[Skip to Content]
[Skip to Content Landing]

Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19A Randomized Clinical Trial

Educational Objective
To learn the effect of treatment with convalescent plasma on clinical outcomes in patients with severe and life-threatening COVID-19.
1 Credit CME
Key Points

Question  What is the effect of convalescent plasma therapy added to standard treatment, compared with standard treatment alone, on clinical outcomes in patients with severe or life-threatening coronavirus disease 2019 (COVID-19)?

Finding  In this randomized clinical trial that included 103 patients and was terminated early, the hazard ratio for time to clinical improvement within 28 days in the convalescent plasma group vs the standard treatment group was 1.40 and was not statistically significant.

Meaning  Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment did not significantly improve the time to clinical improvement within 28 days, although the trial was terminated early and may have been underpowered to detect a clinically important difference.

Abstract

Importance  Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed.

Objective  To evaluate the efficacy and adverse effects of convalescent plasma therapy for patients with COVID-19.

Design, Setting, and Participants  Open-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, from February 14, 2020, to April 1, 2020, with final follow-up April 28, 2020. The trial included 103 participants with laboratory-confirmed COVID-19 that was severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation). The trial was terminated early after 103 of a planned 200 patients were enrolled.

Intervention  Convalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity.

Main Outcomes and Measures  Primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]). Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours.

Results  Of 103 patients who were randomized (median age, 70 years; 60 [58.3%] male), 101 (98.1%) completed the trial. Clinical improvement occurred within 28 days in 51.9% (27/52) of the convalescent plasma group vs 43.1% (22/51) in the control group (difference, 8.8% [95% CI, −10.4% to 28.0%]; hazard ratio [HR], 1.40 [95% CI, 0.79-2.49]; P = .26). Among those with severe disease, the primary outcome occurred in 91.3% (21/23) of the convalescent plasma group vs 68.2% (15/22) of the control group (HR, 2.15 [95% CI, 1.07-4.32]; P = .03); among those with life-threatening disease the primary outcome occurred in 20.7% (6/29) of the convalescent plasma group vs 24.1% (7/29) of the control group (HR, 0.88 [95% CI, 0.30-2.63]; P = .83) (P for interaction = .17). There was no significant difference in 28-day mortality (15.7% vs 24.0%; OR, 0.59 [95% CI, 0.22-1.59]; P = .30) or time from randomization to discharge (51.0% vs 36.0% discharged by day 28; HR, 1.61 [95% CI, 0.88-2.95]; P = .12). Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87.2% of the convalescent plasma group vs 37.5% of the control group (OR, 11.39 [95% CI, 3.91-33.18]; P < .001). Two patients in the convalescent plasma group experienced adverse events within hours after transfusion that improved with supportive care.

Conclusion and Relevance  Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days. Interpretation is limited by early termination of the trial, which may have been underpowered to detect a clinically important difference.

Trial Registration  Chinese Clinical Trial Registry: ChiCTR2000029757

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Authors: Zhong Liu, MD, PhD, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, 26 Huacai Rd, Longtan Industry Zone, Chenghua District, 610052, Chengdu, Sichuan, China (liuz@ibt.pumc.edu.cn); Yanyun Wu, MD, PhD, University of Miami, Department of Pathology, 1611 NW 12th Ave, Miami, FL 33136 (yxw1366@med.miami.edu).

Accepted for Publication: May 23, 2020.

Published Online: June 3, 2020. doi:10.1001/jama.2020.10044

Correction: This article was corrected on August 4. 2020, to fix some odds ratios in the Abstract, Results, and Table 3; some baseline laboratory data in Table 1; corresponding data in Supplement 3; and eFigure 1.

Author Contributions: Dr Z. Liu had full access to all of the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs L. Li, W. Zhang, and Y. Hu are co–first authors. Drs L. Li, W. Zhang, Y. Hu, X. Tong, S. Zheng, J. Yang, Y. Kong, L. Ren, Q. Wei, H. Mei, C. Hu, C. Tao, R. Yang, J. Wang, and Y. Yu contributed equally to the study.

