Next Article in Journal
Comprehensive Metabolite Profiling of Cinnamon (Cinnamomum zeylanicum) Leaf Oil Using LC-HR/MS, GC/MS, and GC-FID: Determination of Antiglaucoma, Antioxidant, Anticholinergic, and Antidiabetic Profiles
Next Article in Special Issue
Efficacy of Convalescent Plasma to Treat Long-Standing COVID-19 in Patients with B-Cell Depletion
Previous Article in Journal
Safflower (Carthamus tinctorius L.) Response to Cadmium Stress: Morpho-Physiological Traits and Mineral Concentrations
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

WHO Is Recommending against the Use of COVID-19 Convalescent Plasma in Immunocompromised Patients?

Division of Transfusion Medicine, Carlo Poma Hospital, 46100 Mantua, Italy
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21287, USA
Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN 55902, USA
North-Western Tuscany Blood Bank, Pisa University Hospital, 56124 Pisa, Italy
Author to whom correspondence should be addressed.
Life 2023, 13(1), 134;
Submission received: 2 December 2022 / Revised: 29 December 2022 / Accepted: 30 December 2022 / Published: 3 January 2023
(This article belongs to the Special Issue COVID-19 Convalescent Plasma for Immuno-Compromised Patients)
Since December 2019, SARS-CoV-2 is ravaging the globe, currently accounting for over 660 million infected people and more than 6.6 million deaths. As convalescent plasma had been successfully used in previous viral outbreaks [1], collection anhd transfusion of COVID-19 convalescent plasma (CCP) was rapidly deployed worldwide to treat patients with Coronavirus Disease-19 (COVID-19). The results of the numerous studies assessing the clinical efficacy of CCP were inconsistent and ranged from about 50% efficacy in reducing mortality to no effect, reflecting great inter-study methodological heterogeneities and inconsistencies [2]. Despite these limitations, a significant proportion of the literature supported the clinical benefit of this antibody-based treatment when administered early (within 72 h since onset of symptoms) and with a high titer of neutralizing antibodies (nAb) [2].
Interest in CCP faded during 2021, following the marketing authorization of small molecule antivirals and anti-Spike monoclonal antibodies (mAb). Nevertheless, the advent of the Omicron variant of concern (VOC) renewed the interest in CCP, because of its immune-escape to mAb-based therapies [3]. On the contrary, CPP has preserved efficacy against Omicron sublineages [4], including the recent BQ.1.1 and XBB sublineages [5]. With most humans having some immunity to SARS-CoV-2 from vaccines and/or prior infection, the Omicron variant is still life-threatening for immunocompromised (IC) patients, who are not able to mount a sufficiently protective antibody response after vaccination or infection [6]. COVID-19 in the IC population is a difficult management problem. IC patients present two interdependent problems in the form of high viral loads and reduced immunological capacity to clear the infection. A high viral load implies a high likelihood for generation of variants capable of escaping antiviral therapy.
A recent systematic review and meta-analysis including four randomized controlled trials (RCTs) and five controlled studies conducted in IC COVID-19 patients showed a clinical benefit from CCP versus standard of care (risk ratio for mortality 0.65) [7]. For such reasons, several national and international scientific societies currently recommend CCP among possible therapies in COVID-19 patients with hematological or solid cancers or other underlying congenital or acquired causes of immunosuppression. Table 1 summarizes the recommendations from six of these societies, all being favorable to the use of CCP in this particularly frail category of patients. The analysis of this table permits us to make some considerations.
  • The strength of recommendation for CCP use in IC patients should be updated and upgraded, taking into account the increasing level of evidence derived from recently published RCTs. As with other fields of COVID-19 science, the research on CCP use in IC patients is rapidly evolving, and societies should create ad hoc committees that perform living systematic literature reviews to provide updated recommendations. The time from writing to publication should be expedited to avoid publishing outdated guidelines [8].
  • Other continental oncohematology or transplant societies (e.g., ASH, AST, EHA, and ESOT) and international health organizations should urgently provide clear indications on CCP use in IC patients. In particular, the World Health Organization (WHO) recommendations against using CCP [9] dating from December 7, 2021, and based on outdated information, should be urgently updated to recognize the particular value of CCP in IC patients and the lack of affordable alternatives in low- and middle-income countries [10]. It took WHO 120,000 cases to declare COVID-19 a pandemic [11], and 2 years to admit that SARS-CoV-2 is airborne [12]: clearly, delays about therapeutic guidelines are unacceptable.
  • The collection of CCP should restart worldwide from vaccinated people preferentially recovered from Omicron variants, in order to transfuse variant of concern (VOC)-matched high-titer CCP [4,5,13].
