IVIG Therapy Shows Insignificant Benefit to Reducing Mortality, Length of Hospitalization in Patients with COVID-19

The pathogenesis of COVID-19 appears to be driven by both the direct viral damage and an aggressive host inflammatory response, according to the authors of a study published in Reviews in Medical Virology. Intravenous immunoglobulin (IVIg) has been suggested as a treatment option in patients with COVID-19 due to its potential to target the viral and inflammatory segments in the disease’s pathogenesis. In prior research, it was shown to successfully treat inflammatory and autoimmune conditions that had multiple proposed immunomodulatory mechanisms. The authors of the current study analyzed prior research to investigate the potential impact of IVIg on mortality and the length of hospitalization in adult patients with COVID-19.

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A total of 2313 patient outcomes were evaluated across 13 studies. The studies involved were prospective, randomized, controlled trials or retrospective studies with control groups. The total numbers of mortality rates were extracted from patients in the experimental (IVIg; 1104) and control groups (1209), as well as the number of deceased patients. Further, for multiple timepoint mortality data reported in a particular study, a 28-day mortality was used. Hospital stay data were reported with the mean and standard deviation (SD) of days of hospitalization for both groups. The analysis excluded studies that evaluated IVIg use in pediatric COVID-19 cases or used a convalescent anti-SARS-CoV-2 plasma or immunoglobulins from convalescent anti-SARS-CoV-2 plasma.

Overall, the results from the evaluated studies suggest that there is no significant benefit to mortality or reducing length of hospitalization in adult patients with COVID-19 who receive IVIg therapy. Prospective study results suggest that IVIg therapy may increase the length of hospitalization in patients with severe COVID-19 infections.

Using a fixed effect model, 7 of the analyzed studies found no statistically significant benefit to mortality in severe and non-severe patient groups; however, a significant effect (risk ratio [RR] 0.57 [0.42; 0.79]) in the critically ill COVID-19 patient group had favored IVIg treatment. Further, of the remaining 6 studies, 3 had reported on patients who were critically ill with COVID-19 and found no significant effects to IVIg therapy (RR 0.86 [0.45; 1.57]).

A similar meta-analysis reported a lack of efficacy of IVIg affecting patient mortality outcomes, but it did find a statistically significant (MD −2.24 [−3.20; −1.27]) association with the length of hospital stay for patients in the moderate severity subgroup. Alternatively, the current analysis found that IVIg may increase the length of patient hospital stay; however, it found no significant effect on mortality. Due to the insignificant effect regarding mortality, it would appear unlikely that the increase in the duration of hospital stay is a result of the lower mortality in this patient subgroup, but serious adverse events associated with IVIg treatment (eg, renal impairment, thromboses, arrhythmias) could be a possibility, according to the study authors.

Further, the results indicate that the repurposing of IVIg to treat patients hospitalized with COVID-19 would not be beneficial to the lack of efficacy IVIg has on COVID-19. The study authors note that this could be due to the different SARS-CoV-2 variants evading antibodies in IVIg and the lack of standardized anti-SARS-CoV-2 titers in IVIg that lead to underdosing. In addition, IVIg’s production process is not efficient enough to match the development of new, invasive SARS-CoV-2 variants (eg, Omicron BA.2 12.1, BA.4, and BA.5) that can evade neutralizing antibodies occurring after vaccination.

Limitations of the meta-analysis includes the use of studies written in English despite IVIg therapy being primarily used in China, and most of the included studies were retrospective (7) whereas 2 studies were randomized, placebo-controlled, double-blind trials. In addition, the dosage and length of IVIg treatment varied between studies; however, the conducted meta-regression results demonstrate that the differences had no significant impact on patient outcomes. Further, a moderate to serious risk of bias was observed in the included non-randomized studies, and because the protocol for the meta-analysis was not prospectively registered, investigator bias is a possibility.

The analysis results demonstrate a lack of support for the use of IVIg in adult patients who are hospitalized with COVID-19. Additional high-quality, double-blind, randomized, placebo-controlled trials should be conducted to determine specific patient subgroups who may benefit from IVIg therapy, according to the study authors.

Reference

Marcec, R, Dodig, VM, Radanovic, I, Likic, R. Intravenous immunoglobulin (IVIg) therapy in hospitalised adult COVID-19 patients: a systematic review and meta-analysis. Rev Med Virol. 2022; 32(6):e2397. doi:10.1002/rmv.2397