Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis

Niveditha Devasenapathy; Zhikang Ye; Mark Loeb; Fang Fang; Borna Tadayon Najafabadi; Yingqi Xiao; Rachel Couban; Philippe Bégin; Gordon Guyatt

doi:10.1503/cmaj.200642

Submit a Response to This Article

Compose Response

Title *

References

Author Information

Contributors

First Name and Middle Initial *

First or given name, e.g. 'Peter'.

Last Name *

Your last, or family, name, e.g. 'MacMoody'.

Degrees

Email Address *

Your email address, e.g. higgs-boson@gmail.com

Occupation *

Your role and/or occupation, e.g. 'Orthopedic Surgeon'. Minimum 7 characters.

Affiliation *

Your organization or institution (if applicable), e.g. 'Royal Free Hospital'. Minimum 12 characters.

Address

Your organization, institution's or residential address.

Statement of Competing Interests

Competing interests? *

Yes

Please describe the competing interests

Vertical Tabs

Jump to comment:

RE:Convalescent plasma safety and efficacy
David Toms [BSc MD]

Posted on: 05 August 2020
Convalescent plasma safety
Neil Blumberg [MD]

Posted on: 02 June 2020
Convalecent plasma: safe or not?
beuy joob and viroj wiwanitkit [MD]

Posted on: 25 May 2020
Cytokine storm in Paediatric multisystem inflammatory syndrome temporally associated with COVID-19: Is it amenable to covalescent plasma?
Siddharth Madan [M.B.B.S, M.S, D.N.B (Ophthalmology), F.I.C.O] and Sarita Beri [M.B.B.S, M.D]

Posted on: 25 May 2020
RE: convalescent plasma for COVID 19
Stephen Arif [BA MD CCFP]

Posted on: 22 May 2020

Posted on: (5 August 2020)

RE:Convalescent plasma safety and efficacy
David Toms [BSc MD], Retired radiologist, Charlottetown, PE
The following remarks are based on the Mayo Clinic convalescent plasma (CP) for Covid-19 webinar of August 1, 2020 and subsequent reporting in the August 4 edition of the Wall Street Journal (1). My reluctance to use unpublished data presented by some distinguished speakers limits what I can write; it was a remarkable webinar (America at its best) and I hope that uploads and/or published results will become generally available. The information derives from the Expanded Access Program initiated by the FDA and coordinated by the Mayo Clinic with input from other centers such as Johns Hopkins. More than 53,000 infusions of CP have been given involving over 2,500 sites (2). Inevitably it was not a randomized controlled trial (RCT), but some useful information has emerged.

Satisfactory safety was established, first after 5,000 infusions (3) and later after 20,000 infusions (4).

Timing of infusion with respect to time of diagnosis turns out to be very important, corresponding to over a century of experience with CP/serum treatments: In 1937 Cecil stated “It is a fundamental principle in all serum therapy that to obtain the best results the serum must be given early in the disease” (5). Exploratory analysis of data from some 3000 CP infusions indicated that treatment within three days of diagnosis, using plasma with high antibody levels for Covid-19, resulted in 50% mortality reduction at 7 days and 36% reduction at 30 days (1). This information should help provi...
Show More

The following remarks are based on the Mayo Clinic convalescent plasma (CP) for Covid-19 webinar of August 1, 2020 and subsequent reporting in the August 4 edition of the Wall Street Journal (1). My reluctance to use unpublished data presented by some distinguished speakers limits what I can write; it was a remarkable webinar (America at its best) and I hope that uploads and/or published results will become generally available. The information derives from the Expanded Access Program initiated by the FDA and coordinated by the Mayo Clinic with input from other centers such as Johns Hopkins. More than 53,000 infusions of CP have been given involving over 2,500 sites (2). Inevitably it was not a randomized controlled trial (RCT), but some useful information has emerged.

Satisfactory safety was established, first after 5,000 infusions (3) and later after 20,000 infusions (4).

