What do pharmacists need to know about the Emergency Use Authorization for convalescent plasma for COVID-19?

Introduction

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 is COVID-19 convalescent plasma (herein after referred to as “convalescent plasma”), which received an FDA Emergency Use Authorization (EUA) for use in hospitalized patients on August 23, 2020.6 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.2,7 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 due to a lack of data and theoretical risks (eg, antibody-dependent enhancement of infection and transfusion-associated lung injury [TRALI]).5

 

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-2.5,8-10 These antibodies exert their therapeutic effect by neutralizing the virus in the recipient.9,10 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 convalescent plasma dose and preferred timing of administration during the course of a COVID-19 infection has not been established.8 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 (eg, polio and Ebola), including respiratory infection outbreaks, such as the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and 2012 Middle East Respiratory Syndrome coronavirus (MERS-CoV) epidemic.9 Once convalescent plasma is administered, the duration of the circulating antibodies’ therapeutic effect is unclear and depends on the amount of antibody given, but may last weeks to months.9,10 Table 1 provides additional characteristics of COVID-19 convalescent plasma.

Table 1. COVID-19 convalescent plasma characteristics. 6,8,9,11
Product Characteristics

  • Available as FFP and FP24

  • Shelf life is 1 year frozen or 5 days after thawing
Product Dose

  • No universal dose established; EUA states that a starting dose of 1 unit (~200 mL) can be considered with additional doses based on clinical judgement

  • Patients with heart failure or cardiac dysfunction may require smaller doses or longer infusion times

  • Transfusion of 1 to 2.5 units (~200 to 500 mL) has been reported in literature

  • Some clinical trials are planning doses of 1 unit for post-exposure prophylaxis and 1-2 units for treatment
Abbreviations: EUA=Emergency Use Authorization; FFP=fresh frozen plasma; FP24=plasma frozen within 24 hours of phlebotomy

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.2,5,8,12 Most of the available data consists of small observational studies from China and the United States.13-29 A Cochrane living systematic review of 4 controlled studies (n=339) concluded that effectiveness of convalescent plasma in hospitalized COVID-19 patients was uncertain based on inconsistentencies in the reported results.30 More recently, mortality data from 1 small randomized trial and several larger cohort studies have been published (Table 2).15-21 Much of the literature is limited by lack of control groups, variable doses and antibody titers of transfused convalescent plasma, and administration of several other concurrent therapies, which complicate the determination of convalescent plasma’s true effect in COVID-19.13,15,17-29,31

Numerous randomized controlled trials (RCTs) with convalescent plasma are underway in the United States and internationally.8 The 2 RCTs with published results were conducted in China and the Netherlands and both were terminated early.16,27 The primary analysis of the RCT 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.16,32 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 compared to standard of care patients. The RCT conducted in the Netherlands terminated prematurely because the majority of patients already had high virus neutralizing antibody titers at baseline that was comparable to the titers of the donors, leading to concerns of the potential benefit of convalescent plasma.27

A meta-analysis by Sarkar et al, which included the 2 RCTs, found that convalescent plasma significantly reduced mortality and increased viral clearance, although the authors noted that the derived evidence was of low quality.15  Similarly, an analysis of aggregated patient data (n=4,113) from 12 controlled studies found a mortality rate of 10% in patients who received convalescent plasma for severe or life-threatening COVID-19 and 22% in patients who did not receive convalescent plasma (odds ratio, 0.43; p<0.001).33

The Mayo Clinic’s Expanded Access Program cohort study (released prior to peer review on a pre-print server) found that factors such as high antibody titers and an earlier time to transfusion of convalescent plasma were associated with lower rates of 7- and 30-day mortality.19 Similar trends were reported in the case-control study by Salazar et al.18 In Mayo Clinic’s study, the high antibody titer convalescent plasma resulted in a pooled relative risk of 0.65 (95% confidence interval [CI], 0.47 to 0.92) for 7-day mortality and 0.77 (95% CI, 0.63 to 0.94) for 30-day mortality compared to low antibody titer convalescent plasma.19,34 An additional Kaplan-Meier survival analysis reported by the FDA found significantly improved survival in non-intubated patients (p=0.032) and even further survival benefit in a subgroup of non-intubated patients less than 80 years of age who received convalescent plasma within 3 days of COVID-19 diagnosis (p=0.0081).6 However, applicability of these findings is limited by the cohort study design, including lack of a traditional placebo control arm and the likely presence of confounders.19

