The efficacy and safety of convalescent plasma for COVID-19 patients: A meta-analysis based on double-blinded parallel-arm randomized placebo-controlled trials

The efficacy and safety of convalescent plasma for COVID-19 patients: A meta-analysis based on double-blinded parallel-arm randomized placebo-controlled trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The efficacy and safety of convalescent plasma for COVID-19 patients: A meta-analysis based on double-blinded parallel-arm randomized placebo-controlled trials Ranran Du, Jincheng Yang, Wenjing Yang, Peiyuan Liao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4741126/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Jan, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted 4 You are reading this latest preprint version Abstract Background Convalescent plasma (CP) was demonstrated promising benefit for clinical practice involved in efficacy and safety in previous corona virus pandemics, however, the efficacy of CP from COVID-19 sufferers are still controversial and unascertainable based on current randomized controlled trials (RCTs). The urgent needs for affirmative replies on the efficacy and safety of CP for COVID-19 patients must be developed as soon as possible. Objective To corroborate the efficacy and safety of CP based on high-quality double-blinded, parallel-arm placebo-control randomized clinical trials and provide evidence-based support for clinical application of CP against COVID-19. Methods Such medical electronic databases as Embase, PubMed, and Web of Science were retrieve d from inception to March 12, 2022. This meta-analysis synthesizes such dichotomous outcomes as the incidences of 28-day mortality, hospitalization rate, invasive mechanical ventilation, adverse events (AEs)and serious AEs using intention-to-treat (ITT) analysis. Statistical analysis, using Review Manager (RevMan) 5.4.1 software, Mantel-Haenszel (M-H) statistical method and random effects (RE) analysis model, risk ratios (RRs) plus their 95% confidence intervals (CIs) as effect measures, were performed. Two reviewers independently searched, screened, included the eligible clinical trials, extracted data of concern from the mand assessed the risks of bias (ROB) of the included articles with the Cochrane ROB tool 1.0 and Rev Man 5.4.1 software. The effect measures of RRs plus their 95% CIs in this meta-analysis will be computed as dichotomous outcomes of interest. Statistical heterogeneities, subgroup analysis and sensitivity analysis will be fulfilled to explore the heterogeneities and their causes. We evaluate the quality of evidence and put forward strength of recommendations for clinical practice based on the GRADE approach. This prospective meta-analysis protocol has been registered on PROSPERO. Results 697 references were preliminarily identified from the data bases of concern and manual retrieves , and 9 eligible double-blinded, parallel-arm, placebo-control randomized clinical trialswith 1898 subjects in the intervention group and 1696 participants in the control group were ultimately included in the meta-analysis. 7, 4, 3, 3 and 3 eligible trials are adjudged as low ROB for mortality, the rate of hospitalization, the incidence of invasive mechanical ventilation, AEs and serious AEs, respectively; all the rest of included trials are defined as high risk corresponding to the respective outcome. The meta-analysis on the hospitalization rate was abandoned because of high heterogeneity ( I 2 = 92%) among the inclusion trials. The RRs, 95%CIs and P -values were 0.78 [0.62, 0.97], P = 0.03 on mortality; 0.84 [0.50, 1.42], P = 0.51 on invasive mechanical ventilation; 1.01 [0.78, 1.32], P = 0.92 on AEs; 0.96 [0.73, 1.28], P = 0.80 on serious AEs, respectively, with low or medium levels of heterogeneity; which indicate that CP infusion in COVID-19 patients can efficaciously reduce mortality by 22%, and exhibit excellent safety and not decrease the incidence of invasive mechanical ventilation. Sensitivity analysis on mortality with the combining effect measure (RR 0.83 [0.66, 1.06], I 2 0%, Z-value 1.46, P = 0.14) after deleting the study by O’Donnell showed that there is not different between the intervention group and control group, hinting that the deleted study may be more efficacious for reducing mortality. Subgroup analysis on mortality based on age showed that CP therapy in COVID-19 patients aged ≤ 60 years old may more efficaciously reduce mortality by 36%. Sensitivity analyses and subgroup analyses on the other outcomes present robust pooling outcomes. The registration code on PROSPERO is CRD42022324324. Conclusions Administration of CP to COVID-19 patients, especially to COVID-19 patients aged ≤ 60 years old, may efficaciously reduce mortality with excellent safety, but does not reduce the incidence of invasive mechanical ventilation. Coronavirus disease 2019 (COVID-19) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CP) outcome efficacy safety adverse events (AEs) serious AEs meta-analysis Figures Figure 1 Figure 2 Introduction Coronavirus disease 2019 (COVID-19), caused by these very acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is one of seven known human-infected coronaviruses, was identified in Hubei province, China in December of 2019andcaused a pleomorphic spectrum of clinical presentations from asymptomatic infection to critical illness, life-threatening status and death 1 . COVID-19induced by multiple variants currently has dispersed to most parts of the world, triggered ahumancrisis and globally endangered public health and socioeconomic status. The typical clinical characteristics of COVID-19include such three domains as fever, dry cough, dyspnea, fatigue, myalgia, anosmia, and ageusia in symptoms and signs 2 , ground-glassopacityin posterior and peripheralareas of the bilateral lungs in computed tomography and lymphopenia, elevated inflammatory biomarkers, and D-dimers in laboratory parameter 3 . Although the action mechanisms of CP directed against COVID-19 are not comprehended yet, the potential therapeutic mechanisms may be simultaneously or/and separately touch upon the following profiles, intensified neutralizing antibodies from CP targeted against the membrane spike protein of SARS-Cov-2 should retard the attachment of the SARS-CoV-2 to angiotensin converting enzyme 2 receptors resided in host cell surface and block viral entry into the host cell 4 ,such the immunomodulatory mechanisms as disturbing complement activation, antibody-dependent cytotoxicity and phagocytosis associated with CP infusion may facilitate restricting the more deleterious inflammatory cascade than the virus itself 5 , the IgG of anti-A isoagglutinin lying in subjects with O-type blood would prevent the coupling of SARS-CoV-2 with its receptor and block the virus entry into the targeted cells 6 . CP infusion in previous coronavirus pandemics 7–10 , in early observational studies 11, 12 , RCTs 13–15 and Meta-Analysis 16, 17 demonstratedpromisingbenefit for clinical outcomes in patients with COVID-19; but the recent RCTs 3, 18 exhibited no favorable and satisfactory clinical efficacies. Up to now, there are still no favorable specific therapy options for COVID-19, some promising and encouraging therapeutic attempts to treat this disease are still on the road 3 .The CP from sufferers infected by SARS-CoV 10 and influenza virus 9 has long been successfully used and shown conclusive efficacious evidence for a few decades. However, the efficacy of CP from COVID-19 sufferers is still controversial and unascertainable based on current clinical trials with different efficacy in term of mortality either favorable efficacy from several studies 11–15 or unfavorable efficacy from the otherstudies 3, 18 . A hypothesis is that the intravenous infusion of CP with high titers of neutralizing antibodies would benefit improvement in clinical outcomes in COVID- 19 patients. The main goals of this meta-analysis are to evaluate the specific efficacy and safety of CP for COVID-19 patients based on randomized, double-blinded, placebo-controlled, parallel-arm clinical trials and provide evidence-based support for clinical practice. Methods This investigator-initiated systematic review and meta-analysis are implemented with a prospective protocol registration on PROSPERO ( https://www.crd.york.ac.uk/PROSPERO/#myprospero ) and as per the present methods as recommended in AMSTAR 2 19 , the PRISMA statement 20 , and Cochrane Collaboration recommendations 21 . Inclusion criteria The qualified papers will satisfy all the following requirements:①the published original randomized, double-blinded, placebo-controlled, parallel-arm clinical trials involved in the efficacy or safety of the CP therapy;②all included participants must meet the following requirements: aged 18 years or older, laboratory-confirmed COVID-19, with or without underlying diseases;③CP plus local standard care in the intervention group, placebo (normal saline (NS) or non-convalescent plasma) plus local standard care or merely local standard care in the control group; ④eligible studies at least included one of such outcomes of concern as the incidences of 28-day mortality, hospitalization, invasive mechanical ventilation, AEs and serious AEs. Exclusion criteria The papers with one of the following requirements, such as articles on non-RCT, crossover RCT, hyperimmune RCT, trial protocol, single-arm trial, observation trial, case report or cohort trial, review or meta-analysis, position paper, letter, editorial, comment, fingerpost or recommendation, erratum and correction, conference abstract, animal trial, and article unavailable full text, will be discarded. Retrieval, Screening, Data extraction We comprehensively searched such medical databases as PubMed, Embase and Web of Science using the following search strategy formulations: ((convalescent plasma) AND (((Covid-19) OR (Covid 19)) OR (SARS-CoV-2))) AND ((((trial) OR (trials)) AND ((control) OR (controlled))) AND ((randomised) OR (randomized)))to retrieve as accurate and complete studies of concern as possible up to March 12, 2022, abided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart 20 . We included all published original double-blinded, parallel-arm, placebo-controlled randomized, clinical trials on the efficacy and safety of CP infusion for COVID-19 patients limited to English. The two authors (LP and LX) must independently complete retrieval based on the above-mentioned search strategy, screening based-on inclusion and exclusion criteria, extracting data of interest, respectively; any divergences in results of retrieval, screening and data extraction must be settled by mutual negotiation. Risk of bias assessment The Cochrane ROB1.0 tool 22 , which includes such 7 domains of bias as (I) selection bias(random sequence generation), (II)selection bias (allocation concealment), (III) performance bias (blinding for participants and personnel), (IV) detection bias (blinding for outcome assessment), (V) attrition bias (incomplete outcome data), (VI) reporting bias (selective reporting), and (VII) other bias, will be used to evaluate the ROBs of included articles. Two authors (LP and TY) will independently assess the ROBs of all included eligible articles based on ROB 1.0 tool and draw ROB summary with RevMan 5.4.1 software, respectively. Any divergence will be disposed of by discussion with each other when necessary. Sensitivity analysis and subgroup analysis Sensitivity analysis is performed to both demonstrate robustness of conclusions and seek out the reasons for heterogeneity by successively eliminating one included study. If significant heterogeneity is definite( I 2 > 75%), possible sources of heterogeneity must be investigated via subgroup analysis or sensitivity analysis based on specific status. Statistical analysis Statistical analysis is performed using RevMan Version 5.4.1 software, M-H statistical method and RE analysis model to synthetize the eligible inclusion data and arrive at a total effect measure of RR and 95% CI on every outcome of concern. The heterogeneity test is quantitatively assessed using I 2 statistic (significant at P < 0.10). The levels of heterogeneity are defined as high, medium and low levels when I 2 values were 75–100%, 50–75% and 0–50%, respectively.RE analysis model will be applied if I 2 is < 75%. Otherwise, the