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Seroprevalence and risk factors of hepatitis E virus infection in cancer patients in eastern China

  • Meng-Jie Bai
    Affiliations
    State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, PR China
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  • Na Zhou
    Affiliations
    Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, PR China
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  • Wei Dong
    Affiliations
    Weihaiwei People’s Hospital, Weihai, Shandong Province, PR China
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  • Guang-Xing Li
    Affiliations
    State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, PR China

    Holistic Integrative Pharmacy Institutes (HIPI), Hangzhou Normal University, Hangzhou, PR China
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  • Wei Cong
    Correspondence
    Corresponding authors at: State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, Gansu Province, PR China.
    Affiliations
    State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, PR China

    Marine College, Shandong University, Weihai, Shandong Province, PR China
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  • Xing-Quan Zhu
    Correspondence
    Corresponding authors at: State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, Gansu Province, PR China.
    Affiliations
    State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, PR China
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Open AccessPublished:April 12, 2018DOI:https://doi.org/10.1016/j.ijid.2018.04.003

      Abstract

      Objectives

      Hepatitis E virus (HEV) is a single-stranded RNA virus infecting a variety of animals and humans. Little is known of HEV infection among cancer patients in China. This study provides new epidemiological data for the prevalence of HEV co-infection in cancer patients, indicating that HEV infection is common in this group.

      Methods

      A total of 950 cancer patients and 950 control volunteers from Shandong Province, eastern China, were recruited to participate in this investigation. Blood samples from patients and controls were examined for anti-HEV IgG and IgM antibodies using ELISAs.

      Results

      The overall seroprevalence of IgG and IgM antibodies to HEV was significantly higher in cancer patients (247/950, 26.0%) than in controls (123/950, 13.0%) (p< 0.001). In cancer patients, 22.7% of serum samples were anti-HEV IgG-positive, and in control subjects, 11.0% were anti-HEV IgG-positive (p< 0.001). For IgM antibodies, seroprevalence was 4.2% in cancer patients (n = 40) and 2.1% in controls (n = 20) (p = 0.009). The seroprevalence of HEV was higher in cancer patients who had dogs in their home (31.7%) when compared to other cancer patients. The highest seroprevalence of HEV infection was found in leukemia patients (32.3%), followed by liver cancer patients (31.1%); the lowest HEV seroprevalence was detected in patients with gastric cancer (18.9%).

      Conclusions

      This investigation revealed that the seroprevalence of HEV was significantly higher in cancer patients than in controls in eastern China. Therefore, cancer patients are a high-risk population and should be kept away from sources of HEV infection.

