Каковы ограничения для использования перенацеленных препаратов для лечения COVID-19?

Использование перенацеленных лекарств основывается на предположении, что польза (in vitro / клинические данные) перевешивает связанные с этим риски (побочные реакции на лекарства). Одним из ограничений использования является склонность этих препаратов вызывать острую токсичность. Эта острая токсичность может перевесить неопределенную пользу конкретного противовирусного средства. Повышенная токсичность при комбинированной терапии, такая как кардио или печеночная токсичность, создает потенциальный дополнительный риск и потребность в тщательном анализе риск/польза. В целом, недостаток доказательств, демонстрирующих явную пользу, не может оправдать риск применения таких препаратов. Наибольшая обеспокоенность должна быть для пациентов с высоким риском токсичности и в ситуациях, когда побочное действие может помешать включить пациента в клиническое исследование.

 

 

АПФ обозначает ангиотензинпревращающий фермент; БРА, блокатор ангиотензиновых рецепторов; COVID-19, коронавирусная инфекция 2019; и SARS- CoV-2, тяжелый острый респираторный синдром, коронавирус 2.

 

 

Во вставке 1 приведены ссылки на основные американские и международные руководящие документы по клиническому лечению и другие полезные ресурсы по межлекарственному взаимодействий и рекомендации для отдельных популяций больных. Во вставке 2 приведены ответы на часто задаваемые вопросы врачей о клиническом ведении пациентов с COVID-19.

 

 

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Ограничения

Этот обзор имеет несколько ограничений. Во-первых, огромный объем и быстрый темп публикования литературы по лечению COVID-19 означает, что результаты исследований и

 

 

Выводы

Review Clinical Review & Education

рекомендации постоянно развиваются по мере появления новых данных. Во-вторых, опубликованные данные о лечении на сегодняшний день основаны исключительно на обсервационных данных или небольших клинических исследованиях (ни в одном не было более 250 пациентов), что указывает на более высокий риск систематической ошибки или неточности в отношении величины лечебного эффекта. В-третьих, наш обзор сфокусирован только на взрослых пациентах, и данные могут быть не применимы к детям. В-четвертых, статьи ограничивались публикациями или переводами на английском языке, поэтому соответствующие международные данные могли отсутствовать.

Пандемия COVID-19 представляет собой величайший глобальный кризис общественного здравоохранения этого поколения, возможно, со времени вспышки пандемического гриппа в 1918 году. Скорость и объем клинических исследований, начатых для изучения потенциальных методов лечения COVID-19, подчеркивают как необходимость, так и способность производить качественные данные даже в середине пандемии. На сегодняшний день не было найдено эффективных методов лечения.

 

 

 

ARTICLE INFORMATION

Accepted for Publication: April 3, 2020.

Published Online: April 13, 2020. doi:10.1001/jama.2020.6019

Author Contributions: Dr Cutrell had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data:

Monogue, Jodlowski, Cutrell.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Monogue, Jodlowski, Cutrell. Administrative, technical, or material support: Cutrell.

Supervision: Cutrell.

Conflict of Interest Disclosures: Dr Cutrell reported receiving nonfinancial support from Regeneron and Gilead outside the submitted work. No other disclosures were reported.

Additional Contributions: We acknowledge our infectious disease physician and pharmacy colleagues at UT Southwestern and its respective hospital sites, Clements University Hospital, Parkland Hospital, and the VA North Texas Health Care System for their thoughtful discussions regarding COVID-19 clinical management.

Submissions: We encourage authors to submit papers for consideration as a Review. Please contact Edward Livingston, MD, at Edward. [email protected] or Mary McGrae McDermott, MD, at [email protected].

REFERENCES

1. Zhu N, Zhang D, Wang W, et al; China Novel Coronavirus Investigating and Research Team.

A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-733. doi:10.1056/NEJMoa2001017

2. Chinese Clinical Trials. http://www/chictr.org/ enindex.aspx. Accessed March 31, 2020.

3. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. Published online March 4, 2020. doi:10.1016/j.cell.2020.02.052

4. Chen Y, Liu Q, Guo D. Emerging coronaviruses: genome structure, replication, and pathogenesis.

J Med Virol. 2020;92(4):418-423. doi:10.1002/jmv. 25681

5. Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods

Mol Biol. 2015;1282:1-23. doi:10.1007/978-1-4939- 2438-7_1

6. Fung TS, Liu DX. Coronavirus infection, ER stress, apoptosis and innate immunity. Front Microbiol. 2014;5:296. doi:10.3389/fmicb.2014. 00296

7. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect Dis. 2003;3(11):722-727. doi:10.1016/S1473-3099(03) 00806-5

8. Al-Bari MAA. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol Res Perspect. 2017;5(1):e00293. doi:10. 1002/prp2.293

9. Zhou D, Dai SM, Tong Q. COVID-19:

a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. [published online March 20, 2020]. J Antimicrob Chemother. 2020;dkaa114. doi:10. 1093/jac/dkaa114

10. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. Published online March 11, 2020. doi:10.1016/j.ijantimicag.2020.105938

11. Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J

Antimicrob Agents. Published online March 4, 2020. doi:10.1016/j.ijantimicag.2020.105932

12. National Health Commission and State Administration of Traditional Chinese Medicine. Diagnosis and treatment protocol for novel coronavirus pneumonia. Accessed March 18, 2020. https://www.chinalawtranslate.com/wp-content/ uploads/2020/03/Who-translation.pdf

13. Chloroquine [database online]. Hudson, OH: Lexicomp Inc; 2016. Accessed March 17, 2020. http://online.lexi.com

14. Aralen (chloroquine phosphate) [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2008. Accessed March 17, 2020. https://www.accessdata. fda.gov/drugsatfda_docs/label/2018/ 006002s045lbl.pdf

15. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2

(SARS-CoV-2). Clin Infect Dis. Published online March 9, 2020. doi:10.1093/cid/ciaa237

16. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label

non-randomized clinical trial. Int J Antimicrob Agents. Published online March 20, 2020. doi:10.1016/j. ijantimicag.2020.105949

17. Chen J, Liu D, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19).

J Zhejiang Univ (Med Sci). Published online March 6, 2020. doi:10.3785/j.issn.1008-9292.2020.03.03

18. Hydroxychloroquine [database online]. Hudson, OH: Lexicomp Inc; 2016. Accessed March 17, 2020. http://online.lexi.com

19. Plaquenil (Hydroxychloroquine sulfate) [package insert]. St Michael, Barbados: Concordia Pharmaceuticals Inc; 2018. Accessed March 17, 2020. https://www.accessdata.fda.gov/drugsatfda_ docs/label/2019/009768Orig1s051lbl.pdf

20. Lim HS, Im JS, Cho JY, et al. Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax. Antimicrob Agents Chemother. 2009;53(4):1468-1475. doi:10.1128/AAC.00339-08

21. Chu CM, Cheng VC, Hung IF, et al; HKU/UCH SARS Study Group. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-256. doi:10.1136/ thorax.2003.012658

22. de Wilde AH, Jochmans D, Posthuma CC, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014; 58(8):4875-4884. doi:10.1128/AAC.03011-14

23. Cao B, Wang Y, Wen D, et al. A trial of

lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. Published online March 18, 2020. doi:10.1056/NEJMoa2001282

24. Lopinavir/ritonavir [database online]. Hudson (OH): Lexicomp Inc; 2016. Accessed March 17, 2020. http://online.lexi.com

25. Kaletra (Lopinavir and ritonavir) [package insert]. North Chicago, IL: Abbvie; 2019. Accessed March 17, 2020. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2019/021226s048lbl.pdf

26. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral

 

jama.com                                                                                                                                                                                                     E11

Clinical Review & Education Review                                                                    Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19)

 

agents in adults and adolescents with HIV. Accessed March 17, 2020. http://www.aidsinfo.nih. gov/ContentFiles/ AdultandAdolescentGL.pdf

27. Kadam RU, Wilson IA. Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc Natl Acad SciUS A. 2017;114(2):206- 214. doi:10.1073/pnas.1617020114

28. Khamitov RA, Loginova SIa, Shchukina VN, Borisevich SV, Maksimov VA, Shuster AM. Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures [in Russian]. Vopr Virusol. 2008;53 (4):9-13.

29. Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical Features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis. Published online March 16, 2020. doi:10.1093/cid/ciaa272

30. Siegel D, Hui HC, Doerffler E, et al. Discovery and synthesis of a phosphoramidate prodrug of

a pyrrolo[2,1-f][triazin-4-amino] adenine

C-nucleoside (GS-5734) for the treatment of Ebola and emerging viruses. J Med Chem. 2017;60(5): 1648-1661. doi:10.1021/acs.jmedchem.6b01594

31. Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible therapeutic option for the COVID-19. Travel Med Infect Dis. Published online March 5, 2020. doi:10.1016/j.tmaid.2020.101615

32. 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(1):222. doi:10.1038/s41467-019-13940-6

33. Hayden FG, Shindo N. Influenza virus polymerase inhibitors in clinical development. Curr Opin  Infect  Dis. 2019;32(2):176-186. doi:10.1097/ QCO.0000000000000532

34. Avigan (favipiravir) [package insert]. Tokyo, Japan: Taisho Toyama Pharmaceutical Co Ltd; 2017, 4th version. Accessed March 25, 2020.

35. Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. chinaXiv. Preprint posted March 5, 2020. doi:10. 12074/202003.00026

36. Actemra (tocilizumab) [package insert]. South San Francisco, CA: Genentech, Inc; 2019. Accessed March 17, 2020. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2019/ 125276s127,125472s040lbl.pdf

37. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343. doi:10.1371/journal.pmed.0030343

38. 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 (3):e1977. doi:10.1002/rmv.1977

39. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020; 14(1):72-73. doi:10.5582/bst.2020.01047

40. ClinicalTrials.gov. Accessed March 18, 2020. https://clinicaltrials.gov/

41. Kalil AC. Treating COVID-19—off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA. Published March 24, 2020. doi:10.1001/jama.2020.4742

42. Interview with David Juurlink. Coronavirus (COVID-19) update: chloroquine/ hydroxychloroquine and azithromycin. JAMA. March 24, 2020. Accessed April 3, 2020. https://edhub. ama-assn.org/jn-learning/audio-player/18337225

43. Osadchy A, Ratnapalan T, Koren G. Ocular toxicity in children exposed in utero to antimalarial drugs: review of the literature. J Rheumatol. 2011; 38(12):2504-2508. doi:10.3899/jrheum.110686

44. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 2020;14(1):58-60. doi:10.5582/ddt.2020.01012

45. Yao TT, Qian JD, Zhu WY, Wang Y, Wang GQ. A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-A possible reference for coronavirus disease-19 treatment option. [published online February 27, 2020]. J Med Virol. 2020. doi:10.1002/jmv.25729

46. Chan KS, Lai ST, Chu CM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9 (6):399-406.

47. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. Published online March 13, 2020.

48. Foolad F, Aitken SL, Shigle TL, et al. Oral versus aerosolized ribavirin for the treatment of respiratory syncytial virus infections in hematopoietic cell transplant recipients. Clin Infect Dis. 2019;68(10):1641-1649. doi:10.1093/cid/ciy760

49. Arabi YM, Shalhoub S, Mandourah Y, et al. Ribavirin and interferon therapy for critically ill patients with Middle East respiratory syndrome: a multicenter observational study. Clin Infect Dis. Published online June 25, 2019. doi:10.1093/cid/ ciz544

50. Altınbas S, Holmes JA, Altınbas A. Hepatitis C virus infection in pregnancy: an update. Gastroenterol Nurs. 2020;43(1):12-21. doi:10.1097/ SGA.0000000000000404

51. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. Published online February 7, 2020. doi:10. 1001/jama.2020.1585

52. Totura AL, Bavari S. Broad-spectrum coronavirus antiviral drug discovery. Expert Opin Drug Discov. 2019;14(4):397-412. doi:10.1080/ 17460441.2019.1581171

53. Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020;19(3):149-150. doi:10.1038/d41573- 020-00016-0

54. Coleman CM, Sisk JM, Mingo RM, Nelson EA, White JM, Frieman MB. Abelson kinase inhibitors are potent inhibitors of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus fusion. J Virol. 2016;90 (19):8924-8933. doi:10.1128/JVI.01429-16

55. Dyall J, Gross R, Kindrachuk J, et al. Middle East respiratory syndrome and severe acute respiratory syndrome: current therapeutic options and potential targets for novel therapies. Drugs. 2017;77 (18):1935-1966. doi:10.1007/s40265-017-0830-1

56. Pfefferle S, Schöpf J, Kögl M, et al. The

SARS-coronavirus-host interactome: identification

of cyclophilins as target for pan-coronavirus inhibitors. PLoS Pathog. 2011;7(10):e1002331. doi: 10.1371/journal.ppat.1002331

57. de Wilde AH, Zevenhoven-Dobbe JC, van der Meer Y, et al. Cyclosporin A inhibits the replication of diverse coronaviruses.

