Higher prevalence of cytomegalovirus and Epstein–Barr virus in acute-on-chronic liver failure

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BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome characterized by rapid deterioration of organ function in pre-existing chronic liver disease. Patients who develop ACLF within 90 days after decompensation are referred to as pre-ACLF. Known precipitants include bacterial infections and viral hepatitis. However, in 40-60% of patients, the precipitant remains unknown. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are highly prevalent viruses, but their impact on ACLF is unclear. METHODS: 211 patients (43 ACLF, 16 pre-ACLF, and 152 non-ACLF) of the ACLF-I study and an external validation cohort with 153 patients (39 ACLF, 33 pre-ACLF, and 81 non-ACLF) were included. Sera were analyzed for CMV/EBV DNA (multiplex qPCR), cytokines in 102 ACLF-I samples (multiplex assays), and immunoglobulins in 80 case-control matched ACLF-I and 20 validation cohort patients (immunoassays), and correlated with clinical data. RESULTS: In the ACLF-I group, a higher prevalence of CMV DNAemia (8.9% vs. 25.6%, odds ratio [OR] 3.51, 95% CI 1.47-8.34, p <0.01) and EBV DNAemia (6.6% vs. 16.3%, OR 3.01, 95% CI 1.10-8.62, p <0.05) was observed in ACLF compared to non-ACLF cases, despite the absence of clinical signs of viral infections. 54.8% of DNAemic ACLF patients in the validation cohort had no identified precipitant compared to 26.5% in ACLF patients without DNAemia (p <0.05). CMV was associated with liver failure (p <0.001) and with 90-day mortality (p <0.001) in the regression model. DNAemia was associated with a distinct pattern of inflammatory activity. The results were validated externally. Serological analyses revealed that reactivation rather than primary infection occurred in most cases defined as DNAemic. CONCLUSIONS: Presence of CMV/EBV DNAemia in chronic liver disease may contribute to the development of ACLF by exacerbating liver inflammation and impairing hepatocellular function. IMPACT AND IMPLICATIONS: Despite ACLF being a life-threatening syndrome, the underlying precipitant cannot be identified in 30-40% of cases. As a result, intervention in ACLF development is limited to cases with known precipitants. To our knowledge, this is the first time it is shown that previously undiagnosed CMV and EBV DNAemia might act as a precipitating event inducing ACLF. We propose that routine screening and proper treatment for CMV and EBV in decompensated cirrhotic patients can intervene in ACLF development. This hypothesis needs to be assessed in prospective studies. CLINICAL TRIALS REGISTRATION: NCT04975490.

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