rmtОбщая реаниматологияGeneral Reanimatology1813-97792411-7110FSBI "SRIGR" RAMS10.15360/1813-9779-2020-4-0-1rmt-1987Research ArticleОБЗОРЫ И КРАТКИЕ СООБЩЕНИЯREVIEWS & SHORT COMMUNICATIONSЭтиотропная терапия COVID-19: критический анализ и перспективыCausal Therapy of COVID-19: Critical Review and ProspectsБелобородоваН. В.BeloborodovaN. V.

Наталья Владимировна Белобородова

107031, Москва, ул. Петровка, д. 25, стр. 2

Natalia V. Beloborodova

25 Petrovka Str., Bldg. 2, 107031 Moscow

nvbeloborodova@yandex.ruЗуевЕ. В.ZuevE. V.

107031, Москва, ул. Петровка, д. 25, стр. 2; Москва 105203, ул. Нижняя Первомайская, д. 70

Evgeniy V. Zuev

25 Petrovka Str., Bldg. 2, 107031 Moscow; 70 Nizhnyaya Pervomayskaya str., Moscow 105203

ЗамятинМ. Н.ZamyatinM. N.

Москва 105203, ул. Нижняя Первомайская, д. 70

Mikhail N. Zamyatin

70 Nizhnyaya Pervomayskaya str., Moscow 105203

ГусаровВ. Г.GusarovV. G.

Москва 105203, ул. Нижняя Первомайская, д. 70

Vitaliy G. Gusarov

70 Nizhnyaya Pervomayskaya str., Moscow 105203

НИИ общей реаниматологии им. В.А. Неговского ФНКЦ РРРоссияV.A. Negovsky Research Institute of General Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and RehabilitologyRussian FederationНИИ общей реаниматологии им. В.А. Неговского ФНКЦ РР; Национальный медико-хирургический центр им. Н.И. ПироговРоссияV.A. Negovsky Research Institute of General Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology; National Medical and Surgical Center named after N.I. PirogovRussian FederationНациональный медико-хирургический центр им. Н.И. ПироговРоссияNational Medical and Surgical Center named after N.I. PirogovRussian Federation2020301220201666590Copyright © Белобородова Н.В., Зуев Е.В., Замятин М.Н., Гусаров В.Г., 20202020Белобородова Н.В., Зуев Е.В., Замятин М.Н., Гусаров В.Г.Beloborodova N.V., Zuev E.V., Zamyatin M.N., Gusarov V.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.reanimatology.com/rmt/article/view/1987

Эпидемия COVID-19, начавшаяся в декабре 2019 года в Китае, за несколько месяцев распространилась на все страны мира, приняв характер пандемии, число заболевших исчисляется миллионами. Механизмы патогенеза новой коронавирусной инфекции, вызванной неизвестным ранее вирусом SARS-CoV2, остаются недостаточно изученными. Для лечения COVID-19 применяют препараты разных групп, по мере появления опыта рекомендации регулярно пересматриваются. В условиях текущей пандемии важно предоставить специалистам актуальную информацию об эффективности и безопасности лечебных препаратов, применяемых для лечения пациентов с COVID-19, и о перспективных исследованиях в этой области.

 

 

Цель обзора — критический анализ опубликованных результатов лечения COVID-19 с использованием различных групп препаратов для выбора наиболее перспективных лекарственных средств.

Поиск источников провели по базам данных PubMed, Scopus, Cyberleninka, Clinical Trials, Cochrane Library и др., рассматривали преимущественно рандомизированные клинические исследования 2020 года, а также работы по изучению препаратов-претендентов. Материал статьи структурирован по механизму действия препаратов, содержит разделы противовирусной, иммуномодулирующей, антибактериальной терапии. В поиске новой перспективной мишени в лечении COVID-19 концентрировали внимание на матриксных металлопротеиназах (ММР), избыток которых ведет к разрушению внеклеточного матрикса, базальных мембран эпителия и эндотелия, способствует вторичному повреждению легочной ткани. В работе теоретически обосновали применение ингибиторов MMP на примере доксициклина, предложили протокол исследования для оценки эффективности нового подхода к лечению COVID-19.

Заключение

Заключение. Лекарственных средств с доказанной эффективностью в отношении COVID 19 в настоящее время нет. Препараты с разными механизмами действия применяются не по показаниям, часто в комбинациях, в этих условиях трудно избежать суммирования побочных эффектов с неблагоприятными последствиями для пациента. Применение препаратов с недоказанной эффективностью оправдано лишь в рамках клинических исследований с последующим анализом и публикацией результатов, чтобы в случае успеха с уверенностью рекомендовать их большинству пациентов с COVID-19. Ключевые слова: COVID-19; противомалярийные средства; ингибиторы вирусных протеаз; противопаразитарные препараты; ингибиторы интерлейкинов; ингибиторы янус-киназ; интерфероны; плазма реконвалесцентов; кортикостероиды; прокальцитонин; антибиотики; новая мишень; матриксные металлопротеиназы, доксициклин.

The COVID-19 outbreak started in December 2019 in China has spread over all countries of the world within few month acquiring a pandemic nature, the incident population counting millions. The pathogenic mechanisms of the new coronaviral infection caused by never-before-seen virus SARS-CoV2 are yet to be studied. Various drugs are used for COVID-19 treatment and guidelines are continuously revised as new experience is acquired. In the current pandemic situation, it is important to provide specialists with latest information concerning efficacy and safety drugs for COVID-19 patients and promising research in this field.

The purpose of the review is to critically analyze published data on outcomes of COVID-19 treatment with various drugs including potentially promising drugs.

The search has been carried out through such databases as PubMed, Scopus, Cyberleninka, https://www.globalclinicaltrialsdata.com, https://clinicaltrials.gov, Cochrane Library; mostly, randomized clinical trials-2020 and papers dedicated to candidate drugs have been considered. The paper is structured based on the drug’s action mechanism and contains parts dedicated to antiviral, immunomodulatory, and antibacterial therapies. Looking for a new promising target in COVID-19 treatment, the authors focus their attention on matrix metalloproteinases (MMP), which abundance results in the destruction of extracellular matrix, epithelial and endothelial basal membranes and leads to secondary lung tissue injury. The paper provides a theoretic justification of MMP inhibitor use by an example of doxycycline and offers an efficacy study protocol for the new approach to COVID-19 therapy.

Conclusion: as of now, there are no drugs which efficacy for COVID 19 has been proven. Drugs possessing multiple mechanisms of action are employed beside their specified indications, often in combinations; in this situation, additive side effects with adverse consequences for the patient can hardly be avoided. Administration of drugs with unproven efficacy may be justified only in clinical trials followed by subsequent analysis and publication of findings demonstrating that in case of success, recommendations for a majority of COVID-19 patients could be confidently issued.

