Recommendations on the use of COVID-19 Convalescent Plasma to Treat Immunocompromised Patients

Dear Editor,

Since December 2019, the coronavirus disease 2019 (COVID-19) pandemic has caused more than 770 million cases and 7 million deaths worldwide, with an unprecedented global health impact and social crises.[1] Considering the positive clinical experience in previous viral outbreaks, collection and transfusion of COVID-19 convalescent plasma (CCP) was rapidly deployed around the globe to treat patients with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection at different stages of disease severity.[2] Three years into the pandemic outbreak and after more than fifty randomized clinical trials (RCTs) and hundreds of prospective and retrospective studies, which have investigated CCP dose and timing in diverse COVID-19 populations, the optimal positioning of CCP in the therapeutic armamentarium against COVID-19 has been ascertained. This passive antibody-based therapy is particularly useful when administered early (within 3–5 d since symptom onset), containing a high titer of neutralizing antibodies, and used in immunologic naïve patients, as would be anticipated based on historical experiences with CCP and biological plausibility.[3] [4] [5] When the data from the dozens of RCTs were aggregated and analyzed, a clear overall mortality reduction of 9% was evident with CCP use, rising to 30% when used early in the course of hospitalization using high-titer units.[6] Currently, most of humanity has antibody to SARS-CoV-2 from infection, vaccination or both, and there is limited therapeutic need for CCP in this general population of immunocompetent, vaccinated individuals. Thus, the present clinical benefit of CCP is mostly evident in immunocompromised patients, who are not able to mount a sufficiently protective antibody response after vaccination or infection and are thus exposed to the potentially life-threatening complications of SARS-CoV-2.[6] In addition, the safety of CCP has been definitively ascertained on the basis of the analysis of several RCTs, a finding not so obvious considering the high thrombotic risk associated with COVID-19.[7]

Despite such evidence, the interest towards the production and clinical use of CCP has progressively declined since early 2021, due to the marketing of anti-Spike monoclonal antibodies, which are now all ineffective against the more recent omicron variants (i.e., EG.5.1, FL.1.5.1, and BA.2.86).[8] Thus, the current unavailability of high-titer CCP collected from vaccinated donors (the so-called “Vax-CCP”), despite a large pool of potential donors, has created an important therapeutic gap, particularly for fragile individuals in whom drug therapy alone is either inadequate for cure or has potential for adverse concomitant drug reactions. What are scientific societies and health authorities doing to promote this biologic therapy for immunocompromised patients? To answer this important question, we performed a literature search of PubMed (through MEDLINE) electronic database between January 2020 and September 2023 using English language as restriction. The Medical Subject Heading and keywords used were “SARS-CoV-2,” “COVID-19,” “recommendations,” “guidelines,” “position paper,” “expert panel,” “immunocompromised,” “immunosuppressed,” “oncology,” “hematology,” “oncohematology,” “rheumatology,” “cancer,” “transplantation,” “hematopoietic stem cell transplantation,” and “solid organ transplant.” We also screened the reference lists of relevant articles and reviews for further studies not captured in the initial literature search. In addition, the website of the most important national and international scientific societies (internal medicine, hematology, oncology, transplantation, and rheumatology) and health authorities were screened to find additional sources. Overall, 18 recommendations/guidelines form 14 scientific societies (9 oncology and/or hematology, 1 internal medicine, 3 microbiology and infectious diseases, 1 rheumatology) and 5 health authorities were retrieved worldwide (2 international, 4 Europe, 6 USA, 1 Australia-New Zealand, 1 Brazil, 2 Germany, 1 Spain, 1 United Kingdom) ([Table 1]). The oldest was dated March 2021 and the newest August 2023. All but two documents gave indications on the use of CCP in immunocompromised patients. Notably, the National Institute of Health, Care from United Kingdom, and the international World Health Organization did not provide information on the therapeutic use of CCP for immunocompromised patients. The latter was requested by some of us to urgently update its guidelines,[9] but no updates have been forthcoming since 2021. Among the remaining 16 documents, all but 1 supported, although with different levels of evidence and strength of recommendation, the use of CCP in immunocompromised patients. Only the European Myeloma Network did not recommend the CCP use in multiple myeloma patients, based on the lack of specific studies. An RCT has since been published and shown a benefit in multiple myeloma patients,[10] so some of us also requested the members of the hematological association to update their consensus paper.[11]

In conclusion, guidelines/recommendations/panel of experts from many scientific associations and health organizations clearly support the current use of CCP in immunocompromised patients. However, CCP collection has virtually ceased worldwide. As COVID-19 cases are again increasing worldwide, we call for urgent resumption in the collection of Vax-CCP, to guarantee adequate antibody protection for fragile immunocompromised patients infected with SARS-CoV-2.

