine Res 2004; 24: 388-390
    CrossrefPubMedGoogle Scholar
  • 43 Ströher U, DiCaro A, Li Y. et al. Severe acute respiratory syndrome-related coronavirus is inhibited by interferon-α. J Infect Dis 2004; 189: 1164-1167
    CrossrefPubMedGoogle Scholar
  • 44 Morgenstern B, Michaelis M, Baer PC. et al. Ribavirin and interferon-β synergistically inhibit SARS-associated coronavirus replication in animal and human cell lines. Biochem Biophys Res Commun 2005; 326: 905-908
    CrossrefPubMedGoogle Scholar
  • 45 Dahl H, Linde A, Strannegård Ö. In vitro inhibition of SARS virus replication by human interferons. Scand J Infect Dis 2004; 36: 829-831
    CrossrefPubMedGoogle Scholar
  • 46 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
    CrossrefPubMedGoogle Scholar
  • 47 Falzarano D, de Wit E, Rasmussen AL. et al. Interferon-α2b and ribavirin treatment improves outcome in MERS-CoV-infected rhesus macaques. Nat Med 2013; 19: 1313-1317
    CrossrefPubMedGoogle Scholar
  • 48 Chan JFW, Chan KH, Kao RYT. et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect 2013; 67: 606-616
    CrossrefPubMedGoogle Scholar
  • 49 Chan JFW, 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: 1904-1913
    CrossrefPubMedGoogle Scholar
  • 50 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: 571-577
    CrossrefPubMedGoogle Scholar
  • 51 Li HS, Kuok DIT, Cheung MC. et al. Effect of interferon alpha and cyclosporine treatment separately and in combination on Middle East respiratory syndrome coronavirus (MERS-CoV) replication in a human in-vitro and ex-vivo culture model. Antiviral Res 2018; 155: 89-96
    CrossrefPubMedGoogle Scholar
  • 52 Channappanavar R, Fehr AR, Zheng J. et al. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest 2019; 129: 3625-3639
    CrossrefPubMedGoogle Scholar
  • 53 Sheahan TP, Sims AC, Leist SR. et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020; 11: 222 DOI: doi.org/10.1038/s41467-019-13940-6.
    CrossrefPubMedGoogle Scholar
  • 54 Loutfy MR, Blatt LM, Siminovitch KA. et al. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study. JAMA 2003; 290: 3222-3228
    CrossrefPubMedGoogle Scholar
  • 55 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: 715-720
    CrossrefPubMedGoogle Scholar
  • 56 Al-Tawfiq JA, Momattin H, Dib J. et al. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. Int J Infect Dis 2014; 20: 42-46
    CrossrefPubMedGoogle Scholar
  • 57 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: 2129-2132
    CrossrefPubMedGoogle Scholar
  • 58 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; 14: 1090-1095
    CrossrefPubMedGoogle Scholar
  • 59 Arabi YM, Alothman A, Balkhy HH. et al. Treatment of Middle East respiratory syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial. Trials 2018; 19: 81
    CrossrefPubMedGoogle Scholar
  • 60 Cheng VCC, Tang BSF, Wu AKL. et al. Medical treatment of viral pneumonia including SARS in immunocompetent adult. J Infect 2004; 49: 262-273
    CrossrefPubMedGoogle Scholar
  • 61 Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med 2006; 3: e343 doi: 10.1371/journal.pmed.0030343
    CrossrefPubMedGoogle Scholar
  • 62 Wong SSY, Yuen KY. The management of coronavirus infections with particular reference to SARS. J Antimicrob Chemother 2008; 62: 437-441
    CrossrefPubMedGoogle Scholar
  • 63 Morra ME, Van Thanh L, Kamel MG. et al. Clinical outcomes of current medical approaches for Middle East respiratory syndrome: a systematic review and meta-analysis. Rev Med Virol 2018; 28: e1977
    CrossrefPubMedGoogle Scholar
  • 64 Momattin H, Al-Ali AY, Al-Tawfiq JA. A systematic review of therapeutic agents for the treatment of the Middle East respiratory syndrome coronavirus (MERS-CoV). Travel Med Infect Dis 2019; 30: 9-18
    CrossrefPubMedGoogle Scholar
  • 65 Merigan TC, Rand KH, Pollard RB. et al. Human leukocyte interferon for the treatment of herpes zoster in patients with cancer. N Engl J Med 1978; 298: 981-987
    CrossrefPubMedGoogle Scholar
  • 66 Merigan TC, Gallagher JG, Pollard RB. et al. Short-course human leukocyte interferon in treatment of herpes zoster in patients with cancer. Antimicrob Agents Chemother 1981; 19: 193-195
