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REVIEW ARTICLE
Year :   |  Volume :   |  Issue :   |  Page :  

A review of convalescent plasma transfusion in COVID-19: Old wine reserved for special occasions


 Department of Pulmonary Medicine, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India

Date of Submission07-May-2020
Date of Decision31-May-2020
Date of Acceptance09-Jun-2020
Date of Web Publication16-Sep-2020

Correspondence Address:
Gopal Chawla,
Department of Pulmonary Medicine, All India Institute of Medical Sciences, Jodhpur, Rajasthan
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/lungindia.lungindia_350_20

   Abstract 


Convalescent plasma (CP) therapy has been used in past for treating 1918 pandemic flu, measles, Ebola, severe acute respiratory syndrome, and Middle East respiratory syndrome. There is still no definitive treatment available for COVID-19. Considering its effectiveness in other viral illnesses, it has been speculated that CP will be of use in COVID-19. In this study, we reviewed the published literature on the use of CP in COVID-19 till date. All the studies reported a favorable outcome with CP transfusion. However, the quality of evidence is low with only case reports, case series and observational studies. Hence, CP therapy should be considered as an empirical therapy till we await the results from randomized controlled trials.

Keywords: Coronavirus, COVID-19, pandemic, plasma therapy



How to cite this URL:
Deokar K, Chawla G, Joel B, Dutt N. A review of convalescent plasma transfusion in COVID-19: Old wine reserved for special occasions. Lung India [Epub ahead of print] [cited 2020 Nov 27]. Available from: https://www.lungindia.com/preprintarticle.asp?id=295234




   Introduction Top


COVID-19 has been declared a pandemic by the World Health Organization on March 11, 2020.[1] No specific antiviral therapy is yet available and vaccines are still under development. Convalescent plasma (CP) has been used in 1918 pandemic flu, measles, Ebola, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS).[2] However, its efficacy and safety in COVID-19 is still unknown. It has been postulated that the CP will provide short-term humoral immunity which will neutralize the virus and thus halt the progression of disease.


   Methods Top


We searched PubMed, Medline, and Google scholar using keywords “COVID-19” or “SARS-CoV-2,” and “Convalescent plasma.” Articles published from December 1, 2020 to May 5, 2020 were included. As paucity of data was expected, we did not put any restrictions on the type of study setting. We included only articles published in English. Preprint articles which were not peer reviewed were not included. Search was carried out independently by two authors. They independently screened the titles and abstracts. Full text review of selected articles was done to confirm eligibility for inclusion in the study.


   Results Top


We found two prospective observational studies, one case series and two case reports. All the studies have been summarized in [Table 1]. There is no published randomized controlled trial (RCT) on the effect of CP transfusion in COVID-19 patients till date. A total of 27 patients received CP transfusion. The mean age of patients was 57.11 ± 12.98 years. Of the 27 patients, 17 (62.9%) were male while 10 (37.1%) were female. The dose and timing of CP transfusion varied widely in between studies. Ye et al.[7] did not mention the dose of CP used in their patients. In rest of the patients in other studies, dose ranged from 200 ml single dose to 2400 ml in eight divided doses. The interval between admission and CP transfusion varied widely from 6th day to 39th day. Of the studies which we found fever, cough resolved, or decreased within 1–3 days of CP transfusion. Radiological improvement was observed in all the patients. Blood inflammatory markers also decreased. Viral load became negative in all the patients. Oxygenation improved and all intubated patients could be extubated. All the patients survived except one patient in the study by Zhang et al.,[4] who was in an unfenced intensive care unit (ICU) till that manuscript was written. No significant adverse events were observed. One patient in the study by Duan et al. had an evanescent facial red spot. Most of the patients (22 of 27) received steroids and antivirals in addition to CP transfusion. Data regarding use of steroids and antivirals in remaining five patients were not available.
Table 1: Summary of studies on the use of convalescent plasma transfusion in COVID-19

