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CanMEDS Roles addressed: Medical expert, scholar, advocate
A 45-year-old patient is diagnosed with COVID-19 and is receiving supportive care on the inpatient medicine ward. It is early in her clinical course and she continues to require supplemental oxygen via nasal prongs, but remains in stable condition with mild shortness of breath and intermittent fevers. One day while in the hospital she gets a call from her sister on Facetime, who excitedly tells her about a clinical trial that she read about on social media–the trial is studying an experimental treatment called convalescent plasma. The next time that you round on the patient she asks your opinion about convalescent plasma: what is it, what are the risks and benefits, and would she be eligible for the clinical trial?
What is convalescent plasma?
Convalescent plasma is the acellular fraction of blood isolated from people who have recovered from an infection. It is a protein-rich fluid that contains a multitude of antibodies, some of which will target the recently-encountered pathogen. Convalescent plasma from recovered COVID-19 patients could provide temporary immunity when transfused to newly exposed individuals–an idea that has been explored during viral outbreaks dating back to the 1918 Spanish flu. Despite this long history, convalescent plasma’s efficacy remains equivocal with a scarcity of high quality data; however, it is now being studied in earnest for COVID-19 with large-scale randomized trials underway including a major Canadian effort. This article will briefly review the rationale and evidence for studying convalescent plasma as an investigational treatment for COVID-19, along with potential risks and challenges for implementing it as a therapy.
Proposed mechanism of action
In response to a viral infection the immune system generates a repertoire of antibodies that bind to different viral epitopes: some of these can act as neutralizing antibodies that block the virus from infecting cells. SARS-CoV-2 gains entry to cells via its spike protein binding to the ACE2 receptor; neutralizing antibodies have now been identified from convalescent patients that potently inhibit this process.1 Most patients that recover from COVID-19 appear to generate some degree of neutralizing antibody activity against the virus, which is likely important for preventing reinfection. This is supported by preclinical studies showing that neutralizing antibodies isolated from convalescent patients can protect animals against SARS-CoV-2 viral challenge.2 Neutralizing antibodies might therefore provide benefit if given to COVID-19 patients who have not yet mounted their own immune response, and researchers around the globe are working on generating therapeutic monoclonal antibodies with this in mind. In the meantime, convalescent plasma provides a readily available source of neutralizing antibodies that can be transfused to newly exposed COVID-19 patients with the goal of providing passive immunity and clinical benefit.
Evidence from previous viral outbreaks
Convalescent plasma and its derivatives like hyperimmune immunoglobulin (the purified immunoglobulins from plasma that are specific to a virus) have been tested during viral outbreaks for over 100 years, but despite numerous case observational studies there have been very few randomized trials.3 A recent meta-analysis focusing on the use of convalescent plasma for treating severe viral respiratory infections found only 5 studies that met its inclusion criteria out of 1,099 search results (four RCTs for treating influenza; one non-randomized study for SARS-CoV).4 Overall the quality of evidence was deemed very low for all efficacy outcomes, and no statistically significant effects on mortality or length of hospital stay were found. On the other hand, few or no serious adverse events were noted across the studies. There are several issues with interpreting the historical data on convalescent plasma. There is variability around the dosing/timing of convalescent plasma treatment along with the disease severity of patients receiving it. This is compounded by the inherent differences in the activity of convalescent plasma in terms of neutralizing antibody titers, which has not been standardized across previous studies. Finally, the effect of convalescent plasma could be different for different viruses. The most relevant data point as pertaining to COVID-19 is likely the SARS outbreak given the close relationship between the SARS-CoV-1 and SARS-CoV-2 viruses. Unfortunately there were only small, non-randomized studies carried out during the SARS outbreak; however, these did hint towards some degree of efficacy with a good safety profile, particularly when convalescent plasma was given earlier on in the course of infection.5
Evidence from the COVID-19 pandemic
At the outset of the COVID-19 pandemic it was recognized that convalescent plasma might provide a rapidly deployable treatment option. Case reports using convalescent plasma to treat COVID-19 emerged out of China as early as March 2020 6,7 and on March 24th 2020 the US FDA granted convalescent plasma emergency investigational new drug status for patients with severe or immediately life-threatening COVID-19. The Cochrane Library has published a rapid review on the topic that will update as more data becomes available.8 As of May 14th 2020, the review had identified seven case-series and one prospective single-arm study with a total of 32 participants. All of the 32 patients were alive at the end of the reporting period with a handful of adverse reactions documented including one case of severe anaphylactic shock. As would be expected from this uncontrolled observational data, no definitive conclusions could yet be made regarding the efficacy or safety of convalescent plasma for treating COVID-19. Fortunately, there are at least 22 RCTs currently underway that will shed new light on the role of convalescent plasma for treating COVID-19. The first to report results is an RCT out of Wuhan that treated 103 patients, but was terminated early due to low enrolment.9 This study failed to detect a statistically significant difference in the primary outcome of time to clinical improvement (28 days for convalescent plasma group vs. indeterminate in the control group; p = 0.26). However, a statistically significant improvement was noted for convalescent plasma treatment compared to standard of care in the subgroup of patients without life-threatening COVID-19, as well as for the secondary outcome of viral clearance at 72 hours post-treatment. Limitations of this study include that it may have been underpowered due to early termination and that the majority of patients were far along in their disease course with a 27 day median time from symptom onset to randomization along with >50% having life-threatening disease. Larger RCTs are ongoing that focus on providing convalescent plasma earlier on in the disease course, including the Canadian CONCOR trials investigating the use of convalescent plasma in hospitalized adult and pediatric populations. The larger adult trial is seeking to randomize 1,200 hospitalized patients to receive 500 mL of ABO-compatible convalescent plasma vs. standard of care, where the treatment must be given within 12 days of symptom onset (most RCTs are looking at treating early hospitalized patients, but some are also looking at post-exposure prophylaxis).
