Clinical application of interferon gamma in comprehensive therapy of patients with coronavirus infection

Abstract

Background. The problem of effective therapy of coronavirus disease 2019 (COVID-19) at the hospital stage requires urgent resolution. Studies on the role of interferons in the immune response finding showed that interferon gamma is a potent endogenous regulatory cytokine that activates an antiviral immune response while simultaneously exerting its intrinsic antiviral activity, which promises new horizons for effective therapeutic care of patients with COVID-19.

The present study aimed to evaluate the efficacy and safety of complex therapy using interferon gamma 500,000 IU when administered subcutaneously to patients with viral pneumonia.

Material and methods. This prospective, open-labeled, randomized-controlled, single-center, investigator-initiated study included patients aged >18 years with mild COVID-19. The study agent interferon gamma was prescribed for therapeutic purposes at a dose of 500,000 IU subcutaneously once daily for 5 days.

Results. A superior efficacy of therapy with the study agent was noted. A statistically significant difference was observed with reference to the World Health Organization scale for Clinical Improvement when assessed 14 days after the therapy (p=0.024), with a higher patient survival rate (p=0.039). A comparative analysis of the changes showed a statistically significant difference between the groups with respect to the change in the levels of laboratory parameters of lactate dehydrogenase and C-reactive protein, which reflected the degree of damage and inflammation of the lung tissues.

Discussion. Past studies demonstrated the therapeutic efficacy of interferon gamma for coronavirus infection and community-acquired pneumonia. The present clinical experience confirms the past data on the positive effect of interferon gamma on the rate of clinical stabilization and recovery of patients.

Conclusion. Interferon gamma can be recommended for medical use in the complex therapy of patients with moderate COVID-19.

Keywords

interferon gamma / SARS virus / COVID-19 / viral pneumonia

References

[1] Yamin M. Counting the cost of COVID-19. Int J Inf Technol. 2020;12(2):311–317. doi: 10.1007/s41870-020-00466-0.

[2] Yamin M. Counting the cost of COVID-19 // Int J Inf Technol. 2020. Vol. 12, N 2. P. 311–317. doi: 10.1007/s41870-020-00466-0.

[3] Drosten C, Preiser W, Gunther S, et al. Severe acute respiratory syndrome: identification of the etiological agent. Trends Mol Med. 2003;9(8):325–327. doi: 10.1016/s1471-4914(03)00133-3.

[4] Drosten C., Preiser W., Gunther S., et al. Severe acute respiratory syndrome: identification of the etiological agent // Trends Mol Med. 2003. Vol. 9, N 8. P. 325–327. doi: 10.1016/s1471-4914(03)00133-3.

[5] Shchelkanov MY, Popova AY, Dedkov VG, et al. History of investigation and current classification of coronaviruses (nidovirales: coronaviridae). Infektsiia Immun. 2020;10(2):221–246. (In Russ). doi: 10.15789/2220-7619-HOI-1412.

[6] Щелканов М.Ю., Попова А.Ю., Дедков В.Г., и др. История изучения и современная классификация коронавирусов // Инфекция и иммунитет. 2020. Т. 10, № 2. С. 221–246. doi: 10.15789/2220-7619-HOI-1412.

[7] Singhal T. A Review of Coronavirus Disease-2019 (COVID-19). Indian J Pediatr. 2020;87(4):281–286. doi: 10.1007/s12098-020-03263-6.

[8] Singhal T. A Review of Coronavirus Disease-2019 (COVID-19) // Indian J Pediatr. 2020. Vol. 87, N 4. P. 281–286. doi: 10.1007/s12098-020-03263-6.

[9] Rockx B, Kuiken T, Herfst S, et al. Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model. Science. 2020;368(6494):1012–1015. doi: 10.1126/science.abb7314.

[10] Rockx B., Kuiken T., Herfst S., et al. Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model // Science. 2020. Vol. 368, N 6494. P. 1012–1015. doi: 10.1126/science.abb7314.

[11] Kimball A, Hatfield KM, Arons M, et al. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility – King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep. 2020;69(13):377–381. doi: 10.15585/mmwr.mm6913e1.

