Molecular Hydrogen Reverses Sepsis-induced Immunoparalysis: Insights from Longitudinal Deep Immunophenotyping

Abstract

Background/Aim: Refractory septic shock and post-cardiac arrest syndrome (PCAS) can induce lethal immunoparalysis. However, longitudinal evidence on the effects of molecular hydrogen on deep human immunophenotyping remains scarce. Case Report: We report the case of a 49-year-old man with severe tricuspid regurgitation and Child-Pugh class B alcoholic cirrhosis who developed severe pneumonia, refractory septic shock, and PCAS after high-energy thoracic trauma. At a therapeutic impasse marked by high levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) (>35,000 pg/ml) and profound immune depletion, adjuvant hydrogen inhalation was initiated, which led to a 64% reduction in myocardial stress and temporary clinical stabilization. Deep longitudinal flow cytometry unveiled system-wide immunological reprogramming. In the T-cell compartment, hydrogen induced a biphasic resolution of exhaustion in T-helper cells marked by an immediate decline in expression of FAS cell surface death receptor (FAS; also known as CD95) and asynchronous normalization of expression of programmed cell death protein 1 (PD1) and T-cell immunoglobulin and mucin domain 3 (TIM3), alongside bidirectional restoration of physiological immune checkpoints in cytotoxic T-cells. Furthermore, we observed a sequential, compensatory recovery of the regulatory T-cell (Treg)/type 1 regulatory T-cell (Tr1) immune-braking system. In the humoral compartment, despite prolonged bone marrow suppression and loss of transitional/regulatory B-cells, hydrogen therapy was associated with a V-shaped recovery of plasma and double-negative (for both cluster of differentiation 27 and immunoglobulin D) B-cells. It also appeared to protect switched memory B-cells by markedly reducing FAS expression, suggesting an anti-apoptotic effect. Conclusion: Although the patient ultimately succumbed to irreversible chronic comorbidities on day 86, this case of severe tricuspid regurgitation and Child-Pugh class B alcoholic cirrhosis demonstrates profound yet transient immunological rescue. By disrupting the cycle of immune exhaustion and exerting anti-apoptotic effects, molecular hydrogen may represent a promising immunomodulatory adjunct in severe sepsis.