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1.
Outpatient convalescent plasma therapy for high-risk patients with early COVID-19. A randomized placebo-controlled trial
Gharbharan A, Jordans C, Zwaginga L, Papageorgiou G, van Geloven N, van Wijngaarden P, den Hollander J, Karim F, van Leeuwen-Segarceanu E, Soetekouw R, et al
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2022
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Editor's Choice
Abstract
OBJECTIVES The potential benefit of convalescent plasma (CP) therapy for COVID-19 is highest when given early after symptom onset. Our objective was to determine the effectiveness of CP in improving the disease course of COVID-19 in high-risk outpatients. METHODS A multicentre double blind randomized trial was conducted comparing 300mL of CP with non-CP. Patients were 50 years or older, symptomatic for <8 days, had PCR or antigen-test confirmed COVID-19 and at least 1 risk factor for severe COVID-19. The primary endpoint was the highest score on a 5-point ordinal scale ranging from fully recovered (score=1) or not (2) on day 7, over hospital admission (3), ICU admission (4) and death (5) in the 28 days following randomization. Secondary endpoints were hospital admission, symptom duration and viral RNA excretion. RESULTS After enrolment of 421 patients and the transfusion of 416, recruitment was discontinued when the countrywide vaccination uptake in those aged >50 years was 80%. Patients had a median age of 60, symptoms for 5 days and 207 of 416 received CP. During the 28 days of follow-up, 28 patients were hospitalized and 2 died. The odds ratio (OR) for an improved disease severity score with CP was 0.86 (95%credible interval 0.59-1.22). The OR was 0.58 (95%confidence interval 0.33-1.02) for patients with ≤5 days of symptoms. The hazard ratio for hospital admission was 0.61 (95%confidence interval 0.28-1.34). No difference was found in viral RNA excretion nor in the duration of symptoms. CONCLUSIONS In patients with early COVID-19, CP did not improve the 5-point disease severity score. CLINICAL REGISTRY NUMBER NCT04589949.
PICO Summary
Population
High-risk outpatients with early COVID-19 (n= 416).
Intervention
Convalescent plasma (CP), (n= 207).
Comparison
Regular plasma (non-CP, n= 209).
Outcome
Patients had a median age of 60 years old, and symptoms for 5 days. During the 28 days of follow-up, 28 patients were hospitalized and two died. The odds ratio (OR) for an improved disease severity score with CP was 0.86 (95% credible interval: 0.59-1.22). The OR was 0.58 (95% confidence interval: 0.33-1.02) for patients with ≤5 days of symptoms. The hazard ratio for hospital admission was 0.61 (95% confidence interval: 0.28-1.34). No difference was found in viral RNA excretion nor in the duration of symptoms.
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COVID-19 Convalescent Plasma: from donation to treatment - A Systematic Review & Single Center Experience
Fabricius Michela M, Dandachi Dima
Mo Med. 2021;118(1):74-80
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.
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Clinical effectiveness of convalescent plasma in hospitalized patients with COVID-19: a systematic review and meta-analysis
Abeldaño Zuñiga, R. A., González-Villoria, R. A. M., Elizondo, M. V., Osorio, A. Y. N., Martínez, D. G., Coca, S. M.
Therapeutic Advances in Respiratory Disease. 2021;15:17534666211028077
Abstract
AIMS: Given the variability of previously reported results, this systematic review aims to determine the clinical effectiveness of convalescent plasma employed in the treatment of hospitalized patients diagnosed with COVID-19. METHODS We conducted a systematic review of controlled clinical trials assessing treatment with convalescent plasma for hospitalized patients diagnosed with SARS-CoV-2 infection. The outcomes were mortality, clinical improvement, and ventilation requirement. RESULTS A total of 51 studies were retrieved from the databases. Five articles were finally included in the data extraction and qualitative and quantitative synthesis of results. The overall risk of bias in the reviewed articles was established at low-risk only in two trials. The meta-analysis suggests that there is no benefit of convalescent plasma compared with standard care or placebo in reducing the overall mortality and the ventilation requirement. However, there could be a benefit for the clinical improvement in patients treated with plasma. CONCLUSION Current results led to assume that the convalescent plasma transfusion cannot reduce the mortality or ventilation requirement in hospitalized patients diagnosed with SARS-CoV-2 infection. More controlled clinical trials conducted with methodologies that ensure a low risk of bias are still needed.The reviews of this paper are available via the supplemental material section.
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Correlation of Automated Chemiluminescent Method with Enzyme-Linked Immunosorbent Assay (ELISA) Antibody Titers in Convalescent COVID-19 Plasma Samples: Development of Rapid, Cost-Effective Semi-Quantitative Diagnostic Methods
Mendoza, Rachelle Silver Michael Zuretti Alejandro R., Manan, Christian Das Ballabh Norin Allen J., Borgen, Patrick Libien Jenny Bluth Martin H.
