If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MODepartment of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO
Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TXCenter for Molecular and Translational Human Infectious Diseases, Houston Methodist Research Institute, Houston, TXDepartment of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY
Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TXDepartment of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY
Department of Anesthesiology, University of Wisconsin–Madison School of Medicine and Public Health, Madison, Icahn School of Medicine at Mount Sinai, New York, NY
Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NYDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY
Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NYDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY
Department of Epidemiology and Biostatistics, Michigan State University, East LansingDepartment of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing
Correspondence: Address to Michael J. Joyner, MD, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
Affiliations
Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN
To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from 10 randomized clinical trials, 20 matched control studies, 2 dose-response studies, and 96 case reports or case series. Studies published between January 1, 2020, and January 16, 2021, were identified through a systematic search of online PubMed and MEDLINE databases. Random effects analyses of randomized clinical trials and matched control data demonstrated that patients with COVID-19 transfused with convalescent plasma exhibited a lower mortality rate compared with patients receiving standard treatments. Additional analyses showed that early transfusion (within 3 days of hospital admission) of higher titer plasma is associated with lower patient mortality. These data provide evidence favoring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized patients with COVID-19.
There remains a lack of consensus on convalescent plasma use in hospitalized patients with COVID-19.
•
Meta-analyses of randomized clinical trials and matched control data demonstrated that patients with COVID-19 transfused with convalescent plasma exhibited a lower mortality rate compared with patients receiving standard treatments.
•
Additional analyses showed that early transfusion (within 3 days of hospital admission) of high-titer plasma is associated with lower mortality.
•
These data provide evidence favoring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized patients with COVID-19.
Convalescent plasma is a century-old passive antibody therapy that has been used to treat outbreaks of novel infectious diseases, including those affecting the respiratory system.
At the onset of the pandemic, human convalescent plasma was used worldwide as it represented the only antibody-based therapy for coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Despite the emerging availability of monoclonal antibody therapies and vaccines for use in nonhospitalized patients through federal emergency authorization routes, convalescent plasma use has persisted (~100,000 units per month in the United States in early 2021) during subsequent waves of the COVID-19 pandemic because of surging hospitalizations and mortality rates.
American Association of Blood Banks America’s Blood Centers, American Red Cross. Joint statement: blood community encourages individuals to donate blood, convalescent plasma during national blood donor month and beyond.
However, evidence for the efficacy of therapeutic COVID-19 convalescent plasma still requires definitive support from large randomized clinical trials (RCTs). As a result, there remains a lack of consensus on convalescent plasma use in hospitalized patients with COVID-19.
Smaller RCTs, matched control studies, and case series studies investigating convalescent plasma therapy for COVID-19 have emerged and provided a positive efficacy signal.
Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients with Severe and Life-threatening COVID-19: A Randomized Clinical Trial.
The therapeutic effectiveness of convalescent plasma therapy on treating critically-ill COVID-19 patients residing in respiratory care units in hospitals in Baghdad, Iraq.
Most of these studies, however, lacked appropriate statistical power or were terminated early. Also, many studies have transfused patients only after clinical progression to severe COVID-19 respiratory distress, which opposes historical data highlighting the efficacy of early convalescent plasma transfusion and overlooks viral neutralization as the fundamental mechanism for convalescent plasma therapy.
There is an urgent need to determine the efficacy of potential treatments amid the ongoing COVID-19 pandemic. Although a “living” systematic review has summarized a broad-ranging clinical experience with convalescent plasma,
this approach may be limited because it employed stringent inclusion criteria for aggregating patient outcomes, which prevented a preliminary assessment of convalescent plasma efficacy. Given the insufficient patient outcome data available from RCTs, we used a pragmatic approach for study selection to aggregate COVID-19 clinical outcomes, focusing solely on mortality data from RCTs, matched control studies, dose-response investigations, and case series or case reports in real time. Our primary objective was to derive an aggregate estimate of the mortality rates from transfused and nontransfused cohorts of contemporaneous COVID-19 studies. As an exploratory objective, we assessed whether the time from hospital admission to convalescent plasma transfusion was associated with mortality of patients.
