Dysregulated biomarkers of innate and adaptive immunity predict infections and disease progression in cirrhosis

Background & Aims: Cirrhosis-associated immune dysfunction (CAID) affects both innate and adaptive immunity. This study investigated the complement system, immunoglobulins, and acute-phase proteins and their prognostic relevance in patients with advanced chronic liver disease (ACLD).Methods: Patients with ACLD (hepatic venous pressure gradient [HVPG] >-6 mmHg) but without acute decompensation/in-fections were characterised by HVPG and by clinical EASL stages: compensated (cACLD; S0-2) vs. decompensated ACLD (dACLD) with previous variceal bleeding (S3), non-bleeding decompensation (S4), or further decompensation (S5). Com-plement factors (C3c, C4, CH50), immunoglobulins (IgA, IgM, IgG, IgG1-4), acute-phase proteins and systemic inflammation biomarkers (white blood cells, C-reactive protein, IL-6, procalcitonin) were measured.Results: A total of 245 patients (median model for end-stage liver disease score: 11 [9-15], median HVPG: 17 [12-21] mmHg) were included with 150 (61%) presenting dACLD. Complement levels and activity significantly decreased in dACLD substages S4 and S5 (p <0.001). Total IgA/IgM/IgG and IgG1-4 subtype levels increased in patients with dACLD (all p <0.05). Complement and immunoglobulin levels correlated negatively and positively, respectively, with systemic inflammation (all p <0.05). High IgG-1 (adjusted hazard ratio per 100 mg/dl: 1.12, 1.04-1.19, p = 0.002) and IL-6 (adjusted hazard ratio: 1.03, 1.00-1.05, p = 0.023) levels predicted the development of infections during follow-up. High IgA (stratified by median; log-rank p <0.001), high IgG1 (log-rank p = 0.043) and low C3c (log-rank p = 0.003) indicated a higher risk of first/further decompensation or liver-related death (composite endpoint). Next to HVPG and IL-6, low C3c (adjusted hazard ratio per mg/dl: 0.99, 0.97-0.99, p = 0.040) remained independently associated with the composite endpoint on multivariate Cox regression analysis.Conclusions: Complement levels and immunoglobulins may serve as surrogates of cirrhosis-associated immune dysfunction and associate with cirrhosis severity and systemic inflammation. Low complement C3c predicted decompensation and liver -related death, whereas high IgG-1 indicated an increased risk for infections.Impact and Implications: Patients with cirrhosis are at increased risk for infections, which worsen their prognosis. We found a significant dysregulation of several essential components of the immune system that was linked to disease severity and indicated a risk for infections and other complications. Simple blood tests identify patients at particularly high risk, who may be candidates for preventive measures.Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03267615).& COPY; 2023 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).