[12] Kimball A., Hatfield K.M., Arons M., et al. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility – King County, Washington, March 2020 // MMWR Morb Mortal Wkly Rep. 2020. Vol. 69, N. 13. P. 377–381. doi: 10.15585/mmwr.mm6913e1.

[13] Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. doi: 10.1016/S0140-6736(20)30183-5.

[14] Huang C., Wang Y., Li X., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China // Lancet. 2020. Vol. 395, N 10223. P. 497–506. doi: 10.1016/S0140-6736(20)30183-5.

[15] Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020;20(4):425–434. doi: 10.1016/S1473-3099(20)30086-4.

[16] Shi H., Han X., Jiang N., et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study // Lancet Infect Dis. 2020. Vol. 20, N 4. P. 425–434. doi: 10.1016/S1473-3099(20)30086-4.

[17] Ware LB, Matthay MA. The acute respiratory distress syndrome. New England Journal of Medicine. 2000;342(18):1334–1349. doi: 10.1056/NEJM200005043421806.

[18] Ware L.B., Matthay M.A. The acute respiratory distress syndrome // N Engl J Med. 2000. Vol. 342, N 18. P. 1334–1349. doi: 10.1056/NEJM200005043421806.

[19] Nikiforov VV, Suranova TG, Mironov AY, Zabozlaev FG. New coronavirus infection (COVID-19): etiology, epidemiology, clinic, diagnosis, treatment and prevention. Moscow: Akademiya postdiplomnogo obrazovaniya FGBU «FNKTs FMBA Rossii»; 2020. (In Russ).

[20] Никифоров В.А, Суранова Т.Г., Миронов А.Ю., Забозлаев Ф.Г. Новая коронавирусная инфекция (COVID-١٩): этиология, эпидемиология, клиника, диагностика, лечение и профилактика Учебно-методическое пособие. Москва: Академия постдипломного образования ФГБУ «ФНКЦ ФМБА России», ٢٠٢٠.

[21] Gorbalenya AE, Baker SC, Baric R, et al. Severe acute respiratory syndrome-related coronavirus: The species and its viruses–a statement of the Coronavirus Study Group. BioRxiv. 2020.

[22] Gorbalenya A.E., Baker S.C., Baric R., et al. Severe acute respiratory syndrome-related coronavirus: The species and its viruses–a statement of the Coronavirus Study Group // BioRxiv. 2020.

[23] Zou L, Ruan F, Huang M, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med. 2020;382(12):1177–1179. doi: 10.1056/NEJMc2001737.

[24] Zou L., Ruan F., Huang M., et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients // N Engl J Med. 2020. Vol. 382, N 12. P. 1177–1179. doi: 10.1056/NEJMc2001737.

[25] Peiris JS, Chu CM, Cheng VC, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003;361(9371):1767–1772. doi: 10.1016/s0140-6736(03)13412-5.

[26] Peiris J.S., Chu C.M., Cheng V.C., et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study // Lancet. 2003. Vol. 361, N 9371. P. 1767–1772. doi: 10.1016/s0140-6736(03)13412-5.

[27] Xiao F, Tang M, Zheng X, et al. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology. 2020;158(6):1831–1833. doi: 10.1053/j.gastro.2020.02.055.

[28] Xiao F., Tang M., Zheng X., et al. Evidence for Gastrointestinal Infection of SARS-CoV-2 // Gastroenterology. 2020. Vol. 158, N 6. P. 1831–1833. doi: 10.1053/j.gastro.2020.02.055.

[29] Wolfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020; 581(7809):465–469. doi: 10.1038/s41586-020-2196-x.

[30] Wolfel R., Corman V.M., Guggemos W., et al. Virological assessment of hospitalized patients with COVID-2019 // Nature. 2020. Vol. 581, N 7809. P. 465–469. doi: 10.1038/s41586-020-2196-x.

[31] Kang H, Wang Y, Tong Z, Liu X. Retest positive for SARS-CoV-2 RNA of “recovered” patients with COVID-19: Persistence, sampling issues, or re-infection? J Med Virol. 2020;92(11):2263–2265. doi: 10.1002/jmv.26114.

[32] Kang H., Wang Y., Tong Z., Liu X. Retest positive for SARS-CoV-2 RNA of “recovered” patients with COVID-19: Persistence, sampling issues, or re-infection? // J Med Virol. 2020. Vol. 92, N 11. P. 2263–2265. doi: 10.1002/jmv.26114.