Methods
Eligibility
We included RCTs, matched control trials, dose-response studies, and case series or case reports published on preprint servers or peer-reviewed journals that investigated the impact of human convalescent plasma therapy on mortality of patients with COVID-19.
Literature Search and Data Extraction
We performed a systematic search of the online PubMed and MEDLINE databases from January 1, 2020, through January 16, 2021. Keywords used in the search included ((convalescent plasma) OR (convalescent serum)) AND COVID-19 (and medical subject headings) using the following limits: Humans. No language restrictions were imposed. The references of all eligible studies were reviewed to identify other potentially eligible studies. To be considered eligible for inclusion, studies must have included patients with confirmed diagnosis of COVID-19, used convalescent plasma treatment, and reported mortality. Randomized clinical trials, matched control studies, dose-response studies, case series, and case reports were included. Two reviewers (S.A.K. and J.W.S.) independently screened the titles and abstracts of all studies identified by the search to determine eligibility. Studies that were deemed potentially eligible had their full text reviewed (S.A.K. and J.W.S.) to determine whether they met the criteria for inclusion in the review. Disagreement was resolved by consensus. Two reviewers (S.A.K. and J.W.S.) extracted study and patient characteristics as well as clinical information (additional information for each study is available in in Supplemental Tables 1-6, available online at http://www.mayoclinicproceedings.org).
Dose-response studies were evaluated with the Newcastle-Ottawa Scale. The criteria developed by the Mayo Clinic Evidence-Based Practice Research Program informed our assessment of bias in the mortality data reported by case series and case reports.
For RCTs and matched control studies, we recorded the number of survivors and nonsurvivors in transfused and nontransfused cohorts to calculate odds ratios (ORs) with 95% CIs. For dose-response studies, we recorded the number of survivors and nonsurvivors among patients who were transfused with higher titer and lower titer convalescent plasma units to calculate ORs with 95% CIs. Aggregate mortality rates were calculated for transfused and, if applicable, nontransfused patients at the longest reported vital status for each study.
Using the DerSimonian-Laird random effects method,
we computed aggregate ORs with 95% CIs separately for RCTs and matched control studies. We also computed aggregate ORs with 95% CIs for RCTs and matched control studies combined. Simple random effects meta-regression analyses evaluated the moderator variables (ie, cohort age, proportion of cohort receiving mechanical ventilation, and duration of study follow-up) on mortality for all clinical studies. The I2 statistic was used to quantify heterogeneity. On the basis of historical data,
we performed an exploratory subgroup analysis to assess the impact of early transfusion (within 3 days of hospital admission) compared with late transfusion (>3 days after hospital admission) on mortality of patients with COVID-19. All analyses were performed with Comprehensive Meta-analysis software (Biostat, version 3.3.070). Tests were 2 tailed, and α was .05. Figures were made with R software (R Foundation for Statistical Computing). The number needed to treat was calculated using aggregate data from controlled studies.
Dose-response studies, case series, and case reports were not included in the meta-analysis but were described in a narrative.
Certainty of Evidence Assessment
We used the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence regarding the impact of convalescent plasma on mortality of patients with COVID-19.
The risk of bias assessments for RCT and matched control data informed our certainty of evidence assessment.
Results
Search Results
The literature search yielded 780 studies, of which 128 studies met the eligibility criteria and were included in the systematic review (Supplemental Figure 1, available online at http://www.mayoclinicproceedings.org). The analyses included a total of 10 RCTs,
The therapeutic effectiveness of convalescent plasma therapy on treating critically-ill COVID-19 patients residing in respiratory care units in hospitals in Baghdad, Iraq.
Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease. medRxiv. November 4, 2020.
Clinical and immunological benefits of convalescent plasma therapy in severe COVID-19: insights from a single center open label randomised control trial. medRxiv. November 29, 2020.
Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial) [erratum appears in BMJ. 2020;371:m4232].
Efficacy of convalescent plasma therapy compared to fresh frozen plasma in severely ill COVID-19 patients: a pilot randomized controlled trial. medRxiv. October 27, 2020.
Significantly decreased mortality in a large cohort of COVID-19 patients transfused early with convalescent plasma containing high-titer anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein IgG.
