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
› Institutsangaben

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.



Publikationsverlauf

Eingereicht: 24. März 2020

Angenommen: 29. April 2020

Artikel online veröffentlicht:
22. Mai 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
  • 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
  • 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.
  • 4 Mahase E. Coronavirus: covid-19 has killed more people than SARS and MERS combined, despite lower case fatality rate. BMJ 2020; 368: m641
  • 5 Zumla A, Chan JF, Azhar EI. et al. Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov 2016; 15: 327-347
  • 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.
  • 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
  • 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
  • 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
  • 11 Trinchieri G. Type I interferon: Friend or foe?. J Exp Med 2010; 207: 2053-2063
  • 12 Totura AL, Baric RS. SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon. Curr Opin Virol 2012; 2: 264-275
  • 13 Brzoska J, Obert HJ. Interferon gamma: ein janusköpfiger Mediator bei Entzündungen. Drug Res 1987; 37: 1410-1416
  • 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
  • 16 Hündgen M, von Eick H. Interferone. Grundlagen und Anwendung in Klinik und Praxis. Med Monatsschr Pharm 1991; 14: 164-173
  • 17 Friedman RM. Clinical uses of interferons. Br J Clin Pharmacol 2007; 65: 158-162
  • 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
  • 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
  • 20 Stewart WE. The Interferon System. Wien, New York: Springer; 1981
  • 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
  • 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
  • 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
  • 25 Ni L, Lu J. Interferon gamma in cancer immunotherapy. Cancer Med 2018; 7: 4509-4516
  • 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
  • 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
  • 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)
  • 32 Fierlbeck G, d'Hoedt B, Stroebel W. et al. Intraläsionale Therapie von Melanommetastasen mit rekombinantem Interferon-β. Hautarzt 1992; 43: 16-21
  • 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
  • 34 Foster GR. Review article: pegylated interferons: chemical and clinical differences. Aliment Pharmacol Ther 2004; 20: 825-830
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 61 Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med 2006; 3: e343 doi: 10.1371/journal.pmed.0030343
  • 62 Wong SSY, Yuen KY. The management of coronavirus infections with particular reference to SARS. J Antimicrob Chemother 2008; 62: 437-441
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 76 Bhat H, Lang KS, Hardt C. et al. Interferon in the CNS. Neurosignals 2019; 27 (Suppl. 01) 44-53
  • 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
  • 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
  • 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
  • 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.
  • 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
  • 82 Kindler E, Thiel V. SARS-CoV and IFN: too little, too late. Cell Host & Microbe 2016; 19: 139-141
  • 83 Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017; 39: 529-539
  • 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.
  • 85 Kieseier BC. The mechanism of action of interferon-β in relapsing multiple sclerosis. CNS Drugs 2011; 25: 491-502
  • 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
  • 87 Totura AL, Bavari S. Broad-spectrum coronavirus antiviral drug discovery. Expert Opin Drug Discov 2019; 14: 397-412