  • New, well-designed RCTs should be restarted in order to further evaluate CCP efficacy in IC patients, in both inpatient (such as the recently re-opened REMAP-CAP arm [14]) and outpatient settings. Such trials need to incorporate the lessons learned to date including the need for high-titer CCP units and repeated dosing.
E.g., Trottier et al. reported successful treatment of protracted COVID-19 in a patient with chronic lymphocytic leukemia after 30 days of remdesivir, 20 days of Paxlovid™ and a dose of bebtelovimab [15]. Combination therapies have clear biological plausibility, but for COVID-19 in the IC, there is a dearth of high-quality clinical efficacy data. We note inconsistencies in the way that the available clinical evidence is applied to COVID-19 care. For example, none of the small molecule antiviral drugs has been tested in IC patients by RCT [16]. Molnupiravir is prescribed to vaccinated outpatients, despite no evidence that it reduces hospitalizations [17]. Similarly, mAb therapies were enthusiastically adopted for IC patients without RCT evidence or formal subgroup analysis suggesting efficacy in this population. Evusheld™ provides a good example, gaining FDA authorization for IC patients despite the PROVENT RCT authors concluding “efficacy in these groups could not be estimated” [18]. mAb therapies are often used regardless of serostatus, which negates the logic of replacement therapy in those who are seropositive. Remarkably, mAb use has continued despite the evidence of in vitro inefficacy across Europe [19], where EMA never withdrew a single authorization [20], while in the USA all of them were promptly withdrawn as they lost reactivity with Omicron variants [21]. It is paradoxical that many physicians do not trust in vitro surrogate markers when selecting therapy [22,23], but use them for authorizing mAbs without data for clinical efficacy.
The enthusiastic adoption of small molecule antivirals and mAbs in IC patients without hard efficacy data contrasts with the lukewarm interest in CCP as a clear example of double standards. There is considerably more evidence for clinical efficacy supporting CCP in IC patients from observational studies, formal subgroup RCT analysis and at least one RCT [7] than for any other antiviral. In contrast to mAbs, CCP is a polyclonal preparation with antibodies recognizing multiple viral epitopes and isotypes, increasing the likelihood of activity against antigenically different variants that inevitably reside in the high viral loads of IC individuals. Combining CCP with antiviral drugs makes biological sense since IC patients often have antibody deficits. Given the challenge of COVID-19 in the IC, there is a pressing need for prospective studies to evaluate combination therapies in this population. While there can be discomfort at recognizing the failure of drugs that were previously advertised as magic bullets (such as mAbs) as well as at recognizing the efficacy of treatments that were previously labeled as ineffective (such as CCP), we urge our colleagues to review the available CCP efficacy data and incorporate its use in the treatment of this vulnerable population.
Table 1. Summary of the guidelines on the CCP use in COVID-19 immunocompromised patients.
Table 1. Summary of the guidelines on the CCP use in COVID-19 immunocompromised patients.
GuidelineIssuanceIndicationStrength of RecommendationCertainty of EvidenceReference
AABB09/2022Hospitalized: suggested use with standard care.weaklow[24]
Outpatients (immunocompromised or not): suggested use with standard care.weaklow
NIH12/2022There is insufficient evidence for the panel 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.
o Some Panel members would use CCP to treat an immunocompromised patient with significant symptoms attributable to COVID-19 and with signs of active SARS-CoV-2 replication and who is having an inadequate response to available therapies. In these cases, clinicians should attempt to obtain 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.
FDA12/2021COVID-19 convalescent plasma with high titers of anti-SARS-CoV-2 antibodies is authorized for the treatment of COVID-19 in patients with immunosuppressive disease or receiving immunosuppressive treatment, in inpatient or outpatient settings.--[26]
IDSA3/2/2022Recommendation 14: 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.weaklow[27]
ECIL-99/17/2021Mild COVID-19: high-titer CCP is recommended in hematological patients within 72 h from symptom onset and anti-SARS-CoV-2 monoclonal antibodies not available.weakmoderate[28]
Moderate COVID-19: CCP is recommended in seronegative hematological patients.moderatelow
NCCN (CCP obtained from subjects recovered from Omicron and previously vaccinated is preferred)8/19/2022Hospitalized 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.2A 1-[29]
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 1-
1 Category 2A: based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Author Contributions

D.F. and M.F. wrote the first draft; M.J.J. and A.C. revised the manuscript. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Data Availability Statement

This manuscript generated no new dataset.

Conflicts of Interest

The authors declare no conflict of interest.