      Keywords

      Introduction

      Cancer is one of the greatest global threats to human health. Data from 20 world regions reported an estimated 7.6 million cancer deaths in 2008 alone, with 63.0% of cancer deaths occurring in under-developed regions (
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      ). Cancer incidence has been increasing in China, with approximately 4.3 million new cancer cases in 2015 (
      • Chen W.
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      Cancer statistics in China.
      ). There are many factors predisposing individuals to cancer, including genetic, environmental, behavioral, and social factors. It has been known for a long time that pathogen infection can also be a major cause of high cancer death rates, including infections with Toxoplasma gondii, HIV, and hepatitis E virus (HEV) (
      • Atsama M.A.
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      Hepatitis E virus infection as a promoting factor for hepatocellular carcinoma in Cameroon: preliminary observations.
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      Toxoplasma gondii infection in cancer patients: prevalence, risk factors, genotypes and association with clinical diagnosis.
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      ). Epidemiological studies have revealed that almost 15% of cancer incidence is related to microbial infections (
      • Rakoff-Nahoum S.
      Why cancer and inflammation?.
      ). For example, it has been suggested that a hepatitis B virus (HBV) X protein (HBx) is associated with tumor progression in HBV-associated hepatocellular carcinoma (HCC) (
      • Yen C.S.
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      miR-106b promotes cancer progression in hepatitis B virus-associated hepatocellular carcinoma.
      ). Regarding HEV, it can cause mild or moderate liver damage, resulting in the production and regeneration of growth factors or evolution into cirrhosis, and may eventually lead to the development of HCC (
      • Atsama M.A.
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      Hepatitis E virus infection as a promoting factor for hepatocellular carcinoma in Cameroon: preliminary observations.
      ).
      Immunocompromised individuals are more susceptible to protracted and even chronic infections with pathogens, including HEV (
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      ). Hepatitis E, caused by HEV, is usually a self-limiting disease, and the virus can be transmitted via the fecal–oral route (
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      ). Hepatitis E is a much neglected hepatitis in developing and under-developed countries, especially in Asia and Africa, where sanitary conditions are poor (
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      Hepatitis E: epidemiology and natural history.
      ). Previous studies have shown that one-third of the world’s population have been exposed to HEV (
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      Hepatitis E virus: foodborne, waterborne and zoonotic transmission.
      ). Humans infected with HEV present with non-specific symptoms, such as fever, lethargy, vomiting, and jaundice. The disease often leads to acute infection with a mortality rate of approximately 2.0% (
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      ). It is therefore essential to investigate the prevalence of HEV infection worldwide.
      Currently, there are limited reports of HEV co-infection in patients with cancer. Atsama et al. described an association between anti-HEV IgG prevalence and HCC in a study performed in Cameroon (
      • Atsama M.A.
      • Atangana P.J.A.
      • Noah D.N.
      • Moundipa P.F.
      • Pineau P.
      • Njouom R.
      Hepatitis E virus infection as a promoting factor for hepatocellular carcinoma in Cameroon: preliminary observations.
      ), and another case of HCC complicating chronic hepatitis E has been reported in a French cirrhotic patient (
      • Borentain P.
      • Colson P.
      • Bolon E.
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      • Gérolami R.
      Hepatocellular carcinoma complicating hepatitis E virus–related cirrhosis.
      ). Of note, two other hepatitis viruses – HBV and hepatitis C virus (HCV) – are causative agents of liver cancer in the setting of chronic hepatitis and, most often, liver cirrhosis. It makes sense that chronic hepatitis E, which results in liver inflammation and fibrosis, might also lead to liver cirrhosis. The present study examined the seroprevalence of HEV infection in other cancer patients, including those with leukemia, lung, liver, and breast cancers, and investigated associated risk factors.

      Materials and methods

      Ethics statement

      This project was approved by the ethics committees of the Affiliated Hospital of the Qingdao University and the Weihaiwei People’s Hospital in Qingdao and Weihai, China, respectively. The purpose of the study and the procedures used in the study were explained to all participants, and written informed consent was obtained. All serum samples analyzed in this case–control study were provided voluntarily by the participants.

      Study population

      A case-controlled seroprevalence study of 950 cancer patients and 950 members of the healthy population was performed. During the period February 2012 to July 2015, 950 cancer patients from the Affiliated Hospital of the Medical College, Qingdao University and from Weihai People’s Hospital were invited to participate in this study. All patients had received a cancer diagnosis and volunteered to participate in the study. Control subjects (n = 950) were selected randomly from the general healthy population of Weihai and Qingdao cities, Shandong Province, eastern China. Written informed consent was obtained from each of the control participants and they were matched to the cancer patients by sex, age, and area of residence. Serum samples from the cancer patients and the control subjects were examined for the presence of anti-HEV IgG and IgM antibodies.

      Sample collection, transportation, and serological assay

      Approximately 5 ml of venous serum was obtained from the participants. Blood samples were maintained overnight at room temperature to allow clotting and then centrifuged at 1000 × g for 10 min. The serum was collected in 1.5-ml Eppendorf tubes and stored at 4 °C for 24–72 h before being transported in an icebox to the State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Gansu Province, China. Serum samples were then frozen at −20 °C until needed for testing. Serum samples from the cancer patients and controls were analyzed for anti-HEV IgG and IgM antibodies using commercially available HEV IgG and IgM enzyme immunoassay kits (Wantai Biological Pharmacy Enterprise, Beijing, China). In this study, all procedures were performed in accordance with the manufacturer’s instructions.

      Socio-demographic, clinical, and behavioral data

      Socio-demographic, clinical, and behavioral data were collected from the cancer patients and the control subjects using a structured questionnaire and recorded. Socio-demographic data included the participant’s age, sex, place of birth, and current area of residence. Clinical data included the type of cancer diagnosed in the patient. Behavioral data were contact with animals (dogs and/or cats), consumption of raw or undercooked meat, eating raw vegetables, exposure to soil, and the participant’s sources of drinking water (tap water or well).

