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/infections 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). Complement 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).