COVID-19противомалярийные средстваингибиторы вирусных протеазпротивопаразитарные препаратыингибиторы интерлейкиновингибиторы янус-киназинтерфероныплазма реконвалесцентовкортикостероидыпрокальцитонинантибиотикиновая мишеньматриксные металлопротеиназыдоксициклинCOVID-19anti-malaria drugsviral protease inhibitorsanti-parasitic drugsinterleukin inhibitorsJanus kinase inhibitorsinterferonsconvalescents plasmacorticosteroidsprocalcitoninantibioticsnew targetmatrix metalloproteinasesdoxycyclineReferencesStollenwerk N., Harper R.W., Sandrock Ch.E. Bench-to-bedside review: Rare and common viral infections in the intensive care unit — linking pathophysiology to clinical presentation. Critical Care. 2008; 12 (4): 219. DOI: 10.1186/cc6917Stollenwerk N., Harper R.W., Sandrock Ch.E. Bench-to-bedside review: Rare and common viral infections in the intensive care unit — linking pathophysiology to clinical presentation. Critical Care. 2008; 12 (4): 219. DOI: 10.1186/cc6917Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19). Временные методические рекомендации МЗ РФ. Версия 7 от 03.06.2020 https://static-0.rosminzdrav.ru/system/attachments/attaches/000/050/584/origi-nal/03062020_MR_COVID-19_v7.pdfPrevention, diagnosis and treatment of new coronavirus infection (COVID-19). Temporary guidelines of the Ministry of Health of the Russian Federation. Version 7 from 06/03/2020 https://static-0.ros-minzdrav.ru/system/attachments/attaches/000/050/584/original/03062020_MR_COVID-19_v7.pdf [In Russ.]Alexander P.E., Debono V.B., Mammen M.J., Iorio A., Aryal K., Deng D., Brocard E., Alhazzani W. COVID-19 research has overall low methodological quality thus far: case in point for chloroquine/hydroxy-chloroquine. J Clin Epidemiol. 2020; 123: 120-126. PMID: 32330521 PMCID: PMC7194626 DOI: 10.1016/j.jclinepi.2020.04.016Alexander P.E., Debono V.B., Mammen M.J., Iorio A., Aryal K., Deng D., Brocard E., Alhazzani W. COVID-19 research has overall low methodological quality thus far: case in point for chloroquine/hydroxy chloroquine. J Clin Epidemiol. 2020; 123: 120-126. PMID: 32330521 PMCID: PMC7194626 DOI: 10.1016/j.jclinepi.2020.04.016U.S. National Library of Medicine. Clinical Trials.com https://clini-caltrials.gov/ct2/results/details?cond=COVID-19U.S. National Library of Medicine. Clinical Trials.com https://clini-caltrials.gov/ct2/results/details?cond=COVID-19Keyaerts E., Li S., Vijgen L., Rysman E., Verbeeck J., Van Ranst M., Maes P. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrobial agents and chemotherapy. 2009; 53 (8): 3416-3421. DOI: 10.1128/AAC.01509-08Keyaerts E., Li S., Vijgen L., Rysman E., Verbeeck J., Van Ranst M., Maes P. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrobial agents and chemotherapy. 2009; 53 (8): 3416-3421. DOI: 10.1128/AAC.01509-08Vincent M.J., Bergeron E., Benjannet S., Erickson B.R., Rollin P.E., Ksiazek Th.G., Seidah N.G., Nichol St.T. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology journal. 2005; 2 (1): 69. DOI: 10.1186/1743-422X-2-69Vincent M.J., Bergeron E., Benjannet S., Erickson B.R., Rollin P.E., Ksiazek Th.G., Seidah N.G., Nichol St.T. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology journal. 2005; 2 (1): 69. DOI: 10.1186/1743-422X-2-69Wang M., Cao R., Zhang L., Yang X., Liu J., Xu M., Shi Z., Hu Z., Zhong W. and Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell research. 2020; 30 (3): 269-271. DOI: 10.1038/s41422-020-0282-0Wang M., Cao R., Zhang L., Yang X., Liu J., Xu M., Shi Z., Hu Z., Zhong W. and Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell research. 2020; 30 (3): 269-271. DOI: 10.1038/s41422-020-0282-0Delvecchio R., Higa L.M., Pezzuto P, Valadao A.L., Garcez PP, Monteiro F.L., Loiola E.C., Dias A.A., Silva F.J.M., Aliota M.T., Caine E.A., Osorio J.E., Bellio M., O’Connor D.H., Rehen S., de Aguiar R.S., Savarino A., Campanati L., Tanuri A. Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models. Viruses. 2016; 8 (12): 322. DOI: 10.3390/v8120322. PMID: 27916837Delvecchio R., Higa L.M., Pezzuto P., Valadao A.L., Garcez P.P., Monteiro F.L., Loiola E.C., Dias A.A., Silva F.J.M., Aliota M.T., Caine E.A., Osorio J.E., Bellio M., O’Connor D.H., Rehen S., de Aguiar R.S., Savarino A., Campanati L., Tanuri A. Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models. Viruses. 2016; 8 (12): 322. DOI: 10.3390/v8120322. PMID: 27916837te Velthuis A.J.W., van den Worm S.H.E., Sims A.C., Baric R.S., Snijder E.J., van Hemert M.J. Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture. PLoS Pathog. 2010; 6 (11): e1001176. PMID: 32330521 PMCID: PMC7194626 DOI: 10.1016/j.jclinepi.2020.04.016te Velthuis A.J.W., van den Worm S.H.E., Sims A.C., Baric R.S., Snijder E.J., van Hemert M.J. Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture. PLoS Pathog. 2010; 6 (11): e1001176. PMID: 32330521 PMCID: PMC7194626 DOI: 10.1016/j.jclinepi.2020.04.016Gao J., Tian Zh., Yang X Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020; 14: 723. DOI: 10.5582/bst.2020.01047. PMID: http://www.ncbi.nlm.nih.gov/pubmed/32074550Gao J, Tian Zh., Yang X Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020; 14: 723. DOI: 10.5582/bst.2020.01047. PMID: http://www.ncbi.nlm.nih.gov/pubmed/32074550Gautret P., Lagier J.-Ch., Parola Ph.,Hoang V.Th., Meddeb L., Mailhe M., DoudierB., CourjonJ., Giordanengo V, VieiraV.E.,DupontH.T., Honort S., Colson Ph., ChabriereE., La ScolaB., Rolain J.-M., BrouquiPh., Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020: 105949. DOI: 10.1016/j.ijantimicag.2020.105949. PMID: http://www.ncbi.nlm.nih.gov/pubmed/32205204Gautret P., Lagier J.-Ch., Parola Ph.,Hoang V.Th., Meddeb L., Mailhe M., DoudierB., CourjonJ., Giordanengo V, Vieira VE.,DupontH.T, Honort S., Colson Ph., Chabriere E., La Scola B., Rolain J.-M., Brouqui Ph., Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020: 105949. DOI: 10.1016/j.ijantimicag.2020.105949. PMID: http://www.ncbi.nlm.nih.gov/pubmed/32205204Chu C.M., Cheng V.C.C., Hung I.F.N., Wong M.M.L., Chan K.H., Chan K.S., Kao R.Y.T., Poon L.L.M., C.L.P., Guan Y., Peiris J.S.M., Yuen K.Y., HKU/UCH SARS Study Group. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004; 59: 252-256. DOI: 10.1136/thorax.2003.012658Chu C.M., Cheng V.C.C., Hung I.F.N., Wong M.M.L., Chan K.H., Chan K.S., Kao R.Y.T., Poon L.L.M., C.L.P., Guan Y., Peiris J.S.M., Yuen K.Y., HKU/UCH SARS Study Group. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004; 59: 252-256. DOI: 10.1136/thorax.2003.012658Chan K.S., Lai S.T., Chu C.M., Tsui E., Tam C.Y., Wong M.M.L., Tse M.W., Que T.L., Peiris J.S.M., Sung J., Wong V.C.W., Yuen K.Y. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003; 9: 399-406. PMID: 14660806Chan K.S., Lai S.T., Chu C.M., Tsui E., Tam C.Y., Wong M.M.L., Tse M.W., Que T.L., Peiris J.S.M., Sung J., Wong V.C.W., Yuen K.Y. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003; 9: 399-406. PMID: 14660806Cao B., Wang Y., Wen D., Liu W., Wang J., Fan G., Ruan L., Song B., Cai Y., Wei M., Li X., Xia J., Chen N., Xiang J., Yu T., Bai T., Xie X., Zhang L., Li C., Yuan Y., Chen H., Li H., Huang H., Tu S., Gong F., Liu Y., Wei Y., Dong C., Zhou F., Gu X., Xu J., Liu Z., Zhang Y., Li H., Shang L., Wang K., Li K., Zhou X., Dong X., Qu Z., Lu S., Hu X., Ruan S., Luo S., Wu J., Peng L., Cheng F., Pan L., Zou J., Jia C., Wang J., Liu X., Wang S., Wu X., Ge Q., He J., Zhan H., Qiu F., Guo L., Huang C., Jaki T., Hayden F.G., Horby PW, ZhangD., Wang C. A Trial of Lopinavir-Ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020; 382: 17871799. DOI: 10.1056/NEJMoa2001282. PMID: 32187464Cao B., Wang Y., Wen D., Liu W., Wang J., Fan G., Ruan L., Song B., Cai Y., Wei M., Li X., Xia J., Chen N., Xiang J., Yu T., Bai T., Xie X., Zhang L., Li C., Yuan Y., Chen H., Li H., Huang H., Tu S., Gong F., Liu Y., Wei Y., Dong C., Zhou F., Gu X., Xu J., Liu Z., Zhang Y., Li H., Shang L., Wang K., Li K., Zhou X., Dong X., Qu Z., Lu S., Hu X., Ruan S., Luo S., Wu J., Peng L., Cheng F., Pan L., Zou J., Jia C., Wang J., Liu X., Wang S., Wu X., Ge Q., He J., Zhan H., Qiu F., Guo L., Huang C., Jaki T., Hayden F.G., Horby P.W., Zhang D., Wang C. A Trial of Lopinavir-Ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020; 382: 17871799. DOI: 10.1056/NEJMoa2001282. PMID: 32187464Cai Q., Huang D., Ou P., Yu H., Zhu Zh., Xia Zh., Su Y., Ma Zh., Zhang Y., Li Zh., He Q., Liu L., Fu Y., Chen J. COVID-19 in a designated infectious diseases hospital outside Hubei Province, China. MedRxiv. 