[33] Smetanina SV, Nikiforov VV, Kolobukhina LV, et al. New coronavirus infection (COVID-19): etiology, epidemiology, clinic, diagnosis, treatment and prevention. Moscow: Pravitel’stvo Moskvy, Departament Zdravookhraneniya goroda Moskvy; 2020. (In Russ).

[34] Сметанина С.В., Никифоров В.В., Колобухина Л.В., и др. Новая коронавирусная инфекция (COVID-١٩): этиология, эпидемиология, клиника, диагностика, лечение и профилактика. Москва: Правительство Москвы, Департамент здравоохранения города Москвы, 2020.

[35] 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(10223):507–513. doi: 10.1016/S0140-6736(20)30211-7.

[36] 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. Vol. 395, N 10223. P. 507–513. doi: 10.1016/S0140-6736(20)30211-7.

[37] Lee AJ, Ashkar AA. The Dual Nature of Type I and Type II Interferons. Front Immunol. 2018;9:2061. doi: 10.3389/fimmu.2018.02061.

[38] Lee A.J., Ashkar A.A. The Dual Nature of Type I and Type II Interferons // Front Immunol. 2018. Vol. 9, P. 2061. doi: 10.3389/fimmu.2018.02061.

[39] Wijdeven RH, van Luijn MM, Wierenga-Wolf AF, et al. Chemical and genetic control of IFNgamma-induced MHCII expression. EMBO Rep. 2018;19(9):e45553. doi: 10.15252/embr.201745553.

[40] Wijdeven R.H., van Luijn M.M., Wierenga-Wolf A.F., et al. Chemical and genetic control of IFNgamma-induced MHCII expression // EMBO Rep. 2018. Vol. 19, N 9. P. e45553. doi: 10.15252/embr.201745553.

[41] Sologub TV, Golobokov GS, Tsvetkov VV, Tokin II. Interferon-gamma in the treatment of influenza and other respiratory viral infections. Meditsinskii sovet. 2015;(7):54–48. (In Russ).

[42] Сологуб Т.В., Голобоков Г.С., Цветков В.В., Токин И.И. Интерферон-гамма в терапии гриппа и других респираторных вирусных инфекций // Медицинский совет. 2015. № 7. С. 54–48.

[43] Nikiforov VV, Sologub TV, Tokin II, et al. Possibility of using interferon-γ for influenza infection. Epidemiology and infectious diseases. 2015;20(3):11–16. (In Russ).

[44] Никифоров В.В., Сологуб Т.В., Токин И.И., и др. Возможность использования интерферона-γ при гриппозной инфекции // Эпидемиология и инфекционные болезни. 2015. Т. 20, № 3. С. 11–16.

[45] Sologub TV, Midikari AS, Agafonov VN, et al. Efficiency and expediency of using recombinant interferon-gamma in the complex therapy of patients with influenza A (H1N1) PDM09. Epidemiology and infectious diseases. 2017;22(2):58–63. (In Russ).

[46] Сологуб Т.В., Мидикари А.С., Агафонов В.Н., и др. Эффективность и целесообразность использования рекомбинантного интерферона-гамма в комплексной терапии больных гриппом A(H1N1)PDM09 // Эпидемиология и инфекционные болезни. 2017. Т. 22, № 2. С. 58–63.

[47] Estimating mortality from COVID-19. Scientific brief 4 August 2020. WHO reference number: WHO/2019-nCoV/Sci_Brief/Mortality/2020.1. Available at: https://www.who.int/publications/i/item/WHO-2019-nCoV-Sci-Brief-Mortality-2020.1. Accessed: December 18, 2020.

[48] Ministerstvo Zdravookhraneniya Rossiiskoi Federatsii. Vremennye metodicheskie rekomendatsii Profilaktika, diagnostika i lechenie novoi koronavirusnoi infektsii (COVID-19). Versiya 5 (08.04.2020). Available from: https://static-2.rosminzdrav.ru/system/attachments/attaches/000/049/949/original/%D0%92%D1%80%D0%B5%D0%BC%D0%B5%D0%BD%D0%BD%D1%8B%D0%B5_%D0%9C%D0%A0_COVID-19_%D0%B2%D0%B5%D1%80%D1%81%D0%B8%D1%8F_5.pdf. Accessed: Dec 18, 2020. (In Russ).