Journal of Blood Medicine. 2021;12:157-164
Abstract
Background: We investigated the utility of an automated chemiluminescent SARS-CoV-2 IgG antibody assay platform in quantifying the amount of binding antibodies present in donated convalescent plasma Methods: A total of 179 convalescent plasma units were analyzed for the presence of SARS-CoV-2 IgG antibodies using the Beckman-Coulter chemiluminescent immunoassay (CLIA) platform The equipment-derived numerical values (S/Co ratio) were recorded Aliquots from the same units were subjected to enzyme-linked immunosorbent assay (ELISA) that detects IgG antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 S1 protein The relationship between ELISA titers and CLIA S/Co values was analyzed using linear regression and receiver operating characteristics (ROC) curve Results: Twenty-one samples (11 7%) had S/Co values of less than 1 0 and were deemed negative for antibodies and convalescent plasma had S/Co values between > 1 0 and 5 0 (70/179, 39 1%) Fifteen units (8 4%) had negative ELISA titer The majority of the units (95/179 53 1%) had titers ≥ 1:1024 The sensitivities of ELISA to CLIA were comparable (90 5% vs 88 3%, respectively;p=0 18) There was positive linear correlation between CLIA S/Co values and ELISA IgG titer (Rho = 0 75;Spearman’s rank = 0 82, p-value = < 0 0001) The agreement between the two methods was fair, with a κ index of 0 2741 Using the ROC analysis, we identified a CLIA S/Co cutoff value of 8 2, which gives a sensitivity of 90% and a specificity of 82% in predicting a titer dilution of ≥ 1:1024 Conclusion: The utility of automated antibody detection systems can be extended from simply a screening method to a semi-quantitative and quantitative functional antibody analysis CLIA S/Co values can be used to reliably estimate the ELISA antibody titer Incorporation of chemiluminescent-based methods can provide rapid, cost-effective means of identifying anti-SARS-CoV-2 antibody titers in donated plasma for use in the treatment of COVID-19 infection
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Immunomodulatory therapies for SARS-CoV-2 infection: a systematic literature review to inform EULAR points to consider
Alunno, A., Najm, A., Mariette, X., De Marco, G., Emmel, J., Mason, L., McGonagle, D. G., Machado, P. M.
Annals of the rheumatic diseases. 2021
Abstract
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.
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Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease
AlQahtani, M., Abdulrahman, A., Almadani, A., Alali, S. Y., Al Zamrooni, A. M., Hejab, A. H., Conroy, R. M., Wasif, P., Otoom, S., Atkin, S. L., et al
Scientific reports. 2021;11(1):9927
Abstract
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.
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Recovery of innate immune cells and persisting alterations in adaptive immunity in the peripheral blood of convalescent plasma donors at eight months post sars-cov-2 infection
Kostopoulos, I. V., Orologas-Stavrou, N., Rousakis, P., Panteli, C., Ntanasis-Stathopoulos, I., Charitaki, I., Korompoki, E., Gavriatopoulou, M., Kastritis, E., Trougakos, I. P., et al
Microorganisms. 2021;9(3):1-12
Abstract
Persisting alterations and unique immune signatures have been previously detected in the peripheral blood of convalescent plasma (CP) donors at approximately two months after initial SARS-CoV-2 infection This article presents the results on the sequential analysis of 47 CP donors at a median time of eight months (range 7 5–8 5 months) post infection, as assessed by flow cytometry Interestingly, our results show a significant variation of the relevant immune subset composition among CP donors Regarding innate immunity, both non-classical monocytes, and CD11b-granulocytes had fully recovered at eight months post COVID-19 infection Intermediate monocytes and natural killer (NK) cells had already been restored at the two-month evaluation and remained stable Regarding adaptive immunity, the COVID-19-related skewed Th1 and Th2 cell polarization remained at the same levels as in two months However, low levels of total B cells were detected even after eight months from infection A persisting reduction of CD8+ Tregs and changes in the NKT cell compartment were also remarkable CP donors present with a unique immune landscape at eight months post COVID-19 infection, which is characterized by the notable restoration of the components of innate immunity along with a persisting imprint of SARS-CoV-2 in cells of the adaptive immunity © 2021 by the authors Licensee MDPI, Basel, Switzerland
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The Effect of Convalescent Plasma Therapy on COVID-19 Patient Mortality: Systematic Review and Meta-analysis
Klassen, Stephen A., Senefeld, Jonathon W., Johnson, Patrick W., Carter, Rickey E., Wiggins, Chad C., Shoham, Shmuel Grossman Brenda J., Henderson, Jeffrey P., Musser, James Salazar Eric Hartman William R., Bouvier, Nicole M., Liu, Sean T. H., et al
Mayo Clinic Proceedings. 2021
Abstract
To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from 10 randomized clinical trials (RCT), 20 matched-control studies, two dose-response studies, and 96 case-reports or case-series Studies published between January 1, 2020 – January 16, 2021 were identified through a systematic search of online PubMed and MEDLINE databases Random-effects analyses of RCT and matched-control data demonstrated that COVID-19 patients transfused with convalescent plasma exhibited a lower mortality rate compared to 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 COVID-19 patients
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The Effect of Convalescent Plasma Therapy on Mortality Among Patients With COVID-19: Systematic Review and Meta-analysis
Klassen, S. A., Senefeld, J. W., Johnson, P. W., Carter, R. E., Wiggins, C. C., Shoham, S., Grossman, B. J., Henderson, J. P., Musser, J., Salazar, E., et al
Mayo Clinic proceedings. 2021;96(5):1262-1275
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Abstract
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.
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Impact of pathogen-reduction technologies on COVID-19 convalescent plasma potency
Focosi, D., Franchini, M.
Transfus. clin. biol. 2021
Abstract
Pathogen reduction technologies (PRT) have been recommended by many regulatory authorities to minimize the residual risk of transfusion-transmitted infections associated with COVID19 convalescent plasma. While its impact on safety and its cost-effectiveness are nowadays well proven, there is theoretical concern that PRT could impact efficacy of convalescent plasma by altering concentration and/or function of the neutralizing antibodies (nAb). We review here the evidence supporting a lack of significant detrimental effect from PRTs on nAbs.
