Transmission dynamics of hepatitis E among swine: potential impact upon human infection
© Satou and Nishiura; licensee BioMed Central Ltd. 2007
Received: 11 January 2007
Accepted: 10 May 2007
Published: 10 May 2007
Hepatitis E virus (HEV) infection is a zoonosis for which pigs play a role as a reservoir. In Japan, the infection has been enzootic in swine. Clarifying the detailed mechanisms of transmission within farms is required in order to facilitate an understanding of the age-specific patterns of infection, especially just prior to slaughter.
Here we reanalyze a large-scale seroprevalence survey dataset from Japanese pig farms to estimate the force of infection. The forces of infection of swine HEV were estimated to be 3.45 (95% confidence interval: 3.17, 3.75), 2.68 (2.28, 3.14) and 3.11 (2.76, 3.50) [×10-2 per day] in Hokkaido, Honshu and Kyushu, respectively. The estimates with our model assumptions indicated that the average ages at infection ranged from 59.0–67.3 days and that the basic reproduction number, R 0, was in the order of 4.02–5.17. Sensitivity analyses of age-specific incidence at different forces of infection revealed that a decline in the force of infection would elevate the age at infection and could increase the number of virus-excreting pigs at the age of 180 days.
Although our estimates imply that more than 95% of pigs are infected before the age of 150 days, the model shows that a decline in the force of infection could increase the risk of pig-to-human transmission. If the force of infection started to decline, it might be necessary to implement radical countermeasures (e.g. separation of uninfected pigs from infected herds beginning from the end of the suckling stage) to minimize the number of virus-positive pigs at the finishing stage.
Hepatitis E virus (HEV) is a positive-strand RNA virus without an envelope, which is classified as a member of the genus Hepevirus in the family Hepeviridae [1, 2]. The virus is distributed worldwide, especially in the tropical and subtropical regions of Asia, Africa and Latin America, causing acute hepatitis in humans and is thus an important public health problem . HEV infection is a zoonosis mainly seen in humans and pigs [4–8]. In addition to the maintenance of the virus in swine as a reservoir , the infection is also seen in other primates [10–12]. The virus is mainly transmitted via fecal-oral routes among swine [13, 14]. Whereas humans are also enterically infected mainly through contaminated foods, a water-borne outbreak can be caused if drinking water is contaminated with feces containing the virus .
HEV infection in humans is seen not only in developing countries but also in industrialized countries where sporadic cases of infection have been reported . In particular, sporadic cases in various places and settings have been reported in Japan [16–23]. Whereas deer have been suggested to be a source of human infection [17, 18], ingestion of uncooked liver from wild boar is also frequently reported as the cause of infection [19–23]. In addition to the habitual consumption of porcine liver in Japan, it is important to note that the HEV infection is enzootic in swine, facilitating the frequent occurrence of pig-to-human transmission [12, 24, 25]. Seroprevalence surveys in other industrialized countries have also demonstrated the occurrence of virus transmission in swine [14, 26–30]. Although it is still yet to be fully clarified, pigs are believed to be the natural host for the virus [5, 10, 16].
With these points in mind, it is essential to clarify the detailed mechanisms of HEV transmission in swine. For example, it would be very useful to know the average age of individuals acquiring infection in enzootic areas and the age-specific incidence, especially just prior to slaughter. Moreover, to identify effective control measures on the farm (e.g., potential vaccination strategy ), it would be necessary to quantify a key parameter of the transmission, the basic reproduction number, R 0, defined as the average number of secondary cases arising from a single primary case in a fully susceptible population. R 0 gives an indication of the transmission potential, and thus, is one of the most important epidemiologic determinants [32, 33]. For example, in a randomly mixing population, a critical coverage of vaccination to eradicate a disease, p c, can be derived by using R 0; p c > 1-1/R 0 . In enzootic areas, an estimate of R 0 can be approximately obtained by estimating the force of infection (i.e. the rate at which susceptible individuals become infected), λ, which is derived from age-specific seroprevalence data. For nearly half a century, a catalytic model, the most classic type of force of infection model , has been applied to seroprevalence and incidence data and various extensions have been proposed [36–40].