2020; DOI: 10.1101/2020.02.17.20024018. PMID: 32239761Cai Q., Huang D., Ou P., Yu H., Zhu Zh., Xia Zh., Su Y., Ma Zh., Zhang Y., Li Zh., He Q., Liu L., Fu Y., Chen J. COVID-19 in a designated infectious diseases hospital outside Hubei Province, China. MedRxiv. 2020; DOI: 10.1101/2020.02.17.20024018. PMID: 32239761HuL., Chen S., Fu Y., GaoZ., LongH., RenH.-W.,Zuo Y., LiH., Wang J., Xu Q.-B., Yu W.-X., Liu J., Shao Ch., Hao J.-J., Wang Ch.-Zh., Ma Y., Wang Zh., Yanagihara R. J.-M. Wang, Deng Y. Risk factors associated with clinical outcomes in 323 COVID-19 patients in Wuhan, China. medRxiv 2020 DOI: 10.1101/2020.03.25.20037721. PMID: 32361738HuL., Chen S., Fu Y., GaoZ., LongH., RenH.-W.,Zuo Y., LiH., Wang J., Xu Q.-B., Yu W.-X., Liu J., Shao Ch., Hao J.-J., Wang Ch.-Zh., Ma Y., Wang Zh., Yanagihara R. J.-M. Wang, Deng Y. Risk factors associated with clinical outcomes in 323 COVID-19 patients in Wuhan, China. medRxiv 2020 DOI: 10.1101/2020.03.25.20037721. PMID: 32361738Yan D., Liu X.-Y., Zhu Y.-N, Huang L., Dan B.-T., Zhang G.-J., Gao Y.-H. Factors associated with prolonged viral shedding and impact of Lopinavir/Ritonavir treatment in patients with SARS-CoV-2. Eur Respir J. 2020; 56: 2000799. DOI: 10.1183/13993003.00799-2020Yan D., Liu X.-Y., Zhu Y.-N, Huang L., Dan B.-T., Zhang G.-J., Gao Y.-H. Factors associated with prolonged viral shedding and impact of Lopinavir/Ritonavir treatment in patients with SARS-CoV-2. Eur Respir J. 2020; 56: 2000799. DOI: 10.1183/13993003.00799-2020Cai Q., Yang M,. Liu D,. Chen J,. Shu D., Xia J., Liao X., Gu Y., Cai Q., Yang Y., Shen C., Li X., Peng L., Huang D., Zhang J., Zhang S., Wang F., Liu J., Chen L., Chen S., Wang Z., Zhang Z., Cao R., Zhong W., Liu Y., Liu L. Experimental treatment with favipiravir for COVID-19: An open-label control study. Engineering. 2020; DOI: 10.1016/j.eng.2020.03.007Cai Q., Yang M,. Liu D,. Chen J,. Shu D., Xia J., Liao X., Gu Y., Cai Q., Yang Y., Shen C., Li X., Peng L., Huang D., Zhang J., Zhang S., Wang F., Liu J., Chen L., Chen S., Wang Z., Zhang Z., Cao R., Zhong W., Liu Y., Liu L. Experimental treatment with favipiravir for COVID-19: An open-label control study. Engineering. 2020; DOI: 10.1016/j.eng.2020.03.007de Wit E., Feldmann F., Cronin J., Jordan R., Okumura A., Thomas T., Scott D., Cihlar T., Feldmann H. Prophylactic and therapeutic remde-sivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Nat Acad Sci USA. 2020; 117 (12): 6771-6776. DOI: 10.1073/pnas.1922083117. PMID: 32054787de Wit E., Feldmann F., Cronin J., Jordan R., Okumura A., Thomas T., Scott D., Cihlar T., Feldmann H. Prophylactic and therapeutic remde-sivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Nat Acad Sci USA. 2020; 117 (12): 6771-6776. DOI: 10.1073/pnas.1922083117. PMID: 32054787Beigel John H., Tomashek Kay M., Dodd Lori E., Mehta Aneesh K., Zingman Barry S., Kalil Andre C., Hohmann Elizabeth, Chu Helen Y., Luetkemeyer Annie, Kline Susan, Lopez de Castilla Diego, Finberg Robert W., Dierberg Kerry, Tapson Victor, Hsieh Lanny, Patterson Thomas F., Paredes Roger, Sweeney Daniel A., Short William R., Touloumi Giota, Lye David Chien, Ohmagari Norio, Oh Myoung-don, Ruiz-Palacios Guillermo M., Benfield Thomas, Fatkenheuer Gerd, Kortepeter Mark G., Atmar Robert L., Creech C. Buddy, Lundgren Jens, Babiker Abdel G., Pett Sarah, Neaton James D., Burgess Timothy H., Bonnett Tyler, Green Michelle, Makowski Mat, Osinusi Anu, Nayak Seema, Lane H. Clifford. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020. DOI: 10.1056/NEJMoa2015301.Beigel John H., Tomashek Kay M., Dodd Lori E., Mehta Aneesh K., Zingman Barry S., Kalil Andre C., Hohmann Elizabeth, Chu Helen Y., Luetkemeyer Annie, Kline Susan, Lopez de Castilla Diego, Finberg Robert W., Dierberg Kerry, Tapson Victor, Hsieh Lanny, Patterson Thomas F., Paredes Roger, Sweeney Daniel A., Short William R., Touloumi Giota, Lye David Chien, Ohmagari Norio, Oh Myoung-don, Ruiz-Palacios Guillermo M., Benfield Thomas, Fatkenheuer Gerd, Kortepeter Mark G., Atmar Robert L., Creech C. Buddy, Lundgren Jens, Babiker Abdel G., Pett Sarah, Neaton James D., Burgess Timothy H., Bonnett Tyler, Green Michelle, Makowski Mat, Osinusi Anu, Nayak Seema, Lane H. Clifford. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020. DOI: 10.1056/NEJMoa2015301.Mair-Jenkins J., Saavedra-Campos M., Baillie J.K., Cleary P., Khaw F.-M., Lim W.Sh., Makki S., Rooney K.D., Nguyen-Van-Tam J.S., Beck Ch.R. Convalescent Plasma Study Group. 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 (1): 80-90. DOI: 10.1093/infdis/jiu396. PMID: 25030060Mair-Jenkins J., Saavedra-Campos M., Baillie J.K., Cleary P., Khaw F.-M., Lim W.Sh., Makki S., Rooney K.D., Nguyen-Van-Tam J.S., Beck Ch.R. Convalescent Plasma Study Group. 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 (1): 80-90. DOI: 10.1093/infdis/jiu396. PMID: 25030060Shen Ch., Wang Zh., Zhao F., Yang Y., Li J., Yuan J., Wang F., Li D., Yang M., Xing L., Wei J., Xiao H., Yang Y., Qu J., Qing L., Chen L., Xu Zh., Peng L., Li Y., Zheng H., Chen F., Huang K., Jiang Y., Liu D., Zhang Zh., Liu Y., Liu L. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020; 323 (16): 1582-1589. DOI: 10.1001/jama.2020.4783. PMID: 32219428Shen Ch., Wang Zh., Zhao F., Yang Y., Li J., Yuan J., Wang F., Li D., Yang M., Xing L., Wei J., Xiao H., Yang Y., Qu J., Qing L., Chen L., Xu Zh., Peng L., Li Y., Zheng H., Chen F., Huang K., Jiang Y., Liu D., Zhang Zh., Liu Y., Liu L. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020; 323 (16): 1582-1589. DOI: 10.1001/jama.2020.4783. PMID: 32219428Duan K., Liu B., Li C., Zhang H., Yu T., Qu., Zhou M., Chen L., Meng Sh., Hu Y., Peng Ch., Yuan M., Huang J., Wang Z., Yu J., Gao., Wang D., Yu X., Li L., Zhang J., Wu X., Li B., Xu Y., Chen W., Peng Y., Hu Y., Lin L., Liu X., Huang Sh., Zhou Zh., Zhang L., Wang Y., Zhang Zh., Deng K., Xia Zh., Gong Q., Zhang W., Zheng X., Liu Y., Yang H., Zhou D., Yu D., Hou J., Shi Zh., Chen S., Chen Zh., Zhang X., Yang X. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. PNAS. 2020; 117 (17): 9490-9496; first published April 6, 2020. DOI: 10.1073/pnas.2004168117. PMID: 32253318Duan K., Liu B., Li C., Zhang H., Yu T., Qu., Zhou M., Chen L., Meng Sh., Hu Y., Peng Ch., Yuan M., Huang J., Wang Z., Yu J., Gao., Wang D., Yu X., Li L., Zhang J., Wu X., Li B., Xu Y., Chen W., Peng Y., Hu Y., Lin L., Liu X., Huang Sh., Zhou Zh., Zhang L., Wang Y., Zhang Zh., Deng K., Xia Zh., Gong Q., Zhang W., Zheng X., Liu Y., Yang H., Zhou D., Yu D., Hou J., Shi Zh., Chen S., Chen Zh., Zhang X., Yang X. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. PNAS. 2020; 117 (17): 9490-9496; first published April 6, 2020. DOI: 10.1073/pnas.2004168117. PMID: 32253318Pandey S., Vyas G.N. Adverse effects of plasma transfusion. Transfusion. 2012; 52 (Suppl. 1): 65S-79S. DOI: 10.1111/j.1537-2995.2012.03663.xPandey S., Vyas G.N. Adverse effects of plasma transfusion. Transfusion. 2012; 52 (Suppl. 1): 65S-79S. DOI: 10.1111/j.1537-2995.2012.03663.xCaly L., Druce J.D., Catton M.G., Jans D.A., Wagstaff K.M. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research. June 2020; 178: 104787. DOI: 10.1016/j.an-tiviral.2020.104787. PMID: 32251768Caly L., Druce J.D., Catton M.G., Jans D.A., Wagstaff K.M. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research. June 2020; 178: 104787. DOI: 10.1016/j.an-tiviral.2020.104787. PMID: 32251768Rossignol J.