Concept and design: L. Li, W. Zhang, X. Tong, J. Yang, N. Xiong, L. Zhang, J.W. Wang, Y. Wu, Z. Liu.

Acquisition, analysis, or interpretation of data: W. Zhang, S. Zheng, Y. Kong, L. Ren, Q. Wei, H. Mei, C. Hu, C. Tao, R. Yang, Jue Wang, Y. Yu, Y. Guo, X. Wu, Z. Xu, N. Xiong, L. Chen, Juan Wang, N. Man, Y. Liu, H. Xu, E. Deng, X. Zhang, C. Li, C. Wang, S. Su, Y. Hu, Y. Wu, Z. Liu.

Drafting of the manuscript: L. Li, W. Zhang, Y. Kong, L. Ren, H. Xu, E. Deng, C. Wang, Y. Wu, Z. Liu.

Critical revision of the manuscript for important intellectual content: W. Zhang, X. Tong, S. Zheng, J. Yang, Q. Wei, H. Mei, C. Hu, C. Tao, R. Yang, Jue Wang, Y. Yu, Y. Guo, X. Wu, Z. Xu, L. Zeng, N. Xiong, L. Chen, Juan Wang, N. Man, Y. Liu, X. Zhang, C. Li, S. Su, L. Zhang, Juan Wang, Y. Hu, Y. Wu, Z. Liu.

Statistical analysis: J. Yang, Y. Kong, Y. Yu.

Obtained funding: L. Li, Z. Liu.

Administrative, technical, or material support: L. Li, W. Zhang, X. Tong, L. Ren, H. Mei, Jue Wang, Y. Guo, N. Xiong, Y. Liu, H. Xu, E. Deng, C. Wang, S. Su, J.W. Wang, Z. Liu.

Supervision: W. Zhang, J. Yang, H. Mei, Y. Hu.

Conflict of Interest Disclosures: Dr Liu reports holding a pending patent on COVID-19 testing. Dr Wu reports consulting for Verax Medical and Grifols, receiving royalties from UptoDate and AABB, and being a volunteer visiting professor and receiving travel support for giving medical education from the Chinese Institute of Blood Transfusion. No other disclosures were reported.

Funding/Support: This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS) grants 2020-I2M-CoV19-006, 2016-I2M-3-024 (Dr Z. Liu), and 2017-I2M-1-009 (Dr L. Li) and the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences grant 2018PT32016 (Dr Z. Liu).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We would like to thank the following individuals for their guidance, expertise, and assistance with the study design: Peter W. Marks, MD, PhD, Center for Biologics Evaluation and Research, FDA; Anne Eder, MD, PhD, Center for Biologics Evaluation and Research, FDA; Nicole Verdun, MD, Center for Biologics Evaluation and Research, FDA; Tim Uyeki, MD, MPH, MPP, National Center for Immunization and Respiratory Diseases, CDC; Scott Koepsell, MD, PhD, University of Nebraska Medical Center; Annie Winkler, MD, Instrumentation Laboratory; Xuan Qin, PhD, Seattle Children’s Hospital and University of Washington. None received compensation related to this study.