The aim of this paper was to assess the transmission potential of HEV infection in swine using seroprevalence survey data from Japan. To clarify the age-specific mechanisms of transmission in swine raised for human consumption, published data  on age-specific seroprevalence on pig farms was re-examined. With respect to data from farms where pigs are slaughtered immediately after the age of 180 days, there are two specific characteristics which required close epidemiologic attention: (1) since the pigs at the suckling stage (i.e., younger than 30 days of age) are raised in separate housing from those in later stages, and due partly to a very short-lived maternal antibody, those younger than 30 days are not exposed to infection [24, 25], and (2) compared to the demographic time scale (i.e. life expectancy being 180 days), the time required for seroconversion is relatively long and is not insignificant . Thus, we propose our original modeling strategy assuming that exposure starts at the age of 30 days and combining the explicit estimate of the time required for seroconversion with a simple model of the force of infection.
Time required for seroconversion
Estimates of the force of infection
Thus, R 0 (and the 95% CI) was estimated to be 5.17 (4.76, 5.62), 4.02 (3.43, 4.71) and 4.66 (4.13, 5.25) for Hokkaido, Honshu and Kyushu, respectively.
Age-specific incidence at different forces of infection
This study estimated the force of infection of swine HEV for three geographic locations in Japan. For the estimation, we incorporated two realistic aspects of swine HEV transmission: (1) no exposure during the suckling stage and (2) time delay of seroconversion after exposure to the virus. As a result, the force of infection was estimated to be approximately 0.03 day-1 implying that the average age at infection is 63 days after birth. According to the estimates, the basic reproduction number, R 0, was in the order of 4–5, which is relatively high compared to other diseases [32, 41]. To the best of our knowledge, this study is the first to quantify the transmission potential of swine HEV infection. Although the model needs a few rough assumptions, and despite limited precision of the observed data (i.e. seroprevalence data was only collected monthly), our model successfully provides similar estimates of λ for 3 discrete locations. Except for a slight deviation seen in Hokkaido where the samples were taken from numerous sub-regions in the large prefecture, the model adequately explained the basic aspects of the age-specific pattern of HEV seroprevalence in swine. Estimated force of infection was highest in Hokkaido, the northernmost prefecture, while Honshu revealed the lowest estimate. The force of infection depends on various factors influencing transmission (e.g. biological, environmental and demographic factors). In particular, as the disease is transmitted through virus contamination (i.e. fecal-oral route), breeding methods and other determinants affecting exposure are likely to influence the age-specific patterns of prevalence. Whereas the farms in Hokkaido were partly infested with both genotypes III and IV, only genotype III was observed in the other two regions. However, since these two genotypes are immunologically crossreactive each other [5, 42], these could not be separately evaluated without detailed information with respect to differences in natural history and immune reaction.
There are two practical implications from our exercise. First, estimation of the force of infection permitted clarification of the average age at infection (being 63 days). Although our model did not allow more detailed age- and time-specificity of the force of infection to be derived due to limited data [37–40], knowing the average age at infection enables clarification of the age-specific incidence of infection (as shown in Figure 3), thereby providing a reasonable assessment of the risk of HEV excretion in slaughtered pigs. According to rigorous inoculation experiments [9, 13, 43], swine HEV RNA can be detected in the liver, feces, bile and other parts of the body as long as 30 days post-inoculation. In enzootic areas, therefore, pigs should ideally be infected sufficiently far in advance of reaching 150 days of age, so that the probability of virus excretion will be extremely low at 180 days. Although our estimates of the force of infection in Japan imply that the majority of individuals (i.e., more than 95%) are infected before the age of 150 days, it should be noted that any future decline in the force of infection would increase the number of virus-positive pigs at the age of 180 days. Thus, most importantly, it must be remembered that a slight decline in the force of infection could elevate the age at infection and increase the risk of pig-to-human transmission. In addition to consumption of contaminated pork by the general public, the increased risk of infection could also be a particularly risk for veterinarians and boar meat processing workers [44, 45]. If the force of infection is naturally reduced on the farm, this could necessitate radical control measures to minimize the number of virus-excreting pigs at the finishing stage and to eliminate the transmission from the farm. Since the population dynamics model can account for more detailed mechanisms of transmission [46–48], further explicit clarification on this point is a subject of our further studies. Although the time required for seroconversion may be slightly underestimated (because of the estimation using intravenous inoculation rather than that through oral routes), this underestimation would only result in slight underestimation of the force of infection, and thus, the above qualitative discussion of the results and their implications is still valid.
