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Convalescent Plasma

Last Updated: April 21, 2021

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.1 The Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for convalescent plasma for the treatment of certain hospitalized patients with COVID-19.

Recommendation

  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of low-titer COVID-19 convalescent plasma for the treatment of COVID-19 (AIIb).
    • Low-titer COVID-19 convalescent plasma is no longer authorized through the convalescent plasma EUA.

For Hospitalized Patients With COVID-19 Who Do Not Have Impaired Immunity

  • The Panel recommends against the use of COVID-19 convalescent plasma for the treatment of COVID-19 in mechanically ventilated patients (AI).
  • The Panel recommends against the use of high-titer COVID-19 convalescent plasma for the treatment of COVID-19 in hospitalized patients who do not require mechanical ventilation, except in a clinical trial (AI).

For Hospitalized Patients With COVID-19 Who Have Impaired Immunity

  • There is insufficient evidence for the Panel to recommend either for or against the use of high-titer COVID-19 convalescent plasma for the treatment of COVID-19.
    • Observational data including data from case reports, case series, and a retrospective case control study suggest a benefit of COVID-19 convalescent plasma in patients with various primary and secondary humoral immunodeficiencies.2-16
    • Several case reports indicate that patients with impaired humoral immunity may experience persistent SARS-CoV-2 viral replication and therefore, may be at risk for developing viral resistance to SARS-CoV-2 antibodies after treatment with COVID-19 convalescent plasma.17-19
    • High-titer convalescent plasma is authorized under the EUA for the treatment of hospitalized patients with COVID-19 and impaired immunity.

For Nonhospitalized Patients With COVID-19

  • There is insufficient evidence for the Panel to recommend either for or against the use of high-titer COVID-19 convalescent plasma for the treatment of COVID-19 in patients who are not hospitalized, except in a clinical trial.
    • Convalescent plasma is not authorized for nonhospitalized patients with COVID-19 under the EUA.
    • Results from additional adequately powered, well-designed, and well-conducted randomized clinical trials are needed to provide more specific, evidence-based guidance on the role of COVID-19 convalescent plasma in the treatment of nonhospitalized patients with COVID-19.

Rationale for Recommendation

On August 23, 2020, the FDA issued an EUA for convalescent plasma for the treatment of hospitalized patients with COVID-19 based on retrospective, indirect evaluations of efficacy generated from a large Expanded Access Program (EAP). The EAP allowed for the use of convalescent plasma regardless of titer. The Panel reviewed the EAP analyses and determined that the data were not sufficient to establish the efficacy or safety of COVID-19 convalescent plasma due to potential confounding, the lack of randomization, and the lack of an untreated control group.

On February 4, 2021, the FDA revised the convalescent plasma EUA to limit the authorization to high-titer COVID-19 convalescent plasma and only for the treatment of hospitalized patients with COVID-19 early in the disease course or hospitalized patients who have impaired humoral immunity.

Use of Convalescent Plasma in Hospitalized Patients With COVID-19 and Without Impaired Humoral Immunity

An updated retrospective analysis of data collected through the EAP indicated that patients who received high-titer plasma had a lower relative risk of death within 30 days after transfusion than patients who received low-titer plasma (relative risk 0.82; 95% CI, 0.67–1.00).20

  • Among the patients who were on mechanical ventilation before transfusion, no effect of high-titer plasma versus low-titer plasma was observed (relative risk 1.02; 95% CI, 0.78–1.32).
  • Among the patients who were not on mechanical ventilation before transfusion, mortality was lower among patients who received high-titer plasma than among those who received low-titer plasma (relative risk 0.66; 95% CI, 0.48–0.91).20

The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is an open-label, randomized controlled platform trial evaluating potential treatments for COVID-19. In the convalescent plasma portion of the trial, 11,558 patients were randomized to receive either convalescent plasma (n = 5,795) or usual care (n = 5,763) before enrollment was stopped due to futility.21

The trial results demonstrated no significant differences in the primary endpoint of 28-day mortality between the convalescent plasma arm (24%) and the usual care arm (24%; risk ratio 1.00; 95% CI, 0.93–1.07). Additionally, the trial did not meet its two secondary endpoints: time to hospital discharge and, for those not on mechanical ventilation at randomization, receipt of invasive mechanical ventilation or death. The proportion of patients discharged within 28 days was similar in the convalescent plasma arm and the usual care arm (66% vs. 67%; rate ratio 0.98; 95% CI, 0.94–1.03). Among those not requiring invasive mechanical ventilation at baseline, the proportion of those progressing to invasive mechanical ventilation or death was also similar in the convalescent plasma arm and the usual care arm (28% vs. 29%; risk ratio 0.99; 95% CI, 0.93–1.05). The 28-day mortality rate ratio was similar in all prespecified patient subgroups, including in those patients without detectable SARS-CoV-2 antibodies at randomization (32% in the convalescent plasma arm vs. 34% in the usual care arm; rate ratio 0.94; 95% CI, 0.84–1.06). Subgroup analyses suggested a slight trend towards benefit of convalescent plasma in certain subgroups (e.g., those with symptom onset ≤7 days, no requirement for supplemental oxygen at baseline, no concomitant use of corticosteroids). See Table 3b for additional details.

