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J Clin Microbiol. Sep 2012; 50(9): 2888–2893.
PMCID: PMC3421804

High Hepatitis E Virus Seroprevalence in Forestry Workers and in Wild Boars in France

Abstract

Hepatitis E virus (HEV) is a fecally and orally transmitted human pathogen of worldwide distribution. In industrial countries, HEV is observed in an increasing number of autochthonous cases and is considered to be an emerging pathogen. A growing body of evidence suggests that HEV is a zoonotic disease, and pig handlers and pig veterinarians have been reported to be high-risk groups for HEV infection. The aims of the present study were to establish the prevalence of anti-HEV in wild boars in France and to identify whether forestry workers are at a higher risk of HEV infection. Three different anti-HEV tests were used to compare their effectiveness in detecting anti-HEV in the general population. The most sensitive test was then used to investigate HEV seroprevalence in 593 forestry workers and 421 wild boars. Anti-HEV was detected in 31% of the forestry workers and 14% of the wild boars. Detection of anti-HEV in humans was correlated with age, geographical location, and occupational activity and in wild boars was correlated with geographical location. HEV infection is frequent in woodcutters in France, and it varies geographically. Further studies are needed to confirm these findings and to elucidate the transmission route and the exact virus reservoirs.

INTRODUCTION

Hepatitis E virus (HEV) is a nonenveloped, single-strand RNA virus that has been classified as the prototype and sole member in the Hepevirus genus of the Hepeviridae family (29). The viral genome of about 7.2 kb contains 3 partially overlapping open reading frames (ORFs). ORF1 encodes nonstructural viral proteins, ORF2 encodes the capsid protein, and ORF3 encodes a small multifunctional protein. Four major HEV genotypes belonging to a single serotype have been identified (11). Genotype 1 is detected in most cases of human HEV disease (waterborne epidemics and sporadic cases), genotype 2 is rare and has been found in several epidemics in Mexico and central Africa, and genotypes 3 and 4 are detected in swine and in autochthonous HEV infections in industrial countries (5, 19, 20, 30, 34, 39, 45, 49).

HEV is a significant fecally and orally transmitted human pathogen of worldwide distribution, causing self-limited disease with mortality rates of 1 to 3% in the general population and up to 20 to 25% in pregnant women. In developing countries, HEV outbreaks have been attributed to feces-contaminated water supplies. In industrial countries, HEV is observed in travelers returning from countries where HEV is endemic and in an increasing number of individuals with no history of traveling to regions where HEV is endemic, particularly in France (5, 6, 20). Molecular analysis of HEV strains has revealed that the strains identified in nonimported HEV cases form a group of genetically divergent isolates compared to HEV strains in regions where HEV is endemic (31, 39). The modes of transmission of sporadic nonimported cases and of autochthonous cases have rarely been determined, with the exception of zoonotic food-borne transmission from pigs, wild boars, and wild deer (19, 25, 40, 41, 43, 44) and secondary transmission to medical personnel in South Africa and France (6, 36).

Pigs, wild boars, and perhaps certain other species such as deer and rabbits that harbor HEV strains closely related to human strains must be considered reservoir hosts in industrial countries (27, 28). Recent reports that indicate that the virus is detected in 4 to 6% of pig livers in the Netherlands, France, and Germany (1, 37, 48) support the role of undercooked pig products as a source of zoonotic HEV infection in humans. In addition, the higher frequency of detection of anti-HEV antibodies in swine veterinarians and pig farm workers (4, 10, 18, 26) supports the existence of zoonotic infection from domestic swine and is in agreement with the existence of asymptomatic and subclinical hepatitis E in industrial countries (30, 32, 47) in proportions higher than those observed in areas where HEV is endemic (2).

The aims of the study reported here were to evaluate different anti-HEV tests for their ability to detect HEV antibodies in order to establish the prevalence of anti-HEV in wild boar in France and determine whether forestry workers are at a higher risk of HEV infection.

