AGRA – a functional biomarker for humoral immune function predicts the development of severe bacterial infections in cirrhosis

Patients with liver cirrhosis often suffer from severe infections which are commonly accompanied by life-threatening complications. A method to predict the occurrence of severe infection in these patients and therefore improve the chance to prevent them is currently missing. Serum, as many other body fluids and tissues, is rich in antimicrobial peptides and proteins that can kill or inhibit the growth of pathogens, including a wide range of bacteria. Here we describe a novel biomarker, acellular growth retardation ability (AGRA), that is based on these humoral immune responses to determine the infection risk of patients with liver cirrhosis. AGRA was measured in patients with liver cirrhosis (n = 146), pre-cirrhotic chronic hepatitis C (CHC) patients (n = 81) or healthy controls (n = 42). Patients with cirrhosis of various aetiologies (n = 88) were followed-up for a median time of 36 months and severe infections were recorded. Patients with chronic hepatitis C infection with and without cirrhosis underwent antiviral therapy and AGRA was monitored throughout its course. AGRA successfully predicted the occurrence of severe infections in patients with liver cirrhosis (AUROC [95%CI]: 0.8[0.7; 0.9]; p < 0.001) and highlighted the severe impairment of humoral immune responses in CHC patients. Patients with CHC related cirrhosis showed significantly impaired (= higher) AGRA (0.014 ± 0.012ΔOD/h) compared to patients with alcoholic pathogenesis (0.0016 ± 0.009ΔOD/h; p < 0.001) or other types of aetiologies (-0.0022 ± 0.0068ΔOD/h; p < 0.001). CHC patients also showed impaired AGRA in absence of cirrhosis compared to healthy controls (0.010 ± 0.013 and -0.0015 ± 0.0069ΔOD/h, respectively; p < 0.001). After antiviral therapy AGRA significantly improved in patients with (p < 0.001) and without cirrhosis (p = 0.001). AGRA can be used to predict severe infection in cirrhosis and therefore identify patients at risk with increased need for preventive measures. It can also be used to show that impaired humoral immune responses are an extrahepatic manifestation of CHC which can be improved by antiviral therapy.