Table 1 Indications on the use of convalescent plasma against COVID-19 (CCP) in immunocompromised patients from scientific societies and health organizations

Scientific society: Health organization	Country/Release	CCP use supported	Indication	Reference
Association for the Advancement of Blood and Biotherapies (AABB)	United States/September 2022	Yes	CCP transfusion in addition to standard care is suggested in hospitalized patients with COVID-19 and preexisting immunosuppression (weak recommendation, low-certainty evidence) and for outpatients (immunocompromised or not: weak recommendation, moderate certainty evidence)	Estcourt LJ, Cohn CS, Pagano MB, et al. Clinical practice guidelines from the Association for the Advancement of Blood and Biotherapies (AABB): COVID-19 convalescent plasma. Ann Intern Med 2022;175(9):1310–1321
Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular (ABHH)	Brazil/March 2021	Yes	Consider using early (within 72 h of symptom onset), high-titer (≥80 neutralizing antibodies) CCP in immunosuppressed patients (especially those treated with anti-CD20 monoclonal antibodies)	De Santis GC. Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. Special article: compassionate use and clinical trial on CAR-T cells. Hematol Transfus Cell Ther 2021;43 (Suppl 2):S64–S67
Australia and New Zealand Transplant and Cellular Therapies (ANZTCT)	Australia-New Zealand/October 2022	Yes	Convalescent plasma containing high-titer neutralizing antibodies against SARS-CoV-2 is recommended if suitable monoclonal antibody therapies are unavailable	Perram J, Purtill D, Bajel A, et al. Australia and New Zealand Transplant and Cellular Therapies (ANZTCT) position statement: COVID-19 management in patients with haemopoietic stem cell transplant and chimeric antigen receptor T cell. Intern Med J 2023;53(1):119–125
Association of the Scientific Medical Societies in Germany (AWMF)	Germany/July 2021	Not available	The use of CCP in immunocompromised patients is not included in the guidance	Malin JJ, Spinner CD, Janssens U, et al. Key summary of German national treatment guidance for hospitalized COVID-19 patients: key pharmacologic recommendations from a national German living guideline using an Evidence to Decision Framework (last updated May 17, 2021). Infection 2022;50(1):93–106
Center for Disease Control and Prevention (CDC)	United States/May 2023	Yes	Indicated for patients immunocompromised or receiving immunosuppressive treatment	https://www.cdc.gov/coronavirus/2019-ncov/your-health/treatments-for-severe-illness.html
Chronic Lymphocytic Leukemia (CLL) Society	International/January 2023	Yes	High-titer CCP has a beneficial role in active COVID-19 infection, especially when given early, and can be a powerful aid for the immunocompromised patients	https://cllsociety.org/2023/01/high-titer-covid-19-convalescent-plasma-as-a-treatment-option-for-those-who-are-immunocompromised-after-becoming-infected-with-covid-19/
European Alliance of Associations for Rheumatology (EULAR)	Europe/January 2022	Yes	Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients	Alunno A, Najm A, Machado PM, et al. 2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19. Ann Rheum Dis 2022;81(1):34–40
European Conference on Infections in Leukemia (ECIL 9)	Europe/July 2023	Yes	In patients with hematologic malignancy and moderate/severe COVID-19, consider high-titer CCP if monoclonal antibodies are not available or not active against the circulating variants. Considering the loss of activity of monoclonal antibodies against circulating variants, high-titer CCP might be useful in immunocompromised patients	Cesaro S, Mikulska M, Hirsch HH, et al. Update of recommendations for the management of COVID-19 in patients with haematological malignancies, haematopoietic cell transplantation and CAR T therapy, from the 2022 European Conference on Infections in Leukaemia (ECIL 9). Leukemia 2023;37(9):1933–1938
European Myeloma Network (EMN)	Europe/May 2023	No	The use of convalescent plasma is not recommended in multiple myeloma patients due to the lack of evidence from RCTs	Terpos E, Musto P, Engelhardt M, et al. Management of patients with multiple myeloma and COVID-19 in the post pandemic era: a consensus paper from the European Myeloma Network (EMN). Leukemia 2023;37(6):1175–1185
European Society of Clinical Microbiology and Infectious Diseases (ESCMID)	Europe/February 2022	Not available	The CCP use in immunocompromised patients is not included	Bartoletti M, Azap O, Barac A, et al. ESCMID COVID-19 living guidelines: drug treatment and clinical management. Clin Microbiol Infect 2022;28(2):222–238