narrative review must betaken into account. The cumulative effects of outcomes of concern are presented via forest plots, which can simultaneously show the effect parameters of RR and its 95% CIs for each included study. Publication bias is ratedusing visual qualitative funnel plot inspection if enough eligible studies are included. The quality of evidence and recommendation A recommendation on CP infusion in COVID-19 patients is made based on the guideline of GRADE 23 after the quality of evidence is adjudged as high, moderate, low or very low level according to the another guideline 24 . Role of the funding source There was not any financial support for the design, data retrieval and extraction, data synthesis, interpretation in ultimate results, and writing of original article associated with this meta-analysis. Each author has full access to the data associated with the meta-analysis and finally decides to publish it. Results The systematic review and meta-analysis on efficacy and safety of CP infusion in COVID-19 patients is registered at PROSPERO with the registration code of CRD42022324324. A total of 697 articles (173 in PubMed, 392 in Embase and 132 in Web of Science) were obtained via retrieval search in medical electronic databases of concern with the similar search strategy described above.197 and 54 articles were deleted for duplication in the fields of authors, headline, abstract and publish journal via EndNote or by hand, respectively. Subsequentially, the rest of 33 articles, following discarding 413 articles because of contradiction with inclusion criteria or accordance with exclusion criteria by inspecting the title and abstract, are assessed as preliminary eligibility. Finally, 9 articles 2, 14, 15, 18, 25–29 , after eliminating 24 articles with such specific removal causes as 21 open-label RCTs, 2 single-blinded RCTs and one prophylactic RCT by reading full-text, were included in this quantitative meta-analysis. All operation procedures follow the flow diagram of search and selection displayed in Fig. 1. Of 9 studies included in the quantitative synthesis (meta-analysis),a total of 3594 participants were randomized to the intervention group (n = 1898) using CP infusion plus local standard care and the control group (n = 1696) using either NS or non-convalescent plasma plus local standard care or merely local standard care. The ROB assessment for all included studies The ROB assessments were performed using RevMan5.4.1 software and ROB 1.0 tool for the included clinical trials. RevMan5.4.1 software was utilized to create ROB summary in each domain-level evaluation for each inclusion study. Of 9 eligible included studies,7 studies 2, 15, 18, 25, 26, 28, 29 on mortality, 3 studies 2, 26, 29 on invasive mechanical ventilation, 4 studies 2, 15, 26, 29 on hospitalization rate, 3 studies 15, 25, 26 on AEs and 3 studies 18, 26, 28 on serious AEs were judged as low ROB, and the study with at least one high risk or ≥ 3 unclear risks in all 7 domains were identified as high ROB. The results of overall ROB on all outcomes of concern are high risk presented in Supplemental Fig. 1(a-e). Although the qualitative funnel plot test for publication bias is low power when a meta-analysis includes ten or fewer studies or the more confounding factors amongst inclusion trials, the publication bias test on mortality in this meta-analysis using a visual qualitative funnel plot presents some what asymmetry at the bottom of the funnel plot, indicating it is possible that some RCTs with small sample size or negative outcomes were not published showed in Fig. 2 ; the publication bias test using funnel plot on the incidence of hospitalization, invasive mechanical ventilation, AEs and serious AEs in this meta-analysis were discarded owing to too few available studies. General characteristics and key information of the included studies The general characteristics and critical information of a total of 9 eligible studies included in this meta-analysis are presented in Table 1.9, 5, 4 and 5 studies are included in quantitative synthesis on mortality outcome 2, 14, 15, 18, 25–29 (137 deaths from1898 participants in the intervention group vs. 139 deaths from 1696 participants in the control group), invasive mechanical ventilation outcome 2, 14, 26, 27, 29 (36 sufferers from 1016 participants in the intervention group vs. 25 from 898 in the control group), AEs outcome 15, 25–27 (254 cases of 1358 participants in the intervention group vs. 175 of 1245 in the control group) and serious AEs outcome 14, 18, 26–28 (127 of 552 in the intervention group vs. 67 of 340 in the control group), respectively, and RE analysis model was applied owing to the medium or low levels of heterogeneity amongst included clinical trials. The hospitalization rate outcome including 4 studies 2, 15, 26, 29 (169 hospitalized cases from 1106participants in the intervention group vs. 130 from 989 in the control group) is dealt with via narrative analysis because of a high level of heterogeneity among inclusion studies. Primary and secondary outcomes Meta-analysis using quantitative synthesis on hospitalization rate is rejected because heterogeneity ( I 2 = 92%, P < 0.00001) amongst the included trials are significant. Heterogeneity tests on 28- day mortality, invasive mechanical ventilation, AEs and serious AEs amongst the included trials shown in Supplemental Fig. 2 (a-e) reveal homogeneity. 28-day mortality outcome presented in Supplemental Fig. 2a shows a significant statistical difference between the two groups (RR 0.78 [95% CI 0·62–0.97], I 2 0%, P = 0.03), which indicates that the CP infusion is effective for COVID-19 patients in reducing the 28-day mortality by approximately 22%. However, the incidences of invasive mechanical ventilation, AE and serious AE are no statistical significance between the intervention group and the control group, which indicate that CP infusion in COVID-19 patients is safe and does not decrease usage of invasive mechanical ventilation for COVID-19 patients. Table 1 general characteristics and key information of included clinical trials Author and year Alemany2022 Baldeón 2022 Bennett-Guerrero 2021 Libster2021 Ortigoza2022 O’Donnell 2021 Simonovich 2021 Sullivan 2021 van den Berg 2022 T-assess Day 28 Day 28 Day 28 Day 28 Day 28 Day 28 Day 30 Day 28 Day 28 Severity mild and moderate NA moderate to severe mild noninvasive oxygen supplementation severe and critical severe Mild moderate or severe moderate to severe Age(int) Median (IQR) 56 (52–62) mean (SD) 56.3 ± 12.7 mean (SD): 67 (15.8) mean (SD) 76.4 ± 8.7 Median (IQR) 62.0 (51.0–72.0) Median (IQR) 60 (48–71) Median (IQR) 62.5 (53–72.5) Median (IQR) 42 (31.5–54) Median (IQR) 54 (46–62) Age(con) Median (IQR) 56 (53–63) mean (SD) 55.0 ± 13.3 mean (SD) 64 (17.4) mean (SD) 77.9 ± 8.4 Median (IQR) 64.0 (54.0–74.0) Median (IQR) 63 (49–72) Median (IQR) 62 (49–71) Median (IQR) 44 (33–55) Median (IQR) 57 (47–64) Nitt(int) 188 63 59 80 468 150 228 610 52 Nitt(con) 188 95 15 80 473 73 106 615 51 Nmitt(int) 188 63 58 76 462 147 228 592 47 Nmitt(con) 188 95 14 78 462 72 105 589 50 M/F(int) 105/83 42/21 36/23 26/54 284/184 96/54 161/67 269/323(Mitt) 21/31 M/F(con) 98/90 65/30 8/7 34/46 272/201 51/22 64/41 237/352(Mitt) 21/30 T-int-symptoms ≤ 7d NA Median (IQR): 9 ( 6 – 18 ) ≤ 3d Median (IQR) 7( 4 – 9 ) Median: 9d Median (IQR) 8 ( 5 – 10 ) ≤ 8d Median (IQR): 9 ( 6 – 11 ) T-con-symptoms ≤ 7d NA Median (IQR): 9 ( 6 – 15 ) ≤ 3d 7( 4 – 9 ) Median: 9d Median (IQR) 8 ( 5 – 10 ) ≤ 8d Median (IQR): 9 ( 6 – 11 ) Pr-PLB (ml) NS 250ml or 5 ml/kg Non-convalescent pasma 5 ml/kg Standard plasma 480ml NS 250 NS 250ml control plasma 200-250ml NS500 Standard plasma ≥ 175 NS 200 Pr-CP (ml) 250–300ml or 5 ml/kg 5 ml/kg 480ml 250ml 250ml CP 200-250ml Median (IQR) 500(415–600) ≥ 175ml 200–250ml Death toll(int) 0 7 14 2 59 19 25 0 11 Death toll(con) 2 12 4 4 71 18 12 3 13 N in-venti(int) 2 NA NA 2 NA 12 19 NA 1 N in-venti(con) 4 NA NA 4 NA 4 10 NA 3 N int- hosp 22 NA NA 7 NA NA 123 17 NA Ncon- hosp 21 NA NA 12 NA NA 63 37 NA N AE (int) NA NA NA NA 44 NA 153 34 23 N AE (con) NA NA NA NA 39 NA 66 53 17 N SAE (int) NA 0 16 NA NA 39 54 NA 18 N SAE (con) NA 0 4 NA NA 26 19 NA 18 Abbreviations: T-assess = Time at assessing outcome; Age (int) = age in intervention group; Age (con) = age in control group; IQR = interquartile range; SD = standard deviation; Niit(int) = the number of intention-to-treat participants in intervention group; Niit(con) = the number of intention-to-treat participants in control group; Nmiit(int) = the number of modified intention-to-treat participants in intervention group; Nmiit(con) = the number of modified intention-to-treat participants in control group; M/F(int) = male/female in intervention group; M/F(con) = male/female in control group; T-int-symptoms = intervention timing after the onset of symptoms in intervention group; T-con-symptoms = intervention timing after the onset of symptoms in control group; Pr-PBO = Prescription of placebo in control group; Pr-CP = Prescription of convalescent plasma in intervention group; NS = normal saline; int = intervention group; con = control group; ml = milliliters; kg = kilogram; N in-venti(int) = the number of cases using invasive mechanic ventilation in intervention group; N in-venti(con) = the number of cases using invasive mechanic ventilation in control group; N int-hosp = the number of hospitalized cases in intervention group; N con-hosp = the number of hospitalized cases in control group; N AE (int) = the number of cases with any adverse events in intervention group; N AE (con) = the number of cases with any adverse events in control group; N SAE (int) = the number of cases with serious adverse events in intervention group; N SAE (con) = the number of cases with serious adverse events in control group; NA = not available. Sensitivity analysis Sensitivity analyses are performed for all outcomes of interest and their information is presented in Table 2 . From sensitivity analyses on hospitalization rate, the striking heterogeneities showed in Table 2 Cmay indicate more confounders or baseline imbalance amongst inclusion trials and make quantitative synthesis on this outcome be abandoned. After deleting the study by O’Donnell, the combining effect measure on mortality (RR 0.83 [0.66, 1.06], I 2 0%, Z-value 1.46, P = 0.14) is different from the total effect measure in advance of deleting the study, hinting that the deleted study may be more efficacious in reducing mortality or exist additional confounders(e.g.: severe or critical illness); this marked impact on the total effect may require more identical clinical trials to check this effect and explore confounders of concern. Sensitivity analyses on invasive mechanical ventilation, any AEs, and serious AEs presented in Table 2 B, 2 D, 2Eshow that all statistical results are not altered after deleting any trial, which corroborate that the results are robust accompanying with the low to medium levels of heterogeneity amongst inclusion trials. Subgroup analysis Subgroup analyses are performed based on age ≤ 60 years old or > 60 years old. The subgroup analysis on mortality presented in Supplemental Fig. 3a indicates that CP infusion develops more beneficial reduction in mortality by 36% than that in the control group in ≤ 60 years old subgroup. The incidences of hospitalization and invasive mechanical ventilation remain their robustness whether ≤ 60 years old or > 60 years old subgroup, indicating that CP infusion does not reduce the rates of hospitalization and invasive mechanical ventilation no matter ≤ 60 years old or > 60 years old subgroup observed in Supplemental Fig. 3b and 3c CP infusion develops similar AEs compared with placebo regardless of ≤ 60 years old or > 60 years old subgroup; although CP infusion can cause fewer serious AEs compared with control group in ≤ 60 years old subgroup than that in > 60 years old subgroup recorded in Supplemental Fig. 3d and 3e, there is no statistical difference in the incidence of serious AEs between the intervention group and the control groups whether ≤ 60 years old or > 60 years old subgroup, which indicates that CP infusion possesses such remarkable safety. Table 2 Sensitivity analysis Deleted article RR and 95%CI I 2 (%) Z-value P -value A: 28-day mortality and overall effect RR (0.78 [0.62, 0.97], I 2 = 0%, Z = 2.22, P = 0.03 