Effects of potent neutralizing antibodies from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection
Nature Communications. 2021;12(1):3189
In a randomized clinical trial of 86 hospitalized COVID-19 patients comparing standard care to treatment with 300mL convalescent plasma containing high titers of neutralizing SARS-CoV-2 antibodies, no overall clinical benefit was observed. Using a comprehensive translational approach, we unravel the virological and immunological responses following treatment to disentangle which COVID-19 patients may benefit and should be the focus of future studies. Convalescent plasma is safe, does not improve survival, has no effect on the disease course, nor does plasma enhance viral clearance in the respiratory tract, influence SARS-CoV-2 antibody development or serum proinflammatory cytokines levels. Here, we show that the vast majority of patients already had potent neutralizing SARS-CoV-2 antibodies at hospital admission and with comparable titers to carefully selected plasma donors. This resulted in the decision to terminate the trial prematurely. Treatment with convalescent plasma should be studied early in the disease course or at least preceding autologous humoral response development.
COVID-19 Convalescent Plasma: from donation to treatment - A Systematic Review & Single Center Experience
Mo Med. 2021;118(1):74-80
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.
Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review
The Cochrane Database of Systematic Reviews. 2021;5(5):Cd013600
BACKGROUND Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are being investigated as potential therapies for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding benefits and risks of these interventions is required. OBJECTIVES Using a living systematic review approach, to assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19; and to maintain the currency of the evidence. SEARCH METHODS To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease Research Database, MEDLINE, Embase, the Cochrane COVID-19 Study Register, the Epistemonikos COVID-19 L*OVE Platform, and trial registries. Searches were done on 17 March 2021. SELECTION CRITERIA We included randomised controlled trials (RCTs) evaluating convalescent plasma or hyperimmune immunoglobulin for COVID-19, irrespective of disease severity, age, gender or ethnicity. For safety assessments, we also included non-controlled non-randomised studies of interventions (NRSIs) if 500 or more participants were included. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of Bias 2' tool for RCTs, and for NRSIs, the assessment criteria for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence, using the GRADE approach, for the following outcomes: all-cause mortality, improvement and worsening of clinical status (for individuals with moderate to severe disease), development of severe clinical COVID-19 symptoms (for individuals with asymptomatic or mild disease), quality of life (including fatigue and functional independence), grade 3 or 4 adverse events, and serious adverse events. MAIN RESULTS We included 13 studies (12 RCTs, 1 NRSI) with 48,509 participants, of whom 41,880 received convalescent plasma. We did not identify any completed studies evaluating hyperimmune immunoglobulin. We identified a further 100 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, and 33 studies reporting as being completed or terminated. Individuals with a confirmed diagnosis of COVID-19 and moderate to severe disease Eleven RCTs and one NRSI investigated the use of convalescent plasma for 48,349 participants with moderate to severe disease. Nine RCTs compared convalescent plasma to placebo treatment or standard care alone, and two compared convalescent plasma to standard plasma (results not included in abstract). Effectiveness of convalescent plasma We included data on nine RCTs (12,875 participants) to assess the effectiveness of convalescent plasma compared to placebo or standard care alone. Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.92 to 1.05; 7 RCTs, 12,646 participants; high-certainty evidence). It has little to no impact on clinical improvement for all participants when assessed by liberation from respiratory support (RR not estimable; 8 RCTs, 12,682 participants; high-certainty evidence). It has little to no impact on the chance of being weaned or liberated from invasive mechanical ventilation for the subgroup of participants requiring invasive mechanical ventilation at baseline (RR 1.04, 95% CI 0.57 to 1.93; 2 RCTs, 630 participants; low-certainty evidence). It does not reduce the need for invasive mechanical ventilation (RR 0.98, 95% CI 0.89 to 1.08; 4 RCTs, 11,765 participants; high-certainty evidence). We did not identify any subgroup differences. We did not identify any studies reporting quality of life, and therefore, do not know whether convalescent plasma has any impact on quality of life. One RCT assessed resolution of fatigue on day 7, but we are very uncertain about the effect (RR 1.21, 95% CI 1.02 to 1.42; 309 participants; very low-certainty evidence). Safety of convalescent plasma We included results from eight RCTs, and one NRSI, to assess the safety of convalescent plasma. Some of the RCTs reported on safety data only for the convalescent plasma group. We are uncertain whether convalescent plasma increases or reduces the risk of grade 3 and 4 adverse events (RR 0.90, 95% CI 0.58 to 1.41; 4 RCTs, 905 participants; low-certainty evidence), and serious adverse events (RR 1.24, 95% CI 0.81 to 1.90; 2 RCTs, 414 participants; low-certainty evidence). A summary of reported events of the NRSI (reporting safety data for 20,000 of 35,322 transfused participants), and four RCTs reporting safety data only for transfused participants (6125 participants) are included in the full text. Individuals with a confirmed diagnosis of SARS-CoV-2 infection and asymptomatic or mild disease We identified one RCT reporting on 160 participants, comparing convalescent plasma to placebo treatment (saline). Effectiveness of convalescent plasma We are very uncertain about the effect of convalescent plasma on all-cause mortality (RR 0.50, 95% CI 0.09 to 2.65; very low-certainty evidence). We are uncertain about the effect of convalescent plasma on developing severe clinical COVID-19 symptoms (RR not estimable; low-certainty evidence). We identified no study reporting quality of life. Safety of convalescent plasma We do not know whether convalescent plasma is associated with a higher risk of grade 3 or 4 adverse events (very low-certainty evidence), or serious adverse events (very low-certainty evidence). This is a living systematic review. We search weekly for new evidence and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review. AUTHORS' CONCLUSIONS We have high certainty in the evidence that convalescent plasma for the treatment of individuals with moderate to severe disease does not reduce mortality and has little to no impact on measures of clinical improvement. We are uncertain about the adverse effects of convalescent plasma. While major efforts to conduct research on COVID-19 are being made, heterogeneous reporting of outcomes is still problematic. There are 100 ongoing studies and 33 studies reporting in a study registry as being completed or terminated. Publication of ongoing studies might resolve some of the uncertainties around hyperimmune immunoglobulin therapy for people with any disease severity, and convalescent plasma therapy for people with asymptomatic or mild disease.
Patients with COVID-19 (13 studies, n= 48,509).
Convalescent plasma (n= 41,880) or hyperimmune immunoglobulin.
Standard plasma, placebo treatment or standard care alone,
Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 7 RCTs, 12,646 participants; high-certainty evidence). It has little to no impact on clinical improvement for all participants when assessed by liberation from respiratory support (RR not estimable, 8 RCTs, 12,682 participants; high-certainty evidence). It has little to no impact on the chance of being weaned or liberated from invasive mechanical ventilation for the subgroup of participants requiring invasive mechanical ventilation at baseline (RR 1.04, 2 RCTs, 630 participants; low-certainty evidence). It does not reduce the need for invasive mechanical ventilation (RR 0.98, 4 RCTs, 11,765 participants; high-certainty evidence). There was low-certainty evidence on whether convalescent plasma increases or reduces the risk of grade 3 and 4 adverse events (RR 0.90, 4 RCTs, 905 participants), and serious adverse events (RR 1.24, 2 RCTs, 414 participants). No completed studies were identified on quality of life, or hyperimmune immunoglobulin therapy.
