Clinical Burden of Symptomatic HEV ‐3 Infection in Southern Spain

BACKGROUND: Hepatitis E virus genotype 3 (HEV-3) is a major cause of acute hepatitis in Europe. However, the clinical burden of symptomatic infection in routine practice and the relative contribution of host and viral factors to disease severity remain incompletely defined. We aimed to characterise the clinical burden, molecular epidemiology and determinants of adverse outcomes in patients with symptomatic HEV-3 infection. METHODS: Prospective multicentre study including patients with suspected HEV infection from ten hospitals in southern Spain between 2022 and 2025. Samples were analysed at a central laboratory using a standardised diagnostic algorithm based on HEV IgM and HEV RNA testing, with molecular characterisation of viraemic cases. Demographic, clinical and outcome data were extracted from medical records. Multivariable logistic regression analyses were performed to identify factors associated with hospital admission and severe acute hepatitis. RESULTS: Among 1124 tested patients, 267 HEV infections were diagnosed (23.7%). Overall diagnostic positivity remained consistently high throughout the study period. Of the 267 patients, 111 (41.6%) required hospital admission, 14 (5.2%) developed severe acute hepatitis and three died (overall mortality 1.1%), all of whom had major comorbidities. Major comorbidity was independently associated with hospital admission and severe acute hepatitis, whereas HEV-3 clade was not. CONCLUSION: Symptomatic HEV-3 infection in southern Spain was associated with a substantial clinical burden. Adverse outcomes were driven primarily by host comorbidity rather than by the viral features assessed in this cohort, while molecular surveillance provided useful epidemiological context on circulating strains.