J Gen Virol. 2011;92(pt 11):2542-2548. doi:10.1099/ vir.0.034983-0

58. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.

Cell Res. 2020;30(3):269-271. doi:10.1038/s41422- 020-0282-0

59. Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health. 2016;9(3):227-230. doi:10.1016/j.jiph.2016. 04.001

60. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. Published online March 4, 2020. doi:10.1002/ddr. 21656

61. American Heart Association. Patients taking angiotensin converting enzyme inhibitors (ACE-i) or angiotensin receptor blocker (ARB) medications should continue therapy as prescribed [news release]. Published March 17, 2020. Accessed March 18, 2020. https://newsroom.heart.org/ news/patients-taking-ace-i-and-arbs-who-contract- covid-19-should-continue-treatment-unless- otherwise-advised-by-their-physician

62. European Society for Cardiology. Position statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers. Published March 13, 2020. Accessed March 18, 2020. https://www.escardio.org/Councils/Council- on-Hypertension-(CHT)/News/position-

statement-of-the-esc-council-on-hypertension-on- ace-inhibitors-and-ang

63. World Health Organization. WHO R&D blueprint: ad-hoc expert consultation on clinical trials for Ebola therapeutics. Published October 2018. Accessed March 20, 2020. https://www.who. int/ebola/drc-2018/summaries-of-evidence- experimental-therapeutics.pdf

64. Jacobs M, Rodger A, Bell DJ, et al. Late Ebola virus relapse causing meningoencephalitis: a case report. Lancet. 2016;388(10043):498-503. doi:10. 1016/S0140-6736(16)30386-5

65. Holshue ML, DeBolt C, Lindquist S, et al; Washington State 2019-nCoV Case Investigation Team. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382(10):929-936. doi:10.1056/NEJMoa2001191

66. Kujawski SA, Wong K, Collins JP, et al. First 12 patients with coronavirus disease 2019 (COVID-19) in the United States. medRxiv. Preprint posted March 9, 2020. doi:10.1101/2020.03.09.20032896

67. Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA

polymerase. Proc Jpn Acad Ser B Phys Biol Sci. 2017; 93(7):449-463. doi:10.2183/pjab.93.027

68. Mentré F, Taburet AM, Guedj J, et al. Dose regimen of favipiravir for Ebola virus disease. Lancet Infect Dis. 2015;15(2):150-151. doi:10.1016/S1473- 3099(14)71047-3

69. Sissoko D, Laouenan C, Folkesson E, et al; JIKI Study Group. Experimental treatment with favipiravir for Ebola virus disease (the JIKI Trial):

 

E12  JAMA Published online April 13, 2020                                                                                                                                            jama.com

© 2020 American Medical Association. All rights reserved.

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19)                                                                                   Review Clinical Review & Education

 

a historically controlled, single-arm

proof-of-concept trial in Guinea [published correction appears in PLoS Med. 2016;13(4): e1002009]. PLoS Med. 2016;13(3):e1001967. doi:

10.1371/journal.pmed.1001967

70. Shiraki K, Daikoku T. Favipiravir, an

anti-influenza drug against life-threatening RNA virus infections. [published online February 22, 2020]. Pharmacol Ther. 2020;107512. doi:10.1016/j. pharmthera.2020.107512

71. Chinello P, Petrosillo N, Pittalis S, Biava G, Ippolito G, Nicastri E; INMI Ebola Team. QTc interval prolongation during favipiravir therapy in an Ebolavirus-infected patient. PLoS Negl Trop Dis. 2017;11(12):e0006034. doi:10.1371/journal.pntd. 0006034

72. Kumagai Y, Murakawa Y, Hasunuma T, et al. Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults. Int J Clin Pharmacol Ther. 2015;53(10):866-874. doi:10. 5414/CP202388

73. Chen C, Huang J, Cheng Z, et al. Favipiravir versus Arbidol for COVID-19: a randomized clinical trial. medRxiv. Preprint posted March 27, 2020. doi: 10.1101/2020.03.17.20037432

