Intravenous IgM-enriched immunoglobulins in critical COVID-19: a multicentre propensity-weighted cohort study

Abstract

Background A profound inflammation-mediated lung injury with long-term acute respiratory distress and high mortality is one of the major complications of critical COVID-19. Immunoglobulin M (IgM)-enriched immunoglobulins seem especially capable of mitigating the inflicted inflammatory harm. However, the efficacy of intravenous IgM-enriched preparations in critically ill patients with COVID-19 is largely unclear. Methods In this retrospective multicentric cohort study, 316 patients with laboratory-confirmed critical COVID-19 were treated in ten German and Austrian ICUs between May 2020 and April 2021. The primary outcome was 30-day mortality. Analysis was performed by Cox regression models. Covariate adjustment was performed by propensity score weighting using machine learning-based SuperLearner to overcome the selection bias due to missing randomization. In addition, a subgroup analysis focusing on different treatment regimens and patient characteristics was performed. Results Of the 316 ICU patients, 146 received IgM-enriched immunoglobulins and 170 cases did not, which served as controls. There was no survival difference between the two groups in terms of mortality at 30 days in the overall cohort (HRadj: 0.83; 95% CI: 0.55 to 1.25; p = 0.374). An improved 30-day survival in patients without mechanical ventilation at the time of the immunoglobulin treatment did not reach statistical significance (HRadj: 0.23; 95% CI: 0.05 to 1.08; p = 0.063). Also, no statistically significant difference was observed in the subgroup when a daily dose of ≥ 15 g and a duration of ≥ 3 days of IgM-enriched immunoglobulins were applied (HRadj: 0.65; 95% CI: 0.41 to 1.03; p = 0.068). Conclusions Although we cannot prove a statistically reliable effect of intravenous IgM-enriched immunoglobulins, the confidence intervals may suggest a clinically relevant effect in certain subgroups. Here, an early administration (i.e. in critically ill but not yet mechanically ventilated COVID-19 patients) and a dose of ≥ 15 g for at least 3 days may confer beneficial effects without concerning safety issues. However, these findings need to be validated in upcoming randomized clinical trials. Trial registrationDRKS00025794, German Clinical Trials Register, https://www.drks.de. Registered 6 July 2021.

Multifaceted Tissue-Protective Functions of Polyvalent Immunoglobulin Preparations in Severe Infections—Interactions with Neutrophils, Complement, and Coagulation Pathways

“…A larger randomized, controlled clinical trial in patients with severe COVID-19 treated with IgM/IgA-enriched Ig preparations showed a trend towards a reduced composite deterioration/mortality rate (p = 0.096) when treatment was started before invasive mechanical ventilation and before respiratory dysfunction and coagulopathy had progressed into advanced stages [143]. A similar benefit with IgM/IgAenriched Ig preparations was observed in other studies in COVID-19 patients with less advanced disease (Table 1, [144]) [144,145].…”

Rising anti-SARS-CoV-2 titer in a human immunoglobulin preparation

“…The immunomodulatory properties of the antibody molecules may be of greater importance in critically ill patients, as initial clinical data with an IgM-enriched preparation are encouraging [21]. We expect that further clinical trials will provide a better picture of the possibilities of treating COVID-19 with antibodies.…”

Case Series: Efficacy of Polyclonal Intravenous Immunoglobulin for Refractory Clostridioides difficile Infection

“…Changes in galactosylation, fucosylation, and sialylation are now well-established factors which drive differential IgG function, ranging from inhibitory/anti-inflammatory to activating complement and promoting antibody-dependent cellular cytotoxicity [ 42 ]. Finally, in light of recent antibody-based therapy research which has been stimulated by SARS-CoV-2 and which has been met with some success [ 43 , 44 , 45 , 46 , 47 ], consideration should also be given to the development and testing of IgM-enriched IVIg preparations or the utilisation of hyperimmune IVIg to provide standardised and controlled antibody content from patients that have recovered from CDI who have anti-toxin neutralising antibodies in their plasma. It would also be of interest to investigate the role of combinatorial therapy to enhance the capability of IVIg.…”