Alemany 2022 0.78 [0.63, 0.98] 0 2.14 0.03 Baldeón 2022 0.77 [0.61, 0.97] 0 2.22 0.03 Bennett-Guerrero 2021 0.77 [0.61, 0.97] 0 2.22 0.03 Libster 2021 0.78 [0.63, 0.98] 0 2.13 0.03 Ortigoza 2022 0.72 [0.53, 0.99] 0 2.05 0.04 O’Donnell 2021 0.83 [0.66, 1.06] 0 1.46 0.14 Simonovich 2021 0.75 [0.59, 0.96] 0 2.32 0.02 Sullivan 2021 0.78 [0.63, 0.98] 0 2.13 0.03 Van den Berg 2022 0.77 [0.61, 0.98] 0 2.16 0.03 B: Invasive mechanical ventilation and effect RR (0.84[0.50, 1.42], I 2 = 0%, Z = 0.65, P = 0.51 Alemany 2022 0.89 [0.51, 1.54] 0 0.42 0.67 Libster 2021 0.89 [0.51, 1.55] 0 0.42 0.67 O’Donnell 2021 0.71 [0.39, 1.29] 0 1.12 0.26 Simonovich 2021 0.79[0.37, 1.69] 0 0.60 0.55 Van den Berg 2022 0.89[0.52, 1.52] 0 0.44 0.66 C: Hospitalization rate and overall effect RR (1.11 [0.33, 3.67], I 2 = 92%, Z = 0.16, P = 0.87 Alemany 2022 1.09 [0.17, 6.84] 94 0.09 0.93 Libster 2021 1.32[0.34, 5.18] 94 0.40 0.69 Simonovich 2021 0.67 [0.35, 1.26] 52 1.24 0.22 Sullivan 2021 1.55 [0.24, 5.76] 89 0.66 0.51 D: Any AEs and overall effect RR (1.01 [0.78, 1.32], I 2 = 55%, Z = 0.10, P = 0.92 Ortigoza 2022 0.98 [0.67, 1.42] 70 0.13 0.90 Simonovich 2021 0.98 [0.64, 1.52] 66 0.08 0.93 Sullivan 2021 1.11 [0.95, 1.29] 0 1.32 0.19 Van den Berg 2022 0.95[0.69, 1.31] 65 0.31 0.76 E: Serious AEs and overall effect RR (0.96 [0.73, 1.28], I 2 = 16%, Z = 0.25, P = 0.80 Baldeón 2022 0.96 [0.73, 1.28] 16 0.25 0.80 Bennett-Guerrero 2021 0.97 [0.68, 1.38] 44 0.18 0.85 O’Donnell 2021 1.14 [0.82, 1.58] 0 0.78 0.43 Simonovich 2021 0.84 [0.62, 1.13] 0 1.15 0.25 Van den Berg 2022 0.97 [0.64, 1.48] 44 0.13 0.90 Quality of evidence and strength of recommendation The quality of evidence on the CP infusion in COVID-19 patients is high level. Based on current information, a strong recommendation of CP infusion is made for patients with COVID-19 if necessary, especially for COVID-19 patients with ≤ 60 years old. Discussion As far as we know, this meta-analysis is the most all-round systematic review and meta-analysis, based on double-blind, parallel-arm, placebo-control, randomized clinical trials, top robe the efficacy and safety of CP infusion in patients with COVID-19. Because current SARS-CoV-2 with high infectivity has been endangering global healthcare all over the world since the late of 2019, a specific drug targeted to COVID-19 is not available yet. CP, as an alternative passive immunotherapy option, once has been recommended to apply for multiple infectious diseases for more than one hundred years. Multiple study results displayed that CP infusion could significantly decrease the mortality caused by SARS virus 10 , MERS-CoV 8 , influenza virus 9 infection. However, due to the low certainty of evidence on the beneficial effects of CP infusion in COVID-19 patients, the present meta-analysis is performed to confirm its efficacy and safety for future clinical practice. This meta-analysis identified and summarize dup to 9randomized, double-blind, parallel-arm, placebo-controlled, clinical trials. This meta-analysis based on data recorded above shows that CP infusion could significantly lower the mortality, and that the similar results on mortality mentioned above are consistent with the results from RCT 14 and meta-analysis based on RCTs 30, 31 ; but, some RCTs 2, 15, 18, 25–29 did not support this conclusion. Therefore, Although the conclusion is still controversial, the available evidence from this meta-analysis may provide a basis for an option of CP application for COVID-19 treatment until now. Secondary mortality caused by SARS-CoV-2 infection was reduced by CP transfusion, which might be attributable to such multiple complex known or unknown mechanisms of action as restraining complement activation, antagonizing cytokine effects, and down-regulating B- and T-cells functions 5 ,and such other action mechanisms as controlling the attachment of the SARS-CoV-2 to angiotensin converting enzyme 2 receptors by strengthening neutralizing antibodies against the membrane spike protein of SARS-Cov-2 4 and the coupling of SARS-CoV-2 with its receptor by the IgG of anti-A isoagglutinin in O-type blood subjects 6 . Concrete and authentic mechanisms of action which are unclear yet need to be explored using more clinical trials and fundamental research on COVID-19. Sensitivity analysis on mortality after deleting O’Donnell 14 showed that there are significantly different effects before and after deleting O’Donnell, which indicated that CP infusion might make more severe or critical COVID-19 patients keep from death in the deleted study. And subgroup analysis on mortality based on age ≤ 60 years old or > 60 years old showed that CP therapy for patients in ≤ 60 years old subgroup might be more efficacious than that in > 60 years old subgroup, which hinted that onset age might be one of the commonest confounding factors which led to significant heterogeneities, which suggested that CP infusion might be an extremely good alternative option to reduce mortality for COVID-19 patients, the more so as COVID-19 patients are ≤ 60 years old if other efficacious therapeutics aren’t acquired. Owing to the significant heterogeneities among included trials in terms of synthetizing hospitalization rate, which might be attributable to the difference in severity, sample size, age and so on. The outcome on hospitalization rate derived from the inclusion studies cannot be synthetized because of the significant heterogeneities. It is uncertain whether CP infusion can reduce the hospitalization rate or not, which must be verified by performing more homogenous and high-quality randomized controlled trials. CP infusion cannot efficaciously reduce the utilization of invasive mechanic ventilation yet, which is consistent with the studies 2, 27, 29 , sensitivity and subgroup analyses on the utilization of invasive mechanic ventilation exhibit this effect is robust and CP infusion did not make COVID-19 patients benefit from in terms of reduction in invasive mechanic ventilation, some inferred causes might be inappropriate timing and doses of administration. Based on current limited safety data deriving from this meta-analysis,t here are similar and no significant statistical differences in no matter general AEs or serious AEs in both groups, and that most of AEs are mild or moderate. Subgroup analysis displays CP infusion compared with placebo may develop fewer serious AEs in ≤ 60 years old subgroup than those in > 60 years old subgroup and but there are no statistical differences. This meta-analysis authenticates CP infusion may be more safe and well-tolerated for COVID-19 patients, especially for patients aged less than 60 years old. The participants in this meta-analysis merely involved in adults with or without underlying diseases and did not include children and pregnant women with COVID-19. The efficacy and safety data of CP infusion for such special COVID-19 populations as children and pregnant women are lacking, CP infusion may be an optional therapy for children and pregnant women according to the principle of extrapolation, if the COVID-19 illness cannot be held back. Strength and limitation Our ongoing study has several strengths and limitations. Primero Firstly, the main strength is that this meta-analysis deriving from high-quality randomized, double-blinded, placebo-control parallel-arm clinical trials is fewer biases and more high-quality; secondly, CP infusion can efficaciously and reasonably cut down the mortality outcome for COVID-19 patients, especial for COVID-19 patients with ≤ 60 years old. On limitations, this meta-analysis merely includes fewer eligible clinical trials and did not touch upon the optimal timing of infusion, titers and dosage of CP and the duration of administration, which can affect the efficacy and safety of CP transfusion. So, the optimal timing of infusion, dosage, titer of CP and duration of the administration still require more high-quality clinical trials to provide support. Conclusions CP therapy for patients with COVID-19, especially for COVID-19 patients aged less than 60 years old, might be more efficacious in reducing mortality outcome and safer. CP infusion is strongly recommended in order to reduce the mortality in patients with COVID-19 if necessary, especially for COVID-19 patients with ≤ 60 years old, based on high quality of evidence. Declarations Ethics approval and written informed consent from participates Not applicable because this meta-analysis belongs to secondary study. Consent for publication All authors had full access to all the data associated with this meta-analysis and had the final decision to publish it. Availability of data and material Not applicable Competing interests All authors declare that this study was performed without any financial relationships which might lead to a possible conflict of interest. Funding CAMS Innovation Fund for Medical Sciences（CIFMS）2021-I2M-1-001 Authors' contributions LP, YJ and YW designed and alternately reviewed this study and interpreted this data. LP and DR searched, screened, and extracted the related data. LP and YW evaluated ROB. LP wrote the manuscript, interactively revised manuscript with DR and YJ. LP, YW and DR have read and approved the final manuscript to be published. Acknowledgements This meta-analysis is investigator-initiated secondary study without any financial support. References Rajapakse N, Dixit D. Human and novel coronavirus infections in children: a review. Paediatrics Int Child Health. 2021;41(1):36–55. Alemany A, Millat-Martinez P, Corbacho-Monné M, et al. High-titre methylene blue-treated convalescent plasma as an early treatment for outpatients with COVID-19: a randomised, placebo-controlled trial. Lancet Respir Med Mar. 2022;10(3):278–88. De Santis GC, Oliveira LC, Garibaldi PMM, et al. High-Dose Convalescent Plasma for Treatment of Severe COVID-19. Emerg Infect Dis. 2022;28(3):548–55. Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol Apr. 2020;92(4):418–23. Franchini M, Liumbruno GM. Convalescent Plasma for the Treatment of Severe COVID-19. Biologics. 2021;15:31–8. Franchini M, Glingani C, Del Fante C, et al. The protective effect of O blood type against SARS-CoV-2 infection. Vox Sang Feb. 2021;116(2):249–50. Soo YO, Cheng Y, Wong R, et al. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect Jul. 2004;10(7):676–8. Ko JH, Seok H, Cho SY, et al. Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience. AntivirTher. 2018;23(7):617–22. Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med Oct. 2006;17(8):599–609. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis Jan. 2015;1(1):80–90. Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci. 2020;117(17):9490–6. Zeng Q-L, Yu Z-J, Gou J-J, et al. Effect of Convalescent Plasma Therapy on Viral Shedding and Survival in Patients With Coronavirus Disease 2019. J Infect Dis. 2020;222(1):38–43. Bar KJ, Shaw PA, Choi GH et al. A randomized controlled study of convalescent plasma for individuals hospitalized with COVID-19 pneumonia. J Clin Invest Dec 15 2021;131(24). O'Donnell MR, Grinsztejn B, Cummings MJ et al. A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19. J Clin Invest Jul 1 2021;131(13). Sullivan DJ, Gebo KA, Shoham S et al. Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma. medRxiv. Dec 21. 2021. Barreira DF, Lourenço RA, Calisto R, Moreira-Gonçalves D, Santos LL, Videira PA. Assessment of the Safety and Therapeutic Benefits of Convalescent Plasma in COVID-19 Treatment: A Systematic Review and Meta-Analysis. Front Med (Lausanne). 2021;8:660688. Bansal V, Mahapure KS, Mehra I, et al. Mortality Benefit of Convalescent Plasma in COVID-19: A Systematic Review and Meta-Analysis. Front Med (Lausanne). 2021;8:624924. Bennett-Guerrero E, Romeiser JL, Talbot LR, et al. Severe Acute Respiratory Syndrome Coronavirus 2 Convalescent Plasma Versus Standard Plasma in Coronavirus Disease 2019 Infected Hospitalized Patients in New York: A Double-Blind Randomized Trial. Crit Care Med Jul. 2021;1(7):1015–25. Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. Bmj Sep. 2017;21:358:j4008. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med Jul. 2009;21(7):e1000097. Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev Oct. 2019;3:10:Ed000142. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. Bmj Aug. 2019;28:366:l4898. Brożek JL, Akl EA, Compalati E, et al. Grading quality of evidence and strength of recommendations in clinical practice guidelines part 3 of 3. The GRADE approach to developing recommendations. Allergy May. 2011;66(5):588–95. Brozek JL, Akl EA, Alonso-Coello P, et al. Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 1 of 3. An overview of the GRADE approach and grading quality of evidence about interventions. Allergy May. 2009;64(5):669–77. Ortigoza MB, Yoon H, Goldfeld KS, et al. Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial. JAMA Intern Med. 2022;182(2):115–26. Simonovich VA, Pratx LDB, Sabana P, et al. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med Feb. 2021;384(7):619–29. van den Berg K, Glatt TN, Vermeulen M, et al. Convalescent plasma in the treatment of moderate to severe COVID-19 pneumonia: a randomized controlled trial (PROTECT-Patient Trial). Sci Rep Feb. 2022;15(1):2552. Baldeón ME, Maldonado A, Ochoa-Andrade M et al. Effect of convalescent plasma as complementary treatment in patients with moderate COVID-19 infection. Transfus Med Jan 9 2022. Libster R, Marc GP, Wappner D, et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med. 2021;384(7):610–8. Sarkar S, Khanna P, Singh AK. Convalescent Plasma-A Light at the End of the Tunnel: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Indian J Crit Care Med Nov. 2021;25(11):1292–300. Sarkar S, Soni KD, Khanna P. Convalescent plasma is a clutch at straws in COVID-19 management! A systematic review and meta-analysis. J Med Virol Feb. 2021;93(2):1111–8. Additional Declarations No competing interests reported. Supplementary Files 411suppfig.docx Cite Share Download PDF Status: Published Journal Publication published 26 Jan, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 19 Jul, 2024 Editor assigned by journal 19 Jul, 2024 Submission checks completed at journal 19 Jul, 2024 First submitted to journal 15 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4741126","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":329092854,"identity":"6ff9f334-c33c-4029-9034-6860640dd863","order_by":0,"name":"Ranran Du","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Ranran","middleName":"","lastName":"Du","suffix":""},{"id":329092855,"identity":"024e718a-0dca-4019-af02-92117e6a4a43","order_by":1,"name":"Jincheng Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYBACgwNAQoLBhoGNVC1pJGiRbABTh0lwGD/72cMvLGrOy/OxH3668QeDnTwD+9kDeLWw8eSlWUgcu23YxpNmdpuHIdmwgScvAb8WhhwzA8mG2wlsEgxmtxkYmBMYJHgM8GvhfwPScg6ohf3bzR8M9URokcgxfiDZcACohcfsBg/DYWK0vDFjkDiWDPRLTtltHoPjIAYhh+UYf5aosZOXbz++7eaPimp5fvYz+LWAdElLwNkGDETFKfPHD0SoGgWjYBSMghEMAH6MOQPdkv7gAAAAAElFTkSuQmCC","orcid":"","institution":"National Cancer Center, National Clinical Research Center for Cancer, Chinese Academy of Medical Sciences, Peking Union Medical College","correspondingAuthor":true,"prefix":"","firstName":"Jincheng","middleName":"","lastName":"Yang","suffix":""},{"id":329092858,"identity":"cc2bc29b-2883-4c24-9fa3-bc4fc81d7eeb","order_by":2,"name":"Wenjing Yang","email":"","orcid":"","institution":"National Cancer Center, National Clinical Research Center for Cancer, Chinese Academy of Medical Sciences, Peking Union Medical 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1","display":"","copyAsset":false,"role":"figure","size":44774,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy flow diagram of search and selection\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4741126/v1/ffdf699fff6d18a900f80442.jpg"},{"id":62661060,"identity":"a2b866fd-9cf0-42eb-a169-2d3fee2cf50f","added_by":"auto","created_at":"2024-08-17 02:38:09","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":22371,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plot on 28-day mortality\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4741126/v1/97fc956dcbf93d7e97d7b4c0.jpg"},{"id":101690584,"identity":"56642e02-38e1-457b-a443-92f6c376c91b","added_by":"auto","created_at":"2026-02-02 16:06:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1224518,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4741126/v1/f4627680-ddfe-4341-a334-ec3a8b3e9e10.pdf"},{"id":62661063,"identity":"82308e3e-f123-4abb-bf1b-4de960823ea4","added_by":"auto","created_at":"2024-08-17 02:38:10","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":14481716,"visible":true,"origin":"","legend":"","description":"","filename":"411suppfig.docx","url":"https://assets-eu.researchsquare.com/files/rs-4741126/v1/587363f612840b8aefc39de9.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The efficacy and safety of convalescent plasma for COVID-19 patients: A meta-analysis based on double-blinded parallel-arm randomized placebo-controlled trials","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCoronavirus disease 2019 (COVID-19), caused by these very acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is one of seven known human-infected coronaviruses, was identified in Hubei province, China in December of 2019andcaused a pleomorphic spectrum of clinical presentations from asymptomatic infection to critical illness, life-threatening status and death\u003csup\u003e1\u003c/sup\u003e. COVID-19induced by multiple variants currently has dispersed to most parts of the world, triggered ahumancrisis and globally endangered public health and socioeconomic status. The typical clinical characteristics of COVID-19include such three domains as fever, dry cough, dyspnea, fatigue, myalgia, anosmia, and ageusia in symptoms and signs \u003csup\u003e2\u003c/sup\u003e, ground-glassopacityin posterior and peripheralareas of the bilateral lungs in computed tomography and lymphopenia, elevated inflammatory biomarkers, and D-dimers in laboratory parameter\u003csup\u003e3\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAlthough the action mechanisms of CP directed against COVID-19 are not comprehended yet, the potential therapeutic mechanisms may be simultaneously or/and separately touch upon the following profiles, intensified neutralizing antibodies from CP targeted against the membrane spike protein of SARS-Cov-2 should retard the attachment of the SARS-CoV-2 to angiotensin converting enzyme 2 receptors resided in host cell surface and block viral entry into the host cell\u003csup\u003e4\u003c/sup\u003e,such the immunomodulatory mechanisms as disturbing complement activation, antibody-dependent cytotoxicity and phagocytosis associated with CP infusion may facilitate restricting the more deleterious inflammatory cascade than the virus itself\u003csup\u003e5\u003c/sup\u003e, the IgG of anti-A isoagglutinin lying in subjects with O-type blood would prevent the coupling of SARS-CoV-2 with its receptor and block the virus entry into the targeted cells\u003csup\u003e6\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCP infusion in previous coronavirus pandemics\u003csup\u003e7\u0026ndash;10\u003c/sup\u003e, in early observational studies\u003csup\u003e11, 12\u003c/sup\u003e, RCTs\u003csup\u003e13\u0026ndash;15\u003c/sup\u003e and Meta-Analysis\u003csup\u003e16, 17\u003c/sup\u003edemonstratedpromisingbenefit for clinical outcomes in patients with COVID-19; but the recent RCTs\u003csup\u003e3, 18\u003c/sup\u003eexhibited no favorable and satisfactory clinical efficacies. Up to now, there are still no favorable specific therapy options for COVID-19, some promising and encouraging therapeutic attempts to treat this disease are still on the road\u003csup\u003e3\u003c/sup\u003e.The CP from sufferers infected by SARS-CoV\u003csup\u003e10\u003c/sup\u003e and influenza virus\u003csup\u003e9\u003c/sup\u003ehas long been successfully used and shown conclusive efficacious evidence for a few decades. However, the efficacy of CP from COVID-19 sufferers is still controversial and unascertainable based on current clinical trials with different efficacy in term of mortality either favorable efficacy from several studies\u003csup\u003e11\u0026ndash;15\u003c/sup\u003eor unfavorable efficacy from the otherstudies\u003csup\u003e3, 18\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA hypothesis is that the intravenous infusion of CP with high titers of neutralizing antibodies would benefit improvement in clinical outcomes in COVID- 19 patients. The main goals of this meta-analysis are to evaluate the specific efficacy and safety of CP for COVID-19 patients based on randomized, double-blinded, placebo-controlled, parallel-arm clinical trials and provide evidence-based support for clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis investigator-initiated systematic review and meta-analysis are implemented with a prospective protocol registration on PROSPERO (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/PROSPERO/#myprospero\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/PROSPERO/#myprospero\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and as per the present methods as recommended in AMSTAR 2\u003csup\u003e19\u003c/sup\u003e, the PRISMA statement\u003csup\u003e20\u003c/sup\u003e, and Cochrane Collaboration recommendations\u003csup\u003e21\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eInclusion criteria\u003c/h2\u003e \u003cp\u003eThe qualified papers will satisfy all the following requirements:①the published original randomized, double-blinded, placebo-controlled, parallel-arm clinical trials involved in the efficacy or safety of the CP therapy;②all included participants must meet the following requirements: aged 18 years or older, laboratory-confirmed COVID-19, with or without underlying diseases;③CP plus local standard care in the intervention group, placebo (normal saline (NS) or non-convalescent plasma) plus local standard care or merely local standard care in the control group; ④eligible studies at least included one of such outcomes of concern as the incidences of 28-day mortality, hospitalization, invasive mechanical ventilation, AEs and serious AEs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eExclusion criteria\u003c/h2\u003e \u003cp\u003eThe papers with one of the following requirements, such as articles on non-RCT, crossover RCT, hyperimmune RCT, trial protocol, single-arm trial, observation trial, case report or cohort trial, review or meta-analysis, position paper, letter, editorial, comment, fingerpost or recommendation, erratum and correction, conference abstract, animal trial, and article unavailable full text, will be discarded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eRetrieval, Screening, Data extraction\u003c/h2\u003e \u003cp\u003eWe comprehensively searched such medical databases as PubMed, Embase and Web of Science using the following search strategy formulations: ((convalescent plasma) AND (((Covid-19) OR (Covid 19)) OR (SARS-CoV-2))) AND ((((trial) OR (trials)) AND ((control) OR (controlled))) AND ((randomised) OR (randomized)))to retrieve as accurate and complete studies of concern as possible up to March 12, 2022, abided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart\u003csup\u003e20\u003c/sup\u003e. We included all published original double-blinded, parallel-arm, placebo-controlled randomized, clinical trials on the efficacy and safety of CP infusion for COVID-19 patients limited to English. The two authors (LP and LX) must independently complete retrieval based on the above-mentioned search strategy, screening based-on inclusion and exclusion criteria, extracting data of interest, respectively; any divergences in results of retrieval, screening and data extraction must be settled by mutual negotiation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias assessment\u003c/h2\u003e \u003cp\u003eThe Cochrane ROB1.0 tool\u003csup\u003e22\u003c/sup\u003e, which includes such 7 domains of bias as (I) selection bias(random sequence generation), (II)selection bias (allocation concealment), (III) performance bias (blinding for participants and personnel), (IV) detection bias (blinding for outcome assessment), (V) attrition bias (incomplete outcome data), (VI) reporting bias (selective reporting), and (VII) other bias, will be used to evaluate the ROBs of included articles. Two authors (LP and TY) will independently assess the ROBs of all included eligible articles based on ROB 1.0 tool and draw ROB summary with RevMan 5.4.1 software, respectively. Any divergence will be disposed of by discussion with each other when necessary.