Facts about hepatitis E

Introduction

Hepatitis E virus (HEV), the pathogen causing acute hepatitis E, is the most common cause of acute viral hepatitis world-wide [1]. The virus can infect both animals and humans. Four genotypes of HEV are endemic in different regions in the world infecting humans only (HEV-1 and HEV-2) or both humans and animal species (HEV-3 and HEV-4). In developed countries the virus is a zoonosis mainly transmitted to humans through consumption of contaminated, not-properly-cooked pork or game meat or other meat products, but also through shellfish or contaminated vegetables (HEV-3 and HEV-4) while in developing countries the fecal-oral route predominates (HEV-1).

Over the last 10 years, human hepatitis E cases have been increasingly reported in Europe where genotype 3 (HEV-3) is common and mostly responsible for human hepatitis E virus infections. The main reservoir of HEV in Europe are pigs and wild boar. The majority of the infections are asymptomatic or mild. In acute cases the disease is a self-limiting hepatitis affecting mostly male adults above 60 years of age; on rare occasions the infection can result in a severe, fulminant hepatitis with acute liver failure.

Immunosuppressed people e.g. organ transplant recipients under immunosuppressive therapy, are at risk of developing chronic hepatitis E infection. Recently, extrahepatic manifestations have also been described in patients with acute and chronic HEV-3 infection causing neurologic symptoms (e.g. Guillain-Barré Parsonage-Turner syndrome, neuralgic amyotrophy, bilateral brachial neuritis, peripheral neuropathy and encephalitis), organ injuries, or hematological disorders [2].

Case definition

HEV is not notifiable on a European level and no EU-wide case definition is available. Surveillance systems, case definitions and testing recommendations for target groups vary between the EU/EEA Member States.

The pathogen

Hepatitis E is caused by the Hepatitis E virus (HEV), a positive-stranded RNA virus of the Hepeviridae family. The family Hepeviridae, genus Orthohepevirus, comprises 4 species, Orthohepevirus A–D. Orthohepevirus A contains 7 genotypes (HEV-1–7) [3,4]. Genotypes 1 and 2 infect humans only, while genotypes 3, and 4 are zoonotic and can infect humans and other mammals; genotypes 5 and 6 infect animals only. HEV-7 has been recently detected in a dromedary camels and transmitted to an immunosuppressed patient in the Middle East [5]. For each genotype multiple subgenotypes have been classified with 20 reference strains assigned for genotype 3 within two major clades, one containing 6 subtypes (3a, 3b, 3c, 3h, 3i and 3j) and the other with 3 subtypes (3e, 3f, 3g) [3,4].

In Europe, autochthonous infections are mostly related to HEV-3; however, sporadically also infections with other genotypes can be detected that are either locally acquired (HEV-4) or travel-associated.

Clinical features and sequelae

HEV infection in humans is mostly an asymptomatic infection. The majority of cases do not develop any symptoms but seroconvert. The incubation period is estimated to be between two and six weeks (up to 60 days) [6]. In acute cases the infection causes a self-limiting hepatitis initially with fatigue, asthenia, nausea, fever and jaundice. Other signs can be elevated liver enzyme levels and abnormal liver function tests, abdominal pain and hepatosplenomegaly. Most people with an acute infection recover completely within one to five weeks. In a few cases the acute infection can result in fulminant hepatitis with acute liver failure. Patients with pre-existing chronic liver disease are at risk of severe disease progression with liver failure.

HEV-1 and -2, endemic in African and Asian countries, can cause severe disease and fulminant hepatitis particularly in pregnant women, with up to 21% mortality [7]. In Europe, where HEV-3 is endemic, the infection is not associated with severe disease in pregnant women and thus they are not considered as risk group [8].

Chronic infections

Persistent HEV replication can be observed in some patients, and persistence of the virus for more than three months is considered chronic [9]. Immunocompromised patients and those with underlying chronic diseases are at risk to develop chronic HEV infection with prolonged viraemia (>6 months). These patients show limited symptoms of hepatitis or non-specific clinical symptoms and can develop liver cirrhosis with fatal outcome [9]. Patients with solid-organ transplantation, pre-existing liver disease or with haematological malignancy are at increased risk for chronic disease development [10,11]. However, conditions associated with immunodeficiency might not in general be a risk factor for HEV infection and chronic disease progression [12,13].

Extra-hepatic manifestation

Hepatitis E infections do not only affect the liver but have been associated within extra-hepatic manifestations affecting several other organ systems, including neurologic symptoms, organ injuries, or hematological disorders. In solid-organ or bone marrow transplant recipients hepatitis E has caused other symptoms affecting other organ systems [14,15]. Hepatitis E infection has been associated with neurological disorders e.g. Guillain-Barré Parsonage-Turner syndrome, neuralgic amyotrophy, bilateral brachial neuritis, peripheral neuropathy and encephalitis [16,17]. Other extra-hepatic manifestations are renal injuries including membranoproliferative glomerulonephritis with or without cryoglobulinemia and membranous glomerulonephritis, acute pancreatitis, and other autoimmune manifestations such as myocarditis, arthritis and thyroiditis [17]. Thrombocytopenia and other haematological disorders have also been observed [18].

Epidemiology

HEV is the most-common cause of acute viral hepatitis in humans world-wide. The disease is generally self-limiting, but high death rates have been observed among HEV-infected pregnant women in developing countries where genotype 1 is prevalent.

