Abstract
Convalescent plasma is an old treatment for a new disease. The coronavirus disease 2019 (COVID-19) pandemic caused the analysis of convalescent plasma to reemerge as a possible treatment. First, a systematic review summarizes the available research examining the use of convalescent plasma for the treatment of patients with COVID-19. Second, we describe our experience in establishing a single-center convalescent plasma donation program.
Introduction
In 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified amidst an outbreak of respiratory symptoms in Wuhan, China.1,2 This disease spread rapidly into an epidemic during the early winter of 2020. It wasn’t until March 11, 2020, that the World Health Organization (WHO) declared that corona virus disease 2019 (COVID-19) was now a pandemic.3
As of January 11, 2021, the Johns Hopkins Coronavirus Resource Center website reports there are about 90,475,499 total cases with 1,938,349 deaths in 191 countries/regions reporting.4 Furthermore, as of January 11, 2021, the CDC reports that the United States has had more than 22 million confirmed cases of COVID-19 and 373,167 deaths.5
Public health measures such as traffic restriction, social distancing measures, home isolation, centralized quarantine, and improvement of medical resources have been shown to disrupt the spread of this disease.6 Yet, to date, neither specific treatments nor a vaccine are readily available and strategy is largely supportive. 2,7–8 However, by the time this article is published, vaccinations will most likely be available for health care workers and nursing home residents as recommended by the Advisory Committee on Immunization Practices at their December 1, 2020, meeting.9
The potential of convalescent plasma (CP), a form of passive immunity, as a treatment for emerging diseases is not new. Use of this as treatment can be traced back into the early 1900s with the Spanish flu.10 In 2015, a systematic review and meta-analysis revealed significant reduction in the odds of mortality following treatment with convalescent plasma for SARS-CoV-1, H1N1, H5N1, and H1N1.11 Similarly, the WHO prioritized the evaluation of convalescent plasma for the recent Ebola epidemic.12 However, a more recent systematic review and meta-analysis indicated little efficacy of convalescent plasma in the treatment of SARS-CoV-1 or influenza.13 The need for large-scale evaluation of convalescent plasma is imperative.
Translational studies show that the spike (S) protein of SARS-CoV-2 mediates the virus’s entry into cells. It does so via binding to the ACE-2 receptor with its receptor binding domain (RBD).2,14 This S protein has been shown to be the major inducer in the development of neutralizing antibodies.15 Thus, effective convalescent plasma would contain these neutralizing antibodies. Once given to a patient, several mechanisms have been proposed as to the way in which these antibodies would treat COVID-19: direct neutralization of the virus, control of cytokine storm, complement activation and immunomodulation of a hypercoagulable state.16
The contents of this article are two-fold. First, our systematic review summarizes the available research examining the use of convalescent plasma for the treatment of patients with COVID-19. To our knowledge, this literature review is the most up-to-date evaluation that includes recently online published study designs aside from only case reports/series. Second, we describe our experience in establishing a single-center convalescent plasma donation program.
Methods
In mid-June, PubMed, a major database, was searched using the terms “COVID-19 convalescent plasma.” This elicited 110 results of which two were duplicates. The methods sections were screened with respect to study design. Study designs included were as follows: case report, case series, cross-sectional, case-control, systematic review, meta-analysis, and both single and double armed randomized clinical trials (RCT). This yielded 27 articles. Assessment of the articles was premised with the following exclusions: (1) any translational science research; (2) systematic reviews; (3) studies that were unrelated to CP as treatment for COVID-19 specifically; and (4) case series consisting of < 5 patients. After these exclusions, seven articles were qualitatively included (Figure 1).
Figure 1.
PRIMSA flow chart of PubMed database search with respect to CP as a treatment for COVID-19.
Results
Of the seven studies included for qualitative synthesis, four were case series, one was a retrospective observational study, one was a RCT and one was a prospective cohort study.1–2,7–8,17–19 Extracted details regarding sample size, patient age, time from symptom onset to CP transfusion, the amount of CP transfused, titers and patient outcomes are presented (Table 1). Combination of the seven studies encompasses a total of 5,104 patients given CP transfusion for the treatment of COVID-19.
Table 1.