Food and Drug Administration (FDA)	United States/December 2021	Yes	CCP with high titers of anti-SARS-CoV-2 antibodies is authorized for emergency use for the treatment of COVID-19 patients with immunosuppressive disease or receiving immunosuppressive treatment in either the outpatient or inpatient setting	https://www.fda.gov/media/141478/download
German Society for Hematology and Medical Oncology (DGHO)	Germany/December 2022	Yes	CCP early-after symptom onset is recommended in cancer outpatients with COVID-19 (strength of recommendation and quality of evidence: CIIt)[a] It should only be administered if monoclonal antibody preparations efficacious against the locally predominant variants are not available	Giesen N, Busch E, Schalk E, et al. AGIHO guideline on evidence-based management of COVID-19 in cancer patients: 2022 update on vaccination, pharmacological prophylaxis and therapy in light of the omicron variants. Eur J Cancer 2023;181:102–118
Infectious Disease Society of America (IDSA)	United States/April 2023	Qualified use	Among immunocompromised patients hospitalized with COVID-19, the IDSA guideline panel suggests against the routine use of COVID-19 convalescent plasma (conditional recommendation, very low certainty of evidence). Among ambulatory patients with mild-to-moderate COVID-19 at high risk for progression to severe disease who have no other treatment options, the IDSA guideline panel suggests FDA-qualified high-titer CCP within 8 days of symptom onset (conditional recommendation, low certainty of evidence)	https://www.idsociety.org/globalassets/idsa/practice-guidelines/covid-19/treatment/idsa-covid-19-tx-and-mgmt_convalescent-plasma-2023-02-22.pdf
National Comprehensive Cancer Network (NCCN)	United States/August 2022	Yes	Hospitalized COVID-19 cancer patients: consider high-titer CCP in immunocompromised patients, particularly those with B-cell impairment, and when anti-SARS-CoV-2 monoclonal antibodies are not available. COVID-19 cancer outpatients: high-titer CCP may be beneficial in immunocompromised patients, particularly those with B-cell impairment, with persistent SARS-CoV-2 infection (2A)[b]	https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf
National Institute for Health and Care Excellence (NICE)	United Kingdom/August 2023	Not available	The CCP use in immunocompromised patients is not included	https://www.nice.org.uk/guidance/ng191/resources/covid19-rapid-guideline-managing-covid19-pdf-51035553326
National Institutes of Health (NIH)	United States/July 2023	Neutral-qualified use	There is insufficient evidence to recommend either for or against the use of high-titer CCP for the treatment of COVID-19 in hospitalized or nonhospitalized patients who are immunocompromised. High-titer CCP from a vaccinated donor who recently recovered from COVID-19 likely caused by a SARS-CoV-2 variant similar to the variant causing the patient's illness has been used for immunocompromised patients with prolonged viral shedding	https://www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/covid-19-convalescent-plasma/
Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)	Spain/August 2023	Yes	In solid organ transplant recipient hybrid or convalescent plasma 250 to 600 ml IV one or two infusion separated by 5 to 7 days is recommended for mild (level IIID) or moderate (level IIB) COVID-19 and for prolonged viral shedding (level IVD)[b]	Herrera S, Aguado JM, Candel FJ, et al. Executive summary of the consensus statement of the group for the study of infection in transplantation and other immunocompromised host (GESITRA-IC) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) on the treatment of SARS-CoV-2 infection in solid organ transplant recipients. Transplant Rev (Orlando) 2023;37(4):100788.
World Health Organization (WHO)	International/January 2023	Not available	In the section on CCP (updated December 2021), its use in immunocompromised patients is not included	https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2023.1

Abbreviations: CCP, convalescent plasma; COVID-19, coronavirus disease 2019; RCT, randomized clinical trial.

^a CIIt: weak recommendation, evidence from at least one well-designed clinical trial without randomization.

^b 2A: weak recommendation, high quality of evidence; IIB: weak recommendation, moderate quality of evidence; IIID: weak recommendation, low quality of evidence; IVD: weak recommendation, very low quality of evidence.

Authors' Contributions

M.F. performed the literature search and wrote the first draft. D.F., M.J.J., J.W.S., A.C., and D.J.S. revised the manuscript. All the authors approved the final version.

Publication History

Article published online:
20 November 2023

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