Acute sporadic hepatitis E in the Zhejiang coastal area of China: a 14-year hospital-based surveillance study

Hepatitis E virus (HEV) is a non-enveloped positive-sense RNA virus and the only member of the family Hepeviridae [1]. HEV strains frequently related to human infections belong to species Orthohepevirus A, in which there are 8 major genotypes (HEV1–8) [2]. To date, five genotypes of mammalian HEV (genotypes 1–4 and 7) are known to affect humans [2, 3]. HEV1 and 2 only infect humans, and are responsible for waterborne epidemics in developing regions [3], whereas zoonotic genotypes HEV3, HEV4 and HEV7 might infect human beings via foodborne transmission from different animal reservoirs (pigs and camels), but the principal reservoir is domestic pigs (HEV3 and 4), three genotypes are responsible for sporadic cases in both developed and developing countries [3‐5].

Hepatitis E is predominantly circulating in many developing countries in Asia, Africa, and Latin America [6, 7], especially in countries with pig farms and coastal areas [8]. China is recognized as a hyperendemic area for hepatitis E [9, 10], where a high seroprevalence has been observed among the overall population (23.46%) [11]. The epidemiological and etiological changes have been gradually identified in China since the largest HEV outbreak in 1986 in Xinjiang Uighur autonomous region of China [12]. First of all, the predominant HEV genotype in China has changed from genotype 1 to genotype 4 [13]. Secondly, the number of hepatitis E cases increased, with an annual percentage change of 7% in China overall, with eastern China having the highest prevalence [14]. Thirdly, a higher health risk of hepatitis E cases was found in the workers who have direct contact with raw seafood or users of water and consumers of shellfish contaminated by HEV in the Bohai coastal area of China [15, 16]. A series of articles have recorded hepatitis E incidence in the inlands of China, especially in rural areas [9, 10]. However, human beings infected with HEV in the coastal area of eastern China appear to be extremely limited.

This study aimed to elucidate the epidemical trends and changes as well as the related risk factors among east-coast residents in Zhejiang Province, China. We reviewed China’s National Notifiable Disease Report System and hospital information systems (HIS) in four coastal cities (Wenzhou, Taizhou, Ningbo, and Zhoushan cities, Zhejiang Province) along the East China Sea, with 24,287,966 Chinese residents, accounting for 43.45% of the general population (55,899,795) in Zhejiang Province, 2017. This location is one of the most densely populated urban agglomeration areas in Zhejiang. The information extracted from this study is needed to better understand the epidemiological profile of hepatitis E cases, and will be valuable for the extensive administration of the HEV vaccine in coastal areas of China in the future. To our knowledge, this is the largest epidemiological study that has been done on hepatitis E cases in coastal areas of Zhejiang Province.

On the basis of a 14-year period of hospital surveillance, we described an ongoing decreasing trend of acute sporadic hepatitis E in the east-coast area of Zhejiang. Through more than 9000 confirmed hepatitis E cases, this largest study discovered the epidemiological trend and changes as well as high risks for hepatitis E cases who lived in the developed coastal areas of Zhejiang.

This study demonstrated that the number of cases in the east-coast area of Zhejiang showed a decreasing trend since 2007. In coastal areas where swine are raised, swine manure could be a source of HEV contamination of irrigation water or coastal waters with concomitant contamination of produce or shellfish [15, 21]. The consumption of this contaminated seafood and water may contribute to the increasing risk of zoonotic foodborne HEV circulation [15, 16]. Our finding was in stark contrast to the experiences in the other parts of China and European countries [22‐24]. For example, Jiang et al. have reported that the morbidity caused by HEV has been increasing over the recent decade and is centered on the coastal region of Yaitai of eastern China [23]. Mansuy et al. reported that the incidence of hepatitis E in southwest France was stable from 2003 to 2007 [24]. There may be several reasons for the decrease found in Zhejiang. First, the decrease in hepatitis E incidence could have resulted either from a true decrease in the number of cases or from the dominant genotype shift in China from G1 to G4 since 2000 [17, 25]. In coastal areas, seafood consumption increased from 4.15 million tons in 2004 to 4.91 million in 2015 in these areas [2016 Zhejiang Province of China Statistical Yearbook,], greater than the increase in pork consumption during that time; note that domestic pigs serve as an important reservoir for genotypes 3 and 4 [26, 27]. Second, the water supply and sanitation systems have been improved through projects to improve drinking water and lavatories by providing water pipe networks and water purification facilities as well as sewage treatment in rural areas of Zhejiang Province in 2009 (internal data from Zhejiang Centers for Disease Control and Prevention). These steps may have decreased the transmission and infection of HEV in these areas. Third, the decrease in HEV was related to stricter regulations on large-scale swine farming and centralized slaughter in recent years, including restricting release of pollutants such as feces and sewage to the external environment, occupational protection, and HEV surveillance.

The epidemiological analysis indicated no change in the seasonal pattern or demographic features of hepatitis E cases in the past 14 years [14, 17]. Our study showed that cases of acute hepatitis E occurred regularly throughout the year during the study period, but the incidence rate was highest during March. The annual pattern was similar to those of the inland cities of China [6, 17, 28]. However, the seasonality pattern remained distinct from those in northern India and Uganda [29]. The peak time may be associated with the pattern of food preparation and excessive meat and seafood consumption that occurs during this season, which coincides with the Chinese New Year [6, 13].

