Print This Article
Blast from the Past: Convalescent Plasma for COVID-19
by Katie Miles, PharmD Clinical Assistant Professor/Academic Detailing Pharmacist; University of Chicago College of Pharmacy; Heather Ipema, PharmD, BCPS Clinical Assistant Professor; Drug Information Group; University of Chicago College of Pharmacy
Coronavirus disease 2019, better known as COVID-19, is a respiratory infectious disease that has rapidly spread throughout the world.1,2 The first few cases were recognized and reported in Wuhan, China in December 2019. On March 11, 2020, the World Health Organization (WHO) declared COVID-19 a pandemic.1-3 COVID-19 is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1,2 Most cases are considered mild (≥80%) with the remaining 14% of cases reported as serious and 5% as critical.2 Some cases (10%) require hospitalization for COVID-19 pneumonia with 10% of those cases necessitating intensive care unit (ICU) admission due to acute respiratory distress syndrome (ARDS).
At this time, there are no Food and Drug Administration (FDA)-approved treatment options for COVID-19 and no medication has been shown to be safe and effective for this infection.4,5 One potential treatment that has been used and is regulated by the FDA as an investigational product is COVID-19 convalescent plasma (herein after referred to as “convalescent plasma”).5,6 The Infectious Diseases Society of America (IDSA) recommends convalescent plasma in hospitalized patients in the setting of a clinical trial; though, the authors note a knowledge gap for this recommendation.2 The National Institutes of Health (NIH) also address convalescent plasma in their COVID-19 treatment guideline, but are unable to recommend for or against its use (graded as a strong recommendation based on expert opinion [AIII]) due to a lack of data and theoretical risks (e.g., antibody-dependent enhancement of infection and transfusion-associated lung injury [TRALI]).4
COVID-19 Convalescent Plasma Product Information
Convalescent plasma is serum collected from patients who have recovered from COVID-19 and that have produced antibodies to SARS-CoV-2.4,5,7-9 These antibodies exert their therapeutic effect by neutralizing the virus in the recipient.8,9 Additionally, the antibodies can activate complement and initiate antibody-dependent cellular toxicity and phagocytosis. Convalescent plasma provides short-term passive immunity as either prophylaxis or for treatment to reduce viral infectivity. Due to the large population of recovered COVID-19 patients, convalescent plasma is a readily available resource for prophylaxis or treatment.
The dose and preferred timing for administration of convalescent plasma during the course of a COVID-19 infection has not been established.7 Dosing of convalescent plasma in general has been widely variable throughout the history of its use as post-exposure prophylaxis and/or treatment in several viral infections (e.g., polio and Ebola), including respiratory infection outbreaks, including the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and 2012 Middle East Respiratory Syndrome coronavirus (MERS-CoV) epidemic.5,9 Once convalescent plasma is administered, the duration of the circulating antibodies’ therapeutic effect is unclear and dependent on the antibody amount given, but may last weeks to months.8,9 Table 1 provides additional characteristics of COVID-19 convalescent plasma.
Review of COVID-19 Convalescent Plasma Studies for the Treatment of COVID-19
At this time, the efficacy and safety of COVID-19 convalescent plasma are still under investigation.4,5,7 Most of the available data consists of small observational studies from China and the US.4,7,11-22 A systematic review of the lower quality evidence concluded that effectiveness of convalescent plasma in hospitalized COVID-19 patients was uncertain based on inconsistentencies in the reported results.23 More recently, mortality data from 1 small randomized trial and 2 larger cohort studies have been published (Table 2).11-13 Much of the literature is limited by lack of control groups and administration of several other concurrent therapies, which complicates the determination of convalescent plasma’s true effect in COVID-19.12-22, 24
The two completed randomized controlled trials were conducted in China and the Netherlands and several controlled clinical trials are underway in the US and internationally.7,11,20 The primary analysis of the randomized controlled trial by Li et al. did not find statistically significant differences in clinical outcomes between patients that received convalescent plasma in addition to standard of care and patients that received standard of care alone; however, the trial was terminated early due to decreasing new COVID-19 cases in Wuhan, China resulting in an underpowered study.11,25 A subgroup analysis found an association between convalescent plasma and clinical improvement in severely ill patients, but not those with life-threatening COVID-19. Additionally, convalescent plasma was associated with a significantly higher rate of SARS-CoV-2 RNA clearance as compared to standard of care patients.