Treatment of COVID-19 patients using plasma therapy
Journal of Birjand University of Medical Sciences. 2021;28(1):84-87
The symptoms of COVID-19, caused by the newly known type of coronavirus, vary widely from asymptomatic, mild to severe respiratory infection leading to hospitalization or death of patients To date, no specific drug has been reported for the treatment of patients affected by this virus One of the approaches adopted for the treatment of this disease is the use of plasma therapy, which contains antibodies against the virus Following of the plasma therapy have not been reported any serious side effects Currently, the numbers of these studies are limited, and evaluation of the larger population studies can provide stronger evidence for treating physicians about the effectiveness of this therapeutic approach [ABSTRACT FROM AUTHOR] Copyright of Journal of Birjand University of Medical Sciences is the property of Birjand University of Medical Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use This abstract may be abridged No warranty is given about the accuracy of the copy Users should refer to the original published version of the material for the full abstract (Copyright applies to all Abstracts )
Brief report: Production of anti-SARS-CoV-2 hyperimmune globulin from convalescent plasma
BACKGROUND In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus emerged in China and quickly spread into a worldwide pandemic. Prior to the development of specific drug therapies or a vaccine, more immediately available treatments were sought including convalescent plasma. A potential improvement from convalescent plasma could be the preparation of anti-SARS-CoV-2 hyperimmune globulin (hIVIG). STUDY DESIGN AND METHODS Convalescent plasma was collected from an existing network of plasma donation centers. A caprylate/chromatography purification process was used to manufacture hIVIG. Initial batches of hIVIG were manufactured in a versatile, small-scale facility designed and built to rapidly address emerging infectious diseases. RESULTS Processing convalescent plasma into hIVIG resulted in a highly purified immunoglobulin G (IgG) product with more concentrated neutralizing antibody activity. hIVIG will allow for the administration of greater antibody activity per unit of volume with decreased potential for several adverse events associated with plasma administration. IgG concentration and IgG specific to SARS-CoV-2 were increased over 10-fold from convalescent plasma to the final product. Normalized enzyme-linked immunosorbent assay activity (per mg/ml IgG) was maintained throughout the process. Protein content in these final product batches was 100% IgG, consisting of 98% monomer and dimer forms. Potentially hazardous proteins (IgM, IgA, and anti-A, anti-B, and anti-D) were reduced to minimal levels. CONCLUSIONS Multiple batches of anti-SARS-CoV-2 hIVIG that met regulatory requirements were manufactured from human convalescent plasma. The first clinical study in which the hIVIG will be evaluated will be Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) [NCT04546581].
Efficacy of convalescent plasma therapy for COVID-19: A systematic review and meta-analysis
Journal of Clinical Apheresis. 2021
The purpose of this systematic review and meta-analysis was to examine clinical outcomes associated with convalescent plasma therapy in COVID-19 patients. We performed a literature search on PubMed, medRxiv, Web of Science, and Scopus to identify studies published up to December 10th, 2020 that examined the efficacy of convalescent plasma treatment for COVID-19. The primary endpoints were mortality, clinical improvement, and hospital length of stay. We screened 859 studies that met the search criteria, performed full-text reviews of 56 articles, and identified 15 articles that fulfilled inclusion criteria for meta-analysis. The odds of mortality were significantly lower in the convalescent plasma group compared to the control group (OR = 0.59 [95% CI = 0.44; 0.78], P < .001), although results from two key randomized controlled trials did not support the mortality benefit. The odds of clinical improvement were significantly higher in the convalescent plasma group compared to the control group (OR = 2.02 [95% CI = 1.54; 2.65], P < .001). There was no difference in hospital length of stay between the convalescent plasma group and the control group (MD = -0.49 days [95% CI = -3.11; 2.12], P = .713). In all, these data indicate that a mortality benefit with convalescent plasma is unclear, although there remain benefits with convalescent plasma therapy for COVID-19.
How should we use convalescent plasma therapies for the management of COVID-19?