    CrossrefPubMedGoogle Scholar
  • 67 Heidemann E, Obert HJ. Clinical trials and pilot studies with natural interferons in Germany. In: Kirchner H, Schellekens H, Eds. The biology of the Interferon System 1984. Amsterdam, New York, Oxford: Elsevier; 1985: 557–567
  • 68 Haagmans BL, Osterhaus ADME. Coronaviruses and their therapy. Antiviral Res 2006; 71: 397-403
    CrossrefPubMedGoogle Scholar
  • 69 Domke-Opitz I, Straub P, Kirchner H. Effect of interferon on replication of herpes simplex virus types 1 and 2 in human macrophages. J Virol 1986; 60: 37-42
    CrossrefPubMedGoogle Scholar
  • 70 Heidemann E, Wilms K, Treuner J. et al. Fibroblasten-Interferon zur Behandlung des Herpes zoster. Eine Pilotstudie. Dtsch Med Wochenschr 1982; 107: 695-697
    Article in Thieme ConnectPubMedGoogle Scholar
  • 71 Heidemann E, Dietz K, Obert HJ. et al. Günstigerer Verlauf des Herpes zoster bei immunsupprimierten Patienten unter Behandlung mit Fibroblasteninterferon. Onkologie 1984; 7: 210-212
    PubMedGoogle Scholar
  • 72 Hündgen M. Klinische Erfahrungen mit natürlichem Interferon-beta. In: Hofschneider PH, Ed. Ergebnisse der Beta-Interferon-Therapie bei chronisch-aktiver Hepatitis B, Multipler Sklerose und Krebserkrankungen (Aktuelle Immunologie 3). München, Bern, Wien, San Francisco: W Zuckschwerdt; 1988: 45–50
  • 73 Wintergerst U, Belohradsky BH. Acyclovir monotherapy versus acyclovir plus beta-interferon in focal viral encephalitis in children. Infection 1992; 20: 207-212
    CrossrefPubMedGoogle Scholar
  • 74 Wintergerst U, Kugler K, Harms F. et al. Therapy of focal viral encephalitis in children with aciclovir and recombinant beta-interferon - results of a placebo-controlled multicenter study. Eur J Med Res 2005; 10: 527-531
    PubMedGoogle Scholar
  • 75 Daniels BP, Klein RS. Knocking on closed doors: host interferons dynamically regulate blood-brain barrier function during viral infections of the central nervous system. PLoS Pathog 2015; 11: e1005096
    CrossrefPubMedGoogle Scholar
  • 76 Bhat H, Lang KS, Hardt C. et al. Interferon in the CNS. Neurosignals 2019; 27 (Suppl. 01) 44-53
    CrossrefPubMedGoogle Scholar
  • 77 Antonetti F, Finocchiaro O, Mascia M. et al. A comparison of the biologic activity of two recombinant IFN-beta preparations used in the treatment of relapsing-remitting multiple sclerosis. J Interferon Cytokine Res 2002; 22: 1181-1184
    CrossrefPubMedGoogle Scholar
  • 78 Scagnolari C, Selvaggi C, Di Biase E. et al. In vitro assessment of the biologic activity of interferon beta formulations used for the treatment of relapsing multiple sclerosis. J Immunoassay Immunochem 2014; 35: 288-299
    CrossrefPubMedGoogle Scholar
  • 79 Huang C, Wang Y, Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497-506
    CrossrefPubMedGoogle Scholar
  • 80 Guo L, Wei D, Zhang X. et al. Clinical features predicting mortality risk in patients with viral pneumonia: the MuLBSTA score. Front Microbiol 2019; 10 DOI: 10.3389/fmicb.2019.02752.
    CrossrefPubMedGoogle Scholar
  • 81 Ward SE, Loutfy MR, Blatt LM. et al. Dynamic changes in clinical features and cytokine/chemokine responses in SARS patients treated with interferon alfacon-1 plus corticosteroids. Antivir Ther 2005; 10: 263-275
    PubMedGoogle Scholar
  • 82 Kindler E, Thiel V. SARS-CoV and IFN: too little, too late. Cell Host & Microbe 2016; 19: 139-141
    CrossrefPubMedGoogle Scholar
  • 83 Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017; 39: 529-539
    CrossrefPubMedGoogle Scholar
  • 84 Xu Z, Shi L, Wang Y. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; DOI: doi.org/10.1016/S2213-2600(20)30076-X.
    CrossrefPubMedGoogle Scholar
  • 85 Kieseier BC. The mechanism of action of interferon-β in relapsing multiple sclerosis. CNS Drugs 2011; 25: 491-502
    CrossrefPubMedGoogle Scholar
  • 86 Kowalzick L, Rogozinski T, Schober C. et al. Treatment of basal cell carcinoma with intralesional recombinant interferon beta: a dose-finding study. Eur J Dermatol 1994; 4: 430-433
    PubMedGoogle Scholar
  • 87 Totura AL, Bavari S. Broad-spectrum coronavirus antiviral drug discovery. Expert Opin Drug Discov 2019; 14: 397-412
    CrossrefPubMedGoogle Scholar