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   Discussion Top


CP refers to plasma derived from an individual who has recovered from the disease. The transfusion of CP results in transfer of antibodies which provide passive immunity against the infection. Thus, it provides immediate immunity, but it is short-lived.[8] For the therapy to be effective, CP must contain a high titer of neutralizing antibodies. Plasma obtained from individuals who have recovered from COVID-19 will contain antibodies against the virus. Transfusion of this antibody-rich plasma will theoretically result in neutralization of the virus and will thus halt the progression of disease. It has been used previously for treatment of 1918 pandemic flu, measles, Ebola, SARS, and MERS.[2] Mair-Jenkins et al. in their meta-analysis showed that the use of CP in patients with severe acute respiratory illnesses of viral origin was associated with reduced mortality and was found to be safe.[9] With this rationale, the utility of CP in treatment of COVID-19 is being explored. United States-Food and Drug Administration (US-FDA) is regulating its use in COVID-19 as an investigational product.[10]

All the studies in our review reported a favorable outcome with CP transfusion. There was clinical and radiological improvement in all the patients. Blood inflammatory markers also improved and viral load became negative in all patients. All patients survived except one who was still in ICU. However, these data are from case reports, case series, and observational studies and no randomized control trials are available. There are several methodological issues. Most of the cases received multiple other antiviral agents and therefore it is not possible to determine if the beneficial effect was entirely due to CP transfusion. Furthermore, as controls were not available, we do not know if patients would have improved even without CP transfusion. Therefore, larger well-designed randomized controlled trials are necessary to elucidate the safety and efficacy of CP transfusion in COVID-19 patients. Considering this the Indian Council of Medical Research (ICMR) has initiated a Phase II, open label, multicenter, RCT to assess the safety and efficacy of CP to limit Covid-19-associated complications in moderate disease called as the PLACID trial.[11]

Dose and ideal timing of transfusion is still evolving. As the viremia peaks in the 1st week of illness, and therefore, theoretically, CP will be of utmost benefit if transfused during this time. Literature on the use of CP in Spanish influenza and SARS had shown that early administration is associated with a survival benefit.[9],[12],[13] Considering variable viral replication kinetics, the ideal timing and dose of CP transfusion to gain maximum benefit needs to be investigated in COVID-19 patients. The dose of CP used in the ongoing PLACID trial is 200 ml which is repeated after 24 h if no adverse events are reported after the first dose. Thus, a cumulative dose of 400 ml will be used.[11]

As these are still early days in the pandemic and CP therapy is in nascent stage there is a large degree of ambiguity to donor selection. Selection of donors is of paramount as those with high level of neutralizing antibodies against the virus need to be selected.[2] The test recommended to quantify neutralizing antibody titers is high throughput ELISA. However, not all centers have access to it at present. The US-FDA donor eligibility criteria include males or nulliparous females or females with documented HLA-negative status after their recent pregnancy who were COVID-19 confirmed either by a diagnostic test or a positive serology for SARS-COV-2 antibodies and have complete resolution of symptoms at least 14 days before donation, and if available have a neutralizing antibody titer of at least 1:160.[10] The European commission recommends a neutralizing antibody titer of at least 1:320.[14] While the donor eligibility criteria of ICMR PLACID trial include individuals with age >18 years, males or nulliparous females with weight >55 kg, prior diagnosis of RT-PCR confirmed COVID-19 with symptoms and complete resolution of symptoms at least 14 days prior to donation in a patient whose two consecutive 24 h apart nasopharyngeal swab was negative for COVID-19 by RT-PCR. Else, at least 28 days must have lapsed after complete resolution of symptoms. This is in addition to the donor eligibility criteria to be followed in accordance to the Drugs and Cosmetics Act [15] like ABO compatibility and negative screen for infections such as HIV, Hepatitis B, Hepatitis C, Syphilis, and Malaria. If available, the desired titer for IgG antibodies is 1:1024 and for neutralizing antibodies is 1:40.[11]

CP therapy involves many challenges apart from donor availability like donor's readiness, presence of apheresis center, adequacy of antibody titers, storage, and transportation of plasma concentrate. Just like with any other blood product transfusion, certain adverse effects are anticipated, such as transfusion-related acute lung injury, fluid overload, antibody-dependent enhancement of infection, and serum sickness though there is no evidence to suggest any risk of this therapy over routinely used fresh frozen plasma.[8],[16] Considering these limitations and the potential risks, plasma therapy should be used prudently and judiciously.