      Statistical analysis

      The statistical analysis was performed using the software Win Episcope 2.0, SAS 9.1, and IBM SPSS Statistics 22. Variables potentially associated with HEV infection were explored and all behavioral characteristics were studied by multivariable logistic regression; only a p-value of ≤0.10 was considered as statistically significant between levels within factors and interactions. The odds ratio (OR) and 95% confidence interval (CI) were calculated using logistic regression analysis, and a p-value of <0.05 was considered statistically significant.

      Results

      In this study, the overall seroprevalence of anti-HEV antibodies in cancer patients was 26.0% (247/950) and in control participants was 13.0% (123/950); the difference between groups was statistically significant (p< 0.001). Anti-HEV IgG antibodies were found in 216 (22.7%) of the 950 cancer patients and in 104 (11.0%) of the 950 control subjects (p< 0.001). With regard to anti-HEV IgM antibodies, the seroprevalence was 4.2% in cancer patients (n = 40) and 2.1% in controls (n = 20) (p = 0.009) (Table 1, Table 2). Analysis of socio-demographic characteristics revealed that the higher proportion of HEV infection occurred in males (29.0%, 110/379) and the rural group of cancer patients (27.8%, 130/467) (Table 1).
      Table 1Socio-demographic characteristics of cancer patients and controls in Qingdao and Weihai, China.
      CharacteristicCancer patients (n = 950)Control subjects (n = 950)p-Value

      Cancer patients vs. control subjects
      Prevalence of HEV infectionPrevalence of HEV
      No. testedNo. positive%p-ValueNo. testedNo. positive%p-Value
      Age group (years)
       ≤301373626.31011211.90.006
       31–401815027.60.7891772815.80.3680.007
       41–502345523.50.5492472710.90.799<0.001
       51–601524026.30.9942182913.30.7240.002
       >602466626.80.9072072713.00.773<0.001
      Sex
       Male37911029.03764110.9<0.001
       Female57113724.00.0835748214.30.129<0.001
      Residence, place
       Qingdao43610524.15006412.8<0.001
       Weihai51414227.60.2154505913.10.887<0.001
      Residence, area
       Urban48311724.24685712.2<0.001
       Rural46713027.80.2044826613.70.487<0.001
      HEV, hepatitis E virus.
      Table 2Combined IgG and IgM anti-HEV antibody seroprevalence in cancer patients and controls.
      Sero-reactionCancer patients (n = 950)Control subjects (n = 950)p-Value

      Cancer patients vs. control subjects
      No. positive%No. positive%
      IgG21622.710411.0<0.001
      IgM404.2202.10.009
      IgG+/IgM+90.910.10.011
      IgG+/IgM−20721.810310.8<0.001
      IgG−/IgM+313.3192.00.086
      Total24726.012313.0<0.001
      HEV, hepatitis E virus; +, positive; −, negative.
      Table 3 shows the behavioral characteristics of cancer patients and controls. Seven variables were analyzed: cat at home (p = 0.595), dog at home (p = 0.041), non-resident contact with cats and dogs (p = 0.265), consumption of raw/undercooked meat (p = 0.764), consumption of raw vegetables (p = 0.395), exposure to soil (p = 0.845), and the participant’s source of water (p = 0.388). When data were combined for all control participants, there was a significant difference between cancer patients and controls (p< 0.01). However, the prevalence of HEV was significantly higher in cancer patients when compared with members of the general population.
      Table 3Behavioral characteristics of cancer patients and controls in Qingdao and Weihai, China.
      CharacteristicCancer patients (n = 950)Control subjects (n = 950)p-Value

