The HEV genus belongs to the Picornaviridae family. HEVs were originally divided into five subgroups, including polioviruses, group A coxsackieviruses (CVA), group B coxsackeviruses (CVB), echoviruses (ECV), and "newer" EVs. This genus, with the exception of polioviruses, comprises over 90 immunologically distinct serotypes that cause human infections. These viruses are also classified genetically into HEV-A to HEV-D, and shown in Table 113-¹⁶⁾.

EV infections are acquired by ingestion or respiratory droplet that is shed in the feces or upper respiratory tract. Initial viral replication occurs in the mucosal tissues of the intestine and nasopharynx. Initial replication in the pharynx and intestine is followed within days by multiplication in lymphoid tissues such as the tonsils, Peyer's patches, and regional lymph nodes. A primary, transient viremia (minor viremia) results in a spread to distant parts of the reticuloendothelial system, including the liver, spleen, bone marrow, and distant lymph nodes.

Further replication in theses organs leads to a sustained "major" viremia with dissemination of the virus to target organs such as the central nervous system, heart, and skin, resulting in a clinical infection. Tropism to target organs is determined, in part, by the infecting serotype16,¹⁷⁾.

Although most infections in children subside mildly or asymptomatically, HEVs can also be responsible for severe, potentially life-threatening disease¹⁸⁾.

HEVs can cause asymptomatic infections, nonspecific febrile illness, hand-foot-and-mouth disease, herpangina, and acute hemorrhagic conjunctivitis. HEVs can also cause respiratory diseases such as an exacerbation of asthma, apnea, respiratory distress, pneumonia, otitis media, bronchiolitis, croup, parotitis, pharyngotonsillitis, and pleurodynia. HEVs are involved in myocarditis and pericarditis as well as gastrointestinal diseases, such as emesis, abdominal pain, diarrhea, hematochezia, pneumatosis intestinalis, necrotizing enterocolitis, hepatitis, and pancreatitis. HEVs cause genitourinary diseases, such as orchitis, epididymitis, nephritis, and immunoglobulin A nephropathy and neurological manifestations including aseptic meningitis, encephalitis, poliomyelitis-like acute flaccid paralysis, brainstem encephalitis, Guillain-Barré syndrome, transverse myelitis, cerebellar ataxia, opsoclonus-myoclonus syndrome, as well as benign intracranial hypertension. HEVs are involved in cutaneous manifestations such as, exanthem, petechial rashes, purpuric rashes and papular acrodermatitis. HEVs have been associated with myositis, arthritis and neonatal infections.

HEV infections may initiate an inflammatory insult to pancreatic islet cells and thereby contribute to the development of type 1 insulin-dependent diabetes mellitus16,¹⁹⁾.

HEV infections are common in children particularly those <1 year of age20,²¹⁾. Various HEV serotypes are spreading globally by temporal and regional distribution. Epidemics of HEV typically peak during the summer and fall, and predominant serotypes are often associated with a single outbreak²²⁾. The predominant serotypes vary from year to year, and HEV epidemics in Korea may be affected by environmental shifts induced by climate change due to global warming21,²³⁾. Therefore, systemic long-term epidemiological studies should be conducted to prevent the spread of HEVs and to identify proper anti-viral therapies.

HEVs are the leading cause of aseptic meningitis, which is the most frequent central nervous system infection worldwide24,²⁵⁾. The isolation of HEVs often focuses on a single outbreak with aseptic meningitis. Aseptic meningitis in Korea was the most common manifestation in children with enteroviral infection²²⁾, the Chungnam data that is shown in Table 2 show similar results. Followed by aseptic meningitis, HEVs are isolated from patients with respiratory illness, acute gastroenteritis, herpangina, and hand foot mouth disease (HFMD) (Table 2)21,²³⁾. No disease is uniquely associated with any specific serotype, although certain manifestations are preferentially associated with specific serotypes²⁶⁾.

HEVs infect millions of people worldwide each year, mostly children and young adults, and different HEV serotypes are spreading globally each year. The prevalent HEV serotypes vary yearly among ECV6, 9, 18, and 30, but CVB1 is the type most frequently isolated in Europe and the USA in recent years27,²⁸⁾.

Since 1993, when nationwide surveillance began in Korea, there have been reports of summer outbreaks of various HEV types, such as ECV6, 9, 13, 30, and CVA24²⁹⁾. The recent epidemic of HEV serotypes in Chungnam, Korea included EV71, ECV5, 6, 18, 30, and CVB1 and 5 (Table 3) and reflected the national trend21,²³⁾. In a previous study, EV71 was detected in 5 cases among a total 24 enterovirus cases (20%) in 2007 and 12 cases (11%) among 107 cases in 2009. There were no identified cases of EV 71 in 2005, 2006 and 2008 (Table 3). Severe EV 71-induced HFMD with neurological complications was frequently reported in Korea nowadays26,³⁰⁾.

In individuals <1 year of age, the number of tested samples and HEV-positive cases were high in Chungnam, Korea (Table 4)21,²³⁾. Typically, HEV-positive cases are widely distributed throughout the year in tropical and semitropical regions, prominent in the summer and fall, but are far less detected in the winter and spring. The temporal pattern of HEV epidemics in Chungnam, Korea represents a remarkable seasonality, with cases occurring from June to August (Fig. 1)21,²³⁾. The ratio of male to female HEV-positive patients was approximately 1.6:1 in the Chungnam area.

Generally, serotypes of HEVs epidemic were different each year, and epidemic patterns may change due to environmental changes31,³²⁾. HEVs have a high mutation rate due to the absence of proofreading activity during genome replication. Additionally, about a 20% genetic difference occurred between prototype strains and the current widespread strains, and the difference was at the HEV cleavage site31,³²⁾. Thus, the development and screening of antiviral drugs against HEV should focus on the current epidemic strains.

The current antiviral drug armamentarium comprises approximately 40 compounds that have been formally licensed for chemotherapy in humans with viral infection. Most are used to treat infections caused by human immunodeficiency virus, hepatitis B virus, herpesviruses, varicella-zoster virus, cytomegalovirus, influenza virus (IFN), respiratory syncytial virus, and hepatitis C virus. At present, there is no specific antiviral drug to treat or prevent diseases caused by HEVs³⁵⁾.

An easy way to overcome the limitation of antiviral drugs is the screening of traditional medicinal plants. Medicinal plants, for their ability to have multiple targets, minor side effects, low potential to cause resistance, and low cost may be suitable alternative sources of antiviral agents. The screening of medicinal plants as a possible source of antiviral agents has led to the discovery of potent inhibitors of in vitro viral growth and the use of the ethnopharmacological approach which enhances the probability of identifying new bioactive plant compounds45,⁴⁶⁾. The structures of the below listed compounds are also shown in Table 5¹⁸⁾. Oseltamivir, was marketed under the trade name Tamiflu (Roche, Basel, Switzerland), is an IFN antiviral drug that originated from shikimic acid isolated from Chinese star anise, an ancient cooking spice; this herb is also used in traditional Chinese medicine.

The development of a new antiviral drug is a difficult task considering the poorly selective toxicity and cost. To screen traditional medicinal plants is one way to overcome these problems. Another way to accelerate the availability of existing antiviral drugs is to approve them for an HEV antiviral effect. For example, amantadine, an M2 channel inhibitor for IFN and ribavirin that showed antiviral activity against ECV5 and 18 as well as EV71 in an in vitro test (Fig. 2)31,32,⁵⁰⁾.