Although the data from observational studies and case reports are promising, high-quality randomized controlled trials are required to confirm or refute these findings. We are eagerly awaiting the results of ongoing randomized controlled trials especially the PLACID trial to enlighten further.


   Conclusion Top


As we do not have any trustworthy targeted drugs or a vaccine for novel coronavirus, the option of CP is passive yet aggressive approach which seems to boost the immune system of infected patients or susceptible population immediately and help in tiding over acute crisis. The initial published literature has shown a favorable effect of CP therapy in patients with COVID-19 and till the time results of randomized controlled trials are available, it can be considered as an empirical therapy for COVID-19.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
World Health Organization. WHO Director-General's Opening Remarks at the Media Briefing on COVID-19. World Health Organization; 11 March 2020. Available from: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. [Last accessed on 2020 May 04].  Back to cited text no. 1
    
2.
Marano G, Vaglio S, Pupella S, Facco G, Catalano L, Liumbruno GM, et al. Convalescent plasma: New evidence for an old therapeutic tool? Blood Transfus 2016;14:152-7.  Back to cited text no. 2
    
3.
Ahn JY, Sohn Y, Lee SH, Cho Y, Hyun JH, Baek YJ, et al. Use of convalescent plasma therapy in two COVID-19 patients with acute respiratory distress syndrome in Korea. J Korean Med Sci 2020;35:e149.  Back to cited text no. 3
    
4.
Zhang B, Liu S, Tan T, Huang W, Dong Y, Chen L, et al. Treatment with convalescent plasma for critically ill patients with SARS-CoV-2 infection [published online ahead of print, 2020 Mar 31]. Chest 2020. pii: S0012-3692(20)30571-7.  Back to cited text no. 4
    
5.
Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 2020;323:1582–9.  Back to cited text no. 5
    
6.
Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A 2020;117:9490-6.  Back to cited text no. 6
    
7.
Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F, et al. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol. 2020 Apr 15:10.1002/jmv.25882. doi: 10.1002/jmv.25882. Epub ahead of print. PMID: 32293713; PMCID: PMC7262027.  Back to cited text no. 7
    
8.
Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. J Clin Invest 2020;130:1545-8.  Back to cited text no. 8
    
9.
Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: A systematic review and exploratory meta-analysis. J Infect Dis 2015;211:80-90.  Back to cited text no. 9
    
10.
U.S. Department of Health and Human Services. Food and Drug Administration Center for Biologics Evaluation and Research. Investigational COVID-19 Convalescent Plasma-Guidance for Industry; April 2020. Available from: https://www.fda.gov/media/136798/download. [Last updated on 2020 May 01; Last accessed on 2020 May 08].  Back to cited text no. 10
    
11.
Clinical Trials Registry of India. Available from: http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=43149&EncHid=&userName=Convalescent%20plasma. [Last accessed on 2020 Jun 02].  Back to cited text no. 11
    
12.
Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: Convalescent blood products for Spanish influenza pneumonia: A future H5N1 treatment? Ann Intern Med 2006;145:599-609.  Back to cited text no. 12
    
13.
Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis 2005;24:44-6.  Back to cited text no. 13
    
14.
European Commission Directorate-General for Health and Food Safety. An EU Programme of COVID-19 Convalescent Plasma Collection and Transfusion - Guidance on Collection, Testing, Processing, Storage, Distribution and Monitored use. Version 1.0; April 4 2020. Available from: https://ec.europa.eu/health/sites/health/files/blood_tissues_organs/docs/guidance_plasma_covid19_en.pdf. [Last accessed on 2020 May 08].  Back to cited text no. 14
    
15.
Government of India. Drugs and Cosmetics Act 1940 and Rules 1945 (As amended up to the 31st December, 2016). Available from: https://cdsco.gov.in/opencms/export/sites/CDSCO WEB/Pdf-documents/acts rules/2016 Drugs and Cosmetics Act 1940 Rules 1945.pdf. [Last accessed on 2020 Jun 02].  Back to cited text no. 15
    
16.
Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, et al. Molecular Mechanism for antibody-dependent enhancement of coronavirus entry. J Virol 2020;94:e02015-19.  Back to cited text no. 16
    



 
 
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