      Cancer patients vs. control subjects
      Prevalence of HEV infectionPrevalence of HEV infection
      No. testedNo. positive%p-ValueNo. testedNo. positive%p-Value
      Cat at homeYes1844524.51582012.70.006
      No76620226.40.59579210313.00.906<0.001
      Dog at homeYes1996331.7184168.7<0.001
      No75118424.50.04176610714.00.056<0.001
      Contact with cats and dogsYes44812427.75747112.4<0.001
      No50212324.50.2653765213.80.512<0.001
      Consumption of raw meatYes3549426.63033712.2<0.001
      No59615325.70.7646478613.30.644<0.001
      Consumption of raw vegetablesYes2466928.03124414.1<0.001
      No70417825.30.3956387912.40.458<0.001
      Exposure to soilYes39510426.35196813.1<0.001
      No55514325.80.8454315512.80.876<0.001
      Source of drinking waterTap61015325.16398012.5<0.001
      Well3409427.70.3883114313.80.573<0.001
      HEV, hepatitis E virus.
      Analysis of the clinical diagnosis data of the cancer patients examined (Table 4) showed that the highest HEV seroprevalence occurred in patients with leukemia (10/31, 32.3%), followed by liver cancer (31.1%), and the lowest seroprevalence was detected in patients with gastric cancer (10/53, 18.9%). There was a significant difference in HEV seroprevalence between all cancer patient groups and the control subjects (p < 0.05), with the exception of gastric cancer (p = 0.216). Table 5 shows that contact with dogs (OR 1.266, 95% CI 1.240–1.293; p< 0.001) is a potential risk factor for HEV infection.
      Table 4Clinical diagnosis and seroprevalence of hepatitis E virus in cancer patients in Qingdao and Weihai, China.
      Clinical diagnosisCancer patients with anti-HEV antibodies
      No. testedNo. positive% (95% CI)OR (95% CI)ap-Valueb
      Leukemia311032.3 (15.8–48.7)3.2 (1.5–7.0)0.002
      Nasopharynx cancer711723.9 (14.0–33.9)2.1 (1.2–3.8)0.009
      Lung cancer651827.7 (16.8–38.6)2.6 (1.5–4.6)<0.001
      Liver cancer1033231.1 (22.1–40.0)3.0 (1.9–4.8) <0.001
      Thyroid cancer792126.6 (16.8–36.3)2.4 (1.4–4.2)<0.001
      Lymph cancer501428.0 (15.6–40.5)2.6 (1.4–5.0)0.003
      Ovarian cancer651523.1 (12.8–33.3)2.0 (1.1–3.7)0.021
      Brain cancer491326.5 (14.2–38.9)2.4 (1.3–4.7)0.007
      Breast cancer691826.1 (15.7–36.5)2.4 (1.3–4.2)0.002
      Parotid cancer491428.6 (15.9–41.2)2.7 (1.4–5.1)0.002
      Gastric cancer531018.9 (8.3–29.4)1.6 (0.8–3.2)0.216
      Rectal cancer791924.1 (14.6–33.5)2.1 (1.2–3.7)0.006
      Others1874624.6 (18.4–30.8)2.2 (1.5–3.1)<0.001
      HEV, hepatitis E virus; CI, confidence interval; OR, odds ratio.
      a,bAs compared with 13.0% seroprevalence of anti-HEV antibodies in controls (123/950).
      Table 5Odds ratios for characteristics of cancer patients and their association as risk factors with hepatitis E virus infection.
      CharacteristicOR95% CIap-Valueb
      Residence place (Weihai)1.2181.200–1.237<0.001
      Residence area (urban)0.7860.776–0.797<0.001
      Cat at home (yes)0.7670.750–0.784 <0.001
      Dog at home (yes)1.2661.240–1.293<0.001
      Contact with cats and dogs (yes)1.1571.134–1.181<0.001
      Consumption of raw meat (yes)1.0251.011–1.0400.001
      Exposure to soil (yes)1.1201.104–1.136<0.001
      OR, odds ratio; CI, confidence interval.
      a,bAs compared with negative cancer patients.

