- There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of COVID-19 convalescent plasma for the treatment of COVID-19.
Rationale for Recommendation
Thousands of patients in the United States have received COVID-19 convalescent plasma through clinical trials, expanded access treatment trials, and single-patient Emergency Investigational New Drug (EIND) applications. However, the standards and methods for screening donated plasma for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binding and neutralizing antibodies have not been established. The variability in SARS-CoV-2 antibody levels in donor plasma may have an impact on the efficacy of COVID-19 convalescent plasma products. Clinical data are currently insufficient to evaluate the efficacy of convalescent plasma for the treatment of COVID-19. Safety data from a large, multicenter, expanded access program indicated that uncommon (i.e., in <1% of transfusions) but serious risks of convalescent plasma may include transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), allergic reactions, and death.1 Another theoretical risk is potential for antibody-dependent enhancement (ADE) of infection.
Proposed Mechanism of Action and Rationale for Use in Patients With COVID-19
Plasma from donors who have recovered from COVID-19 may contain antibodies to SARS-CoV-2 that may help suppress the virus and modify the inflammatory response.2
Clinical Data to Date
Open-Label, Randomized Clinical Trial of Convalescent Plasma in 103 Hospitalized Patients With Severe or Life-Threatening COVID-19
This open-label, randomized clinical trial of convalescent plasma versus standard of care for patients with severe or life-threatening laboratory-confirmed COVID-19 was conducted in seven medical centers in Wuhan, China, from February 14 to April 1, 2020. The primary outcome was time to clinical improvement within 28 days, which was defined as patient discharged alive or a two-point reduction on a six-point disease severity scale. Only plasma units with a SARS-CoV-2 viral spike-receptor binding domain-specific IgG titer of at least 1:640 were transfused. The median dose of ABO-compatible, transfused convalescent plasma was 200 mL. The time from symptom onset to study randomization was 27 days in the treatment group and 30 days in the control group.3
Due to control of the COVID-19 outbreak in Wuhan, the trial was terminated early after 103 of the planned 200 patients were enrolled. Among the enrolled patients, 45 had severe disease and 58 had life-threatening disease. Baseline severity scores and use of concomitant therapies were similar between the treatment and control groups. Although the groups were well-balanced by age (with a median age of 70 years in the treatment group vs. 69 years in the control group), the proportion of men in the control group (65%) was greater than in the convalescent plasma group (52%). There was no significant difference between the treatment and control groups in the primary outcome of time to clinical improvement within 28 days (hazard ratio 1.40; 95% confidence interval [CI], 0.79–2.49; P = 0.26). Among those with severe disease, 91% of the convalescent plasma recipients and 68% of the control patients improved by Day 28 (difference 23%; odds ratio [OR] 1.34; 95% CI, 0. 98–1.83; P = 0.07). Among those with life-threatening disease, 21% of patients in the treatment group and 24% in the control group improved (difference -3.4%; OR 0.86; 95% CI, 0.33–2.24; P = 0.75). There was no significant difference in mortality between the groups (16% vs. 24% for the treatment and control groups, respectively; OR 0.65; 95% CI, 0.29–1.46; P = 0.30). At 24, 48, and 72 hours, the rates of negative SARS-CoV-2 viral polymerase chain reaction were significantly higher in the convalescent plasma group than in the control group (45% vs. 15%, respectively, at 24 hours, P = 0.003; 68% vs. 33%, respectively, at 48 hours, P = 0.001; and 87% vs. 38%, respectively, at 72 hours, P < 0.001). Two transfusion-related events were reported, including one severe event; both events resolved with supportive care.
The limitations of this study include that it was not blind and that, on average, the convalescent plasma was administered approximately 1 month into the disease course. In addition, the study was terminated early, and thus the sample size was insufficient to detect smaller but clinically meaningful differences in clinical outcomes.
