Enterically infecting viruses: pathogenicity, transmission and significance for food and waterborne infection

Enterically infecting viruses are ubiquitous agents, mostly inducing silent infections. Several are however associated with significant diseases in man from diarrhoea and vomiting to hepatitis and meningitis. These viruses are drawn from a variety of virus families and have different structures and genetic material, yet all are suited to this means of transmission: Normally they are shed in high numbers (assisting environmental transit) and exhibit great particle stability (permitting survival both outside the body and on passage through the stomach). Human activities particularly associated with food and water processing and distribution have the capacity to influence the epidemiology of these viruses. This review provides a description of viruses spreading by these means, their significance as pathogens and considers their behavior in these human-assisted processes. The term virus stems from the Latin virus meaning ‘poison’, and in some ways virus contamination of food resembles toxic contamination more than contamination with other micro-organisms. Viruses are not free living; they are dormant between hosts and have an absolute requirement for living cells in which to replicate. Human viruses require human cells in which to replicate, these are not present in our food and thus such viruses cannot increase in number during storage. The amount of any contaminating viruses should actually decline during storage, and this can be assisted by treatment with chemicals, heat or irradiation. Human viruses do not cause food spoilage and contamination may provide no visible clues to its presence. These features mean that measures to control bacteria will not necessarily control viruses and could actually preserve them. Food-borne viruses are infectious at very low doses and could be introduced at any point in the food chain. Many are difficult (or currently impossible) to culture and detection is no simple task. Outbreaks and sporadic occurrences of food-borne virus infection continue throughout the world. There are simply too many to mention and there is no complete data set. It seems likely that the documented outbreaks are limited only by our ability to document them. The cost of these events is likely to be phenomenal to the community; a single food-borne outbreak of hepatitis A virus (HAV) exposed up to 5000 persons in Colorado. In this case the costs for medical treatment of those infected amounted to approx. $50 000 whilst the cost of tracing and controlling this single outbreak cost over half a million US$ (Dalton et al. 1996). The burden of infectious intestinal disease (IID) in its broader sense is likewise huge, in the UK the cost per case of norovirus (NoV)-induced gastroenteritis involving a GP visit is estimated at £176 and two persons in every 1000 will make such a visit each year (FSA 2000). The interested reader is referred to several recent reviews (Lees 2000; Seymour and Appleton 2001; Sair et al. 2002; Koopmans and Duizer 2004). As enteric viruses cannot replicate outside their hosts, all such virus transmission is in effect person-to-person. Environmental transit time between hosts may be brief or prolonged. Long-distance travel may take place, e.g. through water systems or even the air. Long-distance travel is accompanied by exposure to the environment and dilution; thus viruses having prolonged environmental transit times must be very stable to survive and are (usually) shed in very large numbers. Enteric viruses meet both requirements; they are acid stable and replicate to prodigious titres in the gut before being shed in concentrated doses directly into the sewage system. All potentially food-borne viruses can also be transmitted directly from person to person via faecal contamination of the environment and viewed in this way food is simply another kind of fomite in environmental transmission, it occupies a special niche simply because of its privileged position in terms of its introduction to the body and the potential it may offer for widespread distribution through trade and commerce. The relative importance of food-borne vs more direct person-to-person transmission is unclear; enteric infections are ubiquitous, single occurrences are far too numerous to mention and statistics usually record only outbreaks (when several people are infected in one location or through one common vehicle). However any one outbreak may involve different types of spread; these viruses have a high secondary attack rate and person-to-person transmission will probably follow even if the virus was actually introduced to that setting by food. This can potentially mask food-borne introductions and it is likely therefore that food-borne transmission is underestimated. There are two types of enterically infecting virus – the first are capable