The pro-inflammatory deletion allele of the NF-κ\kappaB1 polymorphism is characterized by a depletion of subunit p50 in sepsis

The functionally important NF-$\kappa$B1 promoter polymorphism (−94ins/delATTG) significantly shapes inflammation and impacts the outcome of sepsis. However, exploratory studies elucidating the molecular link of this genotype-dependent pattern are lacking. Accordingly, we analyzed lipopolysaccharide-stimulated peripheral blood mononuclear cells from both healthy volunteers ($\it n$ = 20) and septic patients ($\it n$ = 10). All individuals were genotyped for the −94ins/delATTG NF-$\kappa$B1 promoter polymorphism. We found a diminished nuclear activity of the NF-$\kappa$B subunit p50 in ID/DD genotypes after 48 h of lipopolysaccharide stimulation compared to II genotypes ($\it p$ = 0.025). This was associated with higher TNF-α (p = 0.005) and interleukin 6 concentrations (p = 0.014) and an increased production of mitochondrial radical oxygen species in ID/DD genotypes ($\it p$ = 0.001). Although ID/DD genotypes showed enhanced activation of mitochondrial biogenesis, they still had a significantly diminished cellular ATP content ($\it p$ = 0.046) and lower mtDNA copy numbers ($\it p$ = 0.010) compared to II genotypes. Strikingly, these findings were mirrored in peripheral blood mononuclear cells taken from septic patients. Our results emphasize the crucial aspect of considering NF-$\kappa$B subunits in sepsis. We showed here that the deletion allele of the NF-$\kappa$B1 (−94ins/delATTG) polymorphism was associated with the lower nuclear activity of subunit p50, which, in turn, was associated with aggravated inflammation and mitochondrial dysfunction

Intravenous IgM-enriched immunoglobulins in critical COVID-19

$\bf Background:$ 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. $\bf Methods:$ 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. $\bf Results:$ 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 ($HR_{adj}$: 0.83; 95% CI: 0.55 to 1.25; $\it p$ = 0.374). An improved 30-day survival in patients without mechanical ventilation at the time of the immunoglobulin treatment did not reach statistical significance ($HR_{adj}$: 0.23; 95% CI: 0.05 to 1.08; $\it p$ = 0.063). Also, no statistically significant difference was observed in the subgroup when a daily dose of $\geq$ 15 g and a duration of $\geq$ 3 days of IgM-enriched immunoglobulins were applied ($HR_{adj}$: 0.65; 95% CI: 0.41 to 1.03; $\it p$ = 0.068). $\bf Conclusions:$ 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 $\geq$ 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