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis and subgroup analysis\u003c/h2\u003e \u003cp\u003eSensitivity analysis is performed to both demonstrate robustness of conclusions and seek out the reasons for heterogeneity by successively eliminating one included study. If significant heterogeneity is definite(\u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;75%), possible sources of heterogeneity must be investigated via subgroup analysis or sensitivity analysis based on specific status.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis is performed using RevMan Version 5.4.1 software, M-H statistical method and RE analysis model to synthetize the eligible inclusion data and arrive at a total effect measure of RR and 95% CI on every outcome of concern. The heterogeneity test is quantitatively assessed using \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e statistic (significant at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.10). The levels of heterogeneity are defined as high, medium and low levels when \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003evalues were 75\u0026ndash;100%, 50\u0026ndash;75% and 0\u0026ndash;50%, respectively.RE analysis model will be applied if \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e is \u0026lt;\u0026thinsp;75%. Otherwise, the narrative review must betaken into account. The cumulative effects of outcomes of concern are presented via forest plots, which can simultaneously show the effect parameters of RR and its 95% CIs for each included study. Publication bias is ratedusing visual qualitative funnel plot inspection if enough eligible studies are included.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eThe quality of evidence and recommendation\u003c/h2\u003e \u003cp\u003eA recommendation on CP infusion in COVID-19 patients is made based on the guideline of GRADE\u003csup\u003e23\u003c/sup\u003eafter the quality of evidence is adjudged as high, moderate, low or very low level according to the another guideline\u003csup\u003e24\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eRole of the funding source\u003c/h2\u003e \u003cp\u003eThere was not any financial support for the design, data retrieval and extraction, data synthesis, interpretation in ultimate results, and writing of original article associated with this meta-analysis. Each author has full access to the data associated with the meta-analysis and finally decides to publish it.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe systematic review and meta-analysis on efficacy and safety of CP infusion in COVID-19 patients is registered at PROSPERO with the registration code of CRD42022324324.\u003c/p\u003e\n\u003cp\u003eA total of 697 articles (173 in PubMed, 392 in Embase and 132 in Web of Science) were obtained via retrieval search in medical electronic databases of concern with the similar search strategy described above.197 and 54 articles were deleted for duplication in the fields of authors, headline, abstract and publish journal via EndNote or by hand, respectively. Subsequentially, the rest of 33 articles, following discarding 413 articles because of contradiction with inclusion criteria or accordance with exclusion criteria by inspecting the title and abstract, are assessed as preliminary eligibility. Finally, 9 articles\u003csup\u003e2, 14, 15, 18, 25\u0026ndash;29\u003c/sup\u003e, after eliminating 24 articles with such specific removal causes as 21 open-label RCTs, 2 single-blinded RCTs and one prophylactic RCT by reading full-text, were included in this quantitative meta-analysis. All operation procedures follow the flow diagram of search and selection displayed in Fig. 1. Of 9 studies included in the quantitative synthesis (meta-analysis),a total of 3594 participants were randomized to the intervention group (n\u0026thinsp;=\u0026thinsp;1898) using CP infusion plus local standard care and the control group (n\u0026thinsp;=\u0026thinsp;1696) using either NS or non-convalescent plasma plus local standard care or merely local standard care.\u003c/p\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eThe ROB assessment for all included studies\u003c/h2\u003e\n \u003cp\u003eThe ROB assessments were performed using RevMan5.4.1 software and ROB 1.0 tool for the included clinical trials. RevMan5.4.1 software was utilized to create ROB summary in each domain-level evaluation for each inclusion study. Of 9 eligible included studies,7 studies\u003csup\u003e2, 15, 18, 25, 26, 28, 29\u003c/sup\u003e on mortality, 3 studies\u003csup\u003e2, 26, 29\u003c/sup\u003e on invasive mechanical ventilation, 4 studies\u003csup\u003e2, 15, 26, 29\u003c/sup\u003e on hospitalization rate, 3 studies\u003csup\u003e15, 25, 26\u003c/sup\u003e on AEs and 3 studies\u003csup\u003e18, 26, 28\u003c/sup\u003e on serious AEs were judged as low ROB, and the study with at least one high risk or \u0026ge;\u0026thinsp;3 unclear risks in all 7 domains were identified as high ROB. The results of overall ROB on all outcomes of concern are high risk presented in Supplemental Fig. 1(a-e).\u003c/p\u003e\n \u003cp\u003eAlthough the qualitative funnel plot test for publication bias is low power when a meta-analysis includes ten or fewer studies or the more confounding factors amongst inclusion trials, the publication bias test on mortality in this meta-analysis using a visual qualitative funnel plot presents some what asymmetry at the bottom of the funnel plot, indicating it is possible that some RCTs with small sample size or negative outcomes were not published showed in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e; the publication bias test using funnel plot on the incidence of hospitalization, invasive mechanical ventilation, AEs and serious AEs in this meta-analysis were discarded owing to too few available studies.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003eGeneral characteristics and key information of the included studies\u003c/h2\u003e\n \u003cp\u003eThe general characteristics and critical information of a total of 9 eligible studies included in this meta-analysis are presented in Table\u0026nbsp;1.9, 5, 4 and 5 studies are included in quantitative synthesis on mortality outcome\u003csup\u003e2, 14, 15, 18, 25\u0026ndash;29\u003c/sup\u003e (137 deaths from1898 participants in the intervention group vs. 139 deaths from 1696 participants in the control group), invasive mechanical ventilation outcome\u003csup\u003e2, 14, 26, 27, 29\u003c/sup\u003e (36 sufferers from 1016 participants in the intervention group vs. 25 from 898 in the control group), AEs outcome\u003csup\u003e15, 25\u0026ndash;27\u003c/sup\u003e (254 cases of 1358 participants in the intervention group vs. 175 of 1245 in the control group) and serious AEs outcome\u003csup\u003e14, 18, 26\u0026ndash;28\u003c/sup\u003e (127 of 552 in the intervention group vs. 67 of 340 in the control group), respectively, and RE analysis model was applied owing to the medium or low levels of heterogeneity amongst included clinical trials. The hospitalization rate outcome including 4 studies\u003csup\u003e2, 15, 26, 29\u003c/sup\u003e (169 hospitalized cases from 1106participants in the intervention group vs. 130 from 989 in the control group) is dealt with via narrative analysis because of a high level of heterogeneity among inclusion studies.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003ePrimary and secondary outcomes\u003c/h2\u003e\n \u003cp\u003eMeta-analysis using quantitative synthesis on hospitalization rate is rejected because heterogeneity (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;92%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001) amongst the included trials are significant. Heterogeneity tests on 28- day mortality, invasive mechanical ventilation, AEs and serious AEs amongst the included trials shown in Supplemental Fig. 2 (a-e) reveal homogeneity. 28-day mortality outcome presented in Supplemental Fig. 2a shows a significant statistical difference between the two groups (RR 0.78 [95% CI 0\u0026middot;62\u0026ndash;0.97], \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e 0%,\u0026nbsp;\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03), which indicates that the CP infusion is effective for COVID-19 patients in reducing the 28-day mortality by approximately 22%. However, the incidences of invasive mechanical ventilation, AE and serious AE are no statistical significance between the intervention group and the control group, which indicate that CP infusion in COVID-19 patients is safe and does not decrease usage of invasive mechanical ventilation for COVID-19 patients.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003egeneral characteristics and key information of included clinical trials\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"10\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAuthor and year\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAlemany2022\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBalde\u0026oacute;n 2022\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBennett-Guerrero 2021\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLibster2021\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOrtigoza2022\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eO\u0026rsquo;Donnell 2021\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSimonovich 2021\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSullivan 2021\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003evan den Berg 2022\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT-assess\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDay 30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDay 28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSeverity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emild and moderate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emoderate to severe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enoninvasive oxygen supplementation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esevere and critical\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esevere\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMild moderate or severe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emoderate to severe\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge(int)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e56 (52\u0026ndash;62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emean (SD)\u003c/p\u003e\n \u003cp\u003e56.3\u0026thinsp;\u0026plusmn;\u0026thinsp;12.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emean (SD):\u003c/p\u003e\n \u003cp\u003e67 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emean (SD)\u003c/p\u003e\n \u003cp\u003e76.4\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e62.0 (51.0\u0026ndash;72.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e60 (48\u0026ndash;71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e62.5 (53\u0026ndash;72.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e42 (31.5\u0026ndash;54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e54 (46\u0026ndash;62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge(con)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e56 (53\u0026ndash;63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emean (SD)\u003c/p\u003e\n \u003cp\u003e55.0\u0026thinsp;\u0026plusmn;\u0026thinsp;13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emean (SD)\u003c/p\u003e\n \u003cp\u003e64 (17.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emean (SD)\u003c/p\u003e\n \u003cp\u003e77.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e64.0 (54.0\u0026ndash;74.