References
1.
Wang  D , Hu  B , Hu  C ,  et al.  Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.   JAMA. 2020;323(11):1061-1069. doi:10.1001/jama.2020.1585 PubMedGoogle ScholarCrossref
2.
Wu  Z , McGoogan  JM .  Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.   JAMA. 2020;323(13):1239-1242. doi:10.1001/jama.2020.2648 PubMedGoogle ScholarCrossref
3.
Garraud  O , Heshmati  F , Pozzetto  B ,  et al.  Plasma therapy against infectious pathogens, as of yesterday, today and tomorrow.   Transfus Clin Biol. 2016;23(1):39-44. doi:10.1016/j.tracli.2015.12.003 PubMedGoogle ScholarCrossref
4.
Cheng  Y , Wong  R , Soo  YO ,  et al.  Use of convalescent plasma therapy in SARS patients in Hong Kong.   Eur J Clin Microbiol Infect Dis. 2005;24(1):44-46. doi:10.1007/s10096-004-1271-9 PubMedGoogle ScholarCrossref
5.
Yeh  KM , Chiueh  TS , Siu  LK ,  et al.  Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital.   J Antimicrob Chemother. 2005;56(5):919-922. doi:10.1093/jac/dki346 PubMedGoogle ScholarCrossref
6.
Arabi  YM , Hajeer  AH , Luke  T ,  et al.  Feasibility of using convalescent plasma immunotherapy for MERS-CoV infection, Saudi Arabia.   Emerg Infect Dis. 2016;22(9):1554-1561. doi:10.3201/eid2209.151164 PubMedGoogle ScholarCrossref
7.
Kraft  CS , Hewlett  AL , Koepsell  S ,  et al; Nebraska Biocontainment Unit and the Emory Serious Communicable Diseases Unit.  The use of TKM-100802 and convalescent plasma in 2 patients with Ebola virus disease in the United States.   Clin Infect Dis. 2015;61(4):496-502. doi:10.1093/cid/civ334 PubMedGoogle ScholarCrossref
8.
Shen  C , Wang  Z , Zhao  F ,  et al.  Treatment of 5 critically ill patients with COVID-19 with convalescent plasma.   JAMA. 2020;323(16):1582-1589. doi:10.1001/jama.2020.4783 PubMedGoogle ScholarCrossref
9.
Duan  K , Liu  B , Li  C ,  et al.  Effectiveness of convalescent plasma therapy in severe COVID-19 patients.   Proc Natl Acad Sci U S A. 2020;117(17):9490-9496. doi:10.1073/pnas.2004168117 PubMedGoogle ScholarCrossref
10.
Recommendations for Investigational COVID-19 Convalescent Plasma. US FDA. Published May 1, 2020. Accessed May 26, 2020. https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma
11.
Position Paper on Use of Convalescent Plasma, Serum or Immune Globulin Concentrates as an Element in Response to an Emerging Virus. In: Network WBR, ed. 2017. Accessed April 18, 2020. https://www.who.int/bloodproducts/brn/en/
12.
National Health Commission of the People’s Republic of China. Covid-19 treatment plan (trial version 6). Accessed April 20, 2020. http://www.nhc.gov.cn/yzygj/s7653p/202002/8334a8326dd94d329df351d7da8aefc2/files/b218cfeb1bc54639af227f922bf6b817
13.
Wang  Y , Zhang  D , Du  G ,  et al.  Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.   Lancet. 2020;395(10236):1569-1578. doi:10.1016/S0140-6736(20)31022-9 PubMedGoogle ScholarCrossref
14.
Kleinbaum  DG . Evaluating the proportional hazards assumption. In:  Survival Analysis. Statistics in the Health Sciences. Springer; 1996:183-184.
15.
Daily update on covid-19. National Health Commission of the People’s Republic of China. Accessed May 24, 2020. http://www.nhc.gov.cn/xcs/yqtb/202003/f01fc26a8a7b48debe194bd1277fdba3.shtml
16.
Annual SHOT (Serious Hazards of Transfusion) Report 2018. Published July 2019. Accessed May 25, 2020. https://www.shotuk.org/
17.
Beigel  JH , Aga  E , Elie-Turenne  MC ,  et al; IRC005 Study Team.  Anti-influenza immune plasma for the treatment of patients with severe influenza A: a randomised, double-blind, phase 3 trial.   Lancet Respir Med. 2019;7(11):941-950. doi:10.1016/S2213-2600(19)30199-7PubMedGoogle ScholarCrossref
18.
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.xPubMedGoogle ScholarCrossref
AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close
Close

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close