      Discussion

      A previous study has shown that inflammation is a key component of cancer progression, and many cancers can be induced by chronic irritation and inflammation (
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      In this case-controlled study, the HEV seroprevalence was found to be significantly higher in cancer patients than in controls (26.0% vs. 13.0%; p< 0.001). This difference may be due to the fact that cancer patients are usually immunosuppressed or immunocompromised and receive blood transfusions, immunosuppressive drugs, or cancer chemotherapy, which leads to higher susceptibility to protracted and even chronic infections, especially chronic infection with HEV. It is worth noting that transfusion is a potential mode of HEV transmission in cancer patients. A recent study examined the prevalence of HEV infection in blood donors in different regions of China and reported that anti-HEV IgM and anti-HEV IgG positivity was 1.1% and 30.0%, respectively; 6.2% of the anti-HEV IgM-positive donors tested positive for HEV RNA (
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      In the present study, the seroprevalence of HEV in cancer patients was not significantly influenced by age, sex, or area or place of residence. The highest HEV seroprevalence was found in male subjects. In a study performed in China, Li et al. reported that the seroprevalence of anti-HEV IgG was 47.1% among male participants and 39.7% among female participants (
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      ). Previous studies have found that HEV IgG prevalence is usually higher in males than in females (
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      HEV seroprevalence in rural cancer patients (130/467, 27.8%) was slightly higher than that in urban cancer patients (117/483, 24.2%) (p = 0.204). It is hypothesized that multiple risk factors might explain this slight difference, including the drinking of well-water and exposure to soil. Human HEV infection also occurs via food-borne and fecal–oral routes (
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      ). Rural areas, in which pigs act as a main reservoir for HEV, play an important role in agriculture and the economy of China. This is one of the most important factors underlying the higher HEV seroprevalence in rural cancer patients than in those living in an urban environment. In addition, the soil is easily contaminated by fecal-shed viruses such as HEV, and rural people are more likely to be exposed to the contaminated soil.
      Previous studies have also indicated that HEV prevalence increases with age (
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      Seroprevalence and risk factors of hepatitis E infection in Jordan’s population: first report.
      ), but this phenomenon was not found in the present study, possibly due to the different living conditions and susceptibility in the studied populations.
      This study examined behavioral characteristics to further probe HEV seroprevalence in cancer patients and controls. As with the social analysis, a significantly higher seroprevalence of HEV was found in cancer patients than in control participants. The highest HEV seroprevalence was observed in cancer patients with dogs at home (63/199, 31.7%), but the group who consumed high levels of raw vegetables had the highest HEV seroprevalence among control subjects (44/312, 14.1%). These results suggest that raising dogs and the consumption of raw vegetables are factors underlying HEV infection in humans.
      Dogs are readily exposed to contaminants and may spread HEV through soil, food, and feces. Recent studies have shown a high prevalence of anti-HEV antibodies in dogs (pet or stray) and humans exposed to dogs, so dogs play an important role as an HEV reservoir and in HEV transmission (
      • Wang L.
      • Zheng Y.
      • Fu C.
      • Huang S.
      • Hong M.
      • Yan Z.
      • et al.
      Seroprevalence of hepatitis E virus infection among dogs in several developed cities in the Guangdong province of China.
      ,
      • Zeng M.Y.
      • Gao H.
      • Yan X.X.
      • Qu W.J.
      • Sun Y.K.
      • Fu G.W.
      • et al.
      High hepatitis E virus antibody positive rates in dogs and humans exposed to dogs in the southwest of China.
      ). Vegetables contaminated with feces may cause HEV infection when eaten undercooked or raw (
      • Terio V.
      • Bottaro M.
      • Pavoni E.
      • Losio M.N.
      • Serraino A.
      • Giacometti F.
      • et al.
      Occurrence of hepatitis A and E and norovirus GI and GII in ready-to-eat vegetables in Italy.
      ). The results of this study showed no statistically significant association with other behavioral characteristics (p> 0.05), but previous studies have reported a link between HEV infection and close contact with cats or drinking contaminated water (
      • Chaussade H.
      • Rigaud E.
      • Allix A.
      • Carpentier A.
      • Touzé A.
      • Delzescaux D.
      • et al.
      Hepatitis E virus seroprevalence and risk factors for individuals in working contact with animals.
      ,
      • Junaid S.A.
      • Agina S.E.
      • Abubakar K.A.
      Epidemiology and associated risk factors of hepatitis E virus infection in plateau state, Nigeria.
      ,
      • Meng X.J.
      Hepatitis E virus: animal reservoirs and zoonotic risk.
      ,
      • Tsega E.
      • Krawczynski K.
      • Hansson B.G.
      • Nordenfelt E.
      • Negusse Y.
      • Alemu W.
      • et al.
      Outbreak of acute hepatitis E virus infection among military personnel in northern Ethiopia.
      ). These risk factors should not be neglected in livestock husbandry and in public health.
      The analysis of the clinical diagnosis revealed that patients with leukemia had the highest HEV seroprevalence (32.3%), which was significantly higher than in the healthy controls (adjusted OR 3.2, 95% CI 15.8–48.7; p< 0.05). This difference may be due to the fact that chronic or acute leukemia is a major hematological malignancy that causes immune deficits. Patients with acute lymphoblastic leukemia often receive stem cell transplants, radiation therapy, immunosuppressive drugs, or blood transfusions, which result in disruption of the immune system. The association between HEV and leukemia has been noted in a previous study conducted in the UK (
      • Woolson K.L.
      • Forbes A.
      • Vine L.
      • Beynon L.
      • McElhinney L.
      • Panayi V.
      • et al.
      Extra-hepatic manifestations of autochthonous hepatitis E infection.
      ). In the present study, the highest HEV seroprevalence was detected in patients with leukemia (32.3%), followed by liver cancer (31.1%), parotid cancer (28.6%), and lymph cancer (28.0%). The higher HEV prevalence in liver cancer is due to the close correlation between HEV infection and liver inflammation and fibrosis. Studies have shown that, as a causative agent of chronic hepatitis and liver cirrhosis, HEV may be associated with liver cancer, as are HBV and HCV (
      • Borentain P.
      • Colson P.
      • Bolon E.
      • Gauchez P.
      • Coso D.
      • Gérolami R.
      Hepatocellular carcinoma complicating hepatitis E virus–related cirrhosis.
      ,
      • Gérolami R.
      • Moal V.
      • Colson P.
      Chronic hepatitis E with cirrhosis in a kidney-transplant recipient.
      ). The present study results suggest that cancer patients represent a high-risk population for HEV infection and need to avoid risk factors to prevent infection.
      There are several limitations in the present study. First, although serum samples positive for IgG and IgM were identified using ELISA technology, no testing of the samples for HEV RNA was performed. Second, data on transfusions and their frequency in the whole population of cancer patients were not available. Nevertheless, despite these shortcomings, this study provides baseline data on HEV seroprevalence in cancer patients in China and has raised awareness of a public health concern, warranting further investigation and intervention.
      In conclusion, this systematic survey of HEV seroepidemiology revealed a highly significant level of anti-HEV IgG and IgM antibodies in cancer patients. More attention must be paid to HEV infection in cancer patients: the associated risk factors must be understood, such as the consumption of raw or undercooked vegetables and contact with dogs. Cancer patients are a high-risk population who should avoid exposure to sources of HEV infection. Moreover, undertaking regular epidemiological surveys and strong educational efforts are essential in order to reduce HEV prevalence in cancer patients.