of spreading elsewhere in the body. Infection by these viruses is often subclinical but they may induce signs and symptoms of disease in nonintestinal tissues. These viruses include enteroviruses (e.g. polio or Coxsackie, which may spread to the meninges, central nervous system; skeletal/heart muscle or pancreas) and hepatitis viruses A and E spreading to the liver. The second type of virus are true gut inhabitants. These replicate in the enteric tract, specific symptoms when they occur, are those of a gastrointestinal infection; usually diarrhoea and vomiting but the extent of each component is variable. Table 1 lists the main viruses associated with enteric infection and summarizes their key properties. The most important are illustrated in Fig. 1. Enteric viruses are drawn from a variety of virus families, they range approximately 10-fold in diameter and 20-fold in terms of genome size and complexity. The major enterically transmitted and thus potentially food/waterborne agents comprise (alphabetically) the human adenoviruses (AdV), astroviruses (HAstV), caliciviruses, hepatitis E virus (HEV), parvoviruses, picornaviruses [including enteroviruses, kobuviruses and hepatitis A (HAV)], and the rotaviruses (RV). Most enteric viruses are childhood infections; spreading largely person-to-person and assisted by the lower hygiene levels in this group. Food-borne transmission may be negligible (AdV) or insignificant (RV) in the developed world. However in the undeveloped world spread of these agents by these routes is poorly characterized. Childhood infection leaves residual immunity that may prevent (or mollify) infection over the rest of an individual's lifetime. Although this is not universally true, in general viruses causing childhood illness are not significant pathogens in healthy adults previously exposed as children. The IID survey in England (FSA 2000) estimated the incidence of GP consultations for intestinal disease by patient age and causative organism. Data from this survey have been reanalysed (Fig. 2) to show the proportion of consultations made for each virus in the age groups <5 and >5 years. As expected GP consultations induced by these viruses were biased towards children <5 years; GP visits by older persons comprised only a small proportion of the total consultations. There were two exceptions to this observation; some 25–50% of GP consultations for NoV infection were made by older children/adults; the highest of any virus, with astroviruses close behind. Food-borne viruses. Electron micrographs of the most import enterically infecting and food-borne viruses found in clinical samples (human faeces). All panels are reproduced at the same magnification; bar represents 100 nm. Panels show: human rotavirus; 2, enteric adenovirus; 3, astrovirus; 4, norovirus; 5, sapovirus Virus identifications in GP consultations for infectious intestinal disease by age of patient. Viruses identified following GP consultations have been segregated into the percentage of cases that involving children below 4 years and those involving older children and adults. Bias for infection of the young emerges clearly, even in the case of noroviruses. Data are re-analysed from FSA (2000) IID survey in England. , NoV; , HastV; , AdV; , RV; , SaV There are 51 serotypes of AdV; all are large icosahedral DNA-containing viruses. About 30% of the serotypes are pathogenic in man; most being upper respiratory tract pathogens spreading primarily via droplets. However, even the respiratory strains grow well in the gut and are present in the faeces. Only types 40 and 41induce gastroenteritis and these are shed in larger numbers. AdV are frequently found in faecally polluted waters and have been identified in shellfish (Girones et al. 1995; Pina et al. 1998a; Vantarakis and Papapetroupoulou 1998; Chapron et al. 2000), but have not been appreciably associated with food-borne illness, presumably because most adults are immune and children do not commonly eat shellfish. However outbreaks of other strains associated with conjunctivitis (shipyard eye) and pharyngitis are commonly associated with exposure to polluted water, normally through recreational use (Crabtree et al. 1997). Adenoviruses 40 and 41 account for 5–20% of US hospital admissions for diarrhoea, mainly in children below age 2 years (Uhnoo et al. 1984; Kotloff et al. 1989). Incubation lasts 3–10 d, and illness (usually a watery diarrhoea) may last a week. As children age, experience with AdV infection gradually increases the levels of population immunity. Only 20% of children below 6 months have antibody to these viruses, but by age 3 for this has risen to 50%. In the IID survey in England AdV infections were confined largely to children under 5 years and accounted for approx. 12% of all viruses identified (FSA 2000). Incidence was determined as 400 and 800 per 100 000 person years in the age groups 0–1 and 1–4 years. Infection is not significant in healthy adults although it may increase in significance again in the elderly (Dupuis et al. 1995); fewer than 4% of enteric AdV GP consultations involved persons over 5 years (Fig. 2). AdV are associated with tumours in mice but no such association has ever been made in man. Astroviruses are usually described as 28 nm rounded particles with a smooth margin. In their centres they may bear a 5 or 6-pointed ‘star’ motif from which they are named (Astron, a star) (see Fig. 1). However, the appearance of these agents is certainly variable, sometimes showing surface projections (Appleton and Higgins 1975) and at other times resembling caliciviruses (Willcocks et al. 1990). Morphology was subsequently used to present a classification scheme for many of these small viruses associated with enteric infection and including the caliciviruses (below) (Caul and Appleton 1982). Cryo electron microscopy studies have now confirmed the presence of surface projections (Matsui et al. 2001). Human astroviruses comprise eight serotypes (HAst1–8); types 1 and 2 are rapidly acquired in childhood; by age 7 years 50% of children are seropositive for type 1 and 75% by age 10 years (Lee and Kurtz 1982; Kurtz and Lee 1984). Exposure to the higher serotypes (4 and above) may not occur until adulthood. Illness is generally mild, lasting 2–3 d after an incubation period of similar length. This has led many to dismiss these viruses as causative agents of significant disease in humans. However astroviruses are the second most commonly identified virus in symptomatic children (Herrmann et al. 1991) and account for 5% of US hospital admissions for diarrhoea – almost entirely of children (Ellis et al. 1984). Adults may be infected by higher serotypes and childhood antibody may not prevent clinical disease: in Japan (1995), 1500 older children and teachers were affected in a widespread food-borne outbreak of HAstV type 4 (Oishi et al. 1994). Finally, astrovirus identification often relies on electron microscopy but virus appearance is not always clear. Astroviruses may be frequently mistaken for small round (parvovirus)-like agents (Willcocks et al. 1991) and even for NoVs (Madore et al. 1986). In England the IID survey conducted between 1992 and 1995 (FSA 2000) found astroviruses comprised 12% of all virus identifications with incidences of 125 and 550 per 100 000 person years in the age groups 0–1 and 2–4 years respectively. However, 16% of GP consultations for astrovirus infection were made by older children and adults (Fig. 2). As this survey identified HAstV only by EM it remains possible that astrovirus infections in the adult population were underestimated. Culture conditions have been described (Willcocks et al. 1990) and recently an ELISA-based detection kit has been produced. Caliciviruses appear under the electron microscope as if covered in cup-like depressions, from which the virus takes its name (calix = a cup). The family includes two genera that infect humans, the NoV and the sapoviruses (SaV). To date neither of these can be cultured in the laboratory. The nomenclature of these viruses has changed several times recently. Formerly they were known by names derived from their morphology (see Fig. 1): the small round structured viruses, e.g. Norwalk virus appeared fuzzy and indistinct whilst the human caliciviruses, e.g. sapporo virus, had a more obvious calicivirus-like appearance (Caul and Appleton 1982). Classification then moved to genomic organization and the groups were renamed the Norwalk-like viruses and the sapporo-like viruses. The nomenclature is now hopefully settled with the refinement of these names to the NoV and SaV respectively. 4.3.1Noroviruses. Analysis suggests that the NoV are the single most significant cause of IID in the developed world. NoVs were first identified following an outbreak of enteric illness amongst children and adults in the town of Norwalk, OH (Alder and Zickl 1969). Although samples were first collected in 1968, viruses were not clearly identified until 1972 when antibody was used to clump the particles (Kapikian et al. 1972). NoVs are now routinely detected by PCR amplification of the RNA-polymerase gene and by commercial ELISA kits, electron microscopy is used as a back up. Sequence analysis of the PCR products divides the NoV into two genogroups; group 1 exemplified by Norwalk virus itself and group 2 by Hawaii virus (Lambden and Clarke 1994; reviewed in Clarke and Lambden 2001). Recently genogroup 2 has been more common in the UK. Infections occur around the globe and throughout the year but may be more common in winter giving rise to its former name ‘winter vomiting disease’. Incubation lasts up to 48 h and is followed by a self-limiting illness lasting 24–48 h. NoV infection is not regarded as severe in otherwise healthy adults, but it is debilitating and very unpleasant. In vulnerable groups, the malnourished or elderly it can be serious and may even precipitate death. It was thought that subclinical and childhood infection was rare but recent studies have shown this does occur in very young children (Carter and Cubitt 1995). The IID study in England estimated that 1% of children < 1 years would contract NoV (FSA 2000). Norovirus differs from other agents of gastroenteritis in three ways: first, it causes disease in adults (teenagers and above), thus NoVs are the most significant diarrhoeal virus in terms of working/education days lost. Secondly, it induces a high level of explosive projectile vomiting that may be the first obvious sign of infection. Many cases are identified at work with serious implications if a food handler should be infected. Thirdly, although there are probably multiple serotypes of NoV, immunity to all seems to be short-lived. Thus individuals may be protected for only a few months following an infection before they become infectable once more by the same virus (Parrino et al. 1977). Some people appear to have an inherent resistance to infection; community outbreaks that stemmed from communal exposure by swimming pool contamination showed familial clustering of symptomatic illness, and even in middle age population antibody levels are only 50%. Many of these seronegative individuals remain symptom-free and it is now thought likely that they lack the cell-surface receptor (a carbohydrate antigen) to which the virus must bind to initiate infection (Hutson et al. 2003). Susceptible persons require several bouts of infection by the same virus before antibody levels are boosted sufficiently to afford some protection. In the recent IID survey in England NoV accounted for 30–40% of all viruses identified, they were the most commonly identified agent in the community study, and the third most common agent that caused persons to seek consultation with their GP (FSA 2000). Several reports across the world have indicated a rise in NoV detection during 2002–03. These included shipboard outbreaks, multistate occurrences in the US, a sudden rise in outbreaks in Canada and numerous hospital outbreaks throughout the UK that forced many to close wards or cease new admissions. These have been attributed in part to the emergence of a new strain of NoV across the world characterized by mutations in the polymerase gene (Lopman et al. 2003, 2004). This might be more infectious than previous strains and if such an event has occurred then the mechanism underlying this process requires investigation: food-borne transmission, perhaps via international trade should be considered. 4.3.2Sapoviruses. Sapoviruses induce symptomatic infections mainly in children. They account for some 3% of hospital admissions for diarrhoea in both the UK and US. Most children are sero-positive by age 12 and seem to become infected between 3 months and 6 years of age. SaV were found most frequently in children below age 4 in the England IID with an incidence of 460 per 100 000 person years in those aged <1 years that to in those between 2 and 4 years (FSA 2000), of GP consultations for SaV infection in those >5 years (Fig. 2). Infection is particularly common in such as and Incubation is between 24–48 h and illness is usually and with diarrhoea However in those cases when SaV have been to infect adults then symptoms are very similar to those of NoV 1989). hepatitis has been and its infectious was in the middle However the causative agent was identified only in 1972 when the developed of immune electron microscopy the particles to be identified (Kapikian et al. 1972). named to it from hepatitis this agent was found to be for the of infectious were mainly in older children and adults but infection was common in children although in these it to be was found to be a of the family (see and was in the However it some in to its genetic and and it was subsequently to a new of which it is the only can be cultured in cells but this is and for Although for most enterically transmitted hepatitis in the developed it was could account for all enterically transmitted hepatitis in the undeveloped world. Thus the of enterically transmitted hepatitis up. This in was in when a new was identified by means et al. reviewed The genetic organization and particle of the Caliciviruses and was in this However the of the genomic organization and the are such that it could not remain in this it now the only of a group the et al. 2000). is rare in the developed world with cases generally limited to are poorly characterized as agents of enteric infection. is on electron Although associated clearly with gut infection in (e.g. the only infectious human characterized to date is a agent causing a in children. have been associated with gastroenteritis in and secondary in the UK and and et al. et al. Appleton 2001). The agent was identified following a large outbreak in England (Appleton and and was associated with of There is a that of these viruses may actually be caliciviruses (Willcocks et al. infecting the gut were all in the have a appearance under the electron microscope and include the and Most grow well in such as or Formerly the of has polio and the to this virus for this were thought not to be usually associated with diarrhoeal symptoms in but this changed in when was as the agent for an outbreak of gastroenteritis et al. could be in cells and study showed that it had a genome organization of the picornaviruses et al. However the particle in from other picornaviruses and surface projections similar to those of These viruses have now been as a new in the family the are large viruses to the family particles are and may be into the are visible and in the EM the of the can appear the of a from which the virus is named a Illness after an incubation period of d and usually as diarrhoea and vomiting lasting approx. 7 Viruses are shed in high numbers over per of and is a simple Virus is detected by direct by EM or et al. or ELISA account for some million cases of diarrhoea in the US to of hospital admissions for diarrhoea et al. children each year in the US from this virus and in the undeveloped world may amount to et al. 2003). occur in groups but only groups infect humans. A is by far the most common with sporadic to group group is limited largely to Only group A viruses can be these are in each group are into serotypes on their group A there are types of and approx. of This great infections which may be The age for illness is between 6 months and 2 by 4 years most persons have been infected. to is thus exposure to immunity and of illness with age. secondary can occur in for and this provides another means for the virus to spread in the were the most commonly identified enteric in children years in England and and comprised of the virus identification made in this study (FSA 2000). Only of GP consultations for were made by persons >5 years. However this two first not all adult infections are and this small percentage may actually a number of adult GP consultations for infection than for NoV (FSA 2000). viruses replicate and the the upper third of the intestinal cells do not virus of cells the of water from the gut and diarrhoea The in to and the surface for the same time the cells and the with as yet These cells are to virus infection but cannot the of those that have been they require time to Thus until the cells can the This in the is central to in viruses do not attack the cells such infections do occur (e.g. they in diarrhoea from which may not be possible in a young Although most viruses do not some are and induce the of a that can induce diarrhoea if et al. 1996). has no to et al. 1995). It via a it has no effect on and is of the The mechanism of et al. 1997). The also has direct on et al. 2000). It is that at one of is from infected cells and to cells et al. 2000). A and E viruses via the gut and may replicate however both rapidly to the and the features of both viruses are similar although is more severe and may have a rate of in has a incubation period than d vs 48 and a more prolonged et al. 1995; and 1997). The make identification of the of infection as food will usually have been or of before illness by the is and a shed in the and in the into the The and of the and become is from the by the and Virus particles are shed into the and in the but in to the caused by gastroenteritis viruses there is only with activities and new viruses are to the immune 2–3 after infection and to immune attack on infected It is this than the virus itself that causes the signs of the immune all infected cells thus the from the body. may be prolonged and some of cases may follow a over 12 months or viruses A and E have been affected by human In former infection occurred in often whilst protected by infections to be or viruses are rare is This has exposure and the age at which first infection in 30% of those under were seropositive in by this had to only although in the elderly In in has been for many of persons over have no antibody to have been This in age at infection increases the of below 3 infection is always but symptomatic infections by 5 years and with age et al. over years of age account for only 12% of the cases of but have a rate higher than 1994; 2004). This in infection a pool of individuals to in the community and conditions for Analysis of incidence in the US of 2004). The for 000 cases occurred on per year between and most were or free but 000 cases were et al. that 5% of cases are The in the UK has been et al. 2001). The of adults in some of the world is significant in the of food-borne infection trade that could food in of high to of low could a for adults in those (see E virus is not significant in the UK or most infections are limited to of are

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