Safety Analysis of the First Consecutive 20,000 Patients to Receive Open-Label COVID-19 Convalescent Plasma Through a National Expanded Access Program
The Expanded Access to Convalescent Plasma for the Treatment of Patients with COVID-19 program is an ongoing, open-label, nonrandomized protocol primarily designed to provide adult patients who have severe or life-threatening (critical) COVID-19 with access to convalescent plasma, which is an investigational product in the United States. Secondary objectives are to obtain data on the safety of the intervention. The program is sponsored by the Mayo Clinic and includes a diverse range of clinical sites. Criteria for plasma donors include documented COVID-19, with complete resolution of symptoms for ≥14 days before donation, and either no history of pregnancy or a negative human leukocyte antigen test after a donor’s most recent pregnancy. SARS-CoV-2 antibody testing of plasma donors and assessment of SARS-CoV-2 neutralization potential are not mandated. Patients are transfused with 1 or 2 units (200–500 mL) of convalescent plasma. ABO-compatible plasma is used preferentially, but in the absence of ABO-compatible plasma, patients may receive either Group A plasma or low anti-A titer Group O plasma, as available. The main outcomes for the safety analysis are serious adverse events (SAEs), including death; SAEs are reported at 4 hours and at 7 days after transfusion, or as they occur.4
The safety analysis describes the first 20,000 plasma recipients, enrolled between April 3 and June 2, 2020. One-third of the participants were aged ≥70 years, 60% were male, and 71% had severe or life-threatening COVID-19. Twenty percent of the participants were African American, 35% were Hispanic/Latino, and 5% were Asian. SAEs within 4 hours of transfusion were reported in 146 (<1%) patients and included 63 deaths. Among the deaths, 13 were determined to be possibly or probably related to the convalescent plasma treatment. The 83 nonfatal SAEs included 37 TACO events, 20 TRALI events, and 26 severe allergic reactions. Life-threatening cardiac events and thrombotic events reported up to 7 days after transfusion included 87 thrombotic/thromboembolic complications, 406 sustained hypotension events, and 643 cardiac events. The overall mortality rate was 8.6% at 7 days. In this study, COVID-19 convalescent plasma therapy was associated with a low incidence (<1%) of serious transfusion-related events.
The study design, which does not include a control arm, precludes an assessment of efficacy or the occurrence of ADE of COVID-19.
Retrospective, Single-Center, Case-Control Study Evaluating Convalescent Plasma Plus Standard of Care Versus Standard of Care Without Convalescent Plasma
This study has not been peer reviewed.
This case-control study reports clinical outcomes among 39 consecutive patients who received COVID-19 convalescent plasma through the Food and Drug Administration (FDA) single-patient EIND program while hospitalized at Mount Sinai Hospital in New York City between March 24, 2020, and April 8, 2020. Recipients were transfused with 2 units of ABO-compatible convalescent plasma from donors with a SARS-CoV-2 anti-spike antibody titer of 1:320 dilution. The control group (n = 156) was identified retrospectively from the hospital’s electronic health records database. The control patients were hospitalized during the same period as the treated patients, had confirmed COVID-19, did not receive convalescent plasma, and were matched 4:1 to convalescent plasma recipients using propensity scores to correct for measured confounders.5
The mean age of the convalescent plasma recipients was 55 years, and 64% of the recipients were male. At the time of transfusion, 34 recipients (87%) required supplemental oxygen (noninvasive), and four recipients (10%) were mechanically ventilated. By Day 14, the clinical condition had worsened in 18% of the convalescent plasma patients and 24% of the control patients (P = 0.17). As of May 1, 2020, 13% of the plasma recipients and 24% of the matched control patients had died (P = 0.04, log-rank test), and 72% and 67% of the transfused patients and control patients, respectively, had been discharged from the hospital.
The study’s lack of randomization and the potential for unmeasured patient selection bias limit interpretation of the study results.
