








key: cord-282252-07uzz649
authors: Sahu, Kamal Kant; Jindal, Vishal; Siddiqui, Ahmad Daniyal; Cerny, Jan; Gerber, Jonathan M.
title: Convalescent Plasma Therapy: A Passive Therapy for An Aggressive COVID‐19
date: 2020-05-21
journal: J Med Virol
DOI: 10.1002/jmv.26047
sha: 
doc_id: 282252
cord_uid: 07uzz649

As of May 19, 2020, there are in total 4,986,200 laboratory‐confirmed Coronavirus disease‐2019 (COVID‐19) cases. 2% (45,425) out of 2,657,390 active COVID‐19 cases are critically ill and might be requiring intensive care support.(1,2) Unfortunately, even after six months since its first detection, we still do not have any definitive treatment options for COVID‐19 pneumonia. This article is protected by copyright. All rights reserved.

Author Contribution Statement: All authors have seen the manuscript and agree to the content and data. All the authors played a significant role in the paper 

The basic concept for use of convalescent plasma in COVID-19 is as a delivery system for viral neutralizing antibodies, that is to confer passive immunity. Given the fact that we do not have reliable targeted drugs or a vaccine yet, the option of convalescent plasma seems reasonable to boost the immune system of infected patients or susceptible population immediately. This is not a new concept, rather this has been utilized for over 100 years, even predating the discovery of antibiotics. With regards to the previous outbreaks, experience with convalescent plasma have shown mixed results(4-6). Soo et al reported a low mortality rate (p =0.049) and shorter hospital stay (p= 0.001) in patients with SARS by using convalescent plasma (4) . Contrarily, the use of convalescent plasma therapy has been found to be of uncertain benefit in the 2013 African Ebola epidemic (6) . This article is protected by copyright. All rights reserved.

Many studies have confirmed that not all Ebola survivors have anti-Ebola antibodies and hence plasma extraction from such donors might not be beneficial for the treatment of Ebola disease (7) .

Preliminary results on using convalescent plasma in COVID-19 patients have shown positive results (8, 9) . Shen patients (10, 11) The major findings of this review were [1] reduced mortality in critically ill patients [2] disappearance of SARS-CoV-2 RNA was observed in the majority of patients [3] improvement in clinical symptoms and radiological shadows of the patients after convalescent plasma therapy [4] No significant adverse effects secondary to plasma therapy were noted.

Although the convalescent plasma therapy concept is old, the COVID-19 disease is just six months old. Hence, a large degree of uncertainty exists as to donor selection, patient eligibility, indications, and side effects that merit further discussion (11) . This article is protected by copyright. All rights reserved. 

should have completely resolved at least 14 days before donation AND negative COVID-19 PCR from nasopharyngeal swab.

Once it is confirmed that the proposed donor is no longer contagious, the next step would be to see if the donor has sufficient antibody levels to donate? This can be done by measuring SARS-CoV-2 antibody levels to ensure sufficient titers in the donor's circulation. The FDA recommends a SARS-CoV-2 neutralizing antibody titer of at least 1:160 as an inclusion criterion for donor selection. If such a matched unit is not available, the FDA suggests that a titer of 1:80 may be considered acceptable.

Convalescent plasma therapy involves many logistical challenges, including the donor's availability and willingness; apheresis center capacity; storage and transportation of plasma concentrate; and testing for the adequacy of antibody titers. Considering the aforementioned limitations and the potential risks, appropriate triage systems should be utilized; hence, plasma therapy use is currently restricted only to critically ill patients. This article is protected by copyright. All rights reserved.

The FDA recommends two clinical indications for the current usage of convalescent plasma therapy in COVID-19 patients(12) Scenario A (Severe disease) which is defined as one or more of the following:

Dyspnea, RR ≥ 30/min, blood oxygen saturation ≤ 93%, paO2 / FIO2 Ratio < 300, and radiological worsening with the appearance of lung infiltrates > 50% within 24 to 48 hours. It is unknown how long such protection might last but based on the amount and type of transfused antibody, immunity could last from weeks to months. Another important factor is the timing of plasma therapy infusion. As viremia is expected to be maximum in the first week, the early infusion is likely to give the best response. Possible mechanisms are viral neutralization and antibody-dependent cellular cytotoxicity and/or phagocytosis. This helps in not only clearing the viremia but also could potentially eradicate the reservoir of infected host cells. Currently, the only antibody source available for urgent use is from convalescent plasma from recovered patients. It is anticipated that as more people contract and recover from COVID-19, the number of potential donors will rise. This article is protected by copyright. All rights reserved.

On April 3, 2020, the FDA cleared the path for the use of this potential lifesaving therapy under any of the following three routes- [1] enrollment in a clinical trial, [2] via the national expanded access treatment protocol, and [3] under a single patient emergency investigational new drug application (eIND). Armed with FDA approval, researchers are now in the process of conducting placebo-controlled trials to test convalescent plasma, at numerous hospitals, including Johns Hopkins, the Mayo Clinic (NCT04325672), and Washington University in St. Louis (Table 1) . Lacking a vaccine and with limited antiviral options against SARS-CoV-2, this is an ideal time to try convalescent plasma therapy in COVID-19 patients.

Preliminary results are very encouraging, and none of the studies have thus far shown any significant adverse reactions. However, as experience is still limited, vigilance for potential side effects of convalescent plasma therapy is advised. As with any other blood product transfusion, there are certain common, predictable, or known side effects that also apply to convalescent plasma therapy, such as transfusion-related infections, serum sickness, fluid overload, and transfusion-related acute lung injury. By following diligent modern blood banking techniques and transfusion precautions, the incidence of these unwanted events can be minimized at any center; and the cumulative risk of any lifethreatening reactions is < 1%. Although a theoretical risk that of antibody-dependent enhancement of infection, this has not been witnessed to date.; and there are no data thus far to suggest any increased risk of convalescent plasma over ordinary fresh frozen plasma (13) . This article is protected by copyright. All rights reserved.

While awaiting an effective vaccine and/or antiviral agent for COVID-19, experimental therapies are currently being testing in clinical trials (14) . Plasma therapy has so far provided encouraging outcomes, without any serious events. We anticipate an upsurge in the use of convalescent plasma over the next several months, for the treatment of severely ill patients and perhaps with a role earlier in the course of illness and/or for prophylaxis.

The American Red Cross, the U.S. government, investigators at Mayo Clinic (www.uscovidplasma.org), and many others across the country are now hard at work identifying appropriate donors and establishing testing to confirm neutralizing antibodies in a timely fashion. As antibody testing is validated, it should help guide the more effective use of convalescent plasma. In addition, efforts are underway to pursue production of a COVID-19 immune globulin, which might provide a more reliable, more effective, and more readily available plasma-based therapy against this formidable virus. 

Latest updates on COVID-2019: A changing paradigm shift

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Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients

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Evaluation of convalescent plasma for Ebola virus disease in Guinea

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Treatment of 5 Critically Ill Patients with COVID-19 with Convalescent Plasma

Effectiveness of convalescent plasma therapy in severe COVID-19 patients

Convalescent plasma transfusion for the treatment of COVID-19: Systematic review. Journal of medical virology

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12. Recommendations for Investigational COVID-19 Convalescent Plasma | FDA

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