Data from several other randomized clinical trials, all of which were underpowered, have not demonstrated the efficacy of convalescent plasma for the treatment of hospitalized patients with COVID-19.22-29 See Table 3b for details.

Additionally, two large, randomized trials evaluating convalescent plasma in hospitalized patients have been paused or have limited enrollment due to futility.

  • The CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1) trial, which evaluated convalescent plasma versus usual care, was stopped after an interim analysis of 614 patients met the predefined threshold for futility.30
  • The Randomised, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP), which evaluated convalescent plasma in hospitalized patients, paused enrollment for patients in intensive care units after a preliminary analysis that included 912 participants indicated that convalescent plasma was unlikely to benefit this patient group.31 REMAP-CAP continues to recruit hospitalized patients who do not require intensive care support into the trial’s convalescent plasma evaluation domain.

Results from adequately powered, well-designed, and well-conducted randomized clinical trials are needed to provide more specific, evidence-based guidance on the role of convalescent plasma in the treatment of hospitalized patients with COVID-19 who do not have impaired humoral immunity.

Use of Convalescent Plasma in Hospitalized Patients With COVID-19 and Impaired Humoral Immunity

Data from case reports, case series, and a retrospective case-control study suggest a benefit of convalescent plasma in patients with primary and secondary humoral immunodeficiencies, including patients with hematologic malignancy, common variable immune deficiency, and agammaglobulinemia, and those who have received a transplanted solid organ.2-13,15,16 Several case reports indicate that patients with impaired humoral immunity may experience persistent SARS-CoV-2 viral replication and, therefore, may be at risk for developing viral resistance to SARS-CoV-2 antibodies after treatment with convalescent plasma.

Results from adequately powered, well-designed, and well-conducted randomized clinical trials are needed to provide more specific, evidence-based guidance on the role of convalescent plasma in the treatment of patients with COVID-19 who have impaired humoral immunity.17-19

Use of Convalescent Plasma in Nonhospitalized Patients With COVID-19

Current data are insufficient to establish the safety or efficacy of convalescent plasma in outpatients with COVID-19.

  • Data from a double-blind, placebo-controlled randomized trial of high-titer convalescent plasma in elderly outpatients with <72 hours of mild COVID-19 symptoms suggested a potential for benefit.32 However, the trial included relatively few participants, and only a small number of clinical events related to COVID-19 occurred. See Table 3b for details.
  • The Clinical Trial of COVID-19 Convalescent Plasma of Outpatients (C3PO) evaluated convalescent plasma for the treatment of nonhospitalized patients with ≤7 days of mild or moderate COVID-19 symptoms and at least one risk factor for severe COVID-19. The trial was halted after an interim analysis indicated no benefit of convalescent plasma for this group of patients. The trial enrolled 511 of the planned 900 participants before the study was halted.

Convalescent plasma is not authorized for nonhospitalized patients with COVID-19 under the EUA.

Clinical Data to Date

Table 3b includes a summary of key studies of convalescent plasma for the treatment of COVID-19.

Considerations in Pregnancy

The safety and efficacy of using COVID-19 convalescent plasma during pregnancy have not been evaluated. Pathogen-specific immunoglobulins are used clinically during pregnancy to prevent infection from varicella zoster virus and rabies virus and have been used in clinical trials of congenital cytomegalovirus infection.33 Some ongoing clinical trials that are evaluating COVID-19 convalescent plasma include pregnant individuals.34

Considerations in Children

The safety and efficacy of COVID-19 convalescent plasma have not been evaluated in pediatric patients outside of evaluations described in single-center reports. Clinical trials of COVID-19 convalescent plasma in children are ongoing. There is insufficient evidence for the Panel to recommend either for or against the use of convalescent plasma for the treatment of COVID-19 in hospitalized children who do not require mechanical ventilation. The Panel recommends against the use of convalescent plasma for the treatment of COVID-19 in mechanically ventilated pediatric patients (AIII). In consultation with a pediatric infectious disease specialist, high-titer convalescent plasma may be considered on a case-by-case basis for children with COVID-19 who meet the EUA criteria.