Timing of infusion with respect to time of diagnosis turns out to be very important, corresponding to over a century of experience with CP/serum treatments: In 1937 Cecil stated “It is a fundamental principle in all serum therapy that to obtain the best results the serum must be given early in the disease” (5). Exploratory analysis of data from some 3000 CP infusions indicated that treatment within three days of diagnosis, using plasma with high antibody levels for Covid-19, resulted in 50% mortality reduction at 7 days and 36% reduction at 30 days (1). This information should help provide a framework for RCT designs. In the meantime, consideration might be given to having high-antibody frozen plasma on hand as treatment decisions evolve.
Show Less
Competing Interests: None declared.
References
1. Dockser Marcus A. Convalescent Plasma Reduced Death Rate Among Covid -19 Patients, Study Signals. Wall Street Journal Aug 4, 2020 https://www.wsj.com/articles/convalescent-plasma-reduced-death-rate-among-covid-19-patients-study-data-signals-11596594390
2. COVID-19 expanded access program. uscovidplasma.org
3. Joyner MJ, Wright RS, Fairweather D et al. Early safety indicators of COVID-19 convalescent plasma in 5000 patients. J Clin Invest (Clinical Medicine) June 11 2020 https://doi.org/10.1172/JCI140200
4. Joyner MJ, Bruno KA, Klassen SA et al. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clinic Proceedings, In Press
5. Cecil RL. Effects of very early serum treatment in pneumococcal type 1 pneumonia. JAMA 1937; 108: 689-692.
Posted on: (2 June 2020)

Convalescent plasma safety
Neil Blumberg [MD], Hematology/Transfusion Medicine, University of Rochester Medical Center
A major issue of convalescent plasma safety is that most studies have only included events that occur within a few hours of infusion as potentially plasma infusion related. Examples include hemolysis, acute lung injury, volume overload, anaphylaxis, urticaria, etc. However, the observational literature suggests that allogeneic plasma infusion may contribute to such less acute, but no less serious adverse events as nosocomial infection due to immunomodulation, subacute lung injury, myocardial injury, thrombosis and multi-organ failure. Some of these events may take days to be detectable. Thus I think there are still significant questions about the safety of allogeneic plasma in this and other settings. Large randomized trials of the sort planned in the USA through the Hopkins directed CTSI network will be needed to provide a definitive assessment of convalescent plasma efficacy and safety.
Competing Interests: None declared.
References
Niveditha Devasenapathy, Zhikang Ye, Mark Loeb, et al. Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis. CMAJ 2020;10.1503/cmaj.200642.
4 Contemporary Risk Factors and Outcomes of Transfusion-Associated Circulatory Overload. Roubinian NH, Hendrickson JE, Triulzi DJ, Gottschall JL, Michalkiewicz M, Chowdhury D, Kor DJ, Looney MR, Matthay MA, Kleinman SH, Brambilla D, Murphy EL; National
Plasma transfusion is associated with postoperative infectious complications following esophageal resection surgery: a retrospective cohort study. Subramanian A, Berbari EF, Brown MJ, Allen MS, Alsara A, Kor DJ. J Cardiothorac Vasc Anesth. 2012 Aug;26(4
Posted on: (25 May 2020)

Convalecent plasma: safe or not?
beuy joob, acedemic consultant, private medical acedemic consultant
Other Contributors:
viroj wiwanitkit, physician, medical professor
We found that the report on "Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis" is very interesting. Devasenapathy et al. concluded that "Studies of non- COVID-19 severe respiratory viral infections provide indirect, very low-quality evidence that raises the possibility that convalescent plasma has minimal or no benefit in the treatment of COVID-19 and low-quality evidence that it does not cause serious adverse events [1]." Despite a lack of scientific evidence to support the advantage of convalescent plasma therapy, it is promoted and used in many settings. We agree that we need emergency management of COVID-19 during the pandemic but that does not mean we can use anything for treatment of the problem. Like a sera treatment, there is no doubt that convalescent plasma can cause unwanted immunological effects. In addition, the protective immuni ty in plasma of the patient recovered from COVID-19 is still a controversial issue [2]. There are some more safe alternatives such as known drugs that might be effective in disease managment (such as antirheumatic drug and anti HIV drug). We should not forget that we should use the most safe option that does not harm the patient regardless of the existence of a pandemic or not.
Competing Interests: None declared.
References
, . Convalecent plasma: safe or not? . 2020;:-.
2. Hoang VT, Dao TL, Gautret P. Recurrence of positive SARS-CoV-2 in patients recovered from COVID-19. J Med Virol. 2020 May 25. doi: 10.1002/jmv.26056. Online ahead of print.
Posted on: (25 May 2020)