Safety Concerns of COVID-19 Convalescent Plasma
Convalescent plasma transfusion has several theoretical risks associated with its use based on known risks associated with standard plasma transfusions that are therefore not unique to this specific product (Table 3).4,7-9, 26 These potential adverse effects have not been fully established for COVID-19 convalescent plasma.7 The historical data from SARS and MERS suggest that convalescent plasma use in coronavirus infections is potentially safe, although two case reports of possible convalescent plasma-induced TRALI events have been described in a patient with Ebola and a patient with MERS.8,9, 26-28 Possible transfusion-related adverse events that resolved with corticosteroid treatment were reported in two patients in the randomized controlled trial by Li et al.11 Additionally, Joyner et al. reported limited cases of transfusion-associated circulatory overload (TACO), TRALI, and severe allergic reactions, but no significant adverse events were reported in most of the COVID-19 studies or in several previous SARS-associated coronavirus and severe influenza studies.13, 14, 16-22, 29
Access to COVID-19 Convalescent Plasma in the United States
The FDA has published recommendations for the use of convalescent plasma.5,7,30 The guidance covers COVID-19 convalescent plasma access, collection, labeling, record keeping, and patient eligibility criteria. In the United States, COVID-19 convalescent plasma is restricted to three pathways: clinical trials, an expanded access investigational new drug (IND) application, and a single patient emergency investigational new drug (eIND) application. The FDA recommendations for investigational convalescent plasma contain more detail on recipient eligibility.5 Mayo Clinic is the leading institution collecting and providing COVID-19 convalescent plasma for the National Expanded Access Program.31 A dedicated website provides a map of the registered sites for COVID-19 convalescent plasma administration (https://www.uscovidplasma.org/family).
COVID-19 Convalescent Plasma Donation
The FDA has set forth certain eligibility criteria for COVID-19 convalescent plasma donation (Table 4).5,7,30 Convalescent plasma can be donated at blood donation centers or through the American Red
Cross.31,32 Blood donation centers can be located through the American Association of Blood Banks (AABB) website.32 One donor of COVID-19 convalescent plasma is estimated to provide enough plasma to treat two to three patients.33
COVID-19 convalescent plasma is an investigational treatment for COVID-19 that has shown potential benefit. Randomized controlled trials are needed to further establish efficacy and safety. As therapy and
evidence continue to evolve, the use of this investigational product is likely to increase. ■
- Fauci AS, Lane HC, Redfield RR. Covid-19 - navigating the uncharted. N Engl J Med. 2020;382:1268-1269.
- Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Clin Infect Dis. 2020.
- World Health Organization. WHO director-general's opening remarks at the media briefing on COVID-19 - 11 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020 (accessed 2020 July 10).
- National Institutes of Health. COVID-19 treatment guidelines (updated May 12, 2020). https://covid19treatmentguidelines.nih.gov/therapeutic-options-under-investigation/host-modifiers-immunotherapy/ (accessed 2020 July 10).
- Food and Drug Administration. Recommendations for investigational COVID-19 convalescent plasma (updated May 1, 2020). https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma (accessed 2020 July 10).
- Food and Drug Administration. Coronavirus disease 2019 (COVID-19) resources for health professionals (updated July 6, 2020). https://www.fda.gov/health-professionals/coronavirus-disease-2019-covid-19-resources-health-professionals (accessed 2020 July 10).
- American Society of Health-System Pharmacists. Assessment of evidence for COVID-19-related treatments (updated July 2, 2020). https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx (accessed 2020 July 10).
- Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. J Clin Invest. 2020;130:1545-1548.