MATERIALS AND METHODS

Study groups.

Serum samples were collected in 2002 to 2003 from 2,975 healthy subjects (mainly forestry workers) from the Alsace, Lorraine, Franche-Comté, Champagne-Ardenne, and Bourgogne administrative regions of France for investigation of the seroprevalence of Lyme borreliosis and tick-borne encephalitis (46). Subjects were interviewed to establish their socioeconomic status and type of occupation. In all, 671 of these serum samples were selected according to the type of work and geographical location of the participants and then investigated for anti-HEV antibodies. The occupations of the subjects investigated were woodcutters (n = 358), silviculturists (n = 105), game or fishing keepers or rangers (n = 130), and controls (n = 78; subjects with no direct contact with the forest environment, including drivers, gardeners, and traders). In 2011, serum samples from additional controls (n = 57) from the same administrative regions were collected. In addition, anonymous serum samples from 92 1- to 10-year-old children living in the Ferrara region of northern Italy were also investigated for anti-HEV antibodies. Sera were taken from discarded laboratory analysis samples in Sant'Anna Hospital, Ferrara, Italy, for investigation of simian virus 40 antibodies. Anonymously collected sera were coded with indications of age and gender only. None of these subjects had evidence of immunosuppression, although HIV status was not systemically investigated. The County Ethics Committee of Ferrara approved the project. Consent from participants was not requested for HEV testing, and samples were therefore deidentified and analyzed anonymously.

In order to evaluate the risk of transmission from wild animals, anti-HEV antibodies were also investigated in wild boars. No serum samples were obtained specifically for this study. They were from the serobank of Anses (Nancy and Ploufragan, France) and had been collected between 2000 and 2004, during the national serological investigation of wild boars to collect information on brucella, trichinella, and Aujesky's disease. The 421 wild boars tested originated from the northern (n = 109), central (n = 144), and southern (n = 168) parts of France. All serum samples were stored at −20°C until investigated for anti-HEV antibodies.

Serological screening.

Antibodies to hepatitis E virus were investigated with a recently available commercial test (HEV enzyme-linked immunosorbent assay [ELISA], version 4.0; MP Biomedicals SAS, Illkirch, France). This test (test 1) is a double-antigen sandwich ELISA using a recombinant HEV ORF2 capsid protein (ORF2 amino acids 394 to 606) and was used according to the manufacturer's instructions with serum samples tested at a dilution of 1/5. This assay is species independent and detects HEV IgG, IgM, and IgA. This assay has been reported to have an overall specificity of 98.8% for human samples (12). All human and wild boar serum samples were investigated with this test.

In addition, for purposes of comparison, an in-house test (test 2) and another commercial test (test 3) were also used to investigate a randomly selected subset of 297 human samples. These two tests are indirect ELISAs in which the specific immunoglobulins captured on HEV antigens attached to the wells of microtiter plates are detected using labeled anti-IgG antibodies. Test 2 was an in-house ELISA based on recombinant HEV virus-like particles (VLPs; ORF2 amino acids 112 to 660) produced in Sf21 insect cells and purified as previously described (35). Half of the microplate wells of a microtiter plate (Maxisorp; Nunc, ATGC, France) were coated with purified HEV particles at 200 ng per well and then postcoated with 1% newborn calf serum (NBS). Duplicate wells (one test well and one control well) were incubated with sera diluted 1/100 in 5× phosphate-buffered saline containing 10% NBS and 2% Tween 20. Following incubation for 90 min at 45°C, bound antibodies were detected with mouse anti-human IgG or IgM antibodies covalently linked to horseradish peroxidase (Southern Biotechnology Associates, Birmingham, AL). After incubation for 90 min at 45°C and 4 washes, 100 μl of substrate solution containing o-phenylenediamine and H2O2 was added. The reaction was stopped after 30 min by addition of 100 μl of 4 N H2SO4, and the results were obtained by photometric comparison (Multiskan Ex; Thermo Electron Corporation) of the optical density (OD) of test and control wells at 492 nm. For data analysis, the OD values obtained in the absence of HEV antigens were subtracted from the OD values of the test samples. Tests were considered positive for differences in OD values greater than or equal to 0.200.