Summary of studies utilizing CP as a treatment for COVID-19.
| Study & Design | Sample size (n) & Sex | Age (years) | Time from Symptom Onset to CP transfusion (days) | Amount of CP Transfused (mL) + donor NAb titer | Patient Outcomes |
|---|---|---|---|---|---|
|
Shen et al.1 Case Series |
5 (2 female) | 36–65 | 14–24 | 200–250 (2x) 400 total 1:40 |
|
|
Ye et al.2 Case Series |
6 (3 female) | 28–75 | 32–49 (#5 asymptomatic) | 200 (1–3x) 200–600 total _ |
|
|
Duan et al.7 Case Series |
10 (4 female) | 52.5 (median) IQR, 45–59.5 |
16.5 (median) IQR, 11–19.3 |
200 (1x) 200 total 1:160 |
|
|
Salazar et al.17 Case Series |
25 (14 female) | 51 (median) IQR, 42.5–60 |
10 (median) IQR, 7.5–12.5 |
300 (1–2x) 300–600 total _ |
|
|
Zeng et al.18 Retrospective Observational Study Treatment Group: standard treatment + CP Control: standard treatment |
19 6 treatment (1 female) 15 control (4 female) |
Treatment Group: 61.5 (median) IQR, 31.5–77.8 Control Group: 73 (median) IQR, 60–79 |
21.5 (median) IQR, 17.8–23 Onset of symptoms described as viral shedding |
300 (median) IQR, 200–600 _ |
|
|
Li et al.8 RCT Treatment Group: standard treatment + CP Control: standard treatment |
103 52 treatment (27 female) 51 control (18 female) |
70 (median) IQR, 62–78 |
30 (median) IQR, 20–30 |
4–13 mL/kg NAb titer 1:80 ≈ S-RBD-specific IgG 1:1280 |
|
|
Joyner et al.19 Prospective Cohort |
5,000 _ |
62 (median) Range, 18–97 |
_ | 200–500 _ |
|
Discussion
Study Designs & Limitations
Six of the seven studies that were examined were observational, and five of these were case series (Table 1). Our search did include one RCT, however, the authors noted that their study had an early termination with a small sample size, and likely was underpowered. Early termination was due to the COVID-19 epidemic being contained in Wuhan, China, with no new cases reported for seven consecutive days after March 24, 2020.8 Furthermore, the retrospective observational study notes that COVID-19 had been nearly finished outside of Wuhan when CP had finally become available.18 Herein lie two opposing forces: the need for rapid containment with public measures as compared to the greater length of time and number of patients needed to establish a well-developed RCT. This is likely why there is a lack of RCTs regarding CP, though additional clinical trials are currently underway.19
Age and Gender
Reported medians were all greater than 50 years of age (Table 1). These findings are consistent with the epidemiologic data published indicating that younger people are less likely to be affected.6,20–21 Of note, the CP patients in all studies were critically, severely or life-threateningly ill due to COVID-19. Increased age is associated with increased comorbidities which may worsen prognosis. In our review, of the studies that reported gender, 43.5% of patients were female (Table 1). It is unclear in these studies whether or not there was a significant difference in outcome with respect to gender. Yet, a study of 32,583 confirmed COVID-19 cases in China revealed that females had a higher rate of confirmed cases than males. But, that critically ill patients were more likely to be male and the crude fatality rate was higher among men (2.8% vs 1.7%).6
Time from Symptom Onset
All four case series showed improvement in symptoms despite differing amounts of time between symptom onset and the first transfusion of CP. Three had a median between 10–20 days while one case series transfused all six of their patients after 30 days. All reported positive outcomes in symptom improvement or recovery (Table 1). The study by Zeng et al. depicted that while CP treatment contributed to the discontinuation of SARS-CoV-2 shedding and longer survival in patients with COVID-19, it did not reduce mortality in critically ill patients with end stage COVID-19.18 The median time from viral shedding to CP transfusion in this study was 21.5 days. For SARS-CoV-1, viremia typically peaks in the first week after infection and patients build their immune response by day 10–14. It was also found that for SARS-CoV-1, a higher day-22 discharge rate was observed in patients given CP before day 14 of illness (58.3% vs 15.6%; P<.001).22 In essence, CP may be most effective if given earlier in the disease which could be why the Zeng et al. study did not show a reduction in mortality. Furthermore, in the RCT by Li et al., CP was given at least 14 days after disease onset. This study also showed no significant difference in 28-day mortality but did show significant antiviral activity.8 Further studies are needed to determine the timing in which CP should be administered for SARS-CoV-2, especially with respect to mortality.
