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Medical News & Perspectives
April 30, 2020

Testing an Old Therapy Against a New Disease: Convalescent Plasma for COVID-19

JAMA. 2020;323(21):2114-2117. doi:10.1001/jama.2020.7456

As deaths from coronavirus disease 2019 (COVID-19) continue to mount, desperation has driven physicians to try therapies backed by little or no evidence.

Perhaps the greatest excitement surrounds convalescent plasma, a treatment more than a century old that has gone in and out of fashion—in when infectious disease outbreaks occurred and then out when treatments and vaccines that could be mass-produced were developed to contain them.

Taken from healthy people (or in the earliest reported cases, animals) who have recovered from the infectious disease of interest, antibody-rich convalescent plasma is thought to give recipients’ immune systems a running start.

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    9 Comments for this article
    Immunologic Effects of Allogeneic Plasma
    Neil Blumberg, MD | University of Rochester Medical Center
    It is worth noting that there is an observational literature suggesting that allogeneic plasma infusion can modulate recipient immune function, including both innate and adaptive immunity. These potential effects include pro-inflammatory effects, dysregulation of T cell immunity and associations with increases in nosocomial infection, thrombosis and organ failure. Thus the control arm of non-immune plasma could have either positive or negative immunologic effects on patients. And timing may be critical. Plasma might conceivably be effective due to antibody neutralization early on in infection and deleterious when the inflammatory response is fully developed. Or vice versa. No one knows. But the notion that only antibody effects on virus neutralization (or enhancement) are immunologically possible is likely incorrect.

    Finally, the common transfusion service practice of infusing ABO non-identical, so-called "compatible plasma" is almost certainly not immunologically neutral. Infusion of large amounts of soluble antigen (e.g., AB plasma to other ABO types) creates circulating immune complexes which in observational studies have been associated with increased bleeding, acute lung injury (ARDS), sepsis and mortality. Thus the degree to which ABO identical plasma is infused is a variable worth considering in data analysis.
    Plasma is More than Antibodies
    Marica Bakovic, PhD | University of Guelph
    Considering that a number of serum factors other than antibody, including IgG, ITFs, lipids, and others could help COVID-19 patients, plasma from unaffected donors may not be a good control.
    Control Group
    Loren Latta, PhD | Loren Latta, Dept. Orthopaedics, Univ. Miami
    What is the hypothesis: does injection of convalescent plasma improve outcome of patients compared to injection of “other” plasma? Even if the hypothesis proves correct, it doesn’t answer the question about giving convalescent plasma to patients that have had no injections of any type of plasma. Why “create” a small, randomly selected group that may not match well at all? Besides, giving the random control group something with unknown “serum factors” [1], could produce another confounding variable. There are over 1 million cases in the US alone to choose from to “create” a large control group that can be very well matched. After the patients are enrolled, search the database of over 1 million cases and match them with a group of patients that have a similar stage of COVID-19 and were not treated with serum of any type. The ratio of potential “control” cases to the 500 in this study is 2000:1. That should produce a better matched, safer control group.


    [1] Marica Bakovic, PhD, JAMA letters to the editor, April 30, 2020
    Old Technology
    Camilo Colaco, PhD | ImmunoBiology Ltd
    Does it matter if its 'Old Technology' if it works?
    If Convalescent Plasma Shows Safety and Effectivenes It Should be Stocked up for the Second Wave
    Giovanni Ghirga, Chief of Ped/Neon Unit | Giovanni Ghirga, MD. San Paolo Hospital, Civitavecchia, Italy
    In the meantime, until the results of a randomized trial on the effectiveness of convalescent plasma will be available, this treatment modality should be used in hospitalized patients with SARS-CoV-2 infection. If it is confirmed to be safe and effective, it should be stocked up in preparing for the second wave if it will come unless a specific drug or a vaccine will be available.
    Really a Need for a Control Group?
    Bdg Bdg, Med Chem Researcher | University of Urbino
    What is needed is to study the correct dilution of the plasma to be infused and, I believe, this could be done with an in vitro test, using a microscope, a cellular line, or a blood sample with the virus itself, to look for the effect of different plasma concentration samples on virus infectivity.

    About a control group I wonder: what type of control group is used to demonstrate the effectiveness of a vaccine in a clinical trial?

    And I wonder: why people should look for an anti-covid-19 vaccine if we cannot demonstrate that the plasma from convalescent
    people works?
    Why Not Use Serum Instead of Plasma?
    Esbjorn Telemo, Professor, Immunolgy | Sahlgrenska Academy, University of Goteborg, Sweden
    To avoid the potential increased clotting risk when giving control plasma to the control group, it would be safer to use serum in both experimental and control group.
    Convalescent Plasma as Vaccine?
    Dr Chemy Sheehy, Chemistry | Retired
    What is the level of antibodies that your body produces in response to a flu vaccine relative to the amount of antibodies found in the convalescent serum of a person who has had the flu? If the ratio is very low it would be interesting to inject health care workers who work with covid patients with convalescent serum to see how it works as a vaccine. If you can vaccinate 100 people with the serum from one person it may be the way to go for vaccinating everyone in the next year.

    Based on the poor outcome
    of other convalescent studies on the flu and the mediocre outcomes of most antiviral studies for respiratory viruses, I just can't get too optimistic about treating covid patients after they have come down with the disease - particularly after they have had it for several days.
    CoVig-19 Plasma Alliance
    Christopher King, MB BS MA | National University Hospital Singapore
    It was recently announced that an alliance of major plasma fractionators (now 10) have started recruiting Covid-19 survivors as plasmapheresis donors to eventually produce an unbranded hyperimmune immunoglobulin against SARS-CoV-2, which they are naming CoVig-19. This has potential advantages over convalescent plasma, arguably the most important being it will contain a fixed dose of antibody. Failure of CP either in a patient or in a trial may not mean much if there was never sufficient antibody present. As a plasma-derived medicinal product, it also should avoid most of the potential problems of plasma which may be significant in sick patients (TRALI, TACO, TRIM, ABO incompatibility etc).

    It's understood most of the plasma will be collected at donor centres in the US and some European countries, although its not clear whether donors will be paid. It's unlikely the processing of CP will have any significant impact on the supply of regular plasma-derived products (PDMPs) and in theory it's possible to use CP to manufacture PDMPs. The Alliance have communicated that CoVig-19 will be provided free of charge and allocated to countries on a need basis.

    Clearly once it is available trials are needed. If it truly proves effective then its role in relation to vaccination (particularly if repeat vaccinations are required) may become significant. If Covid-19 mortality in Africa remains limited, post-exposure prophylaxis of target populations with hyperimmune immunoglobulin may prove more pragmatic than repeat vaccinations of large populations.
    CONFLICT OF INTEREST: Speaker Fees re use of Fibrinogen Concentrate- Octopharma