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e63 (49\u0026ndash;72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e62 (49\u0026ndash;71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e44 (33\u0026ndash;55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e57 (47\u0026ndash;64)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNitt(int)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e468\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e228\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e610\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNitt(con)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e473\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e615\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNmitt(int)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e462\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e147\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e228\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e592\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNmitt(con)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e462\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e589\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eM/F(int)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e105/83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42/21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36/23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26/54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e284/184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96/54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e161/67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e269/323(Mitt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21/31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eM/F(con)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98/90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65/30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34/46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e272/201\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51/22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64/41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e237/352(Mitt)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21/30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT-int-symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR):\u003c/p\u003e\n \u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;3d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e7(\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian: 9d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e8 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;8d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR):\u003c/p\u003e\n \u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT-con-symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;7d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR):\u003c/p\u003e\n \u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;3d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7(\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian: 9d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003cp\u003e8 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;8d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR):\u003c/p\u003e\n \u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePr-PLB (ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNS 250ml or\u003c/p\u003e\n \u003cp\u003e5 ml/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-convalescent pasma 5 ml/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStandard plasma 480ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNS 250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNS 250ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003econtrol plasma 200-250ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNS500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStandard plasma\u0026thinsp;\u0026ge;\u0026thinsp;175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNS 200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePr-CP (ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e250\u0026ndash;300ml or 5 ml/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 ml/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e480ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e250ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e250ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCP 200-250ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (IQR) 500(415\u0026ndash;600)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;175ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e200\u0026ndash;250ml\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeath toll(int)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeath toll(con)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN in-venti(int)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN in-venti(con)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN int-\u003cstrong\u003ehosp\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e123\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNcon-\u003cstrong\u003ehosp\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003csub\u003eAE\u003c/sub\u003e (int)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003csub\u003eAE\u003c/sub\u003e (con)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003csub\u003eSAE\u003c/sub\u003e (int)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003csub\u003eSAE\u003c/sub\u003e (con)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"10\"\u003e\n \u003cp\u003eAbbreviations: T-assess\u0026thinsp;=\u0026thinsp;Time at assessing outcome; Age (int)\u0026thinsp;=\u0026thinsp;age in intervention group; Age (con)\u0026thinsp;=\u0026thinsp;age in control group; IQR\u0026thinsp;=\u0026thinsp;interquartile range; SD\u0026thinsp;=\u0026thinsp;standard deviation; Niit(int)\u0026thinsp;=\u0026thinsp;the number of intention-to-treat participants in intervention group; Niit(con)\u0026thinsp;=\u0026thinsp;the number of intention-to-treat participants in control group; Nmiit(int)\u0026thinsp;=\u0026thinsp;the number of modified intention-to-treat participants in intervention group; Nmiit(con)\u0026thinsp;=\u0026thinsp;the number of modified intention-to-treat participants in control group; M/F(int)\u0026thinsp;=\u0026thinsp;male/female in intervention group; M/F(con)\u0026thinsp;=\u0026thinsp;male/female in control group; T-int-symptoms\u0026thinsp;=\u0026thinsp;intervention timing after the onset of symptoms in intervention group; T-con-symptoms\u0026thinsp;=\u0026thinsp;intervention timing after the onset of symptoms in control group; Pr-PBO\u0026thinsp;=\u0026thinsp;Prescription of placebo in control group; Pr-CP\u0026thinsp;=\u0026thinsp;Prescription of convalescent plasma in intervention group; NS\u0026thinsp;=\u0026thinsp;normal saline; int\u0026thinsp;=\u0026thinsp;intervention group; con\u0026thinsp;=\u0026thinsp;control group; ml\u0026thinsp;=\u0026thinsp;milliliters; kg\u0026thinsp;=\u0026thinsp;kilogram; N in-venti(int)\u0026thinsp;=\u0026thinsp;the number of cases using invasive mechanic ventilation in intervention group; N in-venti(con)\u0026thinsp;=\u0026thinsp;the number of cases using invasive mechanic ventilation in control group; N int-hosp\u0026thinsp;=\u0026thinsp;the number of hospitalized cases in intervention group; N con-hosp\u0026thinsp;=\u0026thinsp;the number of hospitalized cases in control group; N\u003csub\u003eAE\u003c/sub\u003e (int)\u0026thinsp;=\u0026thinsp;the number of cases with any adverse events in intervention group; N\u003csub\u003eAE\u003c/sub\u003e (con)\u0026thinsp;=\u0026thinsp;the number of cases with any adverse events in control group; N\u003csub\u003eSAE\u003c/sub\u003e (int)\u0026thinsp;=\u0026thinsp;the number of cases with serious adverse events in intervention group; N\u003csub\u003eSAE\u003c/sub\u003e (con)\u0026thinsp;=\u0026thinsp;the number of cases with serious adverse events in control group; NA\u0026thinsp;=\u0026thinsp;not available.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eSensitivity analysis\u003c/h2\u003e\n \u003cp\u003eSensitivity analyses are performed for all outcomes of interest and their information is presented in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. From sensitivity analyses on hospitalization rate, the striking heterogeneities showed in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eCmay indicate more confounders or baseline imbalance amongst inclusion trials and make quantitative synthesis on this outcome be abandoned. After deleting the study by O\u0026rsquo;Donnell, the combining effect measure on mortality (RR 0.83 [0.66, 1.06], \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e 0%, Z-value 1.46, P\u0026thinsp;=\u0026thinsp;0.14) is different from the total effect measure in advance of deleting the study, hinting that the deleted study may be more efficacious in reducing mortality or exist additional confounders(e.g.: severe or critical illness); this marked impact on the total effect may require more identical clinical trials to check this effect and explore confounders of concern. Sensitivity analyses on invasive mechanical ventilation, any AEs, and serious AEs presented in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB, \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eD, 2Eshow that all statistical results are not altered after deleting any trial, which corroborate that the results are robust accompanying with the low to medium levels of heterogeneity amongst inclusion trials.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eSubgroup analysis\u003c/h2\u003e\n \u003cp\u003eSubgroup analyses are performed based on age\u0026thinsp;\u0026le;\u0026thinsp;60 years old or \u0026gt;\u0026thinsp;60 years old. The subgroup analysis on mortality presented in Supplemental Fig. 3a indicates that CP infusion develops more beneficial reduction in mortality by 36% than that in the control group in \u0026le;\u0026thinsp;60 years old subgroup. The incidences of hospitalization and invasive mechanical ventilation remain their robustness whether \u0026le;\u0026thinsp;60 years old or \u0026gt;\u0026thinsp;60 years old subgroup, indicating that CP infusion does not reduce the rates of hospitalization and invasive mechanical ventilation no matter\u0026thinsp;\u0026le;\u0026thinsp;60 years old or \u0026gt;\u0026thinsp;60 years old subgroup observed in Supplemental Fig. 3b and 3c CP infusion develops similar AEs compared with placebo regardless of \u0026le;\u0026thinsp;60 years old or \u0026gt;\u0026thinsp;60 years old subgroup; although CP infusion can cause fewer serious AEs compared with control group in \u0026le;\u0026thinsp;60 years old subgroup than that in \u0026gt;\u0026thinsp;60 years old subgroup recorded in Supplemental Fig. 3d and 3e, there is no statistical difference in the incidence of serious AEs between the intervention group and the control groups whether \u0026le;\u0026thinsp;60 years old or \u0026gt;\u0026thinsp;60 years old subgroup, which indicates that CP infusion possesses such remarkable safety.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSensitivity analysis\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDeleted article\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRR and 95%CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e(%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eZ-value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003eA: 28-day mortality and overall effect RR (0.78 [0.62, 0.97], \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, Z\u0026thinsp;=\u0026thinsp;2.22, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlemany 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.78 [0.63, 0.98]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBalde\u0026oacute;n 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.77 [0.61, 0.97]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBennett-Guerrero 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.77 [0.61, 0.97]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLibster 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.78 [0.63, 0.98]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOrtigoza 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.72 [0.53, 0.99]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eO\u0026rsquo;Donnell 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.83 [0.66, 1.06]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSimonovich 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.75 [0.59, 0.96]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSullivan 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.78 [0.63, 0.98]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVan den Berg 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.77 [0.61, 0.98]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003eB: Invasive mechanical ventilation and effect RR (0.84[0.50, 1.42], \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, Z\u0026thinsp;=\u0026thinsp;0.65, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlemany 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.89 [0.51, 1.54]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLibster 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.89 [0.51, 1.55]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eO\u0026rsquo;Donnell 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.71 [0.39, 1.29]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSimonovich 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.79[0.37, 1.69]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVan den Berg 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.89[0.52, 1.52]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003eC: Hospitalization rate and overall effect RR (1.11 [0.33, 3.67], \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;92%, Z\u0026thinsp;=\u0026thinsp;0.16, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlemany 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.09 [0.17, 6.84]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLibster 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.32[0.34, 5.18]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSimonovich 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.67 [0.35, 1.26]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSullivan 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.55 [0.24, 5.76]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003eD: Any AEs and overall effect RR (1.01 [0.78, 1.32], \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;55%, Z\u0026thinsp;=\u0026thinsp;0.10, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOrtigoza 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.98 [0.67, 1.42]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSimonovich 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.98 [0.64, 1.52]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSullivan 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.11 [0.95, 1.29]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVan den Berg 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.95[0.69, 1.31]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003eE: Serious AEs and overall effect RR (0.96 [0.73, 1.28], \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;16%, Z\u0026thinsp;=\u0026thinsp;0.25, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBalde\u0026oacute;n 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.96 [0.73, 1.28]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBennett-Guerrero 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.97 [0.68, 1.38]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eO\u0026rsquo;Donnell 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.14 [0.82, 1.58]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSimonovich 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.84 [0.62, 1.13]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVan den Berg 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.97 [0.64, 1.48]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003eQuality of evidence and strength of recommendation\u003c/h2\u003e\n \u003cp\u003eThe quality of evidence on the CP infusion in COVID-19 patients is high level. Based on current information, a strong recommendation of CP infusion is made for patients with COVID-19 if necessary, especially for COVID-19 patients with \u0026le;\u0026thinsp;60 years old.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs far as we know, this meta-analysis is the most all-round systematic review and meta-analysis, based on double-blind, parallel-arm, placebo-control, randomized clinical trials, top robe the efficacy and safety of CP infusion in patients with COVID-19. Because current SARS-CoV-2 with high infectivity has been endangering global healthcare all over the world since the late of 2019, a specific drug targeted to COVID-19 is not available yet. CP, as an alternative passive immunotherapy option, once has been recommended to apply for multiple infectious diseases for more than one hundred years. Multiple study results displayed that CP infusion could significantly decrease the mortality caused by SARS virus\u003csup\u003e10\u003c/sup\u003e, MERS-CoV\u003csup\u003e8\u003c/sup\u003e, influenza virus\u003csup\u003e9\u003c/sup\u003e infection. However, due to the low certainty of evidence on the beneficial effects of CP infusion in COVID-19 patients, the present meta-analysis is performed to confirm its efficacy and safety for future clinical practice.\u003c/p\u003e \u003cp\u003eThis meta-analysis identified and summarize dup to 9randomized, double-blind, parallel-arm, placebo-controlled, clinical trials. This meta-analysis based on data recorded above shows that CP infusion could significantly lower the mortality, and that the similar results on mortality mentioned above are consistent with the results from RCT\u003csup\u003e14\u003c/sup\u003e and meta-analysis based on RCTs\u003csup\u003e30, 31\u003c/sup\u003e; but, some RCTs\u003csup\u003e2, 15, 18, 25\u0026ndash;29\u003c/sup\u003e did not support this conclusion. Therefore, Although the conclusion is still controversial, the available evidence from this meta-analysis may provide a basis for an option of CP application for COVID-19 treatment until now. Secondary mortality caused by SARS-CoV-2 infection was reduced by CP transfusion, which might be attributable to such multiple complex known or unknown mechanisms of action as restraining complement activation, antagonizing cytokine effects, and down-regulating B- and T-cells functions\u003csup\u003e5\u003c/sup\u003e,and such other action mechanisms as controlling the attachment of the SARS-CoV-2 to angiotensin converting enzyme 2 receptors by strengthening neutralizing antibodies against the membrane spike protein of SARS-Cov-2\u003csup\u003e4\u003c/sup\u003e and the coupling of SARS-CoV-2 with its receptor by the IgG of anti-A isoagglutinin in O-type blood subjects\u003csup\u003e6\u003c/sup\u003e. Concrete and authentic mechanisms of action which are unclear yet need to be explored using more clinical trials and fundamental research on COVID-19. Sensitivity analysis on mortality after deleting O\u0026rsquo;Donnell\u003csup\u003e14\u003c/sup\u003e showed that there are significantly different effects before and after deleting O\u0026rsquo;Donnell, which indicated that CP infusion might make more severe or critical COVID-19 patients keep from death in the deleted study. And subgroup analysis on mortality based on age\u0026thinsp;\u0026le;\u0026thinsp;60 years old or \u0026gt;\u0026thinsp;60 years old showed that CP therapy for patients in \u0026le;\u0026thinsp;60 years old subgroup might be more efficacious than that in \u0026gt;\u0026thinsp;60 years old subgroup, which hinted that onset age might be one of the commonest confounding factors which led to significant heterogeneities, which suggested that CP infusion might be an extremely good alternative option to reduce mortality for COVID-19 patients, the more so as COVID-19 patients are \u0026le;\u0026thinsp;60 years old if other efficacious therapeutics aren\u0026rsquo;t acquired.\u003c/p\u003e \u003cp\u003eOwing to the significant heterogeneities among included trials in terms of synthetizing hospitalization rate, which might be attributable to the difference in severity, sample size, age and so on. The outcome on hospitalization rate derived from the inclusion studies cannot be synthetized because of the significant heterogeneities. It is uncertain whether CP infusion can reduce the hospitalization rate or not, which must be verified by performing more homogenous and high-quality randomized controlled trials.\u003c/p\u003e \u003cp\u003eCP infusion cannot efficaciously reduce the utilization of invasive mechanic ventilation yet, which is consistent with the studies\u003csup\u003e2, 27, 29\u003c/sup\u003e, sensitivity and subgroup analyses on the utilization of invasive mechanic ventilation exhibit this effect is robust and CP infusion did not make COVID-19 patients benefit from in terms of reduction in invasive mechanic ventilation, some inferred causes might be inappropriate timing and doses of administration.\u003c/p\u003e \u003cp\u003eBased on current limited safety data deriving from this meta-analysis,t here are similar and no significant statistical differences in no matter general AEs or serious AEs in both groups, and that most of AEs are mild or moderate. Subgroup analysis displays CP infusion compared with placebo may develop fewer serious AEs in \u0026le;\u0026thinsp;60 years old subgroup than those in \u0026gt;\u0026thinsp;60 years old subgroup and but there are no statistical differences. This meta-analysis authenticates CP infusion may be more safe and well-tolerated for COVID-19 patients, especially for patients aged less than 60 years old.\u003c/p\u003e \u003cp\u003eThe participants in this meta-analysis merely involved in adults with or without underlying diseases and did not include children and pregnant women with COVID-19. The efficacy and safety data of CP infusion for such special COVID-19 populations as children and pregnant women are lacking, CP infusion may be an optional therapy for children and pregnant women according to the principle of extrapolation, if the COVID-19 illness cannot be held back.\u003c/p\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eStrength and limitation\u003c/h2\u003e \u003cp\u003eOur ongoing study has several strengths and limitations. Primero Firstly, the main strength is that this meta-analysis deriving from high-quality randomized, double-blinded, placebo-control parallel-arm clinical trials is fewer biases and more high-quality; secondly, CP infusion can efficaciously and reasonably cut down the mortality outcome for COVID-19 patients, especial for COVID-19 patients with \u0026le;\u0026thinsp;60 years old. On limitations, this meta-analysis merely includes fewer eligible clinical trials and did not touch upon the optimal timing of infusion, titers and dosage of CP and the duration of administration, which can affect the efficacy and safety of CP transfusion. So, the optimal timing of infusion, dosage, titer of CP and duration of the administration still require more high-quality clinical trials to provide support.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eCP therapy for patients with COVID-19, especially for COVID-19 patients aged less than 60 years old, might be more efficacious in reducing mortality outcome and safer. CP infusion is strongly recommended in order to reduce the mortality in patients with COVID-19 if necessary, especially for COVID-19 patients with \u0026le;\u0026thinsp;60 years old, based on high quality of evidence.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;approval\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and written informed consent\u0026nbsp;from participates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot\u0026nbsp;applicable\u0026nbsp;because this meta-analysis belongs to secondary study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors had full\u0026nbsp;access\u0026nbsp;to all the data associated with this meta-analysis and had the final decision to\u0026nbsp;publish\u0026nbsp;it.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that this study was performed without any financial relationships which might lead to a possible conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCAMS Innovation Fund for Medical Sciences（CIFMS）2021-I2M-1-001\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLP, YJ and YW\u0026nbsp;designed and alternately\u0026nbsp;reviewed this study and interpreted this data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLP and DR searched, screened, and extracted\u0026nbsp;the\u0026nbsp;related\u0026nbsp;data.\u003c/p\u003e\n\u003cp\u003eLP and YW evaluated ROB.\u003c/p\u003e\n\u003cp\u003eLP wrote the manuscript, interactively\u0026nbsp;revised\u0026nbsp;manuscript with DR and YJ.\u003c/p\u003e\n\u003cp\u003eLP, YW and DR have read and approved the final manuscript to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis meta-analysis is investigator-initiated\u0026nbsp;secondary\u0026nbsp;study\u0026nbsp;without any financial support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRajapakse N, Dixit D. Human and novel coronavirus infections in children: a review. Paediatrics Int Child Health. 