Kinetics of SARS-CoV-2 antibody responses pre-and post–COVID-19 convalescent plasma transfusion in patients with severe respiratory failure: an observational case-control study. medRxiv. December 11, 2020.
Covid-19 Plasma Task Force. Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma. A proof of concept single arm multicenter trial.
Clinical and laboratory evaluation of patients with SARS-CoV-2 pneumonia treated with high-titer convalescent plasma: a prospective study. medRxiv. August 4, 2020.
Compassionate use of convalescent plasma for treatment of moderate and severe pneumonia in COVID-19 patients and association with IgG antibody levels in donated plasma.
Convalescent plasma treatment of persistent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in patients with lymphoma with impaired humoral immunity and lack of neutralising antibodies.
Br J Haematol.2020 Dec 13; ([Online ahead of print])
Severe acute respiratory syndrome coronavirus 2 neutralizing antibody titers in convalescent plasma and recipients in New Mexico: an open treatment study in patients with coronavirus disease 2019.
A retrospective study on the effects of convalescent plasma therapy in 24 patients diagnosed with COVID-19 pneumonia in February and March 2020 at 2 centers in Wuhan, China.
Convalescent plasma therapy: helpful treatment of COVID-19 in a kidney transplant recipient presenting with severe clinical manifestations and complex complications.
Initial experience in Mexico with convalescent plasma in COVID-19 patients with severe respiratory failure, a retrospective case series. medRxiv. July 20, 2020.
The use of convalescent plasma therapy and remdesivir in the successful management of a critically ill obstetric patient with novel coronavirus 2019 infection: a case report.
A 63-year-old woman with a history of non-Hodgkin lymphoma with persistent SARS-CoV-2 infection who was seronegative and treated with convalescent plasma.
A case of COVID-19, with cytokine storm, treated by consecutive use of therapeutic plasma exchange followed by convalescent plasma transfusion: a case report.
Long-term positive severe acute respiratory syndrome coronavirus 2 ribonucleic acid and therapeutic effect of antivirals in patients with coronavirus disease: case reports.
Impact of convalescent plasma transfusion (CCP) in patients with previous circulating neutralizing antibodies (nAb) to COVID-19. medRxiv. December 11, 2020.
Overall, these studies reported outcomes from 35,055 patients with COVID-19 in 31 countries (Tables 1 and 2; Supplemental Table 3, available online at http://www.mayoclinicproceedings.org). The age of patients enrolled in these studies ranged from 4 to 100 years, with a greater proportion of men than of women in most studies (proportion of women, 0%-100%; Supplemental Tables 4-6). All studies included patients with diagnosed COVID-19, with most studies including hospitalized patients with severe or life-threatening COVID-19. At the time of plasma transfusion, the proportion of patients on mechanical ventilation varied by study from 0% to 100%. The duration of follow-up ranged from 2 to 118 days (Supplemental Tables 4-6). In most studies, patients were eligible to receive concomitant and experimental therapies, such as antivirals, steroids, and chloroquine or hydroxychloroquine.
Table 1Mortality Rates Among COVID-19 Patients: Randomized Clinical Trials and Matched Control Studies
The therapeutic effectiveness of convalescent plasma therapy on treating critically-ill COVID-19 patients residing in respiratory care units in hospitals in Baghdad, Iraq.
Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease. medRxiv. November 4, 2020.
Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients with Severe and Life-threatening COVID-19: A Randomized Clinical Trial.
Clinical and immunological benefits of convalescent plasma therapy in severe COVID-19: insights from a single center open label randomised control trial. medRxiv. November 29, 2020.
Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial) [erratum appears in BMJ. 2020;371:m4232].
Efficacy of convalescent plasma therapy compared to fresh frozen plasma in severely ill COVID-19 patients: a pilot randomized controlled trial. medRxiv. October 27, 2020.
Covid-19 Plasma Task Force. Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma. A proof of concept single arm multicenter trial.
Significantly decreased mortality in a large cohort of COVID-19 patients transfused early with convalescent plasma containing high-titer anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein IgG.
Clinical and laboratory evaluation of patients with SARS-CoV-2 pneumonia treated with high-titer convalescent plasma: a prospective study. medRxiv. August 4, 2020.