Article
Interventions
Outcomes
Sarkar et al. (2020)15

Meta-analysis of 7 trials (2 RCTs, 5 cohort studies) in 5,444 patients
Convalescent plasma group (n not specified)
  • Variable doses and antibody titers of convalescent plasma transfused
  • Some studies specify a variety of concomitant therapies given
Control groups not specified

Safety
  • 2 studies reported no AEs, 1 study reported <1% of serious AEs (eg, TACO [n=7], TRALI [n=11], and severe allergic reactions [n=3]), 1 study reported TRALI (n=1) and rash (n=1), and 1 study reported rash (n=1) (no details were provided for the remaining 2 studies)

Clinical
  • Convalescent plasma resulted in clinical improvement compared to patients that did not receive convalescent plasma (p=NS)

Mortality
  • Convalescent plasma reduced mortality risk (OR, 0.44; 95% CI, 0.25 to 0.77; I2=0%)
SARS-CoV-2 RNA
  • Convalescent plasma increased viral clearance (OR, 11.29; 95% CI, 4.9 to 25.9; I2=0%)
Li et al. (2020)16

Open-label, multicenter, RCT of 103 patients in China
Convalescent plasma group (n=52)
  • 1 transfusion of COVID-19 convalescent plasma 200 mL (median dose; S-RBD-specific IgG titer of ≥1:640) received 30 days (median) after symptom onset
  • Standard treatment: antiviral agents,a antibiotics, glucocorticoids, immunoglobulin, Chinese herbal medicines, antifungals, and/or interferon
Control group (n=51)
  • Standard treatment as described in the convalescent plasma group
Safety
  • AEs: chills and rash (n=1) within 2 hours of transfusion and shortness of breath, cyanosis, and severe dyspnea (n=1) within 6 hours of transfusion
Clinical
  • 51.9% of the convalescent plasma group vs 43.1% of the control group had clinical improvement within 28 days (p=NS)
  • 51% of the convalescent plasma group vs 36% of the control group were discharged by day 28 following randomization (p=NS)
Mortality
  • Mortality at 28 days was 15.7% in the convalescent plasma group vs 24% in the control group (p=NS)
SARS-CoV-2 RNA
  • 87.2% of the convalescent plasma group vs 37.5% of the control group had a negative viral PCR at 72 h (OR, 11.39; 95% CI, 3.91 to 33.18; p<0.001)
Abolghasemi et al. (2020)17

Case-control study of 189 patients
Convalescent plasma group (n=115)
  • 1-2 transfusions of COVID-19 convalescent plasma 500 mL received within <3 days of hospital admission
  • Routine treatment: antiviral therapyb, hydroxychloroquine, and an anti-inflammatory agent

Control group (n=74)
  • Routine treatment as described in the convalescent plasma group
Safety
  • AEs: Transient mild fever and chills (n=1)

Clinical
  • Average length of hospital stay was 9.54 days in the convalescent plasma group vs 12.88 days in the control group (p=0.002)
  • 7% of patients in the convalescent plasma group vs 20.3% of patients in the control group required intubation (p=0.006)

Mortality
  • All-cause mortality occurred in 14.8% of patients in the convalescent plasma group vs 24.3% of patients in the control group (p=NS)
Salazar et al. (2020)18

Case-control (propensity-matched) study of 316 patients (interim analysis)
Convalescent plasma group (n=143)
  • 1-2 transfusions of COVID-19 convalescent plasma (anti-RBD IgG titer range: <1:150 to ≥1:1350)
  • Other medications: steroids, azithromycin, hydroxychloroquine, antiviral therapyc, and/or tocilizumab

Control group (n=173)
  • Other medications described in the convalescent plasma group
Mortality
  • Mortality at 28 days was 3.7% in the convalescent plasma group vs 7.6% in the control group (p=NS)
  • Decreased 28-day mortality rates were seen in patients that received convalescent plasma transfusion within 72 h of admission vs the control group (1.8% and 6.3%; respectively; p=NS) and in patients that received transfusion with high titer (≥1:1350) convalescent plasma within 72 h of admission vs the control group (1.2% vs 7%; p=NS)
Joyner et al. (2020)19

