Proteomics guided biomarker discovery, validation, and pathway perturbation in infection-related acute decompensation of cirrhosis.

Abstract

Background and aims: Inappropriate treatment of infections fuels drug-resistance, organ failures, and costs in cirrhosis. We explored proteomics to improve infection diagnosis and management in acutely decompensated (AD) cirrhosis.

Methods: We enrolled 391 patients with AD(92% males, median-age: 41 years), 84 in discovery-cohort(54 infected, 30 non-infected), 147 in validation-cohort-I(106 infected, 41 non-infected), and 160 in validation-cohort-II(108 infected, 52 non-infected). High-throughput proteomics identified biomarkers in discovery cohort, validated through ELISA in subsequent cohorts. A model for infection was evaluated through discrimination, calibration, and decision curves, and was externally validated.

Results: Infected patients exhibited higher leucocyte-counts, procalcitonin, organ failures, MELD, and 30-day mortality(p<0.001 each). Proteomics identified 516 proteins, 27 upregulated and 38 downregulated in infections. LGALS3BP, PLTP, CFP, and GPX3 were independently linked to infections (adjusting for severity and SIRS), with composite-AUC of 0.854(0.787-0.922) in validation-cohort-I. A PACIFY model(LGALS3BP+procalcitonin+CLIF-COF+lactate) predicted infections with AUC of 0.965;0.933-0.997 and 0.906;0.860-0.952 in validation-cohorts-I and II, outperforming procalcitonin, SIRS, WBC, NLR, neutrophil%, and composite models(p<0.001). Model demonstrated fair calibration, with decision curves indicating net benefit of model in treating infections, and reducing unnecessary antimicrobials use. Consistent findings were observed on external validation(AUC: 0.949; 0.916-0.982) re-enforcing the accuracy and clinical utility of model. A deployable app was developed for infection risk estimation, enhancing practical applicability. Impaired phagocytosis, complement functions, hypocoagulation, hypofibrinolysis, dysregulated carbohydrate metabolism, autophagy, heightened cell death, and proteolysis were key perturbed pathways in infections.

Conclusion: The study identifies novel protein signatures and pathways linked with infections in AD. A biomarker guided treatment of infections can limit unnecessary antimicrobials use and the burden of drug-resistance in cirrhosis.