COVID-19 convalescent plasma;
neutralizing antibodies;
monoclonal antibodies;
variant of concern;
randomized clinical trial.
American Association of Blood Banks;
National Institute of Health;
Food and Drug Administration;
Infectious Diseases Society of America;
European Conference on Infections in Leukemia;
National Comprehensive Cancer Network.


  1. Casadevall, A.; Pirofski, L.-A. The convalescent sera option for containing COVID-19. J. Clin. Investig. 2020, 130, 1545–1548. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Focosi, D.; Franchini, M.; Pirofski, L.A.; Burnouf, T.; Paneth, N.; Joyner, M.J.; Casadevall, A. COVID-19 Convalescent Plasma and Clinical Trials: Understanding Conflicting Outcomes. Clin. Microbiol. Rev. 2022, 35, e0020021. [Google Scholar] [CrossRef] [PubMed]
  3. Focosi, D.; McConnell, S.; Casadevall, A.; Cappello, E.; Valdiserra, G.; Tuccori, M. Monoclonal antibody therapies against SARS-CoV-2. Lancet Infect. Dis. 2022, 22, 00311–00315. [Google Scholar] [CrossRef] [PubMed]
  4. Sullivan, D.J.; Franchini, M.; Joyner, M.J.; Casadevall, A.; Focosi, D. Analysis of anti-Omicron neutralizing antibody titers in different convalescent plasma sources. Nat. Comm. 2022, 13, 6478. [Google Scholar] [CrossRef]
  5. Sullivan, D.J.; Franchini, M.; Senefeld, J.W.; Joyner, M.J.; Casadevall, A.; Focosi, D. Plasma after both SARS-CoV-2 boosted vaccination and COVID-19 potently neutralizes BQ1.1 and XBB. bioRxiv 2022. [Google Scholar] [CrossRef]
  6. Khoury, E.; Nevitt, S.; Madsen, W.R.; Turtle, L.; Davies, G.; Palmieri, C. Differences in Outcomes and Factors Associated With Mortality Among Patients With SARS-CoV-2 Infection and Cancer Compared With Those Without Cancer: A Systematic Review and Meta-analysis. JAMA Netw Open 2022, 5, e2210880. [Google Scholar] [CrossRef]
  7. Senefeld, J.W.; Franchini, M.; Mengoli, C.; Cruciani, M.; Zani, M.; Gorman, E.K.; Focosi, D.; Casadevall, A.; Joyner, M.J. COVID-19 convalescent plasma for the treatment of immunocompromised patients: A systematic review and meta-analysis. JAMA Netw. Open 2022, in press. [Google Scholar] [CrossRef]
  8. Focosi, D.; Franchini, M.; Senefeld, J.; Casadevall, A.; Joyner, M. Convalescent plasma for COVID-19 in oncohematological patients: A call for revision of the European Conference on Infections in Leukemia-9 guidelines. JCV Plus 2022, 3, 100128. [Google Scholar] [CrossRef]
  9. World Health Organization (WHO). WHO Recommends against the Use of Convalescent Plasma to Treat COVID-19. Available online: (accessed on 25 August 2022).
  10. Paneth, N.; Casadevall, A.; Pirofski, L.A.; Henderson, J.P.; Grossman, B.J.; Shoham, S.; Joyner, M.J. WHO covid-19 drugs guideline: Reconsider using convalescent plasma. BMJ 2022, 376, o295. [Google Scholar] [CrossRef]
  11. Mahase, E. Covid-19: WHO declares pandemic because of “alarming levels” of spread, severity, and inaction. BMJ 2020, 368, m1036. [Google Scholar] [CrossRef]
  12. Lewis, D. Why the WHO Took Two Years to Say COVID Is Airborne. Available online: (accessed on 25 August 2022).
  13. Franchini, M.; Focosi, D.; Percivalle, E.; Beccaria, M.; Garuti, M.; Arar, O.; Pecoriello, A.; Spreafico, F.; Greco, G.; Bertacco, S.; et al. Variant of Concern-Matched COVID-19 Convalescent Plasma Usage in Seronegative Hospitalized Patients. Viruses 2022, 14, 1443. [Google Scholar] [CrossRef] [PubMed]
  14. Sample, I. Doctors Treat First UK Patient in Covid ’Super Donor ’Blood Trial. The Guardian. Available online: (accessed on 3 August 2022).
  15. Trottier, C.A.; Wong, B.; Kohli, R.; Boomsma, C.; Magro, F.; Kher, S.; Anderlind, C.; Golan, Y. Dual Antiviral Therapy for Persistent Coronavirus Disease 2019 and Associated Organizing Pneumonia in an Immunocompromised Host. Clin. Infect. Dis. 2022. [Google Scholar] [CrossRef] [PubMed]