Other smaller, uncontrolled case series that describe clinical outcomes in COVID-19 patients have been reported and also suggest that SAEs are uncommon following COVID-19 convalescent plasma treatment.2,6-11
Clinical Data for Other Viral Infections
The use of convalescent plasma has been evaluated for other viral diseases, such as SARS, with some suggestion of potential benefit.12-14 However, no convalescent blood products are currently licensed by the FDA.
Randomized clinical trials to evaluate convalescent plasma for the treatment of COVID-19 are underway; a list is available at ClinicalTrials.gov.
The FDA has provided recommendations for the use of COVID-19 convalescent plasma through EIND applications for individual patients and traditional or expanded access IND applications. The FDA has also approved a national expanded access program for the use of convalescent plasma for the treatment of patients with COVID-19. Clinicians can refer to the National COVID-19 Convalescent Plasma Project website for more information on that specific program and other trials evaluating convalescent plasma. People who have fully recovered from COVID-19 for ≥2 weeks and who are interested in donating plasma can contact their local blood donor or plasma collection center or refer to the FDA’s Donate COVID-19 Plasma website.
The risks associated with convalescent plasma transfusion include TRALI, TACO, and allergic transfusion reactions.8,15 Rare complications include the transmission of infectious pathogens and red cell alloimmunization. There is a theoretical risk of antibody-mediated enhancement of infection.
Considerations in Pregnancy
Several ongoing clinical trials evaluating COVID-19 convalescent plasma include pregnant women.
Considerations in Children
Clinical trials of COVID-19 convalescent plasma in children are ongoing.
- Joyner MJ, Wright RS, Fairweather D, et al. Early safety indicators of COVID-19 convalescent plasma in 5,000 patients. J Clin Invest. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32525844.
- Wang X, Guo X, Xin Q, et al. Neutralizing antibodies responses to SARS-CoV-2 in COVID-19 inpatients and convalescent patients. Clin Infect Dis. 2020. Available at: https://pubmed.ncbi.nlm.nih.gov/32497196.
- Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32492084.
- Joyner MJ, Bruno KA, Klassen SA, et al. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clin Proc. 2020. Available at: https://mayoclinicproceedings.org/pb/assets/raw/Health%20Advance/journals/jmcp/jmcp_ft95_6_8.pdf. Accessed: July 9, 2020.
- Liu STH, Lin H, Baine I, et al. Convalescent plasma treatment of severe COVID-19: a matched control study. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.05.20.20102236v1.
- Salazar E, Perez KK, Ashraf M, et al. Treatment of coronavirus disease 2019 (COVID-19) patients with convalescent plasma. Am J Pathol. 2020. Available at: https://pubmed.ncbi.nlm.nih.gov/32473109.
- Ahn JY, Sohn Y, Lee SH, et al. Use of convalescent plasma therapy in two COVID-19 patients with acute respiratory distress syndrome in Korea. J Korean Med Sci. 2020;35(14):e149. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32281317.
- Pei S, Yuan X, Zhang Z, et al. Convalescent plasma to treat COVID-19: Chinese strategy and experiences. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.04.07.20056440v1.
- Ye M, Fu D, Ren Y, et al. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32293713.
- Zeng Q, Yu Z, Gou J, et al. Effect of convalescent plasma therapy on viral shedding and survival inpatients with coronavirus disease 2019. J Infect Dis. 2020:222(1):38-43. Available at: https://pubmed.ncbi.nlm.nih.gov/32348485.
- Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci USA. 2020:117(17):9490-9496. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32253318.
- Burnouf T, Radosevich M. Treatment of severe acute respiratory syndrome with convalescent plasma. Hong Kong Med J. 2003;9(4):309. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12904626.
- 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15616839.
- Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25030060.
- Narick C, Triulzi DJ, Yazer MH. Transfusion-associated circulatory overload after plasma transfusion. Transfusion. 2012;52(1):160-165. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21762464.