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Multicenter Study
. 2022 Jul 7;26(1):204.
doi: 10.1186/s13054-022-04059-0.

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

Tim Rahmel #  1 , Felix Kraft #  2 , Helge Haberl  3 , Ute Achtzehn  4 , Timo Brandenburger  5 , Holger Neb  6 , Dominik Jarczak  7 , Maximilian Dietrich  8 , Harry Magunia  9 , Frieda Zimmer  3 , Jale Basten  10 , Claudia Landgraf  4 , Thea Koch  11 , Kai Zacharowski  6 , Markus A Weigand  8 , Peter Rosenberger  9 , Roman Ullrich  12 , Patrick Meybohm  13 , Axel Nierhaus  7 , Detlef Kindgen-Milles  5 , Nina Timmesfeld  10 , Michael Adamzik  3
Affiliations
Multicenter Study

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

Tim Rahmel et al. Crit Care. .

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 registration DRKS00025794 , German Clinical Trials Register, https://www.drks.de . Registered 6 July 2021.

Keywords: COVID-19; Coronavirus disease; Immunoglobulin M; Immunoglobulins; SARS-CoV-2.

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Conflict of interest statement

TR received a speaker’s honoraria from Biotest AG and grants from Deutsche Forschungsgemeinschaft (DFG) outside of the submitted work. FK has no conflict of interest to declare. HH has no conflict of interest to declare. UA has no conflict of interest to declare. TB has no conflict of interest to declare. HN has no conflict of interest to declare. DJ has no conflict of interest to declare. MD has no conflict of interest to declare. HM received a speaker’s honorarium from CSL Behring (Germany) outside the submitted work. FZ has no conflict of interest to declare. JB has no conflict of interest to declare. CL has no conflict of interest to declare. TK has no conflict of interest to declare. KZ has received honoraria for participation in advisory board meetings for Haemonetics and Vifor and received speaker fees from CSL Behring and GE Healthcare. He is the Principal Investigator of the EU-Horizon 2020 project ENVISION (Intelligent plug-and-play digital tool for real-time surveillance of COVID-19 patients and smart decision-making in Intensive Care Units) and Horizon Europe 2021 project COVend (Biomarker and AI-supported FX06 therapy to prevent progression from mild and moderate to severe stages of COVID-19). MAW received speakers or advisory board honoraria from Biotest, SOBI, Pfizer, Gilead, MSD, Shionogi, Eumedica, BBraun. PR has no conflict of interest to declare. RU received speaker’s honoraria from Biotest AG outside of the submitted work and grants from Apeptico, Bayer and CCORE. He is a founding partner of CCORE, a medical device company. PM received speaker’s honoraria from Biotest AG outside of the submitted work. AN received speaker’s honoraria and travel reimbursement from Biotest AG, and speaker’s honoraria from ThermoFisher Scientific, CyoSorbents and Dräger Medical outside of the submitted work. DKM has received speaker’s honoraria from Biotest AG. NT has no conflict of interest to declare. MA received a speaker’s honoraria from Biotest AG and grants from the State of North Rhine Westphalia outside of the submitted work.

Figures

Fig. 1
Fig. 1
Adjusted hazard ratios of COVID-19 patients regarding 30-day survival. Intergroup imbalances were adjusted using multivariate Cox regression and different propensity score weighting approaches. The rows represent different groups/subgroup analysis of COVID-19 patients
See this image and copyright information in PMC

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