Prevalence of Rocahepevirus ratti (rat hepatitis E virus) in humans and rats in China

Abstract

Background & aims: Rocahepevirus ratti (rat hepatitis E virus; rHEV) is a ubiquitous pathogen of rats that has recently emerged as a cause of hepatitis in humans. Although several rHEV cases have been detected worldwide, the extent of human exposure to this hepatitis agent is still poorly defined. We conducted a multicenter surveillance study in China examining rHEV exposures in demographically diverse human populations from a One Health perspective.

Methods: In this multicenter cross-sectional study, we used fully validated rHEV IgG enzymatic immunoassays and reverse transcription PCR in 1,199 individuals with (n = 655) or without hepatitis (n = 544) recruited from three centers in China (Hainan, Hong Kong, and Shenzhen). The patient population included both urban and rural populations. Characteristics of infected individuals and phylogenetic links with rat epizootics were described.

Results: rHEV IgG seroprevalence was higher in the rural Hainan cohort (15/229, 6.6%) compared with Shenzhen (9/427, 2.1%) and Hong Kong cohorts (2/543, 0.4%) (p <0.0001). This difference persisted on multivariable logistic regression with an adjusted odds ratio of 20.52 (95% CI: 13.86-30.39). rHEV exposure was also associated with increasing age and environmental rodent exposure. We observed rHEV viraemia in two hepatitis patients (2/655; 0.3%) in Hainan and Hong Kong with hepatitis B and renal transplantation, respectively. The latter developed chronic hepatitis E. 19/509 (3.7%) rats captured in Hainan harbored rHEV. Both human rHEV isolates were phylogenetically related to rodent-derived rHEV strains circulating in Hainan and Hong Kong, respectively.

Conclusions: Humans are intermittently exposed to rHEV, especially in rural settings with rodent exposure. Overt hepatitis occurs in individuals with liver disease or immunosuppression. Spillover strains are related to epizootics in rodents offering opportunities for targeted disinfestation.

Impact and implications: Building on our previous work finding that Rocahepevirus ratti (rHEV) is a novel cause of sporadic viral hepatitis in humans, we studied rHEV exposures in humans from various epidemiological settings. We found intermittent exposure to rat hepatitis E in individuals living in both urban and rural settings with a markedly higher seroprevalence in the latter. Spillover viremic infections in individuals with underlying liver disease or immunosuppression were closely linked to epizootic rHEV strains circulating in rodents. Physicians and diagnostic laboratories should incorporate rHEV testing in algorithms for viral hepatitis while policymakers should consider rHEV surveillance in rodents to guide disinfestation efforts.

Keywords: Epidemiology; HEV; Hepatitis E virus; One Health; Rodents; Zoonosis.

Graphical abstract

Fig. 1

Optical density values of study participants in the bHEV and rHEV EIAs. Cut-offs of respective EIAs are represented by dotted lines as per Table 2. Patients with hepatitis are represented on the left while patients without hepatitis are represented on the right. Intergroup comparisons of mean ODs were performed using Dunnett’s multiple comparisons test. ∗∗p value <0.05, ∗∗∗∗p value <0.0001. n.s., not significant. bHEV, Paslahepevirus balayani; EIAs, enzymatic immunoassays; rHEV, Rocahepevirus ratti.

Fig. 2

Optical density values in bHEV and rHEV EIAs stratified by age (years) in the Hainan and Shenzhen cohorts. Mean optical density of each age band were compared with the <30 years old reference cohort using Dunnett’s multiple comparisons test. ∗∗p value <0.01. n.s., not significant. bHEV, Paslahepevirus balayani; EIAs, enzymatic immunoassays; rHEV, Rocahepevirus ratti.

Fig. 3

Sampling map of rodents in Hainan Island. (A) Number of rodents testing positive. Counties with detected rodent infestation are marked in red. (B) Phylogenetic tree of complete rHEV genomes and ORF2 sequences from this study. Maximum likelihood phylogenetic tree was inferred from a multiple sequence alignment of complete rHEV genomes and ORF2 sequences from this study (branches highlighted in red/bold) using IQ-TREE. Region of GU345043.1 covered by our ORF2 sequences are appended to the sequence identifiers. The best-fit substitution model selected by ModelFinder was GTR+F+I+R4. Branch supports were assessed using the SH-like approximate likelihood ratio test with 10,000 bootstrap replicates. Branches with less than 70% support were collapsed. Scale bar represents nucleotide substitutions per site.