-F. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. Journal of Infection and Public Health., 2016; 9 (3): 227-230. DOI: 10.1016/j.jiph.2016.04.001Rossignol J.-F. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. Journal of Infection and Public Health., 2016; 9 (3): 227-230. DOI: 10.1016/j.jiph.2016.04.001Sisk J.M., Frieman M.B., Machamer C.E. Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors. J Gen Virol. 2018; 99 (5): 619-630. DOI: 10.1099/jgv.0.001047. PMID: 29557770Sisk J.M., Frieman M.B., Machamer C.E. Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors. J Gen Virol. 2018; 99 (5): 619-630. DOI: 10.1099/jgv.0.001047. PMID: 29557770Alhazzani W, M0ller M.H., Arabi Y.M., Loeb M., Gong M.Ng, Fan E., Oczkowski S., Levy M.M., Derde L., Dzierba A., Du B., Aboodi M., Wun-sch H., Cecconi M., Koh Y., Chertow D.S., Maitland K., Alshamsi F., Bel-ley-Cote E., Greco M., Laundy M., Morgan J.S., Kesecioglu J., McGeer A., Mermel L., Mammen M.J., Alexander P.E., Arrington A., Centofanti J.E., Citerio G., Baw B., Memish Z.A., Hammond N., Hayden F.G., Evans L., Rhodes A. Surviving Sepsis Campaign. Guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Critical Care Medicine.2020; 48 (6): e440-e469 Volume Online First — Issue — DOI: 10.1097/CCM.0000000000004363. PMID: 32222812Alhazzani W., M0ller M.H., Arabi Y.M., Loeb M., Gong M.Ng, Fan E., Oczkowski S., Levy M.M., Derde L., Dzierba A., Du B., Aboodi M., Wun-sch H., Cecconi M., Koh Y., Chertow D.S., Maitland K., Alshamsi F., Bel-ley-Cote E., Greco M., Laundy M., Morgan J.S., Kesecioglu J., McGeer A., Mermel L., Mammen M.J., Alexander P.E., Arrington A., Centofanti J.E., Citerio G., Baw B., Memish Z.A., Hammond N., Hayden F.G., Evans L., Rhodes A. Surviving Sepsis Campaign. Guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Critical Care Medicine.2020; 48 (6): e440-e469 Volume Online First — Issue — DOI: 10.1097/CCM.0000000000004363. PMID: 32222812Isidori, A.M., Arnaldi, G., Boscaro, Falorni M. A., Giordano C., Giordano R., Pivonello R., Pofi R., Hasenmajer V., Venneri M. A., Sbardella E., Sime-oli C., Scaroni C., Lenziet A. COVID-19 infection and glucocorticoids: update from the Italian Society of Endocrinology Expert Opinion on steroid replacement in adrenal insufficiency. Journal of Endocrinolog-icalInvestigation. (43): 1141-1147 DOI: 10.1007/s40618-020-01266-wIsidori, A.M., Arnaldi, G., Boscaro, Falorni M. A., Giordano C., Giordano R., Pivonello R., Pofi R., Hasenmajer V., Venneri M. A., Sbardella E., Sime-oli C., Scaroni C., Lenziet A. COVID-19 infection and glucocorticoids: update from the Italian Society of Endocrinology Expert Opinion on steroid replacement in adrenal insufficiency. Journal of Endocrinological Investigation. (43): 1141-1147 DOI: 10.1007/s40618-020-01266-wArabi Y.M., Mandourah Y., Al-Hameed F., Sindi A.A., Almekhlafi G.A., Hussein M.A., Jose J., Pinto R., Al-Omari A., Kharaba A., Almotairi A., Al Khatib K., Alraddadi B., Shalhoub S., Abdulmomen A., Qushmaq I., Mady A., Solaiman O., Al-Aithan A.M., Al-Raddadi R., Ragab A., Balkhy H.H., Al Harthy A., Deeb A.M., Al Mutairi H., Al-Dawood A., Merson L., Hayden F.G., Fowler R.A., Saudi Critical Care Trial Group. Corticosteroid therapy for critically ill patients with middle east respiratory syndrome. Am J Respir. Crit Care Med. 2018; 197: 757-767. DOI: 10.1164/rccm.201706-1172OC. PMID: 29161116Arabi Y.M., Mandourah Y., Al-Hameed F., Sindi A.A., Almekhlafi G.A., Hussein M.A., Jose J., Pinto R., Al-Omari A., Kharaba A., Almotairi A., Al Khatib K., Alraddadi B., Shalhoub S., Abdulmomen A., Qushmaq I., Mady A., Solaiman O., Al-Aithan A.M., Al-Raddadi R., Ragab A., Balkhy H.H., Al Harthy A., Deeb A.M., Al Mutairi H., Al-Dawood A., Merson L., Hayden F.G., Fowler R.A., Saudi Critical Care Trial Group. Corticosteroid therapy for critically ill patients with middle east respiratory syndrome. Am J Respir. Crit Care Med. 2018; 197: 757-767. DOI: 10.1164/rccm.201706-1172OC. PMID: 29161116Lee N., Chan K.C.A., Hui D.S., Ng E.K.O., Wu A., Chiu R.W.K., Wong V.W.S., Chan P.K.S., Wong K.T., Wong E., Cockram C.S., Tam J.S., Sung J.J.Y., Lo Y.. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. J Clin Virol. 2004; 31: 304-309. DOI: 10.1016/j.jcv.2004.07.006.Lee N., Chan K.C.A., Hui D.S., Ng E.K.O., Wu A., Chiu R.W.K., Wong V.W.S., Chan P.K.S., Wong K.T., Wong E., Cockram C.S., Tam J.S., Sung J.J.Y., Lo Y.. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. J Clin Virol. 2004; 31: 304-309. DOI: 10.1016/j.jcv.2004.07.006.Chen R.-Ch., TangX.-P, Tan Sh.-Y., LiangB.-L., Wan Zh.-Y., Fang J.-Q., Zhong N. Treatment of severe acute respiratory syndrome with glucosteroids. Chest Journal. 2006; 129 (6): 1441-1452. DOI: 10.1378/chest.129.6.1441. PMID: 16778260ChenR.-Ch., TangX.-P, TanSh.-Y., LiangB.-L., WanZh.-Y., FangJ.-Q., Zhong N. Treatment of severe acute respiratory syndrome with glucosteroids. Chest Journal. 2006; 129 (6): 1441-1452. DOI: 10.1378/chest.129.6.1441. PMID: 16778260Zha L., Li Sh., Pan L., Tefsen B., Li Y., French N., Chen L., Yang G., Villanueva E.V. Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19). Medical Journal of Australia. 2020; 212 (9): 416-420 DOI: 10.5694/mja2.50577. PMID: 32296987Zha L., Li Sh., Pan L., Tefsen B., Li Y., French N., Chen L., Yang G., Villanueva E.V. Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19). Medical Journal of Australia. 2020; 212 (9): 416-420 DOI: 10.5694/mja2.50577. PMID: 32296987Keskin O., Farzan N., Birben E., H.Akel, Karaaslan C., Maitland-van der Zee A.H., Wechsler M.E., Vijverberg S.J., Kalayci O. Genetic associations of the response to inhaled corticosteroids in asthma: a systematic review. Clin Transl Allergy. 2019; 9: 2. Published online 2019 Jan 9. DOI: 10.1186/s13601-018-0239-2. PMID: 30647901Keskin O., Farzan N., Birben E., H.Akel, Karaaslan C., Maitland-van der Zee A.H., Wechsler M.E., Vijverberg S.J., Kalayci O. Genetic associations of the response to inhaled corticosteroids in asthma: a systematic review. Clin Transl Allergy. 2019; 9: 2. Published online 2019 Jan 9. DOI: 10.1186/s13601-018-0239-2. PMID: 30647901Zhang X., Song K., Tong F., Fei M., Guo H., Lu Zh., Wang J., Zheng Ch. First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab. Blood Advances. 2020; 4 (7): 1307-1310. DOI:10.1182/bloodadvances.2020001907. PMID: 32243501Zhang X., Song K., Tong F., Fei M., Guo H., Lu Zh., Wang J., Zheng Ch. First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab. Blood Advances. 2020; 4 (7): 1307-1310. DOI:10.1182/bloodadvances.2020001907. PMID: 32243501Case Study: Treating COVID-19 in a Patient with Multiple Myeloma [news release]. Washington. Published April 3, 2020. hematology.org/newsroom/press-releases/2020/case-study-treat-ing-covid-19. Accessed April 7, 2020.Case Study: Treating COVID-19 in a Patient with Multiple Myeloma [news release]. Washington. Published April 3, 2020. hematology.org/newsroom/press-releases/2020/case-study-treat-ing-covid-19. Accessed April 7, 2020.Jones G., Ding Ch. Tocilizumab: A Review of Its Safety and Efficacy in Rheumatoid Arthritis. Clin Med Insights Arthritis Musculoskelet Disord. 2010; 3: 81-89. DOI: 10.4137/CMAMD.S4864Jones G., Ding Ch. Tocilizumab: A Review of Its Safety and Efficacy in Rheumatoid Arthritis. Clin Med Insights Arthritis Musculoskelet Disord. 2010; 3: 81-89. DOI: 10.4137/CMAMD.S4864Gritti G., Raimondi F., Ripamonti D., Riva I., Landi F., Alborghetti L., Frigeni M., Damiani M., Mico C., Fagiuoli S., Cosentini R., Lorini FL., Fabretti F., . Morgan J.H, Owens B.M.J., Kanhai K., Cowburn J., Rizzi M., Di Marco F., Rambaldi A. Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support. medRxiv. preprint DOI: 10.1101/2020.04.01.20048561Gritti G., Raimondi F., Ripamonti D., Riva I., Landi F., Alborghetti L., Frigeni M., Damiani M., Mico C., Fagiuoli S., Cosentini R., Lorini F.L., Fabretti F., . Morgan J.H, Owens B.M.J., Kanhai K., Cowburn J., Rizzi M., Di Marco F., Rambaldi A. Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support. medRxiv. preprint DOI: 10.1101/2020.04.01.20048561Treatment of COVID-19 Patients With Anti-interleukin Drugs (COV-AID). ClinicalTrials.gov Identifier: NCT04330638. https://clinicaltri-als.gov/ct2/show/record/NCT04330638Treatment of COVID-19 Patients With Anti-interleukin Drugs (COV-AID). ClinicalTrials.gov Identifier: NCT04330638. https://clinicaltri-als.gov/ct2/show/record/NCT04330638Regeneron and sanofi provide update on u.s. phase 2/3 adaptive-designed trial of kevzara® (sarilumab) in hospitalized covid-19 patients. TARRYTOWN, N.Y. and PARIS, April 27, 2020 /PRNewswire/ — https://www.prnewswire.com/news-releases/regeneron-and-sanofi-pro-vide-update-on-us-phase-23-adaptive-designed-trial-of-kevzara-sar-ilumab-in-hospitalized-covid-19-patients-301047326.htmlRegeneron and sanofi provide update on u.s. phase 2/3 adaptive-designed trial of kevzara® (sarilumab) in hospitalized covid-19 patients. TARRYTOWN, N.Y. and PARIS, April 27, 2020 /PRNewswire/ — https://www.prnewswire.com/news-releases/regeneron-and-sanofi-pro-vide-update-on-us-phase-23-adaptive-designed-trial-of-kevzara-sar-ilumab-in-hospitalized-covid-19-patients-301047326.htmlCavalli G., De Luca G., Campochiaro C., Della-Torre E., Ripa M., Canetti D., Oltolini Ch., Castiglioni B., Din Ch.T., Boffini N., Tomelleri A., Farina N., Ruggeri A., Rovere-Querini P., Di Lucca G., Martinenghi S., Scotti R., Tresoldi M., Ciceri F., Landoni G., Zangrillo A., Scarpellini P., Dagna L. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020; 2 (6): e325-e331. Published Online May 7. DOI: 10.1016/S2665-9913(20)30127-2. PMID: 32501454Cavalli G., De Luca G., Campochiaro C., Della-Torre E., Ripa M., Canetti D., Oltolini Ch., Castiglioni B., Din Ch.T., Boffini N., Tomelleri A., Farina N., Ruggeri A., Rovere-Querini P., Di Lucca G., Martinenghi S., Scotti R., Tresoldi M., Ciceri F., Landoni G., Zangrillo A., Scarpellini P., Dagna L. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020; 2 (6): e325-e331. Published Online May 7. DOI: 10.1016/S2665-9913(20)30127-2. PMID: 32501454O’Shea J.J., Kontzias A., Yamaoka K., Tanaka Y., Laurence A. Janus kinase Inhibitors in autoimmune diseases. Ann Rheum Dis. Author manuscript; 2013; 72 (Suppl 2): ii111-5. DOI: 10.1136/annrheumdis-2012-202576. PMID: 23532440O’Shea J.J., Kontzias A., Yamaoka K., Tanaka Y., Laurence A. Janus kinase Inhibitors in autoimmune diseases. Ann Rheum Dis. Author manuscript; 2013; 72 (Suppl 2): ii111-5. DOI: 10.1136/annrheumdis-2012-202576. PMID: 23532440Cantini F., Niccoli L., Matarrese D., Nicastri E., Stobbione P., Goletti D. Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact. J Infect. 2020; 81 (2): 318-356. PMID: 32333918 PMCID: PMC7177073 DOI: 10.1016/j.jinf.2020.04.017Cantini F., Niccoli L., Matarrese D., Nicastri E., Stobbione P., Goletti D. Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact. J Infect. 2020; 81 (2): 318-356. PMID: 32333918 PMCID: PMC7177073 DOI: 10.1016/j.jinf.2020.04.017Safety and Efficacy of Ruxolitinib for COVID-19. ClinicalTrials.gov Identifier: NCT04348071. https://clinicaltrials.gov/ct2/show/NCT04348071Safety and Efficacy of Ruxolitinib for COVID-19. ClinicalTrials.gov Identifier: NCT04348071. https://clinicaltrials.gov/ct2/show/NCT04348071Acalabrutinib Study With Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized With COVID-19. CALAVI (Calquence Against the Virus) (ACE-ID-201). ClinicalTrials.gov Identifier: NCT04346199. https://clinicaltrials.gov/ct2/show/NCT04346199Acalabrutinib Study With Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized With COVID-19. CALAVI (Calquence Against the Virus) (ACE-ID-201). ClinicalTrials. gov Identifier: NCT04346199. https://clinicaltrials.gov/ct2/show/NCT04346199TOFAcitinib in SARS-CoV2 Pneumonia. ClinicalTrials.gov Identifier: NCT04332042. https://clinicaltrials.gov/ct2/show/NCT04332042TOFAcitinib in SARS-CoV2 Pneumonia. ClinicalTrials.gov Identifier: NCT04332042. https://clinicaltrials.gov/ct2/show/NCT04332042Isaacs A., Lindenmann J. Virus interference. I. The interferon. Proc R Soc London Ser B. 1957; 147: 258-267. DOI: 10.1098/rspb.1957.0048Isaacs A., Lindenmann J. Virus interference. I. The interferon. Proc R Soc London Ser B. 1957; 147: 258-267. DOI: 10.1098/rspb.1957.0048Charles E. Samuel. Antiviral Actions of Interferons. Clin Microbiol Rev. 2001; 14 (4): 778-809. DOI: 10.1128/CMR.14.4.778-809.2001Charles E. Samuel. Antiviral Actions of Interferons. Clin Microbiol Rev. 2001; 14 (4): 778-809. DOI: 10.1128/CMR.14.4.778-809.2001Sheahan TP, Sims A.C., Leist S.R., Schafer A., Won J., Brown A.J., Montgomery S.A., Hogg A., Babusis D., Clarke M.O., Spahn J.E., Bauer L., Sellers S., PorterD.,Feng J.Y., Cihlar T, JordanR.,DenisonM.R.,BaricR.S. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun., 2020; 11. 222. DOI: 10.1038/s41467-019-13940-6. PMID: 31924756Sheahan T.P., Sims A.C., Leist S.R., Schafer A., Won J., Brown A.J., Mont-gomerySA,Hogg A., BabusisD., ClarkeM.O., Spahn J.E., BauerL., Sellers S.,PorterD.,Feng J.Y., Cihlar T, JordanR.,DenisonM.R.,BaricR.S. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun., 2020; 11. 222. DOI: 10.1038/s41467-019-13940-6. PMID: 31924756Omrani A.S., Saad M.M., Baig K., Bahloul A., Abdul-Matin M., Alaida-roos A.Y., Almakhlafi G.A., Albarrak M.M., Memish Z.A., Albarrak A.M. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect. Dis. 2014; 14: 1090-1095. DOI: 10.1016/S1473-3099(14)70920-X. PMID: 25278221Omrani A.S., Saad M.M., Baig K., Bahloul A., Abdul-Matin M., Alaida-roos A.Y., Almakhlafi G.A., Albarrak M.M., Memish Z.A., Albarrak A.M. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect. Dis. 2014; 14: 1090-1095. DOI: 10.1016/S1473-3099(14)70920-X. PMID: 25278221Arabi Y.M., Shalhoub S., Mandourah Y., Al-Hameed F., Al-Omari A., Al Qasim E., Jose J., Alraddadi B., Almotairi A., Al Khatib K., Abdulmomen A., Qushmaq I., Sindi A.A., Mady A., Solaiman O., Al-Raddadi R., Maghrabi K., Ragab A., Al Mekhlafi G.A., Balkhy H.H., Al Harthy A., Kharaba A., Gramish J.A., Al-Aithan A.M., Al-Dawood A., Merson L., Hayden F.G., Fowler R. Ribavirin and interferon therapy for critically ill patients with middle east respiratory syndrome: A multicenter observational study. Clin Infect Dis. 2020; 70 (9): 1837-1844. DOI: 10.1093/cid/ciz544. PMID: 31925415Arabi Y.M., Shalhoub S., Mandourah Y., Al-Hameed F., Al-Omari A., Al Qasim E., Jose J., Alraddadi B., Almotairi A., Al Khatib K., Abdulmomen A., Qushmaq I., Sindi A.A., Mady A., Solaiman O., Al-Raddadi R., Maghrabi K., Ragab A., Al Mekhlafi G.A., Balkhy H.H., Al Harthy A., Kharaba A., Gramish J.A., Al-Aithan A.M., Al-Dawood A., Merson L., Hayden F.G., Fowler R. Ribavirin and interferon therapy for critically ill patients with middle east respiratory syndrome: A multicenter observational study. Clin Infect Dis. 2020; 70 (9): 1837-1844. DOI: 10.1093/cid/ciz544. PMID: 31925415National institutes of health. immune-based therapy under evaluation for treatment of COVID-19. Last Updated: May 12, 2020. https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/National institutes of health. immune-based therapy under evaluation for treatment of COVID-19. Last Updated: May 12, 2020. https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/Hung I.F.-N., Lung K.-Ch., Tso E.Y.-K., Liu R., Chung T.W.-H., Chu M.-Y., Ng Y.-Y., Lo J., Chan J., Tam A.R., Shum H.-P., Chan V., Wu A.K.-L., Sin K.-M., Leung W.-Sh., Law W.-L., Lung D.Ch., Sin S., YeungP, Yip C.Ch.-Y., Zhang R.R., Fung A.Y.-F., Yan E.Y.-W., Leung K.-H., Ip J.D., Chu A.W.-H., Chan W.-M., Ng A.Ch.-K., Lee R., Fung K., Yeung A., Wu T.-Ch., Chan J.W.-M., Yan W.-W., Chan W.-M., Chan J. F.-W., Lie A.K.-W., Tsang O.T.-Y., Cheng V.Ch.-Ch., Que T.-L., Lau Ch.-S., Chan K.-H., To K.K.-W., Yuen K.-Y. 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. PMID: 32401715Hung I.F.-N., Lung K.