Protocol and registration
This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. The protocol has been registered with the registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (Registration Number CRD42022303199).
Search strategy and selection criteria
A literature review of all of the relevant English language studies was undertaken in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase by two authors (HJL and QLZ) independently, from January 1, 2019 through January 12, 2022. Keywords of immunoglobulin, Coronavirus Disease 2019, COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), acute respiratory distress syndrome (ARDS), severe, severely ill, critically ill, mechanical ventilation (MV), outcome, mortality, or intensive care unit (ICU) were used. Reference lists of included studies were manually searched for pertinent studies.
Title and abstract screen were conducted for all relevant records based on the electronic literature search. Full-text review was done for potentially relevant records. Randomized, or observational reports were eligible to be included in present analysis if they 1) enrolled adult patients (≥ 18 yr old), 2) severe or critically ill COVID-19 population, 3) included control group which patients do not receiving IVIG therapy. Meeting abstracts, case reports/series, pediatric studies, reviews and editorial/comments were excluded.
The methodological quality of each study was assessed using the Cochrane Collaboration tool for Randomized Controlled Studies and the Newcastle-Ottawa scale for Nonrandomized Controlled Studies by two reviewers (WW and HWT) independently. For Newcastle-Ottawa scale, each study was scored from 0 to 9, based on eight criteria covering selection of cohort, comparability of groups, and outcome. Discrepancies between the two authors (FH and YFJ) were resolved by consensus.
Data Extraction and Synthesis
Data collected from each study included 1) general information (author, publication year, study design and region), 2) characteristics of the participants (including gender, age, inclusion and exclusion criteria), 3) interventions: treatment approaches and comparison methods, 4) outcome measurements, including overall mortality (When >1 value for mortality was provided by the article, the mortality for the longest complete follow-up was preferentially used in the meta-analysis.), ICU and hospital mortality, ICU and hospital LOS, need for IMV and ventilators free days(VFDs).
Dichotomous variables were expressed as counts and proportions. Means and SDs were used to describe normally distributed continuous variables, whereas LOS and VFDs were often not normally distributed, some studies reported the LOS and VFDs data using the median and the first and third quartiles. To be able to use these data in present study, we estimated, for these studies, the sample mean and SD based on the method presented by Wan et al. and Luo et al. This method is based on the assumption that the data are normally distributed, which we know is not the case.
Sensitivity and subgroup analysis
Sensitivity analyses were performed by 1) removing each study individually in order to determine whether an individual report has higher contribution to the heterogeneity or overall effect estimate 2) including only patients with COVID-19 associated moderate-to-severe ARDS. Subgroup analyses examined: 1) RCTs versus retrospective cohort studies (study design), 2) Asia versus Europe and America (study region), 3) single center versus multi-center (study center), 4) equal versus less than 2.0g/kg/day (dosage of IVIG).
Data Synthesis and Analysis
The data retrieved from the relevant articles were computerised and analysed by Review Manager V.5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen). MD with 95% CI for continuous outcomes (ICU and hospital LOS, VFDs), and OR with 95% CIs for dichotomous outcomes (mortality and need for IMV) were used to estimate the pooled effects. Random-effects model was used for better accommodation of heterogeneity. Heterogeneity was tested using the Cochran Q statistic (p＜0.1) and quantified with the I2 statistic, with a range of 0%–30% representing no or mild heterogeneity, 30%–60% as moderate heterogeneity and >60% as high heterogeneity. Publication bias was examined using funnel plots for qualitative assessment, using Egger’s linear regression test for quantitative assessment.
Trial sequential analysis
Trial sequential analysis (TSA) was performed to estimate the optimal sample size for the plausible conclusion in the use of IVIG in treatment for critically ill patients with COVID-19. Trial Sequential Analysis V.0.9.5.10 beta (Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark, available from www.ctu.dk/tsa) was used. Statistical significance was set at a two-tailed 0.05 level to establish hypothesis.