Amount of CP Transfused
The amount of CP transfused to COVID-19 patients ranged from a total of 200 – 600 mL. This was typically at doses of 200–300 mL given one to three times (Table 1). Interestingly, Li et al. was the only study to give a plasma dosage based on patient weight.8 Weight-based dosing would make more sense in that it would be a better mechanism in ensuring that patients are given at least the minimal dose of neutralizing antibodies. The variability of amount of CP across studies further adds to the degree of incoherence in being able to define and develop an accurate protocol for its use.
Patient Outcomes
All case series showed improvement in clinical outcomes and symptoms after CP (n=46). They also reported no adverse events. Zeng et al. showed that there was no significant difference in mortality but that the survival period was longer in the treatment group than in the control group (P=0.03).18 Li et al. revealed that the rate of viral shedding for CP patients was significantly different than in control patients (44.7% vs 15.0%, P=.003 at 24h; 68.1 vs 32.5%, P=.001 at 48h; 87.2% vs 37.5%, P<.001 at 72h).8 Though, mortality and clinical improvement revealed no significant difference between groups. Joyner et al. revealed that the seven-day mortality for 5,000 patients was found to be 14.9% (95% CI, 13.8–16.0%) and that <1% of transfusions had serious adverse events reported.19 Overall, there is evidence that CP for COVID-19 may improve clinical symptoms and viral shedding. More research needs to be done on mortality especially in that for patients with end stage COVID-19, CP may be unable to avert a poor outcome.18
Antibody Titers of Donors
Not every study reported the measured antibody titers for donor plasma (Table 1). Li et al. found that levels of 1:1280 S-RBD-specific IgG positively correlated with a titer of 1:80 for neutralizing antibodies (r=0.622, P=0.03).8 Shen et al. used a NAb titer of > 40 and Duan et al. used a NAb titer of > 1:160. 2,7 The measurement of specific neutralizing antibodies is preferential over singularly measuring SARS-CoV-2 antibodies. This is because neutralizing antibodies are the actual antibodies involved in neutralizing the virus, so it is imperative that plasma contain these.23 The specific level of NAb that both donors and transfused patients should have remains unclear.
Review of Donor Process
On March 24, 2020, in major news, the United States Food and Drug Administration (FDA) announced that they would facilitate access to convalescent plasma for the treatment of COVID-19.24 The three main pathways by which clinicians can access COVID-19 convalescent plasma (CCP) are summarized below:25
Clinical Trials – Through the Investigational New Drug (IND) regulatory pathway, investigators wishing to study CCP would submit requests to the FDA. This would allow them to participate in clinical trials for CCP.
Expanded Access Program (EAP) – The EAP allowed institutions to register themselves under Mayo Clinic’s Institutional Review Boards (IRB). Here they expanded access for institutions to give CP to those with severe or life-threatening COVID-19, or those at high risk of progression to severe or life-threatening disease. They also provided standardized guidelines regarding the donor eligibility process and patient infusion procedures.
Single Patient Emergency IND (eIND) – Also referred to as “compassionate use,” this pathway allows clinicians to administer CCP to their patients with serious or immediately life-threatening infection. This pathway is particularly important for those patients or areas who may not have access to participate in either a clinical trial or the EAP.
University of Missouri Establishes COVID-19 Convalescent Plasma Program
In early April 2020 the University of Missouri- Columbia enrolled in the EAP and within a span of weeks, we implemented a COVID-19 convalescent plasma program. The aim of this section is to summarize our establishment process as well as provide context with respect to the challenges or successes we faced.
Community Engagement & Recruitment
The recruitment of donors for the COVID-19 convalescent plasma program involved multiple approaches. Primarily, the creation of a webpage within the healthcare system website, described the donation process and the eligibility requirements (https://www.muhealth.org/conditions-treatments/coronavirus/plasma). Most importantly, this webpage included the donor form by which community members could submit a brief interest form with their information. This step was crucial as it provided a singular mechanism by which volunteers could relay their contact information for further screening. Another CCP program at New York Blood Center enterprises (NYBCe) created a similar webpage and submission form.26 Other forms of media, including local news and broadcasting stations, were utilized in efforts to increase community awareness of the CCP Program. Furthermore, news spread via word of mouth either from clinicians or from patients and donors themselves. A method to increase our donor pool which we did not utilize, was actively seeking out COVID-19 positive lists from public health agencies. However, this method could potentially pose an ethical dilemma regarding privacy.
