# Efficacy of High-Dose Polyclonal Intravenous Immunoglobulin in COVID-19: A Systematic Review
## 4 Discussion  
Following the first trial demonstrating the efficacy of high-dose IVIG in patients with severe COVID-19 [23], other studies were conducted in this setting to assess the impact of IVIG on various clinical outcomes, mainly on mortality. High-dose polyclonal IVGs are supposed to be immunosuppressive at doses in the range of 2 g per kg of recipient body weight. Given that COVID-19 largely resembles an autoimmune disorder in the late stages,  
Figure 4: Forest plot of adverse events. IVIGs are presumed to act as an immune modulator by dampening the excessive immune response to SARS-CoV-2 which drives pathology [33; 34]. A systematic review and meta-analysis by [PERSON] and colleagues on three clinical trials and three cohort studies [12] found that the effect of IVIG was associated with the severity of COVID-19, as it was highest in the critical subgroup. Our updated systematic review, performed on a higher number of studies and including more patients, gave different results. Although the length of hospitalization was significantly reduced in the IVIG group versus controls, a subgroup analysis showed that this effect was present only in patients with moderate disease. Regarding the main outcome \"mortality\", the use of IVIG was not associated with a significantly reduced risk of death, independently of COVID-19 severity or type of study (RCT or non-RCT). Such results are in accordance with a recently published living systematic review and network meta-analysis [35]. The majority of trials included in this systematic review were judged to be at high risk or at unclear risk of bias in many of the items of the ROB tool for RCTs and the ROBIN-1 tool for non-RCTs. Of the four RCTs, three were at high risk of performance (open-label trials), three were at unclear risk of detection bias (because it was unclear if the assessor was blinded to treatment allocation) and two at unclear risk of selection bias (because no clear information on allocation concealment was provided). Of the six non-RCTs, four were judged at high risk and two at unclear risk of confounding bias; three were judged at high risk and one at unclear risk of selection bias; all the non-RCTs were judged at unclear risk of bias for the domain bias in the measurement classification of interventions due to the retrospective nature of these studies. Moreover, considering the observed heterogeneity and imprecision in the effect size of the outcomes analyzed, the level of certainty of the available evidence was graded as low or very low. Another potential bias of this systematic review was the wide heterogeneity of IVIG doses in different studies, ranging from 0.1 to 1 g/kg/day. It is therefore possible that sub-immunosuppressive doses have diluted the beneficial effect of fully immunosuppressive doses in the meta-analysis. Adverse events were reported inconsistently and only in 4 of the 10 selected trials. Although overall adverse events and serious adverse events were rarely reported either in IVIG recipients or controls, the available evidence was graded as very low level of certainty due to inconsistency (small number of events and participants) and serious risk of bias. In conclusion, although IVIGs appeared to be safe in COVID-19 patients, their use did not result in a significant reduction in mortality. Thus, the results of this systematic review and meta-analysis do not support the use of high-dose IVIG in COVID-19 patients. Despite the initial signs of heterologous immunity to SARS-CoV-2 from previous seasonal coronavirus infection [36; 37], pre-pandemic sera have been shown to be devoid of neutralizing activity [38], making the occurrence of neutralizing activity extremely unlikely in lots manufactured from plasma collected before 2021. However, the situation is rapidly evolving, with most plasma donors worldwide becoming seropositive because of convalescence and/or vaccination. Baxter reported seropositivity in lots released since September 2020.