Kinetics of SARS-CoV-2 antibody responses pre-and post–COVID-19 convalescent plasma transfusion in patients with severe respiratory failure: an observational case-control study. medRxiv. December 11, 2020.
Compassionate use of convalescent plasma for treatment of moderate and severe pneumonia in COVID-19 patients and association with IgG antibody levels in donated plasma.
When data from the 10 RCTs were aggregated, there was no association between convalescent plasma therapy and mortality (OR, 0.76; 95% CI, 0.54 to 1.09; P=.14; I2=7%; Table 1; Figure). Although the heterogeneity was low, 1 RCT (Agarwal et al
Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial) [erratum appears in BMJ. 2020;371:m4232].
) demonstrated a directionally different effect, had a large statistical weight (34.2), and represented the primary source of heterogeneity (ΔI2=7%). In addition, in the context of COVID-19, neutralizing antibodies are hypothesized to represent the primary active agent in convalescent plasma and the marker of plasma potency.
In this regard, as mentioned later, 2 studies reported a dose-response relationship between convalescent plasma antibody level and mortality, suggesting the need for a sufficient amount of antibody for therapeutic success.
Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial) [erratum appears in BMJ. 2020;371:m4232].
included a large proportion of patients (~70%) in the convalescent plasma arm who received plasma with low levels of SARS-CoV-2 antibodies less than 1:80, with approximately 30% receiving plasma with no detectable antibodies.
Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial) [erratum appears in BMJ. 2020;371:m4232].
Thus, there were strong analytical and biologic rationales to exclude this study from statistical models.
FigureThe effect of human convalescent plasma therapy on mortality of patients with COVID-19. Forest plot illustrating odds ratios (ORs) and 95% CIs computed for each study and aggregated for each study type (DerSimonian-Laird random effects model). Data are separated by study type; randomized clinical trials are presented in blue, and matched control studies are presented in orange. The overall OR pooled across all controlled studies is presented in green. Relative study weights are provided. The I2 values were 0 (randomized clinical trial model), 61 (matched control study model), and 53 (overall model combining randomized clinical trial and matched control studies). aRandom effects model excludes trial by Agarwal et al.
Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial) [erratum appears in BMJ. 2020;371:m4232].
patients transfused with convalescent plasma exhibited a lower mortality rate compared with nontransfused patients with COVID-19 (11% vs 16% mortality; OR, 0.65; 95% CI, 0.43 to 0.98; P=.04; I2=0%; Table 1; Figure). The aggregate OR (0.65) indicates that convalescent plasma was associated with a 35% reduction in the odds of mortality among patients with COVID-19.
Matched Control Studies
When we aggregated mortality data from the 20 matched control studies, patients transfused with convalescent plasma exhibited a lower mortality rate compared with nontransfused patients (21% vs 29% mortality; OR, 0.57; 95% CI, 0.45 to 0.72; P<.001; I2=61%; Table 1; Figure).
Randomized Clinical Trials and Matched Control Studies
Aggregation of mortality data from all controlled studies including RCTs and matched control studies indicated that patients transfused with convalescent plasma exhibited a 42% reduction in mortality rate compared with patients receiving standard treatments (20% vs 28% mortality; OR, 0.58; 95% CI, 0.47 to 0.71; P<.001; I2=53%; Table 1; Figure). Simple random effects meta-regression analyses indicated that cohort age (P=.23), proportion of cohort receiving mechanical ventilation (P=.51), and duration of study follow-up (P=.29) did not affect the aggregate OR computed for all controlled studies.
Subgroup Analysis: Effect of Days Between Hospital Admission and Plasma Transfusion
Sixteen studies (n=6 RCTs, n=10 matched control studies) reported the number of days between hospital admission and convalescent plasma transfusion (Supplemental Table 4). Exploratory analysis revealed that the mortality reduction associated with convalescent plasma transfusion was greater in studies that transfused patients within 3 days of hospital admission (OR, 0.44; 95% CI, 0.32-0.61) compared with studies that transfused patients more than 3 days after hospital admission (OR, 0.79; 95% CI, 0.62 to 0.98; random effects test of heterogeneity between subgroups, P=.005). However, this analysis was strongly influenced by the study by Altuntas et al,
the number of days from hospital admission to transfusion no longer affected the mortality reduction associated with convalescent plasma transfusion (transfusion within 3 days of hospitalization, 0.44 [0.32-0.60]; transfusion >3 days after hospitalization, 0.61 [0.36-0.68]; random effects test of heterogeneity between subgroups, P=.23).