Test 3 was a commercially available enzyme immunoassay (HEV IgG test; Dia.Pro Diagnostic Bioprobes, Milan, Italy) based on recombinant ORF2 and ORF3 proteins, and serum samples were tested at a dilution of 1/20.

Statistical methods.

The kappa statistic was used to measure the strength of agreement between HEV tests using the XLSTat program (Addinsoft, France). The prevalence of anti-HEV antibodies in healthy subjects was analyzed for different ages, socioeconomic variables, and geographical place of work (French regions) and for wild boar of different ages (<12 and >12 months) and geographical origin (north, center, south of France). Univariate and multivariate logistic regression analysis was carried out to determine which variables were significantly associated with detection of HEV antibodies. Logistic regression was performed using SAS, version 9.2 (SAS Institute). A P value of less than 0.05 was considered significant.

RESULTS

Comparison of three ELISAs for detection of anti-HEV antibodies in a healthy population.

One of the aims of this study was to assess the effectiveness of two commercial ELISAs and one in-house ELISA in detecting anti-HEV antibodies in human serum samples of unknown HEV exposure. Comparison of the capacity of the three ELISAs to detect anti-HEV antibodies was undertaken in 297 French adults selected from the study group (Table 1). On the basis of recommended or established cutoff values, 14 samples were positive and 190 samples were negative in all three assays. Thus, 68.7% of serum samples gave identical results. However, tests 1 and 2, which use HEV ORF2 protein as antigen, identified 53 additional positive samples, and test 1 identified 27 additional positive samples. It is of note that 67 out of the 72 serum samples found to be positive with test 2 (93.1%) were also positive with test 1. A concordance of 87.5% was observed between tests 1 and 2, with substantial agreement between the two tests (kappa = 0.70), but a fair level of agreement was observed between tests 1 and 3 (72.1%, kappa = 0.22) and between tests 2 and 3 (77.8%, kappa = 0.21).

Table 1
Concordance between three ELISAs for detection of anti-HEV antibodies in 297 healthy adultsa

The three assays exhibited considerable differences, with 33.3%, 24.2%, and 7.4% of the samples investigated being anti-HEV seropositive with tests 1, 2, and 3, respectively. As 27 samples were positive only with test 1, we investigated serum samples from 92 healthy infants and children aged 1 to 10 years from Italy to verify the specificity of the tests. None of the children's sera was found to be anti-HEV positive with anti-HEV test 1 (sandwich test) or with test 2. In contrast, seven children (7.6%) scored positive with test 3. Due to its greater effectiveness and apparent lack of false-positive detection, test 1 was used for all other anti-HEV determinations.

Detection of anti-HEV in wild boar serum samples.

Serum samples from 421 wild boars from France were investigated for anti-HEV antibodies by test 1 (HEV ELISA, version 4.0; MP Biomedicals SAS). Anti-HEV antibodies were detected in 14.0% of the wild boars (Table 2). Anti-HEV prevalence increased steadily from 10.4% in animals aged less than 12 months to 15.7% in older animals, but the difference was not statistically significant. Detection of anti-HEV varied with the geographical origin of the boar, being 7.3% in the northern part of France, 9.0% in the center, and 22.6% in the southern part of France (Table 2). Univariate and multivariate analysis indicated that wild boars from the south of France are at higher risk of HEV infection than wild boars from northern France, with an age-adjusted odds ratio (AOR) of 3.98 (P = 0.001).

Table 2
Anti-HEV in wild boara

Detection of anti-HEV in forestry workers from eastern France.

