A randomized clinical trial evaluating the immunomodulatory effect of convalescent plasma on COVID-19-related cytokine storm

Pouladzadeh, Mandana; Safdarian, Mehdi; Eshghi, Peyman; Abolghasemi, Hassan; bavani, Alireza Ghorbani; Sheibani, Behnam; Choghakabodi, Parastoo Moradi; Feghhi, Abdolaziz; Boroujerdnia, Mehri Ghafourian; Forouzan, Arash; Far, Mohammad Ali Jalali; Kaydani, Gholam Abbas; Rajaei, Elham; Amin, Mansour; Torabizadeh, Mehdi; Yousefi, Farid; Hadaddezfuli, Reza

doi:10.1007/s11739-021-02734-8

Cited by 45 publications

(72 citation statements)

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“…After screening 52350 titles and abstracts and 1029 full texts, 47 unique randomised controlled trials that evaluated antiviral antibody or cellular treatments were identified as of 21 July 2021 (fig 1). 43444546474849505152535455565758596061626364656667686970717273747576777879808182838485868788 A table of excluded full texts is provided in the supplementary data on bmj.com. Searches of living evidence retrieval services identified 11 publications of eligible randomised trials, which were reconciled with our formal search strategy when necessary 222324254549566466676875838688.…”

Section: Resultsmentioning

confidence: 99%

Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis

Siemieniuk

Bartoszko

Martínez

et al. 2021

BMJ

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Objective To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19). Design Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data. Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021). Study selection Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate. Methods After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm. Results As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) −4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD −4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD −3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD −4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative. Conclusion In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit. Systematic review registration This review was not registered. The protocol established a priori is included as a data supplement. Funding This study was supported by the Canadian Institutes of Health Research (grant CIHR- IRSC:0579001321). Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Interim updates and additional study data will be posted on our website ( www.covid19lnma.com ).

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Section: Resultsmentioning

confidence: 99%

Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis

Siemieniuk

Bartoszko

Martínez

et al. 2021

BMJ

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“…40 41 Convalescent plasma and non-SARS-CoV-2 immunoglobulins Five RCTs (two at high and two at unclear RoB) were retrieved by the search update and one of them was underpowered. [42][43][44][45] None of the studies showed clear efficacy on mortality or other major clinical outcomes by adding convalescent plasma to SOC. One small RCT at high RoB on the use of non-SARS-CoV-2 immunoglobulins was also retrieved by the search update showed some benefit in reducing hospital or ICU stay.…”

Section: Type I Interferonsmentioning

confidence: 99%

Immunomodulatory therapies for the treatment of SARS-CoV-2 infection: an update of the systematic literature review to inform EULAR points to consider

et al. 2021

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ObjectiveTo update the EULAR 2020 systematic literature review (SLR) on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection.MethodsAs part of a EULAR taskforce, a systematic literature search update was conducted from 11 December 2020 to 14 July 2021. Two reviewers independently identified eligible studies and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage of disease. The risk of bias (RoB) was assessed with validated tools.ResultsOf the 26 959 records, 520 articles were eligible for inclusion. Studies were mainly at high or unclear RoB. New randomised controlled trials (RCTs) on tocilizumab clarified its benefit in patients with severe and critical COVID-19, mainly if associated with glucocorticoids. There are emergent data on the usefulness of baricitinib and tofacitinib in severe COVID-19. Other therapeutic strategies such as the use of convalescent plasma and anti-SARS-CoV-2 monoclonal antibodies showed efficacy in subjects not mounting normal anti-SARS-CoV-2 antibody responses.ConclusionThis new SLR confirms that some immunomodulators (tocilizumab and JAK inhibitors) have a role for treating severe and critical COVID-19. Although better evidence is available compared with the previous SLR, the need of RCT with combination therapy (glucocorticoids+anti-cytokines) versus monotherapy with glucocorticoids still remains alongside the need for standardisation of inclusion criteria and outcomes to ultimately improve the care and prognosis of affected people. This SLR informed the 2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19.