Additional Evidence
Dose-Response Studies
Two studies investigated the association between convalescent plasma antibody levels and the risk of mortality from COVID-19.
Compassionate use of convalescent plasma for treatment of moderate and severe pneumonia in COVID-19 patients and association with IgG antibody levels in donated plasma.
Although different criteria were used to categorize convalescent plasma units as higher and lower antibody level, both studies found a dose-response association between antibody level and COVID-19 mortality, such that patient mortality was lower in the subgroups transfused with higher titer plasma. The aggregate mortality rate of patients with COVID-19 transfused with higher titer convalescent plasma was less than that of patients transfused with lower titer plasma (22% vs 29% mortality; Table 2).
Case Series and Case Reports
The aggregate mortality rate among patients with COVID-19 transfused with convalescent plasma reported in uncontrolled studies was 13% (range, 0%-100%), which is comparable to the mortality rates exhibited by transfused cohorts from clinical trials and matched control studies (Supplemental Table 3). Case series and case report data included diverse cohorts of patients with varying inherent risk for COVID-19 complications. Several studies explored immunosuppressed patients with suppressed antibody production due to hematologic malignant neoplasms, cancer-directed therapy, or X-linked agammaglobulinemia and provided an important “experiment of nature” to evaluate convalescent plasma efficacy for COVID-19.
highlighted a series of 3 patients with X-linked agammaglobulinemia with severe COVID-19 who failed to respond to other supportive treatments but demonstrated strong improvements in oxygen requirements and viral clearance within days of receiving convalescent plasma transfusions.
Risk of Bias
Overall, we deemed the risk of bias for mortality data to be low to moderate for RCTs and low to moderate for matched control studies. We present the full judgment for each study in Supplemental Tables 1 and 2. The risk of bias for uncontrolled studies is inherently high. Visual inspection of the funnel plot to assess publication bias shows that 1 study falls below the 95% CI and 2 studies fall above the 95% CI (Supplemental Figure 2, available online at http://www.mayoclinicproceedings.org). The funnel plot shows symmetry in the effect sizes among studies with low standard error and asymmetry among studies with greater standard error, suggesting that smaller studies with larger standard error may be more likely to report an effect of convalescent plasma. However, the Egger regression test suggests that there is no significant asymmetry of the plot (intercept, −0.17; P=.67).
Certainty of Evidence
The certainty in the estimate of the effect of convalescent plasma on mortality is moderate to high.
This judgment was based on the consistency of the results between RCTs and matched control studies and the corroborating evidence from dose-response studies and other uncontrolled case data. In aggregating data from all controlled studies, the meta-analyses provided precise estimates, did not demonstrate substantial heterogeneity, and demonstrated no strong evidence of publication bias. The inherent limitations of the included studies rendered the certainty of evidence judgment to be moderate to high.
Number Needed to Treat
Based on the aggregate OR (0.58; 95% CI, 0.47 to 0.71) computed for all controlled studies and the aggregate mortality rate (28%) expressed by nontransfused cohorts among the controlled studies, to avoid 1 death, the number needed to be transfused with convalescent plasma rather than only to receive the standard of care is 11 (range, 8-16).
Discussion
This analysis represents the most current aggregation of mortality data from contemporaneous COVID-19 convalescent plasma studies. The aggregate mortality rate of transfused patients with COVID-19 was lower than that of nontransfused patients with COVID-19. Additional analyses demonstrated that early transfusion of high-titer plasma reduces mortality among patients with COVID-19. These results favor the efficacy of convalescent plasma as a COVID-19 therapeutic agent. The primary biologic hypothesis for the efficacy of convalescent plasma is antibody-mediated SARS-CoV-2 viral neutralization and interference with viral replication, although other biologic mechanisms may also contribute to the mitigation of symptoms.