Screening
Forty-nine individuals in and around the community were referred to us. Of these, forty-four completed the donor form from the health system website. Five were referred via word of mouth. All forty-nine individuals were then contacted within 72 hours via phone call from a health professional to be asked a list of screening questions. Individuals were asked to confirm their contact information, whether or not they had had a positive COVID-19 laboratory test, the first day in which they experienced symptom recovery, if they had had a follow-up negative COVID-19 laboratory test, their willingness to get retested, and their blood type. Other standard plasma donation screening questions were also asked. Having numerous screening questions in our CCP program seemed necessary to us so as to not overwhelm donation centers. By adding this additional step, we further eliminated the burden that blood collection centers could face.27
Qualification
Donors had to meet the following requirements as specified by the American Red Cross (ARC):28
A confirmatory COVID-19 laboratory test either through nasopharyngeal RT-PCR or antibody serology of IgG anti-SARS-CoV-2
Symptom relief of at least 14 days with a negative RT-PCR test after 14 days or symptom relief of greater than 28 days
Our area had, at first, faced a delay in the availability of testing to community members. For those individuals who had had COVID-19-like symptoms, but had not been tested due to a lack of previously available testing, serology tests were ordered. However, those who needed serology tests were delayed two weeks because such a test had not yet been available. This hindered the quickness and ability to test eight individuals. Those who did not meet the aforementioned requirements were deferred.
Over roughly two months, 26 individuals met screening requirements and were referred to the ARC website (53%). Of the qualified donors, the most common self-indicated blood type was A+ (23%), however most did not know their blood type (46%) (Table 2). There were equal amounts of individuals who were male and female and there were no transgender volunteers. Twenty-eight individuals (47%) did not meet qualification guidelines for a variety of listed reasons (Table 2). Noticeably, 45% of those who did not qualify, were disqualified due to a negative COVID-19 serology test. Interestingly, when these volunteers were notified of their negative serology test results, many displayed some level of frustration in the result. It is unclear as to why this may be.
Table 2.
donor information
| A: Demographics of Approved Donors | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
|
| ||||||||||
| A+ | A− | B+ | B− | AB+ | AB− | O+ | O− | Unknown | Total | |
| Female | 4 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 6 | 13 |
| Male | 2 | 1 | 1 | 0 | 2 | 0 | 1 | 0 | 6 | 13 |
| Total | 6 | 1 | 1 | 0 | 2 | 0 | 3 | 1 | 12 | 26 |
|
| ||||||||||
| B: Reasons for Disqualification of Potential Donors | ||||||||||
|
| ||||||||||
| Negative COVID-19 serology test | 10 | |||||||||
| Never exhibited symptoms | 2 | |||||||||
| Aspirin Intake in the last 48 hours | 3 | |||||||||
| Intake of Blood Thinners | 0 | |||||||||
| Recent blood donation or transfusion | 1 | |||||||||
| Travel history | 1 | |||||||||
| Lost Communication | 4 | |||||||||
| Pregnancy | 1 | |||||||||
| Total | 22 | |||||||||
American Red Cross Partnership
The blood collection center utilized was the American Red Cross. Early on, their partnership with the FDA in being a major blood collection service allowed for a national, cohesive effort.25 In phone call surveys of the 26 who had been referred to the ARC, only six individuals said that they had already donated plasma. The overall success rate of persons donating for our CCP program so far is 12% (6/49). At first the ARC was asking clinicians to submit paper forms indicating the donor’s qualifications as well as to provide physical documentation of test results. This policy quickly changed which made it easier to refer donors through the ARC’s COVID-19 webpage, with no documentation as proof. However, it has not been communicated back to us when one of our donors made an appointment, donated, or if they have neutralizing antibodies or not.
Conclusion
The rapid establishment of a COVID-19 convalescent plasma program proved to be successful. The coordinated efforts of government agencies, research institutions and blood donation services on a national level was instrumental. This allowed for easier access to plasma as well as regulated the guidelines for its distribution and use. Through these guidelines, our institution was able to direct and screen volunteers as potential donors. While this coordinated, national effort synchronized plasma donation programs, much of the local follow-through of donors was lost after an individual was referred for blood donation. However, national coordination will likely be imperative for any future need of convalescent plasma.
Footnotes
Michela M. Fabricius, BS, (above), is a Medical Student and Dima Dandachi, MD, MPH, is Assistant Professor of Clinical Medicine, Medical Director, Outpatient Parenteral Antimicrobial Therapy (OPAT) and Vascular Access, and Medical Director, HIV/AIDS Program; both are at the University of Missouri-Columbia, Columbia, Missouri.
Disclosure
None reported.
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