Convalescent plasma (CP) from blood donors with antibodies to severe acute respiratory syndrome coronavirus 2 may benefit patients with COVID-19 by providing immediate passive immunity via transfusion or by being used to manufacture hyperimmune immunoglobulin preparations Optimal product characteristics (including neutralizing antibody titers), transfusion volume, and administration timing remain to be determined Preliminary COVID-19 CP safety data are encouraging, but establishing the clinical efficacy of CP requires an ongoing international collaborative effort Preliminary results from large, high-quality randomized trials have recently started to be reported
Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease
Scientific reports. 2021;11(1):9927
Convalescent plasma (CP) therapy in COVID-19 disease may improve clinical outcome in severe disease. This pilot study was undertaken to inform feasibility and safety of further definitive studies. This was a prospective, interventional and randomized open label pilot trial in patients with severe COVID-19. Twenty COVID-19 patients received two 200 ml transfusions of convalescent patient CP over 24-h compared with 20 who received standard of care. The primary outcome was the requirement for ventilation (non-invasive or mechanical ventilation). The secondary outcomes were biochemical parameters and mortality at 28 days. The CP group were a higher risk group with higher ferritin levels (p < 0.05) though respiratory indices did not differ. The primary outcome measure was required in 6 controls and 4 patients on CP (risk ratio 0.67, 95% CI 0.22-2.0, p = 0.72); mean time on ventilation (NIV or MV) did not differ. There were no differences in secondary measures at the end of the study. Two patients died in the control and one patient in the CP arm. There were no significant differences in the primary or secondary outcome measures between CP and standard therapy, although a larger definitive study is needed for confirmation. However, the study did show that CP therapy appears to be safe in hospitalized COVID-19 patients with hypoxia.Clinical trials registration NCT04356534: 22/04/2020.
Immunomodulatory therapies for SARS-CoV-2 infection: a systematic literature review to inform EULAR points to consider
Annals of the rheumatic diseases. 2021
OBJECTIVE To summarise the available information on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection. METHODS As part of a European League Against Rheumatism (EULAR) taskforce, a systematic literature search was conducted from January 2019 to 11 December 2020. Two reviewers independently identified eligible studies according to the Population, Intervention, Comparator and Outcome framework and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage. The risk of bias was assessed with validated tools. RESULTS Of the 60 372 records, 401 articles were eligible for inclusion. Studies were at variable risk of bias. Randomised controlled trials (RCTs) were available for the following drugs: hydroxychloroquine (n=12), glucocorticoids (n=6), tocilizumab (n=4), convalescent plasma (n=4), interferon beta (n=2), intravenous immunoglobulins (IVIg) (n=2) and n=1 each for anakinra, baricitinib, colchicine, leflunomide, ruxolitinib, interferon kappa and vilobelimab. Glucocorticoids were able to reduce mortality in specific subsets of patients, while conflicting data were available about tocilizumab. Hydroxychloroquine was not beneficial at any disease stage, one RCT with anakinra was negative, one RCT with baricitinib+remdesivir was positive, and individual trials on some other compounds provided interesting, although preliminary, results. CONCLUSION Although there is emerging evidence about immunomodulatory therapies for the management of COVID-19, conclusive data are scarce with some conflicting data. Since glucocorticoids seem to improve survival in some subsets of patients, RCTs comparing glucocorticoids alone versus glucocorticoids plus anticytokine/immunomodulatory treatment are warranted. This systematic literature review informed the initiative to formulate EULAR 'points to consider' on COVID-19 pathophysiology and immunomodulatory treatment from the rheumatology perspective.
A randomized clinical trial evaluating the immunomodulatory effect of convalescent plasma on COVID-19-related cytokine storm
Internal and emergency medicine. 2021;:1-11
Evaluating the effect of convalescent plasma (CP) on some cytokine storm indices in severe COVID-19 patients. Totally, 62 patients were randomly assigned into two groups for this clinical trial. Patients in the intervention group received one unit (500 mL) plasma on the admission day plus standard drugs while the controls merely received standard treatments. Eventually, primary and secondary outcomes were evaluated. In the CP group, compared with controls, the mean levels of lymphocytes and IL-10 significantly increased while the levels of IL-6, TNF-α, and IFN-γ decreased (p < 0.05). The length of in-hospital stay, and mortality rate did not significantly reduce in the CP group compared with controls (p > 0.05) while WHO severity scores remarkably improved (p = 0.01), despite the higher frequency of underlying diseases among the CP group (66.7%) vs. controls (33.3%). Although CP has a remarkable immunomodulatory and antiviral potential to improve the cytokine storm and disease severity in COVID-19 patients, it did not considerably affect the mortality rate.