-Ch., Tso E.Y.-K., Liu R., Chung T.W.-H., Chu M.-Y., Ng Y.-Y., Lo J., Chan J., Tam A.R., Shum H.-P., Chan V., Wu A.K.-L., Sin K.-M., Leung W.-Sh., Law W.-L., Lung D.Ch., Sin S., Yeung P., Yip C.Ch.-Y., Zhang R.R., Fung A.Y.-F., Yan E.Y.-W., Leung K.-H., Ip J.D., Chu A.W.-H., Chan W.-M., Ng A.Ch.-K., Lee R., Fung K., Yeung A., Wu T.-Ch., Chan J.W.-M., Yan W.-W., Chan W.-M., Chan J. F.-W., Lie A.K.-W., Tsang O.T.-Y., Cheng V.Ch.-Ch., Que T.-L., Lau Ch.-S., Chan K.-H., To K.K.-W., Yuen K.-Y. 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. PMID: 32401715Mantlo E., Bukreyeva N., Maruyama J., Paessler S., Huang Ch. Antiviral activities of type I interferons to SARS-CoV-2 infection. Antiviral Res. 2020; 179: 104811. DOI: 10.1016/j.antiviral.2020.104811. PMID: 32360182Mantlo E., Bukreyeva N., Maruyama J., Paessler S., Huang Ch. Antiviral activities of type I interferons to SARS-CoV-2 infection. Antiviral Res. 2020; 179: 104811. DOI: 10.1016/j.antiviral.2020.104811. PMID: 32360182de Jong H.J.I., Kingwell E., Shirani A., Tervaert J.W.C., Hupperts R., Zhao Y., Zhu F., Evans Ch., van der Kop M.L., Traboulsee A., Gustafson P., Petkau J., Marrie R. A., Tremlett H., British Columbia Multiple Sclerosis Clinic Neurologists. Evaluating the safety of в-interferons in MS: a series of nested case-control studies. Neurology. 2017; 88 (24): 2310-2320. DOI: 10.1212/WNL.0000000000004037. PMID: 28500224de Jong H.J.I., Kingwell E., Shirani A., Tervaert J.W.C., Hupperts R., Zhao Y., Zhu F., Evans Ch., van der Kop M.L., Traboulsee A., Gustafson P., Petkau J., Marrie R. A., Tremlett H., British Columbia Multiple Sclerosis Clinic Neurologists. Evaluating the safety of в-interferons in MS: a series of nested case-control studies. Neurology. 2017; 88 (24): 2310-2320. DOI: 10.1212/WNL.0000000000004037. PMID: 28500224Hu Y., Ye Y., Ye L., Wang X., Yu H. Efficacy and safety of interferon alpha therapy in children with chronic hepatitis B. Medicine (Baltimore). 2019; 98 (32): e16683. DOI: 10.1097/MD.0000000000016683. PMID: 31393369Hu Y., Ye Y., Ye L., Wang X., Yu H. Efficacy and safety of interferon alpha therapy in children with chronic hepatitis B. Medicine (Baltimore). 2019; 98 (32): e16683. DOI: 10.1097/MD.0000000000016683. PMID: 31393369Open-label, Randomized Study of IFX-1 in Patients With Severe COVID-19 Pneumonia (PANAMO). ClinicalTrials.gov Identifier: NCT04333420. https://clinicaltrials.gov/ct2/show/NCT04333420Open-label, Randomized Study of IFX-1 in Patients With Severe COVID-19 Pneumonia (PANAMO). ClinicalTrials.gov Identifier: NCT04333420. https://clinicaltrials.gov/ct2/show/NCT04333420Golchin A., Seyedjafari E., Ardeshirylajimi A. Mesenchymal stem cell therapy for COVID-19: Present or Future. Stem Cell Rev Rep. 2020; Apr 13: 1-7. DOI: 10.1007/s12015-020-09973-w. PMID: 32281052Golchin A., Seyedjafari E., Ardeshirylajimi A. Mesenchymal stem cell therapy for COVID-19: Present or Future. Stem Cell Rev Rep. 2020; Apr 13: 1-7. DOI: 10.1007/s12015-020-09973-w. PMID: 32281052Website of the British society for antimicrobial therapy http://bsac.org.uk/Website of the British society for antimicrobial therapy http://bsac.org.uk/Website of National Institute for Health and Care Excellence [NICE] https://www.nice.org.uk/guidanceWebsite of National Institute for Health and Care Excellence [NICE] https://www.nice.org.uk/guidanceQing Y., Wenyang J., Raoyao L. COVID-19 Patients with Gastrointestinal Symptoms Are More Likely to Develop into Severe Cases «Science and Technology Daily», 21.04.2020 https://gmcc.alibabadoctor.com/news/detail?content_id=1496ca6b1c270a6e8a38ddf92471d795Qing Y., Wenyang J., Raoyao L. COVID-19 Patients with Gastrointestinal Symptoms Are More Likely to Develop into Severe Cases «Science and Technology Daily», 21.04.2020 https://gmcc.alibabadoctor.com/news/detail?content_id=1496ca6b1c270a6e8a38ddf92471d795Белобородова Н.В. «Сепсис. Метаболомный подход». Монография. М.: Издательство Медицинское информационное агентство «МИА»; 2018. 272. ISBN: 978-5-9986-0350-1Beloborodova N.V. «Sepsis. The metabolic approach». Monograph. M.: Publishing house Medical information agency «MIA»; 2018. 272 [In Russ.]. ISBN: 978-5-9986-0350-1Beloborodova N.V., Sarshor Yu.N., Bedova A.Yu., Chernevskaya E.A., Pautova A.K. Involvement of Aromatic Metabolites in the Pathogenesis of Septic Shock. SHOCK. 2018; 50 (3): 273-279. DOI: 10.1097/SHK.0000000000001064Beloborodova N.V., Sarshor Yu.N., Bedova A.Yu., Chernevskaya E.A., Pautova A.K. Involvement of Aromatic Metabolites in the Pathogenesis of Septic Shock. SHOCK. 2018; 50 (3): 273-279. DOI: 10.1097/SHK.0000000000001064Beloborodova N.V., Olenin A.Yu., Pautova A.K. Metabolomic findings in sepsis as a damage of host-microbial metabolism integration. J. of Crit. Care. 2018; 43: 246-255. DOI: 10.1016/j.jcrc.2017.09.014Beloborodova N.V., Olenin A.Yu., Pautova A.K. Metabolomic findings in sepsis as a damage of host-microbial metabolism integration. J. of Crit. Care. 2018; 43: 246-255. DOI: 10.1016/j.jcrc.2017.09.014Черневская Е.А., Белобородова Н.В. Микробиота кишечника при критических состояниях (обзор). Общая реаниматология. 2018. 14 (5): 96-119. DOI: 10.15360/1813-9779-2018-5-96-119Chernevskaya E.A., Beloborodova N.V. Gut Microbiome in Critical Illness (Review). Obshchaya Reanimatologiya=General Reanimatology 2018; 14 (5): 96-119.[In Russ.] DOI: 10.15360/1813-9779-2018-5-96-119Beloborodova N.V., Grechko A.V., Olenin A.Yu. Chapter «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology» in Book «Infection and Sepsis» InTechOpen [online first]. DOI: 10.5772/intechopen.87176Beloborodova N.V., Grechko A.V., Olenin A.Yu. Chapter «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology» in Book «Infection and Sepsis» InTechOpen [online first]. DOI: 10.5772/intechopen.87176Белобородова Н.В. Метаболизм микробиоты при критических состояниях (обзор и постулаты). Общая реаниматология. 2019; 15 (6), 62-79. DOI: 10.15360/1813-9779-2019-6-62-79Beloborodova N.V. Metabolism of Microbiota in Critical Illness (Review and Postulates). Obshchaya Reanimatologiya=General Reanimatology. 2019; 15 (6): 62-79 [In Russ.]. DOI: 10.15360/1813-9779-2019-6-62-79Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19). Временные методические рекомендации МЗ РФ. Версия 3 (03.03.2020), раздел 4.5.1. Особенности клинических проявлений. https://www.garant.ru/products/ipo/prime/doc/73647088/Prevention, diagnosis and treatment of new coronavirus infection (COVID-19). Temporary guidelines of the Ministry of Health of the Russian Federation. Version 3 (03.03.2020), section 4.5.1. Features of clinical manifestations [In Russ.] https://www.garant.ru/products/ipo/prime/doc/73647088/Carsana L., Sonzogni A., Nasr A., Rossi R., Pellegrinelli A., Zerbi P., Rech R., Colombo R., Antinori S., Corbellino M., Galli M., Catena E., Tosoni A., Gianatti A., Nebuloni M. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv. DOI: 10.1101/2020.04.19.20054262CarsanaL., SonzogniA., Nasr A., RossiR., PellegrinelliA., Zerbi P, Rech R., Colombo R., Antinori S., Corbellino M., Galli M., Catena E., Tosoni A., Gi-anatti A., Nebuloni M. Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy. COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv. DOI: 10.1101/2020.04.19.20054262Зайратьянц О.В., СамсоноваМ.В., МихалеваЛ.М., Черняев А.Л., Мишнев О.Д., Крупнов Н.М. Патологическая анатомия легких при COVID-19: атлас. Москва; Рязань: Издательство ГУП РО «Рязанская областная типография», 2020. — 52 с., ил. 62Zayratyants O.V., Samsonova M.V., Mikhaleva L.M., Chernyaev A.L., Mishnev O.D., Krupnov N.M. Pathological anatomy of the lungs in COVID-19: an atlas. Moscow; Ryazan: Publishing house GUP RO «Ryazan Regional Printing House», 2020. — 52 p., il. 62 [In Russ.]Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Zh., Xiang J., Wang Y., Song B., Gu X., Guan L., Wei Y., Li H., Wu X., Xu J., Tu Sh., Zhang Y., Chen H., Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395: 1054-1062. DOI: 10.1016/S0140-6736(20)30566-3.Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Zh., Xiang J., Wang Y., Song B., Gu X., Guan L., Wei Y., Li H., Wu X., Xu J., Tu Sh., Zhang Y., Chen H., Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395: 1054-1062. DOI: 10.1016/S0140-6736(20)30566-3.Self W.H., Balk R.A., Grijalva C.G., Williams D.J., Zhu Y., Anderson E.J., Waterer G.W., Courtney D.M., Bramley A.M., Trabue Ch., Fakhran Sh., Blaschke A.J., Jain S., Edwards K.M., Wunderink R.G. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia (multicenter study). Clin Infect Dis. 2017; 65 (2): 183-190. DOI: 10.1093/cid/cix317. PMID: 28407054Self W.H., Balk R.A., Grijalva C.G., Williams D.J., Zhu Y., Anderson E.J., Waterer G.W., Courtney D.M., Bramley A.M., Trabue Ch., Fakhran Sh., Blaschke A.J., Jain S., Edwards K.M., Wunderink R.G. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia (multicenter study). Clin Infect Dis. 2017; 65 (2): 183-190. DOI: 10.1093/cid/cix317. PMID: 28407054Grondman I., Pirvu A., Riza A., Ioana M., Mihai G., Netea M.G. Biomarkers of inflammation and the etiology of sepsis. Review Article. Biochemical Society Transactions. 2020; 48: 1-14. DOI: 10.1042/BST20190029.Grondman I., Pirvu A., Riza A., Ioana M., Mihai G., Netea M.G. Biomarkers of inflammation and the etiology of sepsis. Review Article. Biochemical Society Transactions. 2020; 48: 1-14. DOI: 10.1042/BST20190029.Guan W.-J., Ni Z.-Y., Hu Y., Liang W.-H., Ou Ch.-Q., He J.-X., Liu L., Shan H., Lei Ch.-L., Hui D.S.C., Du B., Li L.-J., Zeng G., Yuen K.-Y., Chen R.-Ch., Tang Ch.-L., Wang T., Chen P.-Y., Xiang J., Li Sh.-Y., Wang J.-L., Liang Z.-J., Peng Y.-X., Wei L., Liu Y., Hu Y.-H., Peng P., Wang J.-M., Liu J.-Y., Chen Zh., Li G., Zheng Zh.-J., Qiu Sh.-Q., Luo J., Ye Ch.-J., Zhu Sh.-Y., Zhong N.-Sh., China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. New Engl J Med. 2020; 382 (18): 1708-1720. NEJM. org. DOI: 10.1056/NEJMoa2002032. PMID: 32109013Guan W.-J., Ni Z.-Y., Hu Y., Liang W.-H., Ou Ch.-Q., He J.-X., Liu L., Shan H., Lei Ch.-L., Hui D.S.C., Du B., Li L.-J., Zeng G., Yuen K.-Y., Chen R.-Ch., Tang Ch.-L., Wang T., Chen P.-Y., Xiang J., Li Sh.-Y., Wang J.-L., Liang Z.-J., Peng Y.-X., Wei L., Liu Y., Hu Y.-H., Peng P., Wang J.-M., Liu J.-Y., Chen Zh., Li G., Zheng Zh.-J., Qiu Sh.-Q., Luo J., Ye Ch.-J., Zhu Sh.-Y., Zhong N.-Sh., China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. New Engl J Med. 2020; 382 (18): 1708-1720. NEJM. org. DOI: 10.1056/NEJMoa2002032. PMID: 32109013Lippi G., Plebani M. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A Meta-analysis. Clinica Chimica Acta. 2020; 505: 190-191. DOI: 10.1016/j.cca.2020.03.004Lippi G., Plebani M. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A Meta-analysis. Clinica Chimica Acta. 2020; 505: 190-191. DOI: 10.1016/j.cca.2020.03.004Jereb M., Kotar T. Usefulness of procalcitonin to differentiate typical from atypical community-acquired pneumonia. Wien Klin Wochen-schr. 2006; Apr; 118 (5-6): 170-174. DOI: 10.1007/s00508-006-0563-8Jereb M., Kotar T. Usefulness of procalcitonin to differentiate typical from atypical community-acquired pneumonia. Wien Klin Wochen-schr. 2006; Apr; 118 (5-6): 170-174. DOI: 10.1007/s00508-006-0563-8COVID-19 rapid guideline: antibiotics for pneumonia in adults in hospital. National Institute for Health and Care Excellence (NICE). NICE guideline [NG173] Published date: 01 May 2020. https://www.nice.org.uk/guidance/ng173COVID-19 rapid guideline: antibiotics for pneumonia in adults in hospital. National Institute for Health and Care Excellence (NICE). NICE guideline [NG173] Published date: 01 May 2020. https://www.nice.org.uk/guidance/ng173Sorbera L.A., Graul A.I., Dulsat C. Taking aim at a fast-moving target: targets to watch for SARS-CoV-2 and COVID-19. Drugs of the Future. 2020; 45 (4): 1-6 (Advanced Publication). DOI: 10.1358/dof.2020.45.4.3150676SorberaLA., Graul A.I., DulsatC. Taking aim at a fast-moving target: targets to watch for SARS-CoV-2 and COVID-19. Drugs of the Future. 2020; 45 (4): 1-6 (Advanced Publication). DOI: 10.1358/dof.2020.45.4.3150676Bhattacharya S., Sen N., Yiming M.T., Patel R., Parthasarathi K., Quadri S., Issekutz A.C., Bhattacharya J. High tidal volume ventilation induces proinflammatory signaling in rat lung endothelium. Am J Respir Cell Mol Biol. 2003; 28: 218-224. DOI: 10.1165/rcmb.4763.Bhattacharya S., Sen N., Yiming M.T., Patel R., Parthasarathi K., Quadri S., Issekutz A.C., Bhattacharya J. High tidal volume ventilation induces proinflammatory signaling in rat lung endothelium. Am J Respir Cell Mol Biol. 2003; 28: 218-224. DOI: 10.1165/rcmb.4763.Ries C., Petrides P.E. Cytokine regulation of matrix metalloproteinase activity and its regulatory dysfunction in disease. Biol Chem Hoppe Seyler. 1995; 376 (6): 345-355. PMID: 7576228Ries C., Petrides P.E. Cytokine regulation of matrix metalloproteinase activity and its regulatory dysfunction in disease. Biol Chem Hoppe Seyler. 1995; 376 (6): 345-355. PMID: 7576228Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem. 1997; 378: 151-160. PMID: 9165065Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem. 1997; 378: 151-160. PMID: 9165065Bode W., Maskos K. Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases. Review. Biol Chem. 2003; 384 (6): 863-872. DOI: 10.1515/BC.2003.097.Bode W., Maskos K. Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases. Review. Biol Chem. 2003; 384 (6): 863-872. DOI: 10.1515/BC.2003.097.Castro M.M., Kandasamy A.D., Youssef N., Schulz R. Matrix Metalloproteinase Inhibitor Properties of Tetracyclines: Therapeutic Potential in Cardiovascular Diseases. Pharmacol Res. 2011; 64 (6): 551-560. Epub 2011 May 31. DOI: 10.1016/j.phrs.2011.05.005.Castro M.M., Kandasamy A.D., Youssef N., Schulz R. Matrix Metalloproteinase Inhibitor Properties of Tetracyclines: Therapeutic Potential in Cardiovascular Diseases. Pharmacol Res. 2011; 64 (6): 551-560. Epub 2011 May 31. DOI: 10.1016/j.phrs.2011.05.005.Acharya M.R., Venitz J., Figg W.D. Sparreboom A. Chemically modified tetracyclines as inhibitors of matrix metalloproteinases. Drug Resistance Updates.2004; 7 (3): 195-208. DOI: 10.1016/j.drup.2004.04.002Acharya M.R., Venitz J., Figg W.D. Sparreboom A. Chemically modified tetracyclines as inhibitors of matrix metalloproteinases. Drug Resistance Updates.2004; 7 (3): 195-208. DOI: 10.1016/j.drup.2004.04.002Steinberg J., Fink G., Picone A., Searles B., Schiller H., Lee H.M., Nieman G. Evidence of increased matrix metalloproteinase-9 concentration in patients following cardiopulmonary bypass. J Extra Corpor Tech-nol. 2001; 33: 218-222. PMID: 11806432Steinberg J., Fink G., PiconeA., Searles B., Schiller H., Lee H.M., Nieman G. Evidence of increased matrix metalloproteinase-9 concentration in patients following cardiopulmonary bypass. J Extra Corpor Tech-nol. 2001; 33: 218-222. PMID: 11806432Lin T.C., Li C.Y., Tsai C.S., Ku C.H., Wu C.T., Wong C.S., Ho S.T. Neutrophil-mediated secretion and activation of matrix metalloproteinase-9 during cardiac surgery with cardiopulmonary bypass. Anesth Analg. 2005; 100 (6): 1554-1560. DOI: 10.1213/01.ANE.0000154307.92060.84Lin T.C., Li C.Y., Tsai C.S., Ku C.H., Wu C.T., Wong C.S., Ho S.T. Neutrophil-mediated secretion and activation of matrix metalloproteinase-9 during cardiac surgery with cardiopulmonary bypass. Anesth Analg. 2005; 100 (6): 1554-1560. DOI: 10.1213/01.ANE.0000154307.92060.84Joffs C., Gunasinghe H.R., Multani M.M., Dorman B.H., Kratz J.M., Crumbley A.J. 3rd, Crawford F.A. Jr., Spinale F.G. Cardiopulmonary bypass induces the synthesis and release of matrix metalloproteinases. Ann Thorac Surg. 2001; 71: 1518-1523. DOI: 10.1016/s0003-4975(01)02442-0Joffs C., Gunasinghe H.R., Multani M.M., Dorman B.H., Kratz J.M., Crumbley A.J. 3rd, Crawford F.A. Jr., Spinale F.G. Cardiopulmonary bypass induces the synthesis and release of matrix metalloproteinases. Ann Thorac Surg. 2001; 71: 1518-1523. DOI: 10.1016/s0003-4975(01)02442-0Zhang C., Gong W., Liu H., Guo Z., Ge S. Inhibition of matrix metalloproteinase-9 with low-dose doxycycline reduces acute lung injury induced by cardiopulmonary bypass. Int J Clin Exp Med. 2014; 7 (12): 4975-82. eCollection 2014. PMID: 25663995. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307442/Zhang C., Gong W., Liu H., Guo Z., Ge S. Inhibition of matrix metalloproteinase-9 with low-dose doxycycline reduces acute lung injury induced by cardiopulmonary bypass. Int J Clin Exp Med. 2014; 7 (12): 4975-82. eCollection 2014. PMID: 25663995. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307442/Dalvi P.S., Singh A., Trivedi H.R., Ghanchi1 F.D., Parmar D.M., Mistry S.D. Effect of doxycycline in patients of moderate to severe chronic obstructive pulmonary disease with stable symptoms. Annals of Thoracic Medicine. 2011; 6 (4): 221-226. http: //www.thoracicmedicine.org. DOI: 10.4103/1817-1737.84777Dalvi P.S., Singh A., Trivedi H.R., Ghanchi1 F.D., Parmar D.M., Mistry S.D. Effect of doxycycline in patients of moderate to severe chronic obstructive pulmonary disease with stable symptoms. Annals of Thoracic Medicine. 2011; 6 (4): 221-226. http: //www.thoracicmedicine.org. DOI: 10.4103/1817-1737.84777Doroszko A., Hurst Th.S., Polewicz D., Sawicka J., J. Fert-Bober, D.H. Johnson, G. Sawicki. Effects of MMP-9 inhibition by doxycycline on proteome of lungs in high tidal volume mechanical ventilation-induced acute lung injury. Proteome Sci. 2010; 8: 3. Published online 2010 Jan 29. DOI: 10.1186/1477-5956-8-3. PMCID: PMC2824689 PMID: 20205825 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824689/Doroszko A., Hurst Th.S., Polewicz D., Sawicka J., J. Fert-Bober, D.H. Johnson, G. Sawicki. Effects of MMP-9 inhibition by doxycycline on proteome of lungs in high tidal volume mechanical ventilation-induced acute lung injury. Proteome Sci. 2010; 8: 3. Published online 2010 Jan 29. DOI: 10.1186/1477-5956-8-3. PMCID: PMC2824689 PMID: 20205825 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824689/Sochor M., Richter S., Schmidt A., Hempel S., Hopt U.T., Keck T. Inhibition of Matrix Metalloproteinase-9 with Doxycycline Reduces Pancreatitis-Associated Lung Injury. Digestion. 2009; 80 (2): 65-73. DOI: 10.1159/000212080Sochor M., Richter S., Schmidt A., Hempel S., Hopt U.T., Keck T. Inhibition of Matrix Metalloproteinase-9 with Doxycycline Reduces Pancreatitis-Associated Lung Injury. Digestion. 2009; 80 (2): 65-73. DOI: 10.1159/000212080Зырянов С.К., Голуб А.В., Козлов Р.С. Доксициклин в современной клинической практике. Клиническая микробиология и антимикробная химиотерапия. 2020; 22 (1): 21-28. DOI: 10.36488/cmac.2020.1.21-28Zyryanov S.K., Golub A.V., Kozlov R.S. Doxycycline in the current clinical practice. Klinicheskaya mikrobiologiya i antimikrobnaya khimioterapiya.2020; 22 (1): 21-28 [In Russ.]. DOI: 10.36488/cmac.2020.1.21-28Wormser G.P., Dattwyler R.J., Shapiro E.D., Halperin J.J., Steere A.C., Klempner M.S., Krause P.J., Bakken J.S., Strle F., Stanek G., Bockenstedt L., Fish D., Dumler J.S., Nadelman R.B. The clinical assessment, treatment and prevention of Lyme disease, human granulocytic anaplas-mosis and babesiosis: clinical practice guidelines by the infectious diseases society of America. Clin Infect Dis. 2006; 43 (9): 1089-1134. DOI: 10.1086/508667Wormser G.P., Dattwyler R.J., Shapiro E.D., Halperin J.J., Steere A.C., Klempner M.S., Krause P.J., Bakken J.S., Strle F., Stanek G., Bockenstedt L., Fish D., Dumler J.S., Nadelman R.B. The clinical assessment, treatment and prevention of Lyme disease, human granulocytic anaplas-mosis and babesiosis: clinical practice guidelines by the infectious diseases society of America. Clin Infect Dis. 2006; 43 (9): 1089-1134. DOI: 10.1086/508667van Zuuren E.J., Kramer S., Carter B., Graber M.A., Fedorowicz Z. Interventions for rosacea. Cochrane Database Syst Rev. 2011; 3: CD003262. DOI: 10.1002/14651858.CD003262.pub4van Zuuren E.J., Kramer S., Carter B., Graber M.A., Fedorowicz Z. Interventions for rosacea. Cochrane Database Syst Rev. 2011; 3: CD003262. DOI: 10.1002/14651858.CD003262.pub4MUllegger R.R., Glatz M. Skin manifestations of lime borreliosis: diagnosis and management. Am J Clin Dermatol. 2008; 9 (6): 355-368. DOI: 10.2165/0128071-200809060-00002MUllegger R.R., Glatz M. Skin manifestations of lime borreliosis: diagnosis and management. Am J Clin Dermatol. 2008; 9 (6): 355-368. DOI: 10.2165/0128071-200809060-00002Torresani C., Pavesi A., Manara G.C. Clarithromycin versus doxycycline in the treatment of rosacea. Int J Dermatol. 1997; 36 (12): 938946. DOI: 10.1046/j.1365-4362.1997.00301.xTorresani C., Pavesi A., Manara G.C. Clarithromycin versus doxycycline in the treatment of rosacea. Int J Dermatol. 1997; 36 (12): 938946. DOI: 10.1046/j.1365-4362.1997.00301.xHeneghan С., Aronson J., Hobbs R., Mahtani K. Rapidly managing pneumonia in older people during a pandemic. The Centre for Evidence-Based Medicine (CEBM). Oxford COVID-19 Evidence Service Team. March 16, 2020 https://www.cebm.net/covid-19/rapidly-managing-pneumonia-in-older-people-during-a-pandemic/Heneghan С., Aronson J., Hobbs R., Mahtani K. Rapidly managing pneumonia in older people during a pandemic. The Centre for Evidence-Based Medicine (CEBM). Oxford COVID-19 Evidence Service Team. March 16, 2020 https://www.cebm.net/covid-19/rapidly-managing-pneumonia-in-older-people-during-a-pandemic/Dalvi P. S, Singh A., Trivedi H. R, Ghanchi F. D, Parmar D.M, Mistry S.D. Effect of Doxycycline in Patients of Moderate to Severe Chronic Obstructive Pulmonary Disease With Stable Symptoms. Ann Thorac Med 2011; 6 (4): 221-226. DOI: 10.4103/1817-1737.84777Dalvi P. S, Singh A., Trivedi H. R, Ghanchi F. D, Parmar D.M, Mistry S.D. Effect of Doxycycline in Patients of Moderate to Severe Chronic Obstructive Pulmonary Disease With Stable Symptoms. Ann Thorac Med 2011; 6 (4): 221-226. DOI: 10.4103/1817-1737.84777van der Waaij D. Colonization Resistance of the Digestive Tract — Mechanism and Clinical Consequences. Nahrung 1987; 31 (5-6): 507517 DOI: 10.1002/food.19870310551van der Waaij D. Colonization Resistance of the Digestive Tract — Mechanism and Clinical Consequences. Nahrung 1987; 31 (5-6): 507517 DOI: 10.1002/food.19870310551Vollaard E.J., Clasener H.A..L, Van Griethuysen A.J.A., Janssen A.J.H.M., Sanders-Reimers A.H.J., Muller N.F., Huige P.J. Influence of cefaclor, phenethicillin, co-trimoxazole and doxycycline on colonization resistance in healthy volunteers. J Antimicrob Chemother. 1988; 22 (5): 747-758. DOI: 10.1093/jac/22.5.747.Vollaard E.J., Clasener H.A..L, Van Griethuysen A.J.A., Janssen A.J.H.M., Sanders-Reimers A.H.J., Muller N.F., Huige P.J. Influence of cefaclor, phenethicillin, co-trimoxazole and doxycycline on colonization resistance in healthy volunteers. J Antimicrob Chemother. 1988; 22 (5): 747-758. DOI: 10.1093/jac/22.5.747.Gorbach S.L., Barza M., Giuliano M., Jacobus N.V. Colonization resistance of the human intestinal microflora: testing the hypothesis in normal volunteers. Eur J Clin Microbiol Infect Dis. 1988; 7 (1): 98-102. DOI: 10.1007/BF0196219Gorbach S.L., Barza M., Giuliano M., Jacobus N.V. Colonization resistance of the human intestinal microflora: testing the hypothesis in normal volunteers. Eur J Clin Microbiol Infect Dis. 1988; 7 (1): 98-102. DOI: 10.1007/BF0196219Vollaard E.J., Clasener H.A., van Saene H.K., Muller N.F. Effect on colonization resistance: an important criterion in selecting antibiotics. Drug Intel. and Clin. Pharm. 1990; 24 (1): 60-66. DOI: 10.1177/106002809002400113Vollaard E.J., Clasener H.A., van Saene H.K., Muller N.F. Effect on colonization resistance: an important criterion in selecting antibiotics. Drug Intel. and Clin. Pharm. 1990; 24 (1): 60-66. DOI: 10.1177/106002809002400113

The authors declare that there are no conflicts of interest present.