Towards the Improved Accuracy of Hepatitis E Diagnosis in Vulnerable and Target Groups: A Global Perspective on the Current State of Knowledge and the Implications for Practice

Abstract

The hepatitis E virus (HEV) is a positive single-stranded, icosahedral, quasi-enveloped RNA virus in the genus Orthohepevirus of the family Hepeviridae. Orthohepevirus A is the most numerous species of the genus Orthohepevirus and consists of eight different HEV genotypes that can cause infection in humans. HEV is a pathogen transmitted via the fecal-oral route, most commonly by consuming fecally contaminated water. A particular danger is the HEV-1 genotype, which poses a very high risk of vertical transmission from the mother to the fetus. Several outbreaks caused by this genotype have been reported, resulting in many premature births, abortions, and also neonatal and maternal deaths. Genotype 3 is more prevalent in Europe; however, due to the openness of the market, i.e., trade-in animals which represent a natural reservoir of HEV (such as pigs), there is a possibility of spreading HEV infections outside endemic areas. This problem is indeed global and requires increased hygiene measures in endemic areas, which entails special care for pregnant women in both endemic and non-endemic regions. As already highlighted, pregnant women could have significant health consequences due to the untimely diagnosis of HEV infection; hence, this is a population that should be targeted with a specific combination of testing approaches to ensure optimal specificity and sensitivity. Until we advance from predominantly supportive treatment in pregnancy and appraise the safety and efficacy of a HEV vaccine in this population, such screening approaches represent the mainstay of our public health endeavors.

Keywords: diagnosis; hepatitis E; hepatitis E virus; pregnancy.

Figure 1

Hepatitis E virus genome organization. The genome is 7.2 kb positive-strand RNA with a 5′ 7-methylguanosine cap (7 mG cap) and a 3′ polyadenylated tail (polyA). It harbors four open reading frames (ORF). ORF1 codes nonstructural proteins, including a methyltransferase (MET), an RNA helicase (Hel), and an RNA-dependent RNA polymerase (RdRp), as well as less well-characterized domains, such as the Y domain, a papain-like cysteine protease (PCP), a hypervariable region (HVR), and the X domain. ORF2 and ORF3 encode the viral capsid and a small protein involved in virus secretion, respectively, translated from a 2.2 kb subgenomic RNA generated during viral replication. The ORF4 is found in the HEV-1 genotype and codes protein enhanced viral replication.

Figure 2

Hepatitis E virus life cycle consists of (1) attachment to heparan sulfate proteoglycans and entry to host cell; (2) clathrin-dependent endocytosis; (3) release of the positive-strand RNA genome into the cytosol; (4) translation to produce the ORF1 proteins; (5) replication via a negative-strand RNA mediator and synthesis of genomic and 2.2 kb subgenomic RNAs; (6) translation of the subgenomic RNA to produce the ORF2 and ORF3 proteins; and (7) packaging, virion assembly, and release of the newly formed virus.

Figure 3

Algorithm for HEV infection diagnostic. Combining serological and nucleic acid testing is the best. The negative PCR test does not exclude the recent infection. Serology assays are sometimes negative in immunocompromised patients. Both negative test results rule out the HEV infection.