Adverse Effects

Available data suggest that serious adverse reactions following the administration of COVID-19 convalescent plasma are infrequent and consistent with the risks associated with plasma infusions for other indications. These risks include transfusion-transmitted infections (e.g., HIV, hepatitis B, hepatitis C), allergic reactions, anaphylactic reactions, febrile nonhemolytic reactions, transfusion-related acute lung injury, transfusion-associated circulatory overload, and hemolytic reactions. Hypothermia, metabolic complications, and post-transfusion purpura have also been described.21,35,36

Additional risks of COVID-19 convalescent plasma transfusion include a theoretical risk of antibody-dependent enhancement of SARS-CoV-2 infection and a theoretical risk of long-term immunosuppression.

The Panel recommends consulting a transfusion medicine specialist when considering convalescent plasma for patients with a history of severe allergic or anaphylactic transfusion reactions.

Product Availability

On February 4, 2021, the FDA revised the convalescent plasma EUA to limit the authorization to high-titer COVID-19 convalescent plasma.37

  • The revised EUA Letter of Authorization provides an expanded list of anti-SARS-CoV-2 antibody tests and corresponding qualifying results that may be used to determine the suitability of donated convalescent plasma.
  • Please refer to the FDA’s Recommendations for Investigational COVID-19 Convalescent Plasma webpage for guidance on the transfusion of investigational convalescent plasma while blood establishments develop the necessary operating procedures to manufacture COVID-19 convalescent plasma in accordance with the Conditions of Authorization described in the EUA.38

Clinical Trials

Randomized clinical trials that are evaluating convalescent plasma for the treatment of COVID-19 are underway. Please see ClinicalTrials.gov for the latest information.