  16. Sullivan, D.J.; Focosi, D.; Hanley, D.; Franchini, M.; Ou, J.; Casadevall, A.; Paneth, N. Effective antiviral regimens to reduce COVID-19 hospitalizations: A systematic comparison of randomized controlled trials. medRxiv 2022. [Google Scholar] [CrossRef]
  17. Focosi, D. Molnupiravir: From Hope to Epic Fail? Viruses 2022, 14, 2560. [Google Scholar] [CrossRef] [PubMed]
  18. Levin, M.J.; Ustianowski, A.; De Wit, S.; Launay, O.; Avila, M.; Templeton, A.; Yuan, Y.; Seegobin, S.; Ellery, A.; Levinson, D.J.; et al. Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19. N. Engl. J. Med. 2022, 386, 2188–2200. [Google Scholar] [CrossRef] [PubMed]
  19. Focosi, D.; Tuccori, M. Prescription of Anti-Spike Monoclonal Antibodies in COVID-19 Patients with Resistant SARS-CoV-2 Variants in Italy. Pathogens 2022, 11, 823. [Google Scholar] [CrossRef] [PubMed]
  20. ETF Warns that Monoclonal Antibodies May Not be Effective against Emerging Strains of SARS-CoV-2. Available online: (accessed on 11 December 2022).
  21. Anderson, T.S.; O’Donoghue, A.; Mechanic, O.; Dechen, T.; Stevens, J. Administration of Anti–SARS-CoV-2 Monoclonal Antibodies After US Food and Drug Administration Deauthorization. JAMA Netw. Open 2022, 5, e2228997. [Google Scholar] [CrossRef]
  22. Wu, M.Y.; Carr, E.J.; Harvey, R.; Mears, H.V.; Kjaer, S.; Townsley, H.; Hobbs, A.; Ragno, M.; Herman, L.S.; Adams, L.; et al. WHO’s Therapeutics and COVID-19 Living Guideline on mAbs needs to be reassessed. Lancet 2022, 400, 2193–2196. [Google Scholar] [CrossRef]
  23. Stadler, E.; Chai, K.L.; Schlub, T.E.; Cromer, D.; Polizzotto, M.N.; Kent, S.J.; Beecher, C.; White, H.; Turner, T.; Skoetz, N.; et al. Determinants of passive antibody efficacy in SARS-CoV-2 infection. medRxiv 2022. [Google Scholar] [CrossRef]
  24. Estcourt, L.J.; Cohn, C.S.; Pagano, M.B.; Iannizzi, C.; Kreuzberger, N.; Skoetz, N.; Allen, E.S.; Bloch, E.M.; Beaudoin, G.; Casadevall, A.; 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, 1310–1321. [Google Scholar] [CrossRef]
  25. National Institute of Health (NIH). COVID-19 Treatment Guidelines. Available online: (accessed on 2 December 2022).
  26. Food and Drug Administration (FDA). Fact Sheet for Health Care Providers: Emergency Use Authorization (EUA) of COVID-19 Convalescent Plasma for Treatment of Coronavirus Disease 2019 (COVID-19). 2021. Available online: (accessed on 25 August 2022).
  27. IDSA Guidelines on the Treatment and Management of Patients with COVID-19. Available online: (accessed on 25 August 2022).
  28. Cesaro, S.; Ljungman, P.; Mikulska, M.; Hirsch, H.H.; von Lilienfeld-Toal, M.; Cordonnier, C.; Meylan, S.; Mehra, V.; Styczynski, J.; Marchesi, F.; et al. Recommendations for the management of COVID-19 in patients with haematological malignancies or haematopoietic cell transplantation, from the 2021 European Conference on Infections in Leukaemia (ECIL 9). Leukemia 2022, 36, 1467–1480. [Google Scholar] [CrossRef] [PubMed]
  29. National Comprehensive Cancer Network (NCCN). NCCN Guidelines Version 2.2022. Prevention and Treatment of Cancer-Related Infections. Available online: (accessed on 25 August 2022).
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Franchini, M.; Casadevall, A.; Joyner, M.J.; Focosi, D. WHO Is Recommending against the Use of COVID-19 Convalescent Plasma in Immunocompromised Patients? Life 2023, 13, 134.

AMA Style

Franchini M, Casadevall A, Joyner MJ, Focosi D. WHO Is Recommending against the Use of COVID-19 Convalescent Plasma in Immunocompromised Patients? Life. 2023; 13(1):134.

Chicago/Turabian Style

Franchini, Massimo, Arturo Casadevall, Michael J. Joyner, and Daniele Focosi. 2023. "WHO Is Recommending against the Use of COVID-19 Convalescent Plasma in Immunocompromised Patients?" Life 13, no. 1: 134.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop