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Institute of Medicine (US). Improving Food Safety Through a One Health Approach: Workshop Summary. Washington (DC): National Academies Press (US); 2012.

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Improving Food Safety Through a One Health Approach: Workshop Summary.

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Food-borne transmission has been described as one of the modes of transmission for many different viruses, associated with diseases ranging from mild diarrhea to severe neurological symptoms. The potential for such transmission can be studied by using common human pathogens as a model. By genomic epidemiology approaches, this has revealed significant food-related disease for noroviruses and hepatitis A viruses associated with food-handler transmission and sewage-contaminated foods. In the latter category, complex mixtures of viruses and other pathogens may be present in a single food item, creating potential for genetic recombination or reassortment and thus further expansion of the diversity of these pathogens. Therefore, bringing expertise and data together from veterinary, food, and clinical microbiology may help unravel these complexities and identify areas amenable to intervention and prevention.


When it comes to food safety, most people would agree that food has become safer than ever. The potential for contamination with pathogenic bacteria, viruses, and parasites has been recognized and translated into control programs aimed at reducing the burden of food-borne diseases in many parts of the world (Newell et al., 2010). Legislation exists to support countries in these control activities and to advise industries by developing guidelines targeting specific pathogens, commodities, or processes (Havelaar et al., 2004). Nevertheless, food-borne disease remains a significant cause of illness, of which the true burden is difficult to estimate (Scallan et al., 2011). The growing population density impacts upon the environment, for instance through sewage discharges, making it challenging to find clean waters for shellfish production in some parts of the world. Such environmental sources of contamination also may contain a mixture of human and animal pathogens, emphasizing the potential for introduction of animal pathogens into the food chain through routes that are not controlled (Figure A9-1). The increasing demand for seasonal produce year-round has globalised the food market, with the ensuing challenge to work with the same high hygienic standards across the world. While these production programs are largely successful, they also illustrate the vulnerability of the global food supply: if there is a flaw in the process, then contamination may occur with pathogens from across the globe, including those that have recently emerged (Newell et al., 2010). Therefore, thinking in terms of the future of food safety from a public health perspective does require a holistic view, including the careful review of possible scenarios that may require our attention. Here, we focus on viral food-borne disease, reviewing the current state of knowledge with this forward-looking perspective. For detailed reviews of the state of the art, we refer to other recent publications (Baert et al., 2011; Iwamoto et al., 2010; Khuroo and Khuroo, 2008; Koopmans and Duizer, 2004; Strawn et al., 2011).

A diagram showing the complex epidemiology of food and water-borne viruses


Epidemiology of food- and water-borne viruses, showing complexity of transmission and possible sources of infection. Which of the factors shown here apply may differ for different food-borne viruses.

Most Common Viral Food Safety Concerns

Currently known viruses that can infect humans are grouped into 24 families. Food-borne transmission has been documented for viruses belonging to at least 10 of these, and the diseases associated with these infections range from mild diarrheal illness to severe encephalitis. The burden of food-borne illness is thought to be greatest for human viruses that are transmitted through poor hygienic practices, either by food handlers or during food production (Scallan et al., 2011). This applies to viruses that are transmitted by the faecal-oral route, hence infecting their host after ingestion, followed by invasion of cells in the epithelial lining of the gut, and subsequent replication in the same site or elsewhere in the body (Koopmans and Duizer, 2004).

Food-borne transmission can occur by contamination of food by infected food handlers, by contamination of food during the production process (e.g., in shellfish production), or more rarely by consumption of products of animal origin harboring a zoonotic virus. While intuitive, understanding these different potential sources is important because the disease ecology differs for these different sources of contamination. These differences are qualitative but, nevertheless, can help direct outbreak investigations.

Food Handler–Associated Illness

Food handler–associated food-borne illness results from the manual preparation of food by a food handler shedding viruses. The potential impact of such contamination events depends on the product type and preparation. There are numerous reports of food handler–associated viral outbreaks, usually resulting in limited outbreaks (Greig et al., 2007). Understandably, the most frequently identified viruses through this transmission route are highly prevalent. Priority concern in this category are noroviruses (NoVs) as the most common cause of gastroenteritis in all age groups, but outbreaks with several other enteric viruses are possible, particularly with hepatitis A (WHO, 2008). Contamination events are not limited to symptomatic persons, although there is no quantitative information about the relative contribution of symptomatic versus asymptomatic food handlers (Okabayashi et al., 2008; Todd et al., 2008). Food handling may occur throughout the food chain, but reported food handler–associated outbreaks often reflect contamination during the final food preparation or serving. This may be a bias in surveillance, as end-of-the-chain food handler–associated outbreaks are easier to identify through regular outbreak investigations. Risk foods, therefore, are all foods that are handled manually and not further processed before consumption. Freezing is not sufficient to inactivate viral pathogens (Koopmans and Duizer, 2004).

Source Contamination

Food contamination at source occurs when food is contaminated during the primary production, as has been observed in particular in fresh produce such as berries and green onions, or bivalve filter-feeding shellfish. Here the nature of contamination may vary greatly, depending on location of the production area and nature of sewage contamination, but NoV and hepatitis A virus (HAV) were considered to be priority concerns in a coordinated expert meeting of the World Health Organization (WHO), the Food and Agriculture Organization (FAO), and the World Animal Health Organization (OIE) (WHO, 2008). In contrast with food handler–associated contamination, source contamination events may involve multiple pathogens that may be present in sewage, including animal viruses (Myrmel et al., 2006; Pommepuy et al., 2004; Costantini et al., 2006). This simultaneous exposure to mixtures of viruses theoretically increases the probability of recombination or reassortment of viral genomes when a person is simultaneously infected with multiple related viruses (Gallimore et al., 2005; Koopmans and Duizer, 2004; Le Guyader et al., 2006a; Symes et al., 2007). As with food handler– associated outbreaks, this mode of transmission typically involves the most common human viruses that are present in abundance in sewage (Iwai et al., 2009; Myrmel et al., 2006; Pommepuy et al., 2004; Shieh et al., 2003; Victoria et al., 2010; Wolf et al., 2010). However, treatment of sewage appears to selectively reduce levels of contamination with genogroup II NoV, possibly explaining the relatively high frequency of genogroup I viruses in sewage-related food-contamination events (van den Berg et al., 2005).

Zoonotic Food-Borne Viruses

Zoonotic food-borne infection occurs when meat, organs, or other products from an infected animal are consumed. For viruses, this is the least common mode of transmission, although the potential for such transmission is a cause for concern with every emerging disease outbreak. There is evidence that severe acute respiratory syndrome (SARS), monkeypox, and Nipah virus have been transmitted through food-related incidents (Leung et al., 2006; Luby et al., 2006; Rimoin et al., 2010; Wang et al., 2005a). However, more detailed review of these events suggests that it is more likely the process of food preparation (slaughter of the animal) that constitutes the greatest risk. For hepatitis E, there is documentation of food-borne infection through meat consumption.

In the WHO/FAO/OIE expert meeting, conclusions about priority food-commodity combinations of concern were based on available evidence from the literature, but it was also noted that large data gaps exist: trends in disease reporting are available in many parts of the world for hepatitis A, but not for the other viruses. Estimates of the proportion of illness caused by these pathogens that can be attributed to consumption of contaminated food are based on very few studies and would require the addition of systematic strain typing to routine surveillance, and more systematic studies to provide the data for burden estimates (Scallan et al., 2011; WHO, 2008). Finally, testing for viruses in commodities is difficult, and there is considerable debate over interpretation of findings from molecular assays, because these do not provide information on the viability of the pathogens detected (Baert et al., 2011). As a consequence, data from product monitoring are patchy at best.

Short Description of Common Food-borne Viruses


Virological aspects NoVs belong to the Family Caliciviridae, which is divided into genera. Norovirus and Sapovirus are the two out of five genera of the family Caliciviridae that contain viruses that cause infections in humans. NoVs have also been detected in pigs, cattle, mice, cats, dogs, and sheep, and sapoviruses in pigs (Han et al., 2004; Martella et al., 2007, 2008, 2011; Ntafis et al., 2010; Oliver et al., 2006; Smiley et al., 2003; Wang et al., 2005b, 2006; Wobus et al., 2006; Wolf et al., 2009). In humans, NoVs cause gastroenteritis, while the animal viruses can cause a range of different clinical syndromes, including oral lesions, systemic disease with hemorrhagic syndromes, upper respiratory tract infections, and others. Furthermore, one other potential genus comprising viruses detected in rhesus macaques has been described (Farkas et al., 2008). So far, the NoVs and sapoviruses are the only caliciviruses known to cause disease in humans, with the exception of anecdotal zoonotic infection with vesiviruses. NoVs can be divided into distinct genogroups, based on phylogenetic analyses of the capsid protein. To date, five norovirus genogroups (G) have been recognized (GI-GV) (Kroneman et al., 2011; Zheng et al., 2005). Viruses of GI, GII, and GIV are known to infect humans. GII viruses have additionally been detected in pigs, and GIV viruses have been detected in carnivores (a lion cub and a dog). GIII viruses infect cattle and sheep, and GV viruses infect mice. The host barrier is not absolute—a suggestion that there may be opportunity for genetic mixing if circumstances are favourable (Souza et al., 2007). Recombination between viruses from different genogroups is rare, suggesting that this constitutes a species level in taxonomy. Within each genogroup, viruses are further segregated into lineages, termed genotypes (Kroneman et al., 2011; Phan et al., 2007). Where known, these seem to have a global distribution, with little evidence for geographic clustering. Direct comparison of data across countries is challenging because of differences in study design and laboratory diagnostics, resulting in poorly defined biases (Kroneman et al., 2008a, 2008b). This is particularly the case when trying to establish causes of food-borne illness. Here, the less common genotypes of norovirus are likely to play a bigger role, and it is these viruses that are less available for assay test validation studies (Duizer et al., 2007; Fisman et al., 2009; Gray et al., 2007). The development of quality assurance schemes for molecular diagnostics, therefore, is particularly important for detection of such highly diverse viruses.

Epidemiology The etiological importance of NoVs as causes of diarrheal illness has been documented worldwide, but few studies have been performed in a standardized way that allows international comparison and true burden of disease estimates (Hall et al., 2005; Scallan et al., 2011). Community studies have provided evidence for the abundance of NoVs and established that these viruses are the number one cause of community-acquired gastroenteritis, with one out of four or five persons infected per year (de Wit et al., 2001, 2003; Jansen et al., 2008; Kirkwood et al., 2005; Olesen et al., 2005; Patel et al., 2008; Tam et al., 2012; Tompkins et al., 1999; Wheeler et al., 1999). The burden of illness is highest in young children and the elderly (de Wit et al., 2001; Tompkins et al., 1999). The best described feature of NoVs is their propensity to cause outbreaks, resulting from some basic properties: the dose required for productive infection is very low (1-10 particles), and infected persons shed huge amounts of viruses (up to 1010 million per gram of stool) (Atmar et al., 2008; Teunis et al., 2008). In addition to this, the most common NoVs evolve through accumulation of mutations and selection of fitter variants that escape the receptor-blocking activities from antibodies triggered by prior infections (Lindesmith et al., 2008; Lochridge et al., 2005; Siebenga et al., 2007, 2010). In addition, the interaction of NoVs with histo-bloodgroup antigens determines the outcome of exposure, and strain-dependent differences in host susceptibility have been observed (Donaldson et al., 2008; Marionneau et al., 2005; Rydell et al., 2011; Tan and Jiang, 2011). Although there is insufficient literature to substantiate this, the transmissibility is likely to differ between genotypes, and such differences may explain why relatively little diversity is seen in outbreak reporting, particularly when outbreaks notified include those in health care institutions: here, genogroup II.4 viruses are by far the most commonly identified outbreak strains (Kroneman et al., 2008; Sukhrie et al., 2011). In a study in hospitalized patients, the probability of secondary transmission of NoVs differed by age and genotype (Sukhrie et al., 2011). In recent years, the incidence of norovirus outbreaks has increased with the emergence of a particular variant (Lopman et al., 2004; Siebenga et al., 2010). More severe complications are seen in immunocompromised patients, and mortality in the elderly (Siebenga et al., 2008; van Asten et al., 2011; Westhoff et al., 2009).

Estimation of the burden of food-borne infection A challenging question, therefore, is how much disease caused by NoVs can be attributed to the different modes of transmission, in particular food-borne spread (Figure A9-1). One source of information comes from outbreak reporting, for instance the European Union (EU) Community Summary Report, the Centers for Disease Control and Prevention's (CDC's) FoodNet overviews, and the Australian FoodNet reports. These list NoVs as frequent causes of outbreaks (CDC, 2011; EFSA, 2010; Hall et al., 2005; OzFoodNet Working Group, 2009). In the EU, in 2008, crustaceans, shellfish, mollusks, and products thereof were the most frequently implicated food items in NoV and HAV outbreaks, but this may also reflect an ascertainment bias, because testing for the presence of viruses in shellfish is well established across Europe. The use of epidemiological criteria in the United States concluded that an estimated 28 percent of all reported outbreaks with unknown etiology were likely caused by NoVs (Turcios et al., 2006). An important caveat in using these data is that testing of patients with gastroenteritis for NoV is not yet an established routine, although this is rapidly changing (Tam et al., 2012). With that, numbers and proportion of reported viral outbreaks will most likely increase in the near future. In addition to the recognized food-borne outbreaks, the high rate of secondary infections in NoV outbreaks can rapidly mask an initial food-borne introduction. Therefore, a relevant question is what proportion of such outbreaks in fact were triggered by a food contamination event (Verhoef et al., 2010). What remains anecdotal is the geographic spread of most food-borne outbreaks, because this requires systematic incorporation of molecular typing into outbreak investigations and international data sharing to identify clusters (Koopmans et al., 2003). Therefore, the current reporting is likely to reflect the tip of the iceberg of true food-borne incidents. The available data also illustrates current challenges in using the notified outbreaks for action: only 5 percent of all reported NoV outbreaks are fully confirmed, reflecting the challenges of virus detection in or on food items (Kroneman et al., 2008a).

Given the paucity of evidence, few studies have attempted to quantify burden of food-borne illness attributable to viruses. In the Netherlands, approximately 12 to 15 percent of community cases of NoV gastroenteritis were attributed to food-borne transmission, based on risk factor analysis using questionnaire data. This makes NoV as common a cause of food-borne gastroenteritis as Campylobacter and more common than Salmonella (de Wit et al., 2003). A recent analysis of available data estimates that almost 60 percent of illness cases, 26 percent of hospitalizations, and 11 percent of deaths from food-borne illness are caused by NoV (Scallan et al., 2011). Similarly, an estimate based on data from Australia suggests that NoVs are important causes of food-borne illness (Hall et al., 2005).

In studies of outbreak reports, the term “food-borne” has been used loosely and has not been standardised. Also, the ultimate number of persons affected by a food-borne outbreak is rarely known, and reported outbreaks are likely to be biased (Kroneman et al., 2008b; Todd et al., 2008). The average size of reported outbreaks is limited, but there are examples of widespread dissemination, for instance following consumption of wedding cake, sandwiches from an ill baker, deli meat during rafting trips down the Grand Canyon, frozen shellfish, or a manually prepared salad (de Wit et al., 2007; Friedman et al., 2005; Malek et al., 2009; Schmid et al., 2007; Webby et al., 2007). An interesting example was the simultaneous emergence of a new recombinant NoV in nine countries across Europe in 2001 (Ambert-Balay et al., 2005; Koopmans et al., 2003; Reuter et al., 2006). This variant was found in association with four different capsids until equilibrium was reached and the virus continued to circulate in combination with GII3 capsid. These viruses currently are the second most common cause of infection in children hospitalized with NoV (Beersma et al., 2009).

This example also raises the question of where to draw the line in terms of estimation burden of food-borne disease: could the widespread circulation of the GIIb strains have been prevented? Or is it only the first round of infections that should be attributed to food? While difficult to prove with certainty, these examples illustrate the contribution of food-borne introduction to the diversity of viruses circulating in the population, a situation that is not desirable from a virological standpoint: novel combinations of genes may have unpredictable effects on viral behavior and virulence and should be avoided when possible.

Hepatitis A (HAV)

Virology The hepatitis A virus belongs to the family Picornaviridae, genus Hepatovirus. Hepatoviruses have only been found in humans and primates, suggesting there is no risk of introduction from a reservoir. Based on genetic diversity, hepatitis A viruses are divided into six lineages or genotypes, of which genotypes I-III infect humans (Robertson et al., 1992). Genotypes I and II contain subgenotypes (Ia, Ib, IIa, and IIb). In regions with endemic HAV circulation, further segregation into geographically defined clusters is observed, a property that can be used to support source tracing activities in food-borne outbreaks (Costa-Mattioli et al., 2003; Robertson et al., 1992).

Epidemiology HAV is less transmissible than NoVs, and its incidence is greatly reduced in regions with proper sanitation and good hygienic conditions. As a consequence, great differences can be observed in the incidence of HAV in communities across the globe, related to socioeconomic status (Jacobsen and Wiersma, 2010; Mohd Hanafiah et al., 2011). These differences also affect the level of population immunity and, thus, the susceptibility to food-contamination events. In highly endemic regions, HAV is one of the childhood infections that, in the majority of cases, runs an asymptomatic course, while triggering a protective immune response that lasts long, possibly even lifelong (Hollinger and Emerson, 2007). In such regions, sustained circulation of HAV strains is found, resulting in geographically distinct genetic fingerprints (Barameechai et al., 2008; Broman et al., 2010; Cao et al., 2011; Davidkin et al., 2007; Faber et al., 2009; Gharbi-Khelifi et al., 2006; Klevens et al., 2010; Kokkinos et al., 2010; Munné et al., 2007; Nejati et al., 2012; Pérez-Sautu et al., 2011; Sulbaran et al., 2010; Yun et al., 2008). Although this geographical diversity is not robustly defined, this information is used to support investigations into the possible source of an outbreak, or in defining where a patient most likely contracted the disease (Bialek et al., 2007; Petrignani et al., 2010; Shieh et al., 2007).

In regions with high socioeconomic status, HAV circulation is very limited and mostly restricted to risk groups such as men who have sex with men, to immigrant populations from regions with higher endemicity that may reintroduce viruses when infected during family visits in their country of origin, to travelers who contracted infection while visiting an endemic country and may transmit infection to nonimmune contacts, and to food- and water-borne infection. In such regions, population immunity builds up much slower, leading to an increase in the size of the susceptible population, and a right shift of first-time infections to higher age groups (Jacobsen and Wiersma, 2010). With increasing age, the probability of having symptomatic illness increases, and complications such as fulminant hepatitis are more common. This leads to the somewhat contrasting situation that food-contamination events may have a greater impact in regions with low endemicity of hepatitis A than in highly endemic regions (Greig et al., 2007; Koopmans and Duizer, 2004). This different epidemiological pattern also has consequences for the use of molecular typing in HAV source tracing; in low endemic regions, most people with HAV will have contracted the infection in a different region, and, as a consequence, a great diversity of HAV strains may be seen, reflecting the geographic fingerprints from the regions where they contracted the illness. This basic pattern can be greatly influenced by changing the population immune status through vaccination. Vaccination confers clinical protection that is thought to be long lasting (Van Damme et al., 2011). Whether vaccinated individuals contribute to shedding also is not well known.

Evidence for food-borne infection HAV is quite stable outside a host and, therefore, can persist on contaminated environments, food, and water. Food- and water-borne outbreaks have been documented, although again, as for NoVs, the most common mode of transmission occurs between persons (Bosch et al., 2001; Dentinger et al., 2001; Pinto et al., 2009; Sanchez et al., 2002). Because of the risk pattern described above, the biggest risk of food-borne HAV currently is introduction through food into regions where population immunity is relatively limited. Foods of primary importance, therefore, are those susceptible to contamination during the production phase, such as bivalve filter-feeding mollusks (oysters, clams, mussels) or produce that is irrigated with water that may be contaminated (e.g., lettuce, green onions, and soft fruits, such as raspberries and strawberries). An extreme example of the potential impact dates from 1988, when almost 300,000 cases were caused by consumption of clams harvested from a sewage-polluted area (Halliday et al., 1991). A specific problem with shellfish is that the current microbiological quality control criteria are based on testing for bacterial contamination, which does not reliably predict the presence or absence of viruses. Also, mildly polluted products can be put on the market after “rinsing” the shellfish by storing them for a period of time in clean water in a process called depuration. Depurated shellfish have been associated with outbreaks of norovirus, hepatitis A, gastroenteritis, and other viral diseases (Ueki et al., 2007). For NoV, specific binding to histo-bloodgroup antigens in oyster tissues has been demonstrated, possibly further explaining the retention of viruses in these animals (LeGuyader et al., 2006b).

Estimation of the food-borne burden of illness In the CDC assessment of food-borne pathogens, hepatitis A is the second virus listed and is considered a significant cause of severe disease (Scallan et al., 2011). This may be related to the increased severity when HAV infection is first acquired during adulthood, although there also are differences in virulence between genotypes (Yoon et al., 2011).

Hepatitis E Virus (HEV)

Virology Hepatitis E viruses have been listed as genus Hepevirus in the family Hepeviridae in the database of the International Committee for Taxonomy of Viruses, along with the more distantly related avian hepatitis E viruses. The hepatitis E viruses can be grouped into four genotypes, with different geographical distribution and host range. Genotype 1 is endemic in Asia and Africa, and genotype 2 is endemic in Mexico and western Africa. Whereas these genotypes have been found exclusively in humans, genotypes 3 and 4 have also been detected in pigs and other animal species (e.g., wild boar and deer) (Lu et al., 2006; Teo, 2009). Genotype 3 is distributed worldwide, and genotype 4 is found commonly in Southeast Asia, although recent findings suggest these lineages also may be more widespread (Tessé et al., 2012). Nevertheless, current information suggests that the endemic strains found in pigs in Europe, Japan, and the United States are usually of genotype 3. In addition to the HEV genotypes 1 to 4, distinct HEV-like viruses with lower sequence identity to the strains found in humans have been detected in chicken, rats, and farmed rabbits in China (Huang et al., 2004; Johne et al., 2010; Zhao et al., 2009). In addition, serological data suggest the presence of HEV-related agents in cattle, horses, and some pet animals, but these remain to be confirmed by virological methods (Teo, 2009).

Epidemiology Historically, HEV has been considered to be endemic in developing countries, where genotype 1 and 2 HEV strains have been associated with large outbreaks of hepatitis, primarily in Asia and Africa. The most commonly recognized mode of transmission in these outbreaks is water-borne, associated with poor-quality drinking water (Purcell and Emerson, 2001). Although HEV outbreaks are only observed in developing countries, antibodies have been found at lower prevalence levels globally, with estimates ranging from very low (around 1 percent) up to 33 percent. Some of these antibodies reflect exposures to genotypes 1 and 2 HEV in the recognized endemic regions through travel, but an increasing number of non-travel-related cases have been reported (Lewis et al., 2010). This follows the discovery of the presence of other lineages (genotypes 3 and 4) in farmed pigs across the world, with evidence for human infections with genotype 3 viruses in a wide geographic region 3 and for genotype 4 viruses in China, and recently in France (one case) (Liu et al., 2012; Tessé et al., 2012). The broader genetic diversity influences the use of existing commercial antibody tests that show large differences in baseline seroprevalence in populations where HEV genotype 3 strains are endemic in pigs, depending on the test used (Herremans et al., 2007). Therefore, type-specific validated methods are needed before robust conclusions can be drawn about the differences in population immunity across countries (Lewis et al., 2010). However, targeted studies suggest that HEV infections may be as common as HAV in some industrialized countries, although the risk profile of patients suggests that genotype 3 HEV is less virulent for humans because illness is mostly observed in persons with comorbidities (Borgen et al., 2008; Dalton et al., 2007; Fogeda et al., 2009; Wichmann et al., 2008). Men over 50 with comorbidities such as underlying chronic liver disease, liver cirrhosis, or a history of high alcohol consumption are at increased risk for symptomatic HEV. Chronic infections have been found in immunocompromised persons (Haagsma et al., 2008; Kamar et al., 2011).

Person-to-person transmission appears to be rare, but the exact mode of transmission of most HEV cases outside the previously recognized risk areas remains to be established. In addition to water-borne transmission, there is evidence for food-borne transmission, transmission by transfusion of blood products or organs, and maternofetal transmission (Aggarwal and Jameel, 2011).

Evidence for food-borne transmission As indicated above, the sources of most HEV infections remain unknown, but there is some evidence for food-borne transmission of genotype 3 HEV from undercooked wild boar and deer (Li et al., 2005; Tei et al., 2003). Epidemiological studies have provided evidence for consumption of undercooked or raw (wild) pork meat as risk factors for acquisition of HEV infection, but only very few systematic studies have been performed so far (Colson et al., 2010; Lewis et al., 2010; Wichmann et al., 2008).

Estimation of the food-borne burden of illness Currently, there is insufficient information to allow burden-of-illness estimates for food-borne HEV infection.

Detection of Food-borne Viral Disease: Specific Challenges

The detection of food-borne illness relies on a combination of laboratory diagnosis, epidemiological investigation, pathogen typing, and food traceback investigations. All of these activities need to be aligned for optimal detection, and the specific challenges differ for the different viruses discussed above (Figure A9-2).

A pyramid showing the steps and challenges for establishing proof of food-borne illness


Steps required (left) and common challenges (right) for establishing proof of food-borne (viral) infection. SOURCE: Modified from

Diagnosis and Genotyping of NoV, HAV, and HEV in Humans

For NoVs, the incidence in the community and the contribution of person-to-person spread dominate the picture (Figure A9-1). Testing of patients with diarrhea and vomiting for NoVs is not always routine because of the lack of low-cost rapid tests with adequate sensitivity and specificity, and in particular because it usually does not inform the decision making of the treating physician. For diarrheal disease outbreaks, norovirus testing is more common, and this has formed the basis of surveillance in most countries that have surveillance of food-borne viral disease in place. Again, however, the rapid secondary spread of NoVs leads to a bias for outbreaks with person-to-person transmission. More in-depth outbreak investigations that involve taking a detailed food consumption history are needed to identify those outbreaks related to food-borne introduction (Figure A9-2). Here, the use of genetic typing has shown to be informative: NoVs are a diverse genus, infecting humans and animals, and divided in lineages termed genotypes. Analysis of the aggregated data from outbreak reporting across Europe has shown that the probability of a food- or water-borne source differs greatly between genotypes. Therefore, if outbreak investigations need to be triaged for lack of resources, genetic typing may be used to guide this decision making. Clearly, this is not ideal because food-related outbreaks also have been documented for the genotypes that spread most efficiently, hence dominating the reporting when outbreaks in health care settings are included.

For hepatitis A, diagnostic tests are part of the standard diagnostic repertoire; thus, underascertainment of the number of cases in vaccinated individuals is less of a problem than for hepatitis A. The challenge here, however, is the long incubation period, which may be between 15 and 50 days (CDC, 2008). Getting a reliable food consumption history this long after exposure is virtually impossible, unless an incident relates back to a specific event. Analysis of viral sequences may help identify the source of an outbreak (Bosch et al., 2001; Dentinger et al., 2001; Hutin et al., 1999; Sanchez et al., 2002; Shieh et al., 2007; Wheeler et al., 2005); systematic typing of outbreak strains has helped to identify clusters of patients related to food consumption that had not been recognized as such from the notifications, but this is done rarely (Petrignani et al., 2010).

For HEV, routine diagnostic evaluation of patients with acute hepatitis in regions with no known circulation of the human HEV genotypes (1 and 2) is rare, although the recent finding that genotype 3 HEV may cause chronic illness in immunocompromised individuals may change this practice. Therefore, HEV is likely to be largely underdiagnosed. Again, strain typing may be used to identify patient clusters, but this practice currently is limited to specific outbreak investigations and done in research settings.

Detection and Genotyping of NoV, HAV, and HEV in Food (Animals)

For all of the above viruses, there are great challenges in reliable detection in food products, a practice that is seen as an essential part of outbreak investigations (Gentry et al., 2009b; Le Guyader et al., 2008a, 2008b; Li et al., 2011; Rutjes et al., 2006). Recent publications have shown a high prevalence of viral genes on fresh produce, questioning the relevance of such findings as they do not reflect infectious articles (Baert et al., 2011; Stals et al., 2011). A practical problem is that there are no cell culture methods available for noroviruses (Duizer et al., 2004). An elegant study in Europe suggests a correlation between quantities of viral RNA in shellfish and illness in consumers, providing a possible basis for regulatory action (Lowther et al., 2010). Levels of virus contamination, however, vary greatly across production sites, typically reflecting population densities and the ensuing environmental impact from sewage contamination, particularly following heavy rainfall (Boxman et al., 2006; Elamri et al., 2006; Gentry et al., 2009a; Groci et al., 2007; Le Guyader et al., 2008b; Lowther et al., 2010; Myrmel et al., 2004; 2006; Nishida et al., 2007; Nordgren et al., 2009; Pommepuy et al., 2004; Shieh et al., 2003; Suffredini et al., 2008).

Linking Epidemiological and Virological Data for Source Tracing and Attribution

In order to gain a better understanding of the trends in enteric viruses and the possible role of food-borne transmission, the Foodborne Viruses in Europe network was launched in 1999. Participating epidemiologists and virologists from academia, and clinical and public health laboratories, covering medical and food virology agreed to compile data related to outbreaks into a joint database. Since the launch of this network, data have been compiled for more than 8,000 outbreaks involving 13 countries, and some important importations were made. First of all, it became clear that the proportion of food-borne outbreaks reported differed greatly, reflecting differences in the surveillance setup of each county (Koopmans et al., 2003). This background also influenced the diversity of outbreak strains, with limited diversity and strong seasonal effect seen in healthcare–associated outbreaks and greater diversity with limited seasonality in outbreaks reported as food-related (Kroneman et al., 2008). For the common strains for which this was investigated, the strain diversity observed was very similar in different countries, showing that the epidemiology of these viruses is shaped by the global interlinked circulation of pathogens, with little evidence for geographic differences (Lopman et al., 2004; Siebenga et al., 2007, 2009, 2010; Verhoef et al., 2008). Food-borne outbreaks were rarely reported, but their number increased by almost 20-fold when genome sequencing was used to identify linked outbreaks (Verhoef et al., 2010, 2011). The analysis required the availability of both epidemiological and laboratory data, and it included approaches aiming to determine robustness of conclusions drawn, based on choice of target genes and fragment lengths. This was done because international standardization of molecular detection and genetic typing methods across clinical, public health, and food laboratories is very difficult because of the differences in focus and required levels of resolution at each level. In particular the virus detection in food requires such low detection limits that optimal target choice is a luxury that cannot be afforded. By using multiple genome targets to study food-borne NoV outbreaks, multiple recombinant genomes have been identified (Ambert-Balay et al., 2005; Bon et al., 2005; Reuter et al., 2006; Le Guyader et al., 2006). In food-related outbreaks where sewage contamination was the most likely cause, multiple viruses can be found within the same batch, thus favoring conditions for generation of recombinant genomes (Symes et al., 2007).

Emerging Viruses and Food-borne Transmission

Globalization and Risk of Introduction of New Diseases

With changing consumer behavior and the growing preference for consumption of fresh produce with year-round availability, food has become a commodity in the global market, dictated by availability and (low) cost. Seemingly unrelated events can lead to market shifts and, with that, to potential introduction of new risks into the food chain. A recent example is the emergence of a highly lethal infection affecting a high proportion of oysters in European banks (Peeler et al., 2012). Although not documented, the lack of locally grown oysters may move the market to Southeast Asia, which has the fastest growth in the market of aquaculture products. Assuming that failures in the production system may occur, as evidenced from the NoV studies, such incidents would potentially lead to contamination of products with locally circulating strains, such as the distinct lineages of enterovirus 71 viruses causing large outbreaks of hand, foot, and mouth disease in that region only (van der Sanden et al., 2009). Even if this is not the prevailing way of spreading, dissemination of viruses via international food trade could disperse an otherwise localized outbreak. This concern has led to in-depth investigations during the emergence of SARS, highly pathogenic avian influenza, filoviruses in pigs in the Philippines, and Nipah virus outbreaks in Malaysia and Bangladesh (Leung et al., 2003; McKinney et al., 2006; Miranda and Miranda, 2011; Parashar et al., 2000). For all of these viruses, there is evidence of introduction of the viruses into the human population through the harvesting, preparation, and/or consumption of food. For all of these examples, the biggest concern is not widespread food-borne transmission, but the fact that this mode of transmission may favor cross-species infections that are not evident otherwise, with the potential for adaptation of these viruses to humans. A systematic review of emerging infectious disease outbreaks suggested that 76 percent of these resulted from zoonotic introductions, and the pressure on the environment from population growth is increasing the contact rates between humans and animals in biotopes that were previously untouched, attesting to the opportunity for cross-species transmissions (Jones et al., 2008). Consumption of virus-containing food, either through bush meat or food contaminated with excreta from animals, is one of the potential routes (Costantini et al., 2006).

Food Safety and the Era of Virus Discovery

The classical toolbox for virology was greatly expanded when sequencing-based technologies entered the playing field, and with this it also became clear that viruses are among the most prevalent entities in the world. Unbiased sequencing has established that a large proportion of ocean waters contain viral sequences, many of them unknown (Breitbart et al., 2004; Rosario et al., 2009). Based on these studies, an estimated 104 genotypes per kilogram of sediment have been identified, and the current view is that viral communities are powerful manipulators of microbial diversity, biochemistry, and evolution in the marine environment. Similarly, samples collected from humans when subjected to unbiased analysis of the gene content contain high quantities of viral information, with a dominance of plant and bacterial viruses, but also typically multiple human viruses (Breitbart et al., 2003). These findings are opening an entirely new field of research in host/microbiome and pathogen interaction that is likely to fundamentally change how we view infectious diseases. Sequence-based virus discovery programs identify new viruses in humans and (wild) animals with high frequency (Allander et al., 2005). While most of these newly discovered viruses likely have been present for a long time, these observations do underscore the notion that there is ample potential for new human pathogens. There is consensus among virologists that the probability of the emergence of new viruses or the evolution of old viruses into new forms is inevitable, given the demographic, economical, and sociological changes that we are now facing. Therefore, having mechanisms in place to rapidly address the probability and possible consequences of food-borne transmission of a new infectious disease when it emerges should be a priority.

Another consequence is a revision of how we view the detection of viruses in food or clinical samples (Nakamura et al., 2009; Svraka et al., 2010). As the methods develop further, more diversity of viruses (and microbes) are found in any of the samples that have been tested, calling for the challenging task to answer what these findings signify. This is no different in clinical virology, where applications of multiplex polymerase chain reaction–based methods or deep sequencing increasingly find complex mixtures of potential pathogens in patients that are tested. This makes it difficult to decide which one or which combination of these was the cause of the symptoms. Methods will be needed to filter the data for relevance for the question addressed.


Food-borne transmission is common but largely underdiagnosed. While viruses from at least 10 families have been associated with food-borne transmission, NoV and HAV have been listed as priority concerns. By genomic epidemiology approaches, significant food-related disease associated with food handler transmission and sewage-contaminated foods has been identified for these viruses. In the latter category, complex mixtures of human and animal viruses and other pathogens may be present in a single food item, creating the potential for genetic recombination or reassortment and, thus, further expansion of the diversity of these pathogens. Bringing expertise together from veterinary, food, and clinical microbiology may help unravel these complexities and identify areas amenable to intervention and prevention.


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Erasmus University.

Copyright © 2012, National Academy of Sciences.
Bookshelf ID: NBK114484


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