PMID- 33044747 OWN - NLM STAT- MEDLINE DCOM- 20201021 LR - 20221207 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 10 DP - 2020 Oct 12 TI - Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. PG - CD013600 LID - 10.1002/14651858.CD013600.pub3 [doi] AB - BACKGROUND: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required. OBJECTIVES: To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trial registries to identify completed and ongoing studies on 19 August 2020. SELECTION CRITERIA: We followed standard Cochrane methodology. We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of bias' 2.0 tool for randomised controlled trials (RCTs), the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool for controlled non-randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non-controlled NRSIs. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, mortality (time to event), improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events (AEs), and serious adverse events (SAEs). MAIN RESULTS: This is the second living update of our review. We included 19 studies (2 RCTs, 8 controlled NRSIs, 9 non-controlled NRSIs) with 38,160 participants, of whom 36,081 received convalescent plasma. Two completed RCTs are awaiting assessment (published after 19 August 2020). We identified a further 138 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 73 are randomised (3 reported in a study registry as already being completed, but without results). We did not identify any completed studies evaluating hyperimmune immunoglobulin. We did not include data from controlled NRSIs in data synthesis because of critical risk of bias. The overall certainty of evidence was low to very low, due to study limitations and results including both potential benefits and harms. Effectiveness of convalescent plasma for people with COVID-19 We included results from two RCTs (both stopped early) with 189 participants, of whom 95 received convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma. We are uncertain whether convalescent plasma decreases all-cause mortality at hospital discharge (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.22 to 1.34; 1 RCT, 86 participants; low-certainty evidence). We are uncertain whether convalescent plasma decreases mortality (time to event) (hazard ratio (HR) 0.64, 95% CI 0.33 to 1.25; 2 RCTs, 189 participants; low-certainty evidence). Convalescent plasma may result in little to no difference in improvement of clinical symptoms (i.e. need for respiratory support) at seven days (RR 0.98, 95% CI 0.30 to 3.19; 1 RCT, 103 participants; low-certainty evidence). Convalescent plasma may increase improvement of clinical symptoms at up to 15 days (RR 1.34, 95% CI 0.85 to 2.11; 2 RCTs, 189 participants; low-certainty evidence), and at up to 30 days (RR 1.13, 95% CI 0.88 to 1.43; 2 studies, 188 participants; low-certainty evidence). No studies reported on quality of life. Safety of convalescent plasma for people with COVID-19 We included results from two RCTs, eight controlled NRSIs and nine non-controlled NRSIs assessing safety of convalescent plasma. Reporting of safety data and duration of follow-up was variable. The controlled studies reported on AEs and SAEs only in participants receiving convalescent plasma. Some, but not all, studies included death as a SAE. The studies did not report the grade of AEs. Fourteen studies (566 participants) reported on AEs of possible grade 3 or 4 severity. The majority of these AEs were allergic or respiratory events. We are very uncertain whether convalescent plasma therapy affects the risk of moderate to severe AEs (very low-certainty evidence). 17 studies (35,944 participants) assessed SAEs for 20,622 of its participants. The majority of participants were from one non-controlled NRSI (20,000 participants), which reported on SAEs within the first four hours and within an additional seven days after transfusion. There were 63 deaths, 12 were possibly and one was probably related to transfusion. There were 146 SAEs within four hours and 1136 SAEs within seven days post-transfusion. These were predominantly allergic or respiratory, thrombotic or thromboembolic and cardiac events. We are uncertain whether convalescent plasma therapy results in a clinically relevant increased risk of SAEs (low-certainty evidence). AUTHORS' CONCLUSIONS: We are uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. There was limited information regarding grade 3 and 4 AEs to determine the effect of convalescent plasma therapy on clinically relevant SAEs. In the absence of a control group, we are unable to assess the relative safety of convalescent plasma therapy. While major efforts to conduct research on COVID-19 are being made, recruiting the anticipated number of participants into these studies is problematic. The early termination of the first two RCTs investigating convalescent plasma, and the lack of data from 20 studies that have completed or were due to complete at the time of this update illustrate these challenges. Well-designed studies should be prioritised. Moreover, studies should report outcomes in the same way, and should consider the importance of maintaining comparability in terms of co-interventions administered in all study arms. There are 138 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 73 are RCTs (three already completed). This is the second living update of the review, and we will continue to update this review periodically. Future updates may show different results to those reported here. CI - Copyright (c) 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. FAU - Chai, Khai Li AU - Chai KL AD - Transfusion Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. FAU - Valk, Sarah J AU - Valk SJ AD - Jon J van Rood Center for Clinical Transfusion Research, Sanquin/Leiden University Medical Center, Leiden, Netherlands. AD - Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands. FAU - Piechotta, Vanessa AU - Piechotta V AD - Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Kimber, Catherine AU - Kimber C AD - Systematic Review Initiative, NHS Blood and Transplant, Oxford, UK. FAU - Monsef, Ina AU - Monsef I AD - Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Doree, Carolyn AU - Doree C AD - Systematic Review Initiative, NHS Blood and Transplant, Oxford, UK. FAU - Wood, Erica M AU - Wood EM AD - Transfusion Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. FAU - Lamikanra, Abigail A AU - Lamikanra AA AD - Clinical, Research and Development, NHS Blood and Transplant, Oxford, UK. FAU - Roberts, David J AU - Roberts DJ AD - Systematic Review Initiative, NHS Blood and Transplant, Oxford, UK. FAU - McQuilten, Zoe AU - McQuilten Z AD - Transfusion Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia. FAU - So-Osman, Cynthia AU - So-Osman C AD - Sanquin Blood Bank, Amsterdam, Netherlands. AD - Erasmus Medical Centre, Rotterdam, Netherlands. FAU - Estcourt, Lise J AU - Estcourt LJ AD - Haematology/Transfusion Medicine, NHS Blood and Transplant, Oxford, UK. FAU - Skoetz, Nicole AU - Skoetz N AD - Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. LA - eng SI - ClinicalTrials.gov/NCT04434131 SI - ClinicalTrials.gov/NCT04343261 SI - ClinicalTrials.gov/NCT04342182 SI - ClinicalTrials.gov/NCT04338360 SI - ClinicalTrials.gov/NCT04340050 SI - ClinicalTrials.gov/NCT04357106 SI - ClinicalTrials.gov/NCT04321421 SI - ClinicalTrials.gov/NCT04441424 PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20201012 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 SB - IM UOF - Cochrane Database Syst Rev. 2020 Jul 10;7:CD013600. PMID: 32648959 CIN - Transfus Clin Biol. 2021 Aug;28(3):309-310. PMID: 33931305 UIN - Cochrane Database Syst Rev. 2021 May 20;5:CD013600. PMID: 34013969 MH - Bias MH - COVID-19 MH - Cause of Death MH - Coronavirus Infections/mortality/*therapy MH - Humans MH - Immunization, Passive/adverse effects/methods/statistics & numerical data MH - Non-Randomized Controlled Trials as Topic/statistics & numerical data MH - Pandemics MH - Pneumonia, Viral/mortality/*therapy MH - Randomized Controlled Trials as Topic/statistics & numerical data MH - Treatment Outcome MH - COVID-19 Serotherapy EDAT- 2020/10/13 06:00 MHDA- 2020/10/22 06:00 CRDT- 2020/10/12 12:13 PHST- 2020/10/12 12:13 [entrez] PHST- 2020/10/13 06:00 [pubmed] PHST- 2020/10/22 06:00 [medline] AID - 10.1002/14651858.CD013600.pub3 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2020 Oct 12;10:CD013600. doi: 10.1002/14651858.CD013600.pub3.