Who can be a donor?
A challenge of using convalescent plasma at large scale is collecting and standardizing it. First, convalescent patients must be identified and undergo standard donor screening procedures. Second, the presence of neutralizing antibodies should ideally be quantified. We remain in the dark as to the optimal threshold for protective neutralizing antibody titers, but it seems likely that higher titers will be more effective up to a certain point. The US FDA has released guidelines for convalescent plasma: donors must have previously tested positive for SARS-CoV-2 by either PCR or serology, and have been symptom-free for at least 14 days prior to donation. They also recommend measuring neutralizing antibody titers for all samples with a value of at least 1:160 (a larger denominator indicates a greater dilution for the assay, and therefore a more active sample). In Canada, the Canadian Blood Services and Héma-Québec are coordinating a centralized effort to collect and distribute convalescent plasma to treat COVID-19 patients. In Canada, the Canadian Blood Services and Héma-Québec are coordinating a centralized effort to collect and distribute convalescent plasma to treat COVID-19 patients enrolled in trials. The inclusion criteria for donors can be found here. The increasing availability of SARS-CoV-2 serological assays along with the realization that there have been many undocumented mild infections will hopefully allow for a large number of donors to be identified if convalescent plasma proves to be effective.
What are the potential risks?
The most likely risks associated with convalescent plasma are the same as for typical plasma transfusions: febrile non-hemolytic reactions, allergic reactions, transfusion-associated circulatory overload (TACO), and transfusion-related acute lung injury (TRALI). As with any plasma transfusion, convalescent plasma must be ABO matched to avoid hemolytic reactions. Other rare risks would be bacterial or viral contamination, which can be minimized through the standard procedures for blood donor screening and quality control. The largest report on safety to date comes from a study of 5,000 hospitalized patients in the United States with severe or life-threatening COVID-19 who received convalescent plasma. 10 The overall rate of serious adverse events (SAEs) was <1%, with 25 SAEs reported as being related to the plasma transfusion including TACO (n = 7), TRALI (n = 11), and death (n = 4). It was not noted in the study how sick these particular patients were prior to receiving plasma, although ICU patients comprised 66% of the total study population Overall, the authors concluded that there was “no signal of toxicity beyond what is expected from plasma use in severely ill patients.”
A notable concern that has been raised for the use of convalescent plasma is the theoretical risk of antibody-dependent enhancement (ADE). This phenomenon has been observed with certain viruses like Dengue, where it is thought that sub-optimal antibody levels act to increase viral entry into macrophages and other immune cells leading to increased virulence.11 ADE was suspected for SARS-CoV-1 based on animal studies, but this has not been documented in animal models of SARS-CoV-2 nor in the initial clinical experiences with convalescent plasma. Another concern is a possible pro-thrombotic effect of convalescent plasma via the transfer of coagulation factors to already hypercoagulable COVID-19 patients. While the initial safety data are encouraging, it will be important to carefully monitor for these potential risks in ongoing clinical trials.
The patient meets the inclusion criteria for the CONCOR-1 trial as she is within 12 days of symptom onset and requires supplemental oxygen, but is not intubated. After discussing the risks and benefits of convalescent plasma treatment she consents to enrolment and is randomized to the convalescent plasma arm of the trial–on day 3 of admission she is treated with 500 mL of ABO matched convalescent plasma. There are no adverse reactions and the patient remains in stable condition following her transfusion.
- Convalescent plasma from recovered COVID-19 patients contains neutralizing antibodies that might provide passive immunity to newly infected individuals and limit their course of infection; however, the efficacy of convalescent plasma for treating COVID-19 and other viral infections remains uncertain.
- Convalescent plasma appears to be well-tolerated in COVID-19 patients with a risk profile consistent with typical plasma transfusions. The theoretical risks of antibody dependent enhancement and increased thrombosis have so far not materialized, but will need to be carefully monitored for in ongoing studies.
- Convalescent plasma remains an investigational therapy for COVID-19 with over 20 RCTs currently underway. Canadian patients may be eligible for enrolment in the CONCOR studies–RCTs that are comparing convalescent plasma to standard of care in hospitalized adult and pediatric populations.
All the content from the Blood & Clots series can be found here.
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- 8.Valk S, Piechotta V, Chai K, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review. Cochrane Database Syst Rev. 2020;5:CD013600. doi:10.1002/14651858.CD013600
- 9.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. Published online June 3, 2020. doi:10.1001/jama.2020.10044
- 10.Joyner M, Wright R, Fairweather D, et al. Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients. medRxiv. Published online May 14, 2020. doi:10.1101/2020.05.12.20099879
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