  1. 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://www.ncbi.nlm.nih.gov/pubmed/32497196.
  2. Ferrari S, Caprioli C, Weber A, Rambaldi A, Lussana F. Convalescent hyperimmune plasma for chemo-immunotherapy induced immunodeficiency in COVID-19 patients with hematological malignancies. Leuk Lymphoma. 2021:1-9. Available at: https://www.tandfonline.com/doi/full/10.1080/10428194.2021.1872070.
  3. Hueso T, Pouderoux C, Pere H, et al. Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19. Blood. 2020;136(20):2290-2295. Available at: https://ashpublications.org/blood/article/136/20/2290/463806/Convalescent-plasma-therapy-for-B-cell-depleted.
  4. Rahman F, Liu STH, Taimur S, et al. Treatment with convalescent plasma in solid organ transplant recipients with COVID-19: experience at large transplant center in New York City. Clin Transplant. 2020;34(12):e14089. Available at: https://onlinelibrary.wiley.com/doi/10.1111/ctr.14089.
  5. Mira E, Yarce OA, Ortega C, et al. Rapid recovery of a SARS-CoV-2-infected X-linked agammaglobulinemia patient after infusion of COVID-19 convalescent plasma. J Allergy Clin Immunol Pract. 2020;8(8):2793-2795. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345404/.
  6. Fung M, Nambiar A, Pandey S, et al. Treatment of immunocompromised COVID-19 patients with convalescent plasma. Transpl Infect Dis. 2020; 2020/09/30:e13477. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537112/pdf/TID-9999-na.pdf. Accessed March 23, 2021.
  7. Quinti I, Lougaris V, Milito C, et al. A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia. J Allergy Clin Immunol. 2020;146(1):211-213 e214. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0091674920305571?via%3Dihub.
  8. Jin H, Reed JC, Liu STH, et al. Three patients with X-linked agammaglobulinemia hospitalized for COVID-19 improved with convalescent plasma. J Allergy Clin Immunol Pract. 2020;8(10):3594-3596 e3593. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490621/.
  9. Betrains A, Godinas L, Woei AJF, et al. Convalescent plasma treatment of persistent severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection in patients with lymphoma with impaired humoral immunity and lack of neutralising antibodies. 2020. Available at: https://onlinelibrary.wiley.com/doi/10.1111/bjh.17266.
  10. Balashov D, Trakhtman P, Livshits A, et al. SARS-CoV-2 convalescent plasma therapy in pediatric patient after hematopoietic stem cell transplantation. Transfus Apher Sci. 2021;60(1):102983. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33153902.
  11. Thompson MA, Henderson JP, Shah PK, et al. Convalescent plasma and improved survival in patients with hematologic malignancies and COVID-19. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.02.05.21250953v1.
  12. Senefeld JW, Klassen SA, Ford SK, et al. Therapeutic use of convalescent plasma in COVID-19 patients with immunodeficiency. 2020. Available at: https://www.medrxiv.org/content/10.1101/2020.11.08.20224790v1.full.pdf. Accessed March 24, 2021.
  13. Clark E, Guilpain P, Filip IL, et al. Convalescent plasma for persisting COVID-19 following therapeutic lymphocyte depletion: a report of rapid recovery. Br J Haematol. 2020;190(3):e154-e156. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32593180.
  14. Iaboni A, Wong N, Betschel SD. A patient with X-linked agammaglobulinemia and COVID-19 infection treated with remdesivir and convalescent plasma. J Clin Immunol. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33547548.
  15. Van Damme KFA, Tavernier S, Roy NV, et al. Case report: convalescent plasma, a targeted therapy for patients with CVID and severe COVID-19. Front Immunol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714937/.
  16. Tremblay D, Seah C, Schneider T, et al. Convalescent plasma for the treatment of severe COVID‐19 infection in cancer patients. Cancer Medicine. 2020. Available at: https://onlinelibrary.wiley.com/doi/10.1002/cam4.3457.
  17. Choi B, Choudhary MC, Regan J, et al. Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. N Engl J Med. 2020;383(23):2291-2293. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33176080.
  18. Kemp SA, Collier DA, Datir RP, et al. SARS-CoV-2 evolution during treatment of chronic infection. Nature. 2021. Available at: https://www.nature.com/articles/s41586-021-03291-y.
  19. Tarhini H, Recoing A, Bridier-Nahmias A, et al. Long term SARS-CoV-2 infectiousness among three immunocompromised patients: from prolonged viral shedding to SARS-CoV-2 superinfection. The Journal of Infectious Diseases. 2021. Available at: https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab075/6131370.
  20. Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent plasma antibody levels and the risk of death from COVID-19. N Engl J Med. 2021. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2031893.
  21. The RECOVERY Collaborative Group, Horby PW, Estcourt L, et al. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. MedRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.03.09.21252736v1.
  22. Simonovich VA, Pratx LDB, Scibona P, et al. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med. 2021. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2031304.
  23. Agarwal A, Mukherjee A, Kumar G, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371. Available at: https://www.bmj.com/content/bmj/371/bmj.m3939.full.pdf.
  24. 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.
  25. Gharbharan A, Jordans CCE, GeurtsvanKessel C, et al. Convalescent plasma for COVID-19: a randomized clinical trial. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.07.01.20139857v1.
  26. Avendano-Sola C, Ramos-Martinez A, Muñez-Rubio E, et al. Convalescent plasma for COVID-19: a multicenter, randomized clinical trial. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.08.26.20182444v3.full.pdf. Accessed March 23, 2021.
  27. AlQahtani M, Abdulkarim A, Almadani A, et al. Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.11.02.20224303v1.full.
  28. Ray Y, Paul SR, Bandopadhyay P, et al. Clinical and immunological benefits of convalescent plasma therapy in severe COVID-19: insights from a single center open label randomised control trial. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.11.25.20237883v1.
  29. O'Donnell MR, Grinsztejn B, Cummings MJ, et al. A randomized, double-blind, controlled trial of convalescent plasma in adults with severe COVID-19. medRxiv. 2021. Available at: https://www.medrxiv.org/content/10.1101/2021.03.12.21253373v1?%25253fcollection=.
  30. CONCOR-1. Welcome to CONCOR-1 clinical trial website. Available at: https://concor1.ca/. Accessed March 25, 2021.
  31. REMAP-CAP PR. International trial of SARS-CoV-2 convalescent plasma pauses enrollment of critically ill COVID-19 patients. 2021. Available at: https://www.recover-europe.eu/press-release-international-trial-of-sars-cov-2-convalescent-plasma-pauses-enrollment-of-critically-ill-covid-19-patients/. Accessed March 25, 2021.
  32. Libster R, Perez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe COVID-19 in older adults. N Engl J Med. 2021;384(7):610-618. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2033700.
  33. Centers for Disease Control and Prevention. Updated recommendations for use of VariZIG—United States, 2013. MMWR Morb Mortal Wkly Rep. 2013;62(28):574-576. Available at: https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6228a4.htm. Accessed March 26, 2021.
  34. University of Pennsylvania. COVID-19 convalescent plasma for mechanically ventilated population. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04388527. Accessed March 26, 2021.
  35. Food and Drug Administration. EUA of COVID-19 convalescent plasma for the treatment of COVID-19 in hospitalized patients: fact sheet for health care providers. 2020. Available at: https://www.fda.gov/media/141478/download. Accessed September 22, 2020.
  36. Nguyen FT, van den Akker T, Lally K, et al. Transfusion reactions associated with COVID-19 convalescent plasma therapy for SARS-CoV-2. Transfusion. 2021;61(1):78-93. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33125158.
  37. Food and Drug Administration. Convalescent Plasma Letter of Authorization. 2020. Available at: https://www.fda.gov/media/141477/download. Accessed August 31, 2020.
  38. Food and Drug Administration. Recommendations for investigational COVID-19 convalescent plasma. 2021. Available at: https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma. Accessed March 26, 2021.