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“…Another study (24) showed that the mean levels of lymphocytes and IL-10 significantly increased whereas the levels of IL-6, TNF-α, and IFN-γ decreased (p < 0.05) in the CCP group when compared with controls. The lack of laboratory data and the difference cytokine level on baseline limited our discussion about the validity of CCP.…”

Section: Other Purposed Outcomementioning

confidence: 94%

“…We included 16 RCTs (involving the data of RECOVERY, CONCOR-1, and REMAP-CAP), enrolling a total of 16,296 participants in this meta-analysis, of whom 8,526 received CCP, 10 studies concentrated on the severe or critical patients (14,15,(19)(20)(21)(22)(23)(24)(25)(26). Agarwal et al (27) the population of interest of one study is moderate COVID-19 patients, and one study (28) conducted by Romina Libster focused on mildly ill-infected seniors.…”

Section: Study Inclusion and Characteristicsmentioning

confidence: 99%

The Effectiveness of Convalescent Plasma for the Treatment of Novel Corona Virus Disease 2019: A Systematic Review and Meta-Analysis

Cao

Chen

et al. 2021

Front. Med.

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Background: Coronavirus disease 2019 (COVID-19), sweeping across the world, has created a worldwide pandemic. Effective treatments of COVID-19 are extremely urgent.Objective: To analyze the efficacy and safety of convalescent plasma (CCP) on patients with COVID-19.Methods: All the relevant studies were searched from PubMed, EMBASE,Cochrane library, Scopus, Web of Science, CBM, CNKI, Wan fang, VIP, Medrxiv, Biorxiv, and SSRN on July 19, 2021. PICOS criteria were as follows: (P) the study interests were human subjects with the infection of COVID-19; (I) the intervention of interest was CCP; (C) comparator treatments contained placebo, sham therapy, and standard treatment; (O) the primary outcome was mortality rates by the novel coronavirus. The secondary outcomes included the incidence of serious adverse events, the rate of ICU admission and mechanical ventilation (MV); the length of hospital stay; the duration of MV and ICU stay; the antibody levels, inflammatory factor levels, and viral loads. (S) Only randomized controlled trials (RCTs) of CCP were included. Subanalysis, quality assessment, sensitive analysis, and publication bias were conducted by two reviewers independently.Results: Sixteen RCTs were included and enrolled a total of 16,296 participants in this meta-analysis. The pooled data showed that no significant difference was observed in reducing the rate of overall mortality between CCP treatment group and placebo group (OR 0.96; 95% CI 0.90 to 1.03; p = 0.30; I2 = 6%). According to the results of subgroup analysis, severe or critical patients with CCP showed significant difference in reducing the 28-day mortality of compared with placebo (OR 0.58, 95% CI 0.36 to 0.93, p = 0.02, I2 = 0%). CCP groups have a significantly shorter duration of MV compared with the control group (weighted MD −1.00, 95% CI −1.86 to −0.14 d p = 0.02, I2 = 0%). No significant difference was observed in the length of hospital stay, the duration of ICU, and the rate of ICU and MV. There is no conclusive evidence about the safety of CCP.Conclusion: Convalescent plasma can significantly reduce the 28-day mortality of severe or critical COVID-19 patients and the duration of MV. However, more evidence was needed to prove the safety of convalescent plasma.

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A randomized clinical trial evaluating the immunomodulatory effect of convalescent plasma on COVID-19-related cytokine storm

Cited by 45 publications

References 35 publications

Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis

Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis

Immunomodulatory therapies for the treatment of SARS-CoV-2 infection: an update of the systematic literature review to inform EULAR points to consider

The Effectiveness of Convalescent Plasma for the Treatment of Novel Corona Virus Disease 2019: A Systematic Review and Meta-Analysis

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