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 

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.   

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}

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). 

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. ■

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