The mortality reduction associated with convalescent plasma aligns with similar analyses of historical data from convalescent plasma trials for viral diseases, such as the 1918 influenza epidemic,
which concluded that there is insufficient evidence to determine the impact of convalescent plasma on all-cause mortality based on only 2 RCTs, including 1 prematurely terminated RCT (Li 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.
). This discordance reflects differences in the studies included in the analysis. Our approach was pragmatic and used less stringent study inclusion criteria, allowing the inclusion of 30 controlled studies, of which a majority found a directionally similar effect of convalescent plasma, and our analyses stratified by study design (eg, RCTs and matched control studies) revealed similar aggregate ORs.
Mechanistic and clinical data support the reduction in mortality associated with convalescent plasma administration. Importantly, convalescent plasma contains SARS-CoV-2–neutralizing antibodies.
Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients with Severe and Life-threatening COVID-19: A Randomized Clinical Trial.
indicating an antiviral effect. Viral neutralization is then posited to reduce the inflammatory response and thus to lessen the likelihood that an overexuberant immune response progresses to lung damage, interference with gas exchange, and death. Additional evidence arising from animal studies shows that administration of human convalescent plasma is protective against SARS-CoV-2 infection.
Antibody-mediated interference with viral replication may increase tissue repair and eventually be manifested as reduced mortality. In addition, convalescent plasma transfusion is associated with reductions in inflammatory markers, such as chemokines, cytokines, and C-reactive protein.
Concomitant reductions in inflammation and improved gas exchange may underlie the reductions in oxygen requirements associated with convalescent plasma, even in critically ill patients. These findings provide mechanistic evidence for the reduction in mortality observed in patients receiving convalescent plasma.
There are several limitations to this analysis, including the aggregation of mortality data across study populations that varied by the nation of data origin, the timing relative to worldwide progression of the pandemic, the clinical diagnostic and treatment algorithms, the plasma antibody titer and administration volume, the latency between COVID-19 diagnosis and transfusion, and the duration of follow-up after transfusion. Also, we did not consult a librarian when constructing our search terms. However, high-quality evidence from large RCTs remains unavailable, and the continuing global health emergency related to COVID-19 necessitated a practical real-time aggregation of existing mortality data. We note that the reports cited herein include positive results from different countries, suggesting that efficacy is robust across different health care systems. Given the safety of convalescent plasma administered to patients with COVID-19,
the results of this real-time systematic review and meta-analysis provide encouragement for its continued use as a therapy and may have broad implications for the treatment of COVID-19 and design of RCTs. Importantly, many of the patients enrolled in the studies included in the analyses received convalescent plasma transfusions later in their disease course. In this context, before antibiotics and effective vaccinations, convalescent plasma therapy was widely understood to be most efficacious very early in the course of hospitalizations.
As a result, our analysis may underestimate the mortality reduction achievable through early administration of high-titer convalescent plasma for COVID-19.
Conclusion
This real-time systematic review and meta-analysis of contemporaneous studies highlights that the mortality rate of transfused patients with COVID-19 was lower than that of nontransfused patients with COVID-19 and suggests that early transfusion of high-titer plasma represents the optimal use scenario to reduce the risk of mortality among patients with COVID-19. These results favor the efficacy of convalescent plasma as a COVID-19 therapeutic agent.
Acknowledgments
The authors express their gratitude to the convalescent plasma donors.
Drs Klassen, Senefeld, Casadevall, and Joyner contributed equally to this article.
America’s Blood Centers, American Red Cross. Joint statement: blood community encourages individuals to donate blood, convalescent plasma during national blood donor month and beyond.
Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients with Severe and Life-threatening COVID-19: A Randomized Clinical Trial.
The therapeutic effectiveness of convalescent plasma therapy on treating critically-ill COVID-19 patients residing in respiratory care units in hospitals in Baghdad, Iraq.
Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease. medRxiv. November 4, 2020.
Clinical and immunological benefits of convalescent plasma therapy in severe COVID-19: insights from a single center open label randomised control trial. medRxiv. November 29, 2020.
Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial) [erratum appears in BMJ. 2020;371:m4232].
Efficacy of convalescent plasma therapy compared to fresh frozen plasma in severely ill COVID-19 patients: a pilot randomized controlled trial. medRxiv. October 27, 2020.