French forestry workers (n = 593) were investigated for anti-HEV antibodies using the sandwich HEV test (test 1). In all, 185 subjects had anti-HEV antibodies (31.2%), with prevalence increasing steadily from 15.7% in 15- to 34-year-old subjects to 46.2% in subjects older than 55 years of age (Fig. 1). Among the 135 controls with no direct contact with the forest environment (drivers, gardeners, traders), 26 (19.2%) had anti-HEV antibodies, with the prevalence increasing from 4.5% in 15- to 34-year-old subjects to 39.1% in older subjects. It must be noted that in young individuals (15 to 25 years old), anti-HEV antibodies were detected in 12% of the forestry workers and in none of the control population. This increase in anti-HEV prevalence with age was demonstrated statistically in univariate and multivariate analysis (Table 3).

Fig 1
Anti-HEV in French forestry workers (gray bars) and controls (black bars) according to age.
Table 3
Anti-HEV in northwest of France according to age, activity, and regiona

An increase in HEV seroprevalence was observed in game and fishing keepers and rangers (20.0%) and in silviculturists (24.8%) compared to that in controls, but the difference was not statistically significant. Multivariate analysis indicated that woodcutters are at higher risk of HEV infection (37.2% seropositive), with an adjusted OR of 2.24 (P = 0.003). Differences according to region of residence were also observed, with higher anti-HEV seroprevalence in the Alsace and Lorraine regions (44.1 and 32.8%, respectively) than in the Franche-Comté (22.6%), Bourgogne (17.4%), and Champagne-Ardenne (12.4%) regions. Multivariate analysis confirmed that HEV seroprevalence was higher in the Alsace and Lorraine regions, with adjusted ORs of 2.66 (P < 0.0001) and 1.96 (P = 0.019), respectively.

As the original study population was constituted for analysis of Lyme disease in eastern France and to investigate means of protection that could prevent this disease, seropositivity for Lyme disease and the protection from HEV seropositivity afforded by the use of work gloves and work trousers were also investigated (Table 4). Univariate analysis indicated that HEV positivity was associated with positivity for Lyme disease (OR, 1.71; P = 0.011). However, the multivariate analysis did not confirm this association, with a bias due to the fact that most of the individuals seropositive for Lyme disease were woodcutters or were from the Alsace and Lorraine regions. In addition, univariate analysis indicated that protection against HEV infections could be achieved by wearing work trousers (OR, 0.48; P = 0.008). However, this was not confirmed in the multivariate analysis, as most of the individuals wearing work trousers were woodcutters.

Table 4
Anti-HEV in 593 French forestry workersa

DISCUSSION

HEV serological testing uses different formats and different immunoreactive antigens, and thus, tests vary greatly in sensitivity and specificity (17). The results obtained from the comparison of three different anti-HEV tests indicated that the sandwich test (test 1) detected anti-HEV antibodies with greater sensitivity than the other two tests. Test 1 and test 2 showed substantial agreement (kappa = 0.70). However, test 1 was found to perform better in detecting anti-HEV antibodies. This was probably due to the format of the test, being a sandwich test in which serum samples are tested at a dilution of 1/5, compared to a 1/100 dilution in test 2 (in-house test using recombinant VLPs), which was used because of a high background at low serum dilutions. The specificity of test 1 in detecting anti-HEV antibodies was supported by the fact that anti-HEV antibodies were not detected in 1- to 10-year-old children. In addition, anti-HEV prevalence increased regularly with age in adults (Fig. 1), as observed by others (3, 26) but in contrast to other studies in which an age effect was absent or less evident (3, 16, 21). The fact that anti-HEV antibodies were not detected in young children (test 1 and test 2) argued against the possibility of transmission of HEV by processed pork such as ham, which is regularly eaten by children. The findings confirmed that the HEV test in a sandwich format is a valuable tool for the detection of individuals with asymptomatic HEV infection, for detailed investigation of the epidemiology, and to improve identification of the risk factors for transmission to humans.