Uncontrolled cohort study of 35,322 patients
  • Transfusion of ≥1 unit of COVID-19 convalescent plasma ~200 mL
  • Other medications: ARB, ACE-inhibitor, azithromycin, remdesivir, steroids, chloroquine, and/or hydroxychloroquine
Mortality
  • 7-day mortality rate was 8.7% (95% CI, 8.3% to 9.2%) in patients transfused within 3 days of COVID-19 diagnosis vs 11.9% (95% CI, 11.4% to 12.3%) in patients transfused within ≥4 days of diagnosis (p<0.0001)
  • 7-day mortality rate was 13.7% (95% CI, 11.1% to 16.8%) in patients transfused with a low antibody titerd, 11.6% (95% CI, 10.3% to 13.1%) in patients transfused with a medium antibody titere, and 8.9% (95% CI, 6.8% to 11.7%) in patients transfused with a high antibody titerf (p=0.048)
  • 30-day mortality rate was 21.6% (95% CI, 21% to 22.3%) in patients transfused within 3 days of diagnosis vs 26.7% (95% CI, 26.1% to 27.3%) in patients transfused within ≥4 days of diagnosis (p<0.0001)
  • 30-day mortality rate was 29.6% (95% CI, 26% to 33.5%) in patients transfused with a low antibody titerd, 27.4% (95% CI, 25.5% to 29.4%) in patients transfused with a medium antibody titere, and 22.3% (95% CI, 18.9% to 26.1%) in patients transfused with a high antibody titerf (p = 0.028)
Xia et al. (2020)20

Uncontrolled, cohort study of 1,568 patients in China
Convalescent plasma group (n=138)
  • 1 transfusion of COVID-19 convalescent plasma 200 to 1200 mL received 45 days (median) from symptom onset
Standard treatment group (n=1430)
Safety
  • No serious AEs were reported; 3 patients had minor allergic reactions

Clinical
  • ICU admission rate was 2.4% in the convalescent plasma group vs. 5.1% in the standard treatment group (p-value not reported)
  • Within 14 days, 80% of patients in the convalescent plasma group no longer had detectable viral levels
  • Among patients with clinical improvement within 8 weeks, median time to clinical improvement was about 10 days

Mortality
  • At the end of the study period, mortality was 2.2% in the convalescent plasma group and 4.1% in the standard treatment group (p-value not reported)
Joyner et al. (2020)21

Uncontrolled, cohort study of 5,000 patients in the US
  • Tranfusion of COVID-19 convalescent plasma 200 to 500 mL
Safety
  • Serious AEs within 4 h post-transfusion were reported in <1% of all transfusions
  • Serious AEs: TACO (n=7), TRALI (n=11), and severe allergic transfusion reactions (n=3)
Mortality
  • Mortality rate at day 7 was 14.9%
Abbreviations: AE=adverse event; ARB=angiotensin receptor blocker; ACE=angiotensin-converting enzyme; CI=confidence interval; COVID-19=coronavirus disease 2019; I2=statistical heterogeneity; ICU=intensive care unit; NS=non-significant; OR=odds ratio; PCR=polymerase chain reaction; RBD=receptor binding domain; RCT=randomized controlled trial; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; S/Co=signal-to-cut-off ratio; TACO=transfusion-associated circulatory overload; TRALI=transfusion-related acute lung injury
aLopinavir/ritonavir, oseltamivir, umifenovir (not available in the US), ribavirin, and other antivirals
bLopinavir/ritonavir
cLopinavir/ritonavir, remdesivir, and ribavirin
dIgG <4.62 S/Co
e IgG=4.62 to 18.45 S/Co
f IgG >18.45 S/Co

Safety concerns of COVID-19 convalescent plasma

Convalescent plasma transfusion has several theoretical risks based on known risks associated with standard plasma transfusions that are therefore not unique to this specific product (Table 3).5,8-10,35 These potential adverse effects have not been fully established for COVID-19 convalescent plasma.8 The historical data from SARS and MERS suggest that convalescent plasma use in coronavirus infections is potentially safe, although 2 case reports of possible convalescent plasma-induced TRALI events have been described in a patient with Ebola and a patient with MERS.9,10,35-37 Possible transfusion-related adverse events that resolved with corticosteroid treatment were reported in 2 patients in the RCT by Li et al.16

Joyner et al conducted a safety analysis of 20,000 patients in the Mayo Clinic Expanded Access Program cohort and also found a low incidence (n=146; <1%) of serious adverse events within 4 hours of transfusion, which included 83 nonfatal reports of transfusion-associated circulatory overload (TACO) (n=37), TRALI (n=20), and severe allergic reactions (n=26).38 Of the 146 transfusion-related serious adverse events, 63 deaths (0.3% of all transfusions) occurred, with 13 deaths deemed as possibly (n=12) or probably (n=1) related to convalescent plasma treatment.  Additional serious adverse events reported within 7 days of the transfusion included thrombotic/thromboembolic events (n=87), cardiac events (n=643) and sustained hypotensive events requiring vasopressors (n=406); the majority of these complications were deemed unrelated to convalescent plasma treatment. Additionally, Joyner et al reported limited cases of TACO, TRALI, and severe allergic reactions in an earlier safety analysis of 5,000 patients, and no significant adverse events were reported in most of the COVID-19 studies or in several previous SARS-associated coronavirus and severe influenza studies.13,17,21,22,24-29,39

