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Original Investigation
June 3, 2020

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

Author Affiliations
  • 1Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China
  • 2Key Laboratory of Transfusion Adverse Reactions, CAMS, Chengdu, China
  • 3Guanggu District Maternal and Child Health Hospital of Hubei Province, Wuhan, China.
  • 4Department of Respiratory and Critical Care Medicine, First Affiliated Hospital, the Second Military Medical University, Shanghai, China
  • 5Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • 6Department of Pulmonary and Critical Care Medicine, Beijing Hospital, National Respiratory quality control center, National Center of Gerontology, Beijing, China
  • 7Department of Transfusion, General Hospital of Central Theater Command of PLA, Wuhan, China
  • 8State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union, Beijing, China
  • 9NHC Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China
  • 10Key Laboratory of Respiratory Disease Pathogenomics, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
  • 11Department of Blood Transfusion, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • 12Wuhan Red Cross Hospital, Wuhan, China
  • 13Department of Blood Transfusion, Wuhan Asia Heart Hospital, Wuhan, China
  • 14Department of Blood Transfusion, Wuhan Asia General Hospital, Wuhan, China
  • 15Wuhan Blood Center, Wuhan, China
  • 16Peking University Clinical Research Institute, Peking University Health Science Center, Beijing, China
  • 17Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China
  • 18Department of Emergency, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • 19Mianyang Central Hospital, Mianyang, China
  • 20Department of Organ Transplantation, First Affiliated Hospital, the Second Military Medical University, Shanghai, China
  • 21Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • 22Wuhan Pulmonary Hospital, Wuhan, China
  • 23Department of Respiratory Medicine, Wuhan Asia General Hospital, Wuhan, China
  • 24Center for Global Health and Infectious Diseases, Comprehensive AIDS Research Center, and Beijing Advanced Innovation Center for Structural Biology, School of Medicine, Tsinghua University, Beijing, China
  • 25Department of Pathology, University of Miami, Miami, Florida
JAMA. Published online June 3, 2020. doi:10.1001/jama.2020.10044
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, 0.65 [95% CI, 0.29-1.46]; P = .30) or time from randomization to discharge (51.0% vs 36.0% discharged by day 28; HR, 1.61 [95% CI, 0.88-2.93]; 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

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    1 Comment for this article
    EXPAND ALL
    Is Neutralizing Antibody Protective?
    Liz Jenny-Avital, MD | Jacobi Medical Center; Bronx NY
    Thank you for such a lucid and comprehensively detailed study!

    I noticed that 17 patients were excluded since they had S-protein RBD IgG ≥1:640 and 7 others due to negative COVID-19 PCR. This leads to two questions.

    Did the excluded patients with high levels of neutralizing antibody have a better or worse outcome?

    Did those with negative PCR have a better or worse outcome, and did they have high/low neutralizing Ab?

    Incidentally, we have seen progressive COVID19 pneumonia with conversion of NP COVID PCR to negative, but + PCR from endotracheal secretions.

    It would be
    of interest to learn if neutralizing Ab titer, like other inflammatory/thrombotic markers of COVID prognosis, has its own prognostic value--or whether it is merely a marker for prolonged infection.
    CONFLICT OF INTEREST: None Reported
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