[49] Министерство здравоохранения Российской Федерации. Временные методические рекомендации Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19). Версия 5 (08.04.2020). Режим доступа: https://static-2.rosminzdrav.ru/system/attachments/attaches/000/049/949/original/%D0%92%D1%80%D0%B5%D0%BC%D0%B5%D0%BD%D0%BD%D1%8B%D0%B5_%D0%9C%D0%A0_COVID-19_%D0%B2%D0%B5%D1%80%D1%81%D0%B8%D1%8F_5.pdf. Дата обращения: 18.12.2020.

[50] Ministerstvo Zdravookhraneniya Rossiiskoi Federatsii; Vremennye metodicheskie rekomendatsii Profilaktika, diagnostika i lechenie novoi koronavirusnoi infektsii (COVID-19); Versiya 6 (28.04.2020). Available from: http://profilaktika.su/vremennye-metodicheskie-rekomendatsii-minzdrava-rossii-koronavirus-2019-ncov-6-versiya/. Accessed: Dec 18, 2020. (In Russ).

[51] Министерство здравоохранения Российской Федерации; Временные методические рекомендации Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19); Версия 6 (28.04.2020). Режим доступа: http://profilaktika.su/vremennye-metodicheskie-rekomendatsii-minzdrava-rossii-koronavirus-2019-ncov-6-versiya/. Дата обращения: 18.12.2020.

[52] Sologub TV, Midikari AS, Agafonov VN, et al. Efficiency and performance of the use of recombinant interferon gamma in complex therapy of influenza A(H1N1)PDM09 patients. Epidemiology and infectious diseases. 2017;22(2):58–63. (In Russ).

[53] Сологуб Т.В., Мидикари А.С., Агафонов В.Н., и др. Эффективность и целесообразность использования рекомбинантного интерферона-гамма в комплексной терапии больных гриппом A(H1N1)PDM09 // Эпидемиология и инфекционные болезни. 2017. Т. 22, № 2. С. 58–63.

[54] Lu H. Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci Trends. 2020;14(1):69–71. doi: 10.5582/bst.2020.01020.

[55] Lu H. Drug treatment options for the 2019-new coronavirus (2019-nCoV) // Biosci Trends. 2020. Vol. 14, N 1. P. 69–71. doi: 10.5582/bst.2020.01020.

[56] Zhang L, Liu Y. Potential interventions for novel coronavirus in China: A systematic review. J Med Virol. 2020;92(5):479–490. doi: 10.1002/jmv.25707.

[57] Zhang L., Liu Y. Potential interventions for novel coronavirus in China: A systematic review // J Med Virol. 2020. Vol. 92, N 5. P. 479–490. doi: 10.1002/jmv.25707.

[58] Cai Q, Yang M, Liu D, et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering (Beijing). 2020;6(10):1192–1198. doi: 10.1016/j.eng.2020.03.007.

[59] Cai Q., Yang M., Liu D., et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study // Engineering (Beijing). 2020. Vol. 6, N 10. P. 1192–1198. doi: 10.1016/j.eng.2020.03.007.

[60] Wang JB, Wang ZX, Jing J, et al. Exploring an Integrative Therapy for Treating COVID-19: A Randomized Controlled Trial. Chin J Integr Med. 2020;26(9):648–655. doi: 10.1007/s11655-020-3426-7.

[61] Wang J.B., Wang Z.X., Jing J., et al. Exploring an Integrative Therapy for Treating COVID-19: A Randomized Controlled Trial // Chin J Integr Med. 2020. Vol. 26, N 9. P. 648–655. doi: 10.1007/s11655-020-3426-7.

[62] Demidowich AP, Levine JA, Apps R, et al. Colchicine’s effects on metabolic and inflammatory molecules in adults with obesity and metabolic syndrome: results from a pilot randomized controlled trial. Int J Obes (Lond). 2020;44(8):1793–1799. doi: 10.1038/s41366-020-0598-3.