Table 3. Potential adverse effects of convalescent plasma transfusions. 5,8-10,35

  • Allergic reactions

  • Transfusion-associated circulatory overload (TACO)

  • Transfusion-associated acute lung injury (TRALI)

  • Antibody-dependent enhancement of infection

  • Transmission of infectious agents (rare)

  • Red blood cell alloimmunization (rare)

Access to COVID-19 convalescent plasma in the United States

Prior to the recent EUA, access to COVID-19 convalescent plasma was restricted to 3 pathways: clinical trials, an expanded access investigational new drug (IND) application, or a single patient emergency investigational new drug (eIND) application.40 Mayo Clinic was the leading institution collecting and providing COVID-19 convalescent plasma for the National Expanded Access Program, which was discontinued on August 28, 2020 after more than 75,000 patients were treated.41

Under the newly approved EUA, any FDA-registered or licensed blood establishment can now collect or distribute convalescent plasma according to institutional protocols.6 The EUA request document includes information about convalescent plasma collection, labeling, storage, antibody testing, and adverse event monitoring. Clinicians are required to provide recipients with written information about the potential benefits and risks of convalescent plasma via the FDA’s official patient fact-sheet (available at: https://www.fda.gov/media/141479/download).

COVID-19 convalescent plasma donation

Convalescent plasma can be donated at blood donation centers or through the American Red Cross.42,43 Blood donation centers can be located through the American Association of Blood Banks (AABB) website.44 One donor of COVID-19 convalescent plasma is estimated to provide enough plasma to treat 2 to 3 patients.45 As of August 2020, the American Red Cross has distributed 32,000 units of convalescent plasma from more than 14,000 donors, but the supply has not been adequate to meet the demand.46 Consequently, the FDA and other medical organizations have launched promotional campaigns to raise public awareness about the need and opportunity for plasma donation.42,47 To meet eligibility for COVID-19 convalescent plasma donation, the FDA has set forth certain criteria (Table 4).6,8,40

Table 4. COVID-19 convalescent plasma donor eligibility criteria.6,8,40
  • Lab confirmed COVID-19 by 1 of the following:

    • Diagnostic test (eg, nasopharyngeal swab) at time of illness

    • (+) SARS-CoV-2 antibodies after recovery using 2 different tests

  • Complete resolution of symptoms for ≥14 days

  • Previously pregnant female donors must have (-) HLA antibodies tested since most recent pregnancy

  • If available, SARS-CoV-2 neutralizing antibody titers of ≥1:160 (1:80 is an acceptable alternative)

Abbreviations: COVID-19=coronavirus disease 2019; HLA=human leukocyte antigen; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2

Conclusions

COVID-19 convalescent plasma is an emerging treatment that has shown potential benefit in observational or uncontrolled clinical trials. The FDA has authorized its use in the United States under an EUA, but it is not considered an FDA-approved product. The findings of ongoing RCTs are needed to establish efficacy and safety. Knowledge gaps that will hopefully be addressed by forthcoming studies include definitive effects on mortality and other clinical outcomes, efficacy of plasma with high vs low antibody titers, efficacy in children and pregnant women, long-term effects, efficacy in patients with mild disease, and potential for use as prophylaxis.

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  45. COVID-19 and convalescent plasma: frequently asked questions. American Society of Hematology. Published August 25, 2020. Accessed August 28, 2020. https://www.hematology.org/covid-19/covid-19-and-convalescent-plasma
  46. Red Cross response to convalescent plasma emergency authorization. American Red Cross. Updated August 24, 2020. Accessed August 28, 2020. https://www.redcross.org/about-us/news-and-events/press-release/2020/red-cross-response-to-convalescent-plasma-emergency-authorization.html
  47. The fight is in us. Accessed August 28, 2020. https://thefightisinus.org/en-us#home

Katie Miles, PharmD
Heather Ipema, PharmD, BCPS
Clinical Assistant Professors
University of Illinois at Chicago College of Pharmacy

September 2020

The information presented is current as of August 28, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.