74. Liu C, Zhou Q, Li Y, et al. Research and development of therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases. ACS Cent Sci. 2020;6(3):315-331. doi:10. 1021/acscentsci.0c00272

75. Gordon DE, Jang GM, Bouhaddou M, et al.

A SARS-CoV-2-human protein-protein interaction map reveals drug targets and potential

drug-repurposing. bioRxiv. Preprint posted March 22, 2020. doi:10.1101/2020.03.22.002386

76. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020; 395(10223):473-475. doi:10.1016/S0140-6736(20) 30317-2

77. Arabi YM, Mandourah Y, Al-Hameed F, et al; Saudi Critical Care Trial Group. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018;197(6):757-767. doi:10.1164/rccm.201706- 1172OC

78. Ni YN, Chen G, Sun J, Liang BM, Liang ZA. The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis. Crit Care. 2019;23(1):99. doi:10.1186/ s13054-019-2395-8

79. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet.

2020;395(10229):1033-1034. doi:10.1016/S0140-

6736(20)30628-0

80. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with

COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3

81. Sanofi. Sanofi and Regeneron begin global Kevzara (sarilumab) clinical trial program in patients with severe COVID-19 [news release]. Published March 16, 2020. Accessed March 18, 2020. http:// www.news.sanofi.us/2020-03-16-Sanofi-and- Regeneron-begin-global-Kevzara-R-sarilumab- clinical-trial-program-in-patients-with-severe- COVID-19

82. Chen L, Xiong J, Bao L, Shi Y. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis. 2020;20(4):398-400. doi:10.1016/ S1473-3099(20)30141-9

83. Soo YO, Cheng Y, Wong R, et al. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect.

2004;10(7):676-678. doi:10.1111/j.1469-0691.2004.

00956.x

84. Arabi Y, Balkhy H, Hajeer AH, et al. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus. 2015;4:709. doi:10.1186/s40064-015-1490-9

85. Hung IF, To KK, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52(4):447-456. doi:10.1093/cid/ciq106

86. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al; 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 I n f ect Dis. 2015;211(1):80-90. doi:10.1093/infdis/ jiu396

87. Shen C, Wang Z, Zhao F, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020. Published online March 27, 2020. doi:10.1001/jama.2020.4783

88. Cao W, Liu X, Bai T, et al. High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019. Open Forum Infect Dis. Published online March 21, 2020. doi:10.1093/ofid/ofaa102

89. US Food and Drug Administration. Investigational COVID-19 Convalescent plasma: emergency INDs. Updated April 3, 2020. Accessed

March 26, 2020. https://www.fda.gov/vaccines- blood-biologics/investigational-new-drug-ind-or- device-exemption-ide-process-cber/ investigational-covid-19-convalescent-plasma- emergency-inds

90. Wang C, Li W, Drabek D, et al. A human monoclonal antibody blocking SARS-CoV-2 infection. bioRxiv. Preprint posted March 11, 2020. doi:10.1101/2020.03.11.987958.2020

91. 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

92. 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

93. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. Published online February 24, 2020. doi:10.1016/ S2213-2600(20)30079-5

94. Young BE, Ong SWX, Kalimuddin S, et al; Singapore 2019 Novel Coronavirus Outbreak Research Team. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA. Published online March 3, 2020. doi:10.1001/jama.2020.3204

95. Guan WJ, Ni ZY, Hu Y, et al; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. Published online February 28, 2020. doi:10.1056/NEJMoa2002032

96. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19) clinical care. Updated March 30, 2020. Accessed March 18, 2020. https://www.cdc.gov/coronavirus/2019- ncov/hcp/clinical-guidance-management-patients. html

97. World Health Organization. Clinical management of severe acute respiratory infection when COVID-19 is suspected. Updated March 13, 2020. Accessed March 18, 2020. https://www.who. int/publications-detail/clinical-management-of- severe-acute-respiratory-infection-when-novel- coronavirus-(ncov)-infection-is-suspected

98. Kupferschmidt K, Cohen J. WHO launches global megatrial of the four most promising coronavirus treatments. Science. Published March 22, 2020. Accessed March 23, 2020. https://www. sciencemag.org/news/2020/03/who-launches- global-megatrial-four-most-promising-coronavirus- treatments#

 

 

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