Males above 50 years of age represent the majority of acute cases of HEV infection reported across EU/EEA countries [19]. Over the last 10 years a 10-fold increase in reported cases was observed in EU/EEA countries with more than 5 500 cases in 2015. Several EU/EEA countries reported an apparent increase of human cases related to HEV infection in recent years, which might be associated with a better HEV detection and diagnosis but also an increasing awareness among clinicians [19]. More than 50% of the reported cases were reported to be admitted to a hospital. However, the proportion of hospitalised cases has decreased over the last 10 years which suggest that surveillance systems increasingly capture milder cases. Five of 12 EU/EEA countries collecting data on outcome reported 28 deaths between 2005 and 2015. The majority (>95%) of human infections were autochthonous infections due to genotype 3, with the main subtypes HEV-3e, f, c, but all other subtypes are detectable [20]. Only a few travel-associated cases were reported.

Available data on seroprevalence in EU/EEA countries show increasing seropositivity with age and highest values in people aged 60 years or over. The studies differ in terms of the sampled population as well as in the estimates. Seroprevalence estimates differ between, but also within, countries e.g. the average prevalence in Germany and France is around 20% [21,22] while in high-endemic regions in Southern France over 86% of the blood donors are tested HEV positive [11,22,23]. Occupationally exposed persons working in slaughterhouses, forestry workers, hunters, farmers or veterinarians showed higher seropositivity than the general population [23,24]. Central European countries show higher seropositivity than e.g. Nordic European countries.  However, serological findings are significantly influenced by the respective test applied.

Transmission

HEV infections due to genotypes 1, 2 and 4 are related to poor sanitation conditions in developing countries in Asia, Africa and Central America.

In Europe, Hepatitis E is a mainly a zoonotic disease due to genotype 3 viruses. Person-to-person transmission of the European genotype 3 viruses is thought to be rare [25]. HEV has been identified in a wide range of animals, with pigs being the primary reservoir in Europe. Consumption of undercooked pork, game meat or other meat products and occupational contact with pigs or wild boar are risk factors for HEV infection [26,27]. Molecular studies have confirmed infection via contaminated food products, mainly derived from pork [28,29]. Aside from pork meat, shellfish consumption has been shown as source of infection [30]. The differences in seroprevalence between and within countries probably reflect a different exposure of the population to the virus as well as a lower or higher endemicity within the source population pigs. It also reflects regionally different consumer habits that result in higher risk of acquiring HEV infection e.g. through the consumption of raw pig liver products contaminated with HEV. Also occupationally exposed groups with direct contact to infected animals e.g. slaughterhouse and forestry workers, hunters, farmers and veterinarians showed higher seropositivity than the general population.

Transfusion or transplantation transmitted HEV-infections have been observed sporadically and it is considered that asymptomatic infection among blood donors is widespread [14]. The European Medicines Agency (EMA) assessed the viral safety of plasma-derived medicinal products regarding HEV and noted that transmission events have been observed for all blood products, risk assessment should be performed when sufficient data are available for each product [31]. In the last decade, an increasing incidence of HEV genotype 3 positive donations has been documented in several European countries. Prevalence estimates in blood donors show also a regional and age-specific distribution [32,33]. England and Ireland have started selective or universal screening of blood donations and other countries are considering similar screening [34].

Diagnostics

Hepatitis E diagnosis of an acute infection is confirmed with the positive detection of anti-HEV IgM in serum and/or HEV RNA in serum or stool samples. The detection of the HEV genome is usually performed by generic PCR or real-time RT-PCR assays that are able to broadly detect the HEV genotypes 1 to 7 [35]. Resulting PCR products are used for sequencing and typing of the strains.

Antibody–based methods (Western blot or enzyme immunoassays) are applied to detect anti-HEV IgM or IgG antibodies. IgM anti-HEV are used as marker for diagnosis of acute infection and the presence of anti-HEV IgG indicates a previous infection. Studies have shown that different ELISA assays often provide discordant results.

Efficient cell culture system for HEV are lacking. HEV infectivity is either determined in experimental inoculation of animals or with cell culture techniques [36].

Case management and treatment

Acute hepatitis E infection is considered to be a self-limiting disease and no specific treatment is recommended. However, risk groups such pregnant women, people with pre-existing liver disease, or immunosuppressed patients may require antiviral treatment. In some cases, the reduction of immunosuppressive treatment supports the clearance of the virus. Antiviral therapy with Ribavirin and in some cases pegylated interferon alpha is indicated as treatment of chronic infections [37].

Public health control measures

In December 2011, the first HEV recombinant subunit vaccine (Hecolin®) was registered in China for the prevention of HEV infection and HEV-related diseases in humans. So far, it has not been licensed and approved in any other country. Although randomized controlled trials have shown a high efficiency and very low number of serious adverse events following hepatitis E vaccination, it is not recommended by WHO for routine use in children aged under 16 years, pregnant women, people with chronic liver disease, people on organ transplant waiting lists, and travellers [38,39]. The current WHO position concerning routine vaccination programs should not preclude the use of the vaccine in specific situations such as outbreaks where the risk of hepatitis E or of its complications or mortality is particularly high.

Infection control, personal protection and prevention of infection

Overall, consumption of raw or undercooked pig meat and shellfish should be avoided in all parts of the world. It is important to make sure that processed food containing pig meat is well cooked. When travelling to countries with poor sanitation, it is advisable to boil all drinking water, including water used for brushing teeth. Wearing working gloves and boots might reduce HEV infection in those workers with occupational exposure to HEV-infected animals [24]. 

Person to person transmission of the HEV-3 is very rare. Good hygiene practice minimises cross-contamination and should be applied particularly when handling food.

Transfusion or transplantation-related HEV transmission events have been described and the conduction of risk assessment is recommended for each product with special consideration of risk groups. Some assessments stated that transfusion-transmitted infection plays a minor role as source of infection in the risk group of solid-organ recipients and risk factors have been identified to be consumption of pork or game meat [40,41].

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