      Acknowledgements

      The authors thank Dr Hany Elsheikha and Dr Paul Goodwin for their constructive comments on the draft manuscript.

      Funding

      Project support was provided by the Fundamental Research Funds of the Chinese Academy of Agricultural Sciences (grant numbers Y2016JC05 and 1610312017004 ), the Elite Program of Chinese Academy of Agricultural Sciences, and the Agricultural Science and Technology Innovation Program (ASTIP) (grant number CAAS-ASTIP-2016-LVRI-03 ). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

      Ethical approval and consent to participate

      This project was approved by the ethics committees of the Affiliated Hospital of the Qingdao University and the Weihaiwei People’s Hospital in Qingdao and Weihai, China, respectively. The purpose of and procedures used in this study were explained to all participants and written informed consent was obtained. All serum samples from this case–control study were provided voluntarily by the participants.

      Conflict of interest

      The authors declare that they have no competing interests.

      Author contributions

      WC and XQZ conceived and designed the study, and critically revised the manuscript. NZ and WD collected the blood samples and analyzed the clinical data. MJB analyzed the data and wrote the manuscript. GXL participated in the experimentation and data analysis.

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      Linked Article

      • Hepatitis E virus as an agent of hepatocellular carcinoma
        International Journal of Infectious DiseasesVol. 80
        • Preview
          Autochthonous infections with hepatitis E virus (HEV) have increasingly been described in developed countries during the last 12 years (Kupferschmidt, 2016). This emergence has revealed unforeseen features (Kamar et al., 2017). HEV genotypes 3 and 4 have been shown to have a porcine reservoir, and farm pig-derived products, particularly liver sausages, have been described as a major documented source of HEV transmission to humans (Colson and Raoult, 2017). Concurrently, the clinical spectrum of HEV infection has unexpectedly broadened.
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