Second, the critical coverage of vaccination required for eradication, p c, is obtained from R 0, using p c > 1-1/R 0 . Although vaccines are currently under development , our estimate of R 0, ranging from 4.02–5.17, suggests that the HEV transmission on the farm could be prevented if more than 75.1–80.7 % of the pigs were successfully immunized. However, since HEV infection in man is likely to result in asymptomatic or mild disease [3, 16, 49], and because pig-to-human transmission could be partly prevented by dietary changes of humans (i.e. avoiding consumption of fresh liver), potential future vaccination policies for swine need to take account of cost-benefit analyses and the biological feasibility of elimination. For example, the maintenance of the virus by other primates could prevent the elimination of virus transmission in swine [3, 10]. Rather, if it becomes necessary to implement radical control measures, it may be more realistic and less costly to control the transmission within a herd at specific stages; considering that more than four-fifths of infection had happened between the ages of 30 and 90 days, temporal separation of uninfected young pigs from infected herds beginning from the end of suckling stage (e.g. for a certain time period, breed the individuals in a new house) could limit the chance of continued transmission. In this case, tight management of newly-built pig farms (i.e. prevention of contamination from other locations and animals) combined with the possibility of vaccination in the future might be necessary to reduce transmission within the herd.
The force of infection of swine HEV was estimated from three discrete geographic locations in Japan using age-specific seroprevalence data. The estimates ranged from 2.68–3.45 ×10-2 (day-1), indicating that R 0 ranges from 4.02–5.17. The estimates permitted a reasonable prediction of the age-specific incidence including that at the finishing stage. Although our estimates of the force of infection imply that more than 95% are infected before the age of 150 days and the probability of virus-excretion is small at 180 days, the model suggests that a decline in the force of infection could elevate the average age at infection and increase the risk of pig-to-human transmission. If the force of infection started to decline, it might be necessary to implement radical countermeasures (e.g. separation of uninfected pigs from infected herds beginning from the end of the suckling stage) to minimize the number of virus-positive pigs at the finishing stage. As this study showed a reasonable estimation in Japan which is an enzootic area for swine HEV infection, similar seroprevalence survey would be extremely useful to decipher the mechanisms of transmission. Thus, seroepidemiologic studies of swine, human and other animals with time, space and age as well as among specific groups [44, 45] could shed further light on the transmission dynamics of HEV.
Estimation of the time required for seroconversion
where b is the coefficient of the time since inoculation and t m is the median time required for seroconversion. In order to apply a logistic curve to the cumulative distribution, the model has to satisfy G(0) ≈ 0 and G(∞) = 1. The maximum likelihood estimates of b and t m were obtained by minimizing the binomial deviance of the model from the observed data. The 95% CI were determined by using the profile likelihood.
Force of infection
In addition to the estimation of λ, we examined the sensitivity of I(a) and C(a) to the different values of λ to explore the age-specific patterns and clarify the practical implications of λ to farm management.
Convolution equation and maximum likelihood estimation
The maximum likelihood estimate of λ is obtained by minimizing the negative logarithm of Eq. 12. The 95% CI were derived from the profile likelihood. All statistical data were analyzed using the statistical software JMP IN ver. 5.1 (SAS Institute Inc., Cary, NC).
Hepatitis E virus
We thank Prof. Hiroaki Okamoto, Jichi Medical School, for permitting us to reanalyze the seroprevalence data with model. HN thanks to the Banyu Life Science Foundation International for supporting his research in Germany. This study was also supported by the Japanese Ministry of Education, Science, Sports and Culture in the form of a Grant-in-Aid for Young Scientists (#18810024, 2006).
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