The detection of anti-HEV in 14% of wild boars in our study confirmed that HEV is endemic in these animals in France, in agreement with the seroprevalence of 12% recently reported by Rutjes et al. (38) in the Netherlands using the same kind of sandwich HEV ELISA. This confirmed that several sources of exposure to HEV may exist in the French population and they could have a role in the maintenance and transmission of HEV. Increasing evidence has been reported from Japan, where eating wild boar meat or liver is associated with a high risk of acquiring hepatitis E virus infection (24, 25). In Europe, consumption of wild boar meat has also been reported to be associated with HEV infection (49), suggesting that raw or undercooked wild boar products may cause autochthonous HEV infections (38). Although HEV RNA has been detected in 5 to 25% of wild boars in some European countries (7, 14, 23), more recent reports indicate that HEV RNA is detected in only 2 to 2.5% of wild boar livers (13, 38). As HEV is excreted in the feces of infected animals, it can be speculated that HEV could be transmitted directly by contact with wild boar or deer (38) or their feces and indirectly through contaminated water, providing a vehicle for enteric transmission to other susceptible animals and humans.

In the French adult population investigated in this study, anti-HEV antibodies were detected in a high proportion of forestry workers (31%) and in 19% of a small control group, similar to the 15% recently reported in Germany for blood donors (18). Multivariate analysis of the data indicated that HEV prevalence varied according to occupational activity and geographical location. Differences in HEV seroprevalence between rural and urban areas have been described (8, 32), the existence of regional differences has previously been reported (26, 42), and field workers in Germany and the United States have been identified as being at risk (9, 15). In addition, it should be noted that variations in seroprevalence in different French regions did not correlate with the pig population in these regions (Table 5) but correlated with the regional variations in the frequency of car accidents due to wild boars (per 1,000 km2), an indirect means to evaluate the level of contacts between humans and wild boars.

Table 5
Anti-HEV antibodies in humans in different regions from northeast of France and estimates of pig populationsa

Forestry workers have already been identified to be at risk of HEV infection (9), but the present study suggests for the first time that among them, woodcutters are at a particularly high risk of infection. Wild boar stools may provide an additional source of HEV infection for people with close contact with the forest environment. Contact with feces from wild animals (wild boar and deer) could constitute a risk factor for HEV infection. In France, the risk factors identified as being associated with acute HEV infection include consumption of water from a private well or a nearby river (34), direct contact with pigs (33, 47), and also hunting and residing in a rural area (22). Furthermore, the consumption of undercooked wild boar meat and liver, as observed with figatelli, a traditional pig liver sausage commonly consumed raw or undercooked in the south of France (5), and undercooked liver-based preparations, such as fressure from pigs, wild boar, and deer, could represent additional sources of infection for humans (41, 43).

The detection of HEV and HEV-related RNA in a growing number of different animal species suggests a possible role for as yet unidentified animal reservoirs as risk factors associated with HEV seropositivity in humans in areas where HEV is not endemic, and these reservoirs should be further investigated using reliable diagnostic tools. In addition, based on the current evidence, thorough cooking of all pork, wild boar, and deer animal products (particularly those containing liver) and improved education for occupationally exposed people (pig farmers, veterinarians, pork butchers, field workers, and possibly, sewage workers) may help prevent HEV infection.

ACKNOWLEDGMENTS

We thank Anses Nancy and Anses Ploufragant for providing wild boar serum samples. We also thank J. Hars, coordinator of the ONCSF/DGAL (Programme National de Surveillance Sérologique des Sangliers Sauvages, 2001 to 2004), who allowed us to collect serum samples from wild boar under the best conditions, the hunters for collecting samples from wild boar, and departmental veterinary laboratories for their technical assistance.

We have no potential conflicts of interest to report.

Financial support was provided by a grant from ANR (project HEVZOONEPI, grant PRA-008-04) and the Mutualité Sociale Agricole (MSA).

Footnotes

Published ahead of print 20 June 2012

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