2021;41(1):36\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlemany A, Millat-Martinez P, Corbacho-Monn\u0026eacute; M, et al. High-titre methylene blue-treated convalescent plasma as an early treatment for outpatients with COVID-19: a randomised, placebo-controlled trial. Lancet Respir Med Mar. 2022;10(3):278\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Santis GC, Oliveira LC, Garibaldi PMM, et al. High-Dose Convalescent Plasma for Treatment of Severe COVID-19. Emerg Infect Dis. 2022;28(3):548\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol Apr. 2020;92(4):418\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFranchini M, Liumbruno GM. Convalescent Plasma for the Treatment of Severe COVID-19. Biologics. 2021;15:31\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFranchini M, Glingani C, Del Fante C, et al. The protective effect of O blood type against SARS-CoV-2 infection. Vox Sang Feb. 2021;116(2):249\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoo YO, Cheng Y, Wong R, et al. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect Jul. 2004;10(7):676\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKo JH, Seok H, Cho SY, et al. Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience. AntivirTher. 2018;23(7):617\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med Oct. 2006;17(8):599\u0026ndash;609.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMair-Jenkins J, Saavedra-Campos M, Baillie JK, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis Jan. 2015;1(1):80\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDuan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci. 2020;117(17):9490\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZeng Q-L, Yu Z-J, Gou J-J, et al. Effect of Convalescent Plasma Therapy on Viral Shedding and Survival in Patients With Coronavirus Disease 2019. J Infect Dis. 2020;222(1):38\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBar KJ, Shaw PA, Choi GH et al. A randomized controlled study of convalescent plasma for individuals hospitalized with COVID-19 pneumonia. J Clin Invest Dec 15 2021;131(24).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'Donnell MR, Grinsztejn B, Cummings MJ et al. A randomized double-blind controlled trial of convalescent plasma in adults with severe COVID-19. J Clin Invest Jul 1 2021;131(13).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSullivan DJ, Gebo KA, Shoham S et al. Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma. \u003cem\u003emedRxiv.\u003c/em\u003e Dec 21. 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarreira DF, Louren\u0026ccedil;o RA, Calisto R, Moreira-Gon\u0026ccedil;alves D, Santos LL, Videira PA. Assessment of the Safety and Therapeutic Benefits of Convalescent Plasma in COVID-19 Treatment: A Systematic Review and Meta-Analysis. Front Med (Lausanne). 2021;8:660688.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBansal V, Mahapure KS, Mehra I, et al. Mortality Benefit of Convalescent Plasma in COVID-19: A Systematic Review and Meta-Analysis. Front Med (Lausanne). 2021;8:624924.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBennett-Guerrero E, Romeiser JL, Talbot LR, et al. Severe Acute Respiratory Syndrome Coronavirus 2 Convalescent Plasma Versus Standard Plasma in Coronavirus Disease 2019 Infected Hospitalized Patients in New York: A Double-Blind Randomized Trial. Crit Care Med Jul. 2021;1(7):1015\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. Bmj Sep. 2017;21:358:j4008.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med Jul. 2009;21(7):e1000097.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev Oct. 2019;3:10:Ed000142.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. Bmj Aug. 2019;28:366:l4898.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrożek JL, Akl EA, Compalati E, et al. Grading quality of evidence and strength of recommendations in clinical practice guidelines part 3 of 3. The GRADE approach to developing recommendations. Allergy May. 2011;66(5):588\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrozek JL, Akl EA, Alonso-Coello P, et al. Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 1 of 3. An overview of the GRADE approach and grading quality of evidence about interventions. Allergy May. 2009;64(5):669\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrtigoza MB, Yoon H, Goldfeld KS, et al. Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial. JAMA Intern Med. 2022;182(2):115\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimonovich VA, Pratx LDB, Sabana P, et al. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med Feb. 2021;384(7):619\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan den Berg K, Glatt TN, Vermeulen M, et al. Convalescent plasma in the treatment of moderate to severe COVID-19 pneumonia: a randomized controlled trial (PROTECT-Patient Trial). Sci Rep Feb. 2022;15(1):2552.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBalde\u0026oacute;n ME, Maldonado A, Ochoa-Andrade M et al. Effect of convalescent plasma as complementary treatment in patients with moderate COVID-19 infection. Transfus Med Jan 9 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLibster R, Marc GP, Wappner D, et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med. 2021;384(7):610\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSarkar S, Khanna P, Singh AK. Convalescent Plasma-A Light at the End of the Tunnel: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Indian J Crit Care Med Nov. 2021;25(11):1292\u0026ndash;300.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSarkar S, Soni KD, Khanna P. Convalescent plasma is a clutch at straws in COVID-19 management! A systematic review and meta-analysis. J Med Virol Feb. 2021;93(2):1111\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), convalescent plasma (CP), outcome, efficacy, safety, adverse events (AEs), serious AEs, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-4741126/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4741126/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eConvalescent plasma (CP) was demonstrated promising benefit for clinical practice involved in efficacy and safety in previous corona virus pandemics, however, the efficacy of CP from COVID-19 sufferers are still controversial and unascertainable based on current randomized controlled trials (RCTs). The urgent needs for affirmative replies on the efficacy and safety of CP for COVID-19 patients must be developed as soon as possible.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo corroborate the efficacy and safety of CP based on high-quality double-blinded, parallel-arm placebo-control randomized clinical trials and provide evidence-based support for clinical application of CP against COVID-19.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eSuch medical electronic databases as Embase, PubMed, and Web of Science were \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eretrieve\u003c/span\u003ed from inception to March 12, 2022. This meta-analysis synthesizes such dichotomous outcomes as the incidences of 28-day mortality, hospitalization rate, invasive mechanical ventilation, adverse events (AEs)and serious AEs using intention-to-treat (ITT) analysis. Statistical analysis, using Review Manager (RevMan) 5.4.1 software, Mantel-Haenszel (M-H) statistical method and random effects (RE) analysis model, risk ratios (RRs) plus their 95% confidence intervals (CIs) as effect measures, were performed. Two reviewers independently searched, screened, included the eligible clinical trials, extracted data of concern from the mand assessed the risks of bias (ROB) of the included articles with the Cochrane ROB tool 1.0 and Rev Man 5.4.1 software. The effect measures of RRs plus their 95% CIs in this meta-analysis will be computed as dichotomous outcomes of interest. Statistical heterogeneities, subgroup analysis and sensitivity analysis will be fulfilled to explore the heterogeneities and their causes. We evaluate the quality of evidence and put forward strength of recommendations for clinical practice based on the GRADE approach. \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eThis prospective meta-analysis protocol has been registered on PROSPERO.\u003c/span\u003e\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e697 references were preliminarily identified from the \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003edata\u003c/span\u003ebases of concern and manual \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eretrieves\u003c/span\u003e, and 9 eligible double-blinded, parallel-arm, placebo-control randomized clinical trialswith 1898 subjects in the intervention group and 1696 participants in the control group were ultimately included in the meta-analysis. 7, 4, 3, 3 and 3 eligible trials are adjudged as low ROB for mortality, the rate of hospitalization, the incidence of invasive mechanical ventilation, AEs and serious AEs, respectively; all the rest of included trials are defined as high risk corresponding to the respective outcome. The meta-analysis on the hospitalization rate was abandoned because of high heterogeneity (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;92%) among the inclusion trials. The RRs, 95%CIs and \u003cem\u003eP\u003c/em\u003e-values were 0.78 [0.62, 0.97], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03 on mortality; 0.84 [0.50, 1.42], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.51 on invasive mechanical ventilation; 1.01 [0.78, 1.32],\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.92 on AEs; 0.96 [0.73, 1.28], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.80 on serious AEs, respectively, with low or medium levels of heterogeneity; which indicate that CP infusion in COVID-19 patients can efficaciously reduce mortality by 22%, and exhibit excellent safety and not decrease the incidence of invasive mechanical ventilation. Sensitivity analysis on mortality with the combining effect measure (RR 0.83 [0.66, 1.06], \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e 0%, Z-value 1.46, P\u0026thinsp;=\u0026thinsp;0.14) after deleting the study by O\u0026rsquo;Donnell showed that there is not different between the intervention group and control group, hinting that the deleted study may be more efficacious for reducing mortality. Subgroup analysis on mortality based on age showed that CP therapy in COVID-19 patients aged\u0026thinsp;\u0026le;\u0026thinsp;60 years old may more efficaciously reduce mortality by 36%. Sensitivity analyses and subgroup analyses on the other outcomes present robust pooling outcomes. \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eThe registration code on PROSPERO is\u003c/span\u003e CRD42022324324.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eAdministration of CP to COVID-19 patients, especially to COVID-19 patients aged\u0026thinsp;\u0026le;\u0026thinsp;60 years old, may efficaciously reduce mortality with excellent safety, but does not reduce the incidence of invasive mechanical ventilation.\u003c/p\u003e","manuscriptTitle":"The efficacy and safety of convalescent plasma for COVID-19 patients: A meta-analysis based on double-blinded parallel-arm randomized placebo-controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-17 02:38:04","doi":"10.21203/rs.3.rs-4741126/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-19T10:02:02+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-19T08:40:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-19T08:21:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2024-07-15T06:40:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"68eacf35-29ce-4811-9610-cb2f4594259b","owner":[],"postedDate":"August 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T16:02:25+00:00","versionOfRecord":{"articleIdentity":"rs-4741126","link":"https://doi.org/10.1186/s12879-025-12126-4","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2026-01-26 15:59:25","publishedOnDateReadable":"January 26th, 2026"},"versionCreatedAt":"2024-08-17 02:38:04","video":"","vorDoi":"10.1186/s12879-025-12126-4","vorDoiUrl":"https://doi.org/10.1186/s12879-025-12126-4","workflowStages":[]},"version":"v1","identity":"rs-4741126","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4741126","identity":"rs-4741126","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}