Significantly decreased mortality in a large cohort of COVID-19 patients transfused early with convalescent plasma containing high-titer anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein IgG.
Kinetics of SARS-CoV-2 antibody responses pre-and post–COVID-19 convalescent plasma transfusion in patients with severe respiratory failure: an observational case-control study. medRxiv. December 11, 2020.
Covid-19 Plasma Task Force. Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma. A proof of concept single arm multicenter trial.
Clinical and laboratory evaluation of patients with SARS-CoV-2 pneumonia treated with high-titer convalescent plasma: a prospective study. medRxiv. August 4, 2020.
Compassionate use of convalescent plasma for treatment of moderate and severe pneumonia in COVID-19 patients and association with IgG antibody levels in donated plasma.
Convalescent plasma treatment of persistent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in patients with lymphoma with impaired humoral immunity and lack of neutralising antibodies.
Br J Haematol.2020 Dec 13; ([Online ahead of print])
Severe acute respiratory syndrome coronavirus 2 neutralizing antibody titers in convalescent plasma and recipients in New Mexico: an open treatment study in patients with coronavirus disease 2019.
A retrospective study on the effects of convalescent plasma therapy in 24 patients diagnosed with COVID-19 pneumonia in February and March 2020 at 2 centers in Wuhan, China.
Convalescent plasma therapy: helpful treatment of COVID-19 in a kidney transplant recipient presenting with severe clinical manifestations and complex complications.
Initial experience in Mexico with convalescent plasma in COVID-19 patients with severe respiratory failure, a retrospective case series. medRxiv. July 20, 2020.
The use of convalescent plasma therapy and remdesivir in the successful management of a critically ill obstetric patient with novel coronavirus 2019 infection: a case report.
A 63-year-old woman with a history of non-Hodgkin lymphoma with persistent SARS-CoV-2 infection who was seronegative and treated with convalescent plasma.
A case of COVID-19, with cytokine storm, treated by consecutive use of therapeutic plasma exchange followed by convalescent plasma transfusion: a case report.
Long-term positive severe acute respiratory syndrome coronavirus 2 ribonucleic acid and therapeutic effect of antivirals in patients with coronavirus disease: case reports.
Impact of convalescent plasma transfusion (CCP) in patients with previous circulating neutralizing antibodies (nAb) to COVID-19. medRxiv. December 11, 2020.
Grant Support: This work was supported by grants from the National Heart, Lung, and Blood Institute ( 5R35HL139854 to M.J.J.), the National Institute of Diabetes and Digestive and Kidney Diseases ( 5T32DK07352 to J.W.S. and C.C.W.), the Natural Sciences and Engineering Research Council of Canada ( PDF-532926-2019 to S.A.K.), the National Institutes of Health ( 1-F32-HL154320-01 to J.W.S.), the National Institute of Allergy and Infectious Diseases ( R21 AI145356 and R21 AI152318 to D.F.; R01 AI1520789 to A.C.), and the National Heart, Lung, and Blood Institute ( R01 HL059842 to A.C.).
Potential Competing Interests: The authors report no competing interests.
We would like to thank Franchini and Cruciani for their letter in response to our systematic review and meta-analysis studying the effect of convalescent plasma therapy on the mortality of patients diagnosed with coronavirus disease 2019 (COVID-19).1 This letter highlights important new meta-analytical data based on 30 controlled studies (including 14 randomized clinical trials) demonstrating that convalescent plasma transfusion does not increase the risk of adverse events, including thromboembolic events, compared with patients diagnosed with COVID-19 who either were not transfused or were transfused with standard fresh frozen plasma.
We read with interest the systematic review and meta-analysis by Klassen and colleagues,1 recently published in Mayo Clinic Proceedings. The investigators included in their analysis 30 randomized clinical trials (RCTs) and matched control studies, documenting that COVID-19 convalescent plasma (CP) transfusion, especially when it is given within 3 days of hospital admission, is associated with lower mortality of patients with COVID-19 compared with standard treatment. Adverse events analysis, in combination with benefits analysis, is essential to make an informed decision about health intervention.
00140-3&id=gr1.jpg){kind=link}