- Bloch EM, Shoham S, Casadevall A, et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest. 2020.
- American Red Cross. Coronavirus (COVID-19) convalescent plasma clinician information. https://www.redcrossblood.org/donate-blood/dlp/plasma-donations-from-recovered-covid-19-patients/clinician-registration.html (accessed 2020 July 10).
- Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020.
- Xia X, Kening L, Lingxiang W, et al. Improved clinical symptoms and mortality on severe/critical COVID-19 patients utilizing convalescent plasma transfusion. Blood. 2020.
- Joyner M, Wright RS, Fairweather D, et al. Early safety indicators of COVID-19 convalescent plasma in 5,000 patients. medRxiv. 2020.
- Mehmet AE, Sarici A, Berber I, et al. Life-saving effect of convalescent plasma treatment in COVID-19 disease: clinical trial from eastern Anatolia. Transfus Apher Sci. 2020.
- Hartman W, Hess AS, Connor JP. Hospitalized COVID-19 patients treated with convalescent plasma in a mid-size city in the midwest. medRxiv. 2020.
- Hegerova L, Gooley T, Sweerus KA, et al. Use of convalescent plasma in hospitalized patients with COVID-19 – case series. Blood. 2020.
- Salazar E, Perez KK, Ashraf M, et al. Treatment of COVID-19 patients with convalescent plasma. Am J Pathol. 2020.
- Olivares-Gazca JC, Priesca-Marin JM, Ojeda-Laguna M, et al. Infusion of convalescent plasma is associated with clincial improvement in critically ill patients with COVID-19: a pilot study. Rev Invest Clin. 2020;72:159-164.
- Liu STH, Lin H, Baine I, et al. Convalescent plasma treatment of severe COVID-19: a matched control study. medRxiv. 2020.
- Gharbharan A, Jordans CCE, GeurtsvanKessel C, et al. Convalescent plasma for COVID-19. A randomized clinical trial. medRxiv. 2020.
- Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020;117:9490-9496.
- Zeng QL, Yu ZJ, Gou JJ, et al. Effect of convalescent plasma therapy on viral shedding and survival in COVID-19 patients. J Infect Dis. 2020.
- Valk SJ, Piechotta V, Chai KL, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review. Cochrane Database Syst Rev. 2020;5:Cd013600.
- Roback JD, Guarner J. Convalescent plasma to treat COVID-19: possibilities and challenges. JAMA. 2020.
- Casadevall A, Joyner MJ, Pirofski LA. A randomized trial of convalescent plasma for COVID-19-potentially hopeful signals. JAMA. 2020.
- Tiberghien P, de Lamballerie X, Morel P, et al. Collecting and evaluating convalescent plasma for COVID-19 treatment: why and how? Vox Sang. 2020.
- Chun S, Chung CR, Ha YE, et al. Possible transfusion-related acute lung injury following convalescent plasma transfusion in a patient with Middle East Respiratory Syndrome. Ann Lab Med. 2016;36:393-395.
- Mora-Rillo M, Arsuaga M, Ramírez-Olivencia G, et al. Acute respiratory distress syndrome after convalescent plasma use: treatment of a patient with Ebola virus disease contracted in Madrid, Spain. Lancet Respir Med. 2015;3:554-562.
- Mair-Jenkins J, Saavedra-Campos M, Baillie JK, 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(1):80-90.
- Food and Drug Administration. Guidance for industry: investigational COVID-19 convalescent plasma (May 26, 2020). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-covid-19-convalescent-plasma (accessed 2020 July 10).
- Mayo Clinic. COVID-19 expanded access program. https://www.uscovidplasma.org/ (accessed 2020 July 10).
- Mayo Clinic. How do individuals donate plasma for this protocol? https://www.uscovidplasma.org/donate (accessed 2020 July 10).
- American Society of Hematology. COVID-19 and convalescent plasma: frequently asked questions (updated June 8, 2020). https://www.hematology.org/covid-19/covid-19-and-convalescent-plasma (accessed 2020 July 10).