Rat hepatitis E virus as an aetiological agent of acute hepatitis of unknown origin
Javier Caballero‐Gómez, Marı́a Casares-Jiménez, Marina Gallo-Marín, S Couto Pereira, Adrián Beato‐Benítez, Antonio Poyato, Rafael Guerra, Ana Avellón, Katja Schilling‐Loeffler, Carolina Freyre‐Carrillo, Ignacio García‐Bocanegra, Débora Jiménez‐Martín, Diana Corona‐Mata, Isabel Viciana, T. T. Fajardo, Milagros Muñoz-Chimeno, Miguel Ángel Quevedo, Lucía Ríos-Muñoz, Ana Belén Pérez, David Cano‐Terriza, Juan Macías, Ana Fuentes, Reimar Johne, Antonio Rivero‐Juárez, Antonio Rivero
Abstract
BACKGROUND & AIMS: Rat hepatitis E virus (ratHEV) is an emerging cause of acute hepatitis worldwide. The limited number of ratHEV cases may be associated with the lack of a proper method for molecular diagnosis; thus, the clinical impact and breadth of ratHEV as a cause of acute hepatitis remain uncertain. METHODS: The study was carried out in four phases. I) Identification: molecular assays were identified through a literature search. II) Testing: the methods were evaluated in a rodent testing cohort, and the most suitable molecular diagnostic algorithm was established. III) Derivation: the established algorithm was tested in a larger rodent cohort. IV) Clinical validation: the algorithm was used in a cohort of individuals suffering from acute hepatitis of unknown aetiology, thus establishing the frequency of ratHEV as an aetiological agent of acute hepatitis and its clinical impact. RESULTS: We detected differences in the frequency of positive results among the assays evaluated. After comparing all available molecular methods, we established a molecular diagnostic algorithm, which revealed that 17.5% of the 103 rodents in the validation cohort were infected with ratHEV. In the clinical validation cohort, of 562 patients with acute hepatitis of unknown origin, eight cases of ratHEV infection were identified during the 3 years of the study, representing a frequency of 1.4%. One (37.5%) case had severe acute hepatitis; four (50.0%) patients required hospitalization, one of whom (12.5%) died. The strains detected in these patients revealed a close phylogenetic relationship with those found in rats in Spain. CONCLUSIONS: Our study demonstrated that ratHEV is an emerging and underdiagnosed cause of acute hepatitis. The results provide evidence that ratHEV should be monitored and included in the differential diagnosis of acute hepatitis. IMPACT AND IMPLICATIONS: While rat hepatitis E virus (ratHEV) is a newly emerging zoonotic virus worldwide, the results of the present study indicate that the molecular diagnostic methods used for this virus may be inappropriate. After establishing a proper molecular diagnostic algorithm using available assays, we demonstrated that ratHEV is an emerging and underdiagnosed aetiological agent of acute hepatitis of unknown origin. The results also expand our knowledge on the diversity of ratHEV strains capable of infecting humans in Europe. These findings strongly suggest that ratHEV should be monitored and included in the differential diagnosis of acute hepatitis. CLINICAL TRIAL NUMBER: ClinicalTrials.gov Identifier: NCT05062967.