[63] Demidowich A.P., Levine J.A., Apps R., et al. Colchicine’s effects on metabolic and inflammatory molecules in adults with obesity and metabolic syndrome: results from a pilot randomized controlled trial // Int J Obes (Lond). 2020. Vol. 44, N 8. P. 1793–1799. doi: 10.1038/s41366-020-0598-3.

[64] Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial. JAMA Netw Open. 2020;3(6):e2013136. doi: 10.1001/jamanetworkopen.2020.13136.

[65] Deftereos S.G., Giannopoulos G., Vrachatis D.A., et al. Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial // JAMA Netw Open. 2020. Vol. 3, N 6. P. e2013136. doi: 10.1001/jamanetworkopen.2020.13136.

[66] Hung IF-N, Lung K-C, Tso EY-K, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020;395(10238):1695–1704. doi: 10.1016/s0140-6736(20)31042-4.

[67] Hung I.F.-N., Lung K.-C., Tso E.Y.-K., et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial // Lancet. 2020. Vol. 395, N 10238. P. 1695–1704. doi: 10.1016/s0140-6736(20)31042-4.

[68] Tokin I, Nikiforov V, Shabalkin P, et al. Randomized Controlled Parallel-Design Clinical Study of the Efficacy and Safety of Intranasal Interferon gamma in Treatment of Influenza-Like Infections. International Journal of Biomedicine. 2018;8(4):327–332. doi: 10.21103/Article8(4)_OA12.

[69] Tokin I., Nikiforov V., Shabalkin P., et al. Randomized Controlled Parallel-Design Clinical Study of the Efficacy and Safety of Intranasal Interferon gamma in Treatment of Influenza-Like Infections // International Journal of Biomedicine. 2018. Vol. 8, N 4. P. 327–332. doi: 10.21103/Article8(4)_OA12.

[70] Belevskii AS, Berns SA, Lartseva OA, et al. The efficacy and safety of gamma-interferon in the treatment of community-acquired pneumonia: results of the open randomized trial IN/100000-317. Meditsina. 2019;7(4):110–125. (In Russ). doi: 10.29234/2308-9113-2019-7-4-110-125.

[71] Белевский А.С., Бернс С.А., Ларцева О.А., и др. Эффективность и безопасность гаммаинтерферона при лечении внебольничной пневмонии: результаты открытого рандомизированного исследования IN/١٠٠٠٠٠-٣١٧ // Медицина. 2019. Т. 7, № 4. С. 110–125. doi: 10.29234/2308-9113-2019-7-4-110-125.

[72] Costa-Pereira AP, Williams TM, Strobl B, et al. The antiviral response to gamma interferon. J Virol. 2002;76(18):9060–9068. doi: 10.1128/jvi.76.18.9060-9068.2002.

[73] Costa-Pereira A.P., Williams T.M., Strobl B., et al. The antiviral response to gamma interferon // J Virol. 2002. Vol. 76, N 18. P. 9060–9068. doi: 10.1128/jvi.76.18.9060-9068.2002.

[74] Rhein BA, Powers LS, Rogers K, et al. Interferon-gamma Inhibits Ebola Virus Infection. PLoS Pathog. 2015;11(11):e1005263. doi: 10.1371/journal.ppat.1005263.

[75] Rhein B.A., Powers L.S., Rogers K., et al. Interferon-gamma Inhibits Ebola Virus Infection // PLoS Pathog. 2015. Vol. 11, N 11. P. e1005263. doi: 10.1371/journal.ppat.1005263.

[76] Sologub TV, Tokin II, Tsvetkov VV, Deeva EG. Possibilities of using interferon-gamma in complex therapy of patients with chronic hepatitis C. Infectious diseases. 2013;11(2):74–80. (In Russ).

[77] Сологуб Т.В., Токин И.И., Цветков В.В., Деева Э.Г. Возможности использования интерферона-гамма в комплексной терапии больных хроническим гепатитом C // Инфекционные болезни. 2013. Т. 11, № 2. С. 74–80.

[78] Shan L, Fu F, Xue M, et al. Interferon gamma inhibits transmissible gastroenteritis virus infection mediated by an IRF1 signaling pathway. Arch Virol. 2019;164(11):2659–2669. doi: 10.1007/s00705-019-04362-2.

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