The age and gender profile of infection reported in these coastal areas is in agreement with that in previous studies: Men and farmers are at great risk of acute hepatitis E in the inlands of China and Europe, and most are middle aged or elderly [14, 17, 30, 31]. For patients aged over 50 years in particular, HEV infection increased with age. On one hand, these trends could be linked to the behavior of patients, occupational exposure, and/or broad social involvements in comparison with younger patients [13, 32]. On the other hand, HEV4 is the predominant strain among older patients in China, in comparison with epidemic HEV1 and HEV2, which predominate in young age groups [33]. These results are consistent with a study conducted in China’s coastal city of Yantai [23]. Conversely, the low incidence rates and the relative paucity of laboratory-confirmed cases in pediatric populations further strengthen the hypothesis that children are unrecognized or underdiagnosed because of anicteric hepatitis or subclinical infection [34, 35]. Asymptomatic infection is common with HEV3 and HEV4 [3, 33].

The clinical phenotypes of hepatitis E cases ranging from mild to fatal disease and extra-hepatic manifestation [33, 36] are not yet fully understood. Slightly over half of the patients (102 cases, 50.50%) in the current study were severe when admitted to hospital. We searched for the reasons for this disease severity, with a focus on host factors, and found that middle-aged men, especially smokers, had greater disease severity. Furthermore, alcohol consumers carried the highest risk for severe hepatitis E cases. The excessive alcohol consumption in coastal communities may play a role in the presentation of clinically overt hepatitis E infection [37]. Alcohol intake accelerates the degree of hepatic fibrosis, increases the risk of liver diseases, and worsens the clinical outcome of liver diseases [37‐40]. Previous reports suggested an association between severe hepatitis infection and pre-existing diseases [41]. Indeed, 60.39% of the hepatitis E cases had pre-existing chronic liver diseases; among these cases, coinfection with hepatitis B virus and alcoholic liver disease were the most common. Altogether, older men who are high alcohol consumers, those with alcoholic liver disease, and HEV-superinfected individuals have a greater risk of developing severe diseases in the coastal areas of China relative to the other areas in China [13, 39].

We documented 202 cases of autochthonous hepatitis E infection in the eastern coastal area of Zhejiang. The number of hepatitis E cases accounted for approximately 4.4% of AVH. Affected patients in the coastal areas have hepatic symptoms similar to those seen in the inlands of China [20]. We found 84.65% of hepatitis E cases were jaundiced at presentation. The majority of severe hepatitis E infections had liver derangement, of which total bilirubin (TBi) and direct bilirubin (DBi) concentrations significantly increased compared to mild and moderate hepatitis E cases [21]. This finding indicates that these markers are the important predicators of severe hepatitis E infections.

This research found that the clinical progress of hepatitis E cases in the coastal areas of Zhejiang Province is very similar to that in the inland areas of China. The clinical progress and outcome are influenced by several factors, including the patient consultation time, diseases severity, medical diagnosis and treatment, etc. This study showed that the average days from illness onset to being discharged in the severe cases were much longer than in mild and moderate hepatitis E cases. The same result was found in the average days from admission to discharge from the hospital. This could be due to the longer antivirus treatment and restoration of liver functions for these hepatitis E cases [20]. At 4 weeks, all patient had normalized serum bilirubin or ALT levels and survived in these four eastern coastal areas of Zhejiang. The result is not consistent with the Monga et al. study, which found that superimposed acute hepatitis E infection with chronic liver disease has a protracted course (8 weeks) with high morbidity and mortality [42].

This study has several limitations. First, hepatitis E case surveillance was not thorough, and most cases (where the disorder was asymptomatic and mild, or the patient did not seek formal care) went undetected. Second, we did not analyze the changes in the diagnosis and report status in the past 14 years. Third, our study was based on the notifications of surveillance data, without examining the genotypes to estimate the shift of HEV genotypes in these coastal areas in Zhejiang.

A hepatitis E recombinant vaccine (HEV 239) was developed by Chinese scientists and licensed by the Chinese Food and Drug Administration FDA in 2012 [43, 44]. The broad application of HEV vaccination is the most efficient way to reduce hepatitis E cases in at-risk populations, as the HEV vaccine not only protects against hepatitis E infection but also decreases the severity [45]. These findings support the prioritization of HEV vaccination and the optimization of the timing of vaccination for those coastal residents of China in the future.

This is the largest study to investigate the general epidemiology trend and the related risks factors of hepatitis E cases in the east-coast areas of Zhejiang Province, China. The results demonstrate a decrease in the incidence of hepatitis E cases since 2007 in the coastal areas, inconsistent with the increasing trend in the inlands of China. The incidence in coastal areas was much lower than the non-coastal areas. However, the seasonal and demographical features of hepatitis E cases in the coastal cities are similar to those non-coastal cities. Middle-aged men who are alcohol consumers, alcohol hepatic diseases, and superinfection are the three highest independent risk factors that induce severe hepatitis E infections in the eastern coastal areas of China.