Cytokine storm in Paediatric multisystem inflammatory syndrome temporally associated with COVID-19: Is it amenable to covalescent plasma?
Siddharth Madan [M.B.B.S, M.S, D.N.B (Ophthalmology), F.I.C.O], Assistant Professor of Ophthalmology, Lady Department of Ophthalmology, Lady Hardinge Medical College and Associated Hospitals, University Of Delhi
Other Contributors:
Sarita Beri, Director Professor and Head of Department, Department of Ophthalmology, Lady Hardinge Medical College and AssociatedHospitals
This is with reference to the recently published article by Devasenapathy N, Ye Z, Loeb M et al.1 The authors conducted a systematic review of the usefulness of convalescent plasma (CP)in coronavirus disease 2019 (COVID-19) and other severe respiratory viral infections. The available literature on non-COVID-19 severe respiratory viral infections provides indirect yet a relatively very low-quality evidence suggesting minimal to no benefit of convalescent plasma in the treatment of COVID-19.1 Moreover the use does not cause serious adverse events.1 It is well known now that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uncommonly results in severe disease in children. In any case the disease is relatively unexplored in children. The point worth writing this letter was to alert the clinicians of the recently emerging ‘Paediatric multisystem inflammatory syndrome temporally associated with COVID-19’ as labeled by the Royal College of Paediatrics and Child Health.2 It manifests as Kawasaki disease or Kawasaki-like shock syndrome in children between four months to above four years of age. These cases that have been reported across Europe, the USA and India come with increased risk of mortality.3,4 Cytokine storm with raised levels of IL-6 have been noticed. Immunomodulation with Intravenous immune-globulin (IVIG) therapy averted life threatening sequel.2-4 In refractory cases Tocilizumab, IL-6 receptor blocker helped.3-5 This drug is already under clinical trials...
Show More

This is with reference to the recently published article by Devasenapathy N, Ye Z, Loeb M et al.1 The authors conducted a systematic review of the usefulness of convalescent plasma (CP)in coronavirus disease 2019 (COVID-19) and other severe respiratory viral infections. The available literature on non-COVID-19 severe respiratory viral infections provides indirect yet a relatively very low-quality evidence suggesting minimal to no benefit of convalescent plasma in the treatment of COVID-19.1 Moreover the use does not cause serious adverse events.1 It is well known now that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uncommonly results in severe disease in children. In any case the disease is relatively unexplored in children. The point worth writing this letter was to alert the clinicians of the recently emerging ‘Paediatric multisystem inflammatory syndrome temporally associated with COVID-19’ as labeled by the Royal College of Paediatrics and Child Health.2 It manifests as Kawasaki disease or Kawasaki-like shock syndrome in children between four months to above four years of age. These cases that have been reported across Europe, the USA and India come with increased risk of mortality.3,4 Cytokine storm with raised levels of IL-6 have been noticed. Immunomodulation with Intravenous immune-globulin (IVIG) therapy averted life threatening sequel.2-4 In refractory cases Tocilizumab, IL-6 receptor blocker helped.3-5 This drug is already under clinical trials in the USA.3,4 The fact that IVIG has been a life saving measure in these children infected with SARS-CoV-2 gives a pointer that CP may have definitive role in cases of COVID-19 requiring emergency therapy when effective medications and vaccines are unavailable but this needs further validation.5
Show Less
Competing Interests: None declared.
References
Niveditha Devasenapathy, Zhikang Ye, Mark Loeb, et al. Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis. CMAJ 2020;10.1503/cmaj.200642.
2. Multisystem inflammatory syndrome in children and adolescents with COVID-19 [Internet]. [cited 2020 May 22]. Available from: https://www.who.int/publications-detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19
3. Balasubramanian S, Nagendran TM, Ramachandran B, Ramanan AV. Hyper-inflammatory Syndrome in a Child With COVID-19 Treated Successfully With Intravenous Immunoglobulin and Tocilizumab. Indian Pediatr. 2020 May 10; S097475591600180. Online ahead of print
4. Rivera-Figueroa EI, Santos R, Simpson S, Garg P. Incomplete Kawasaki Disease in a Child with Covid-19. Indian Pediatr. 2020 May 9; S097475591600179. Online ahead of print. PMID: 32393680
5. Rojas M, Rodríguez Y, Monsalve DM, Acosta-Ampudia Y, Camacho B, Gallo JE, et al. Convalescent plasma in Covid-19: Possible mechanisms of action. Autoimmun Rev. 2020 May 5;102554.
Posted on: (22 May 2020)

RE: convalescent plasma for COVID 19
Stephen Arif [BA MD CCFP], Rural Family Doctor, Invermere and District Hospital
I believe that the best use for convalescent plasma would be in passive immunization of at risk populations like seniors in residential care.
The amount of antibodies in convalescent plasma is fixed and not active so it is likely inadequate to neutralize the large number of virus particles in an infected patient. However convalescent plasma would have the potential to neutralize a few virus particles in early illness before replication gets too far. We know this from using passive immunization in other viral disease, like Gama globulin for Hep A. Lets not forget our medical history to guide our new therapy.
I would hope that Conversant plasma for passive immunization is being studied for prophylaxis.
Competing Interests: None declared.
References
Niveditha Devasenapathy, Zhikang Ye, Mark Loeb, et al. Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis. CMAJ 2020;10.1503/cmaj.200642.