Occupational Exposure, Environmental Pathways, and the Anonymous Spread of Disease

Epidemiol. Infect. (2013), 141, 2011–2021. © Cambridge University Press 2013 doi:10.1017/S0950268813001131

REVIEW ARTICLE Subclinical infection and asymptomatic carriage of gastrointestinal zoonoses: occupational exposure, environmental pathways, and the anonymous spread of disease

R. S. QUILLIAM1*, P. CROSS2,A.PRYSORWILLIAMS2, G. EDWARDS-JONES2†,R.L.SALMON3,D.RIGBY4,R.M.CHALMERS5, 3 2 D. RH.THOMAS AND D. L. JONES 1 Biological and Environmental Sciences, School of Natural Sciences, University of Stirling, Stirling, UK 2 School of Environment, Natural Resources and Geography, College of Natural Sciences, Bangor University, Bangor, Gwynedd, UK 3 Communicable Disease Surveillance Centre, Public Health Wales, Temple of Peace and Health, Cathays Park, Cardiff, UK 4 School of Social Sciences, University of Manchester, Manchester, UK 5 UK Cryptosporidium Reference Unit, National Public Health Service Microbiology Swansea, Singleton Hospital, Swansea, UK

Received 28 September 2012; Final revision 19 December 2012; Accepted 17 April 2013; ﬁrst published online 10 May 2013

SUMMARY Asymptomatic carriage of gastrointestinal zoonoses is more common in people whose profession involves them working directly with domesticated animals. Subclinical infections (defined as an infection in which symptoms are either asymptomatic or sufficiently mild to escape diagnosis) are important within a community as unknowing (asymptomatic) carriers of pathogens do not change their behaviour to prevent the spread of disease; therefore the public health significance of asymptomatic human excretion of zoonoses should not be underestimated. However, optimal strategies for managing diseases where asymptomatic carriage instigates further infection remain unresolved, and the impact on disease management is unclear. In this review we consider the environmental pathways associated with prolonged antigenic exposure and critically assess the significance of asymptomatic carriage in disease outbreaks. Although screening high-risk groups for occupationally acquired diseases would be logistically problematical, there may be an economic case for identifying and treating asymptomatic carriage if the costs of screening and treatment are less than the costs of identifying and treating those individuals infected by asymptomatic hosts.

Key words: Acquired immunity, community epidemiology, disease management, environmental medicine, public health.

INTRODUCTION 76 million cases in the USA [1, 2], with four of Each year, foodborne diseases account for an esti- the most important pathogens responsible for food- Campylobacter mated 1·3 million cases in England and Wales and borne illnesses being zoonotic ( spp., Salmonella spp., Cryptosporidium spp. and verocytotoxin-producing Escherichia coli (VTEC), * Author for correspondence: Dr R. S. Quilliam, Biological and particularly E. coli O157). In addition to causing Environmental Sciences, School of Natural Sciences, University of acute diarrhoeal symptoms, infection may lead to Stirling, Stirling, FK9 4LA, UK. (Email: [email protected]) more severe complications, e.g. haemolytic uraemic † Deceased. syndrome from E. coli O157, and Guillain–Barré

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Table 1. Occupational and environmental risk exposures associated with gastrointestinal zoonotic pathogens

Zoonotic disease Occupational and environmental risk exposures References

Campylobacteriosis Poultry abattoir workers [11, 14–16, 18–20] Living or working on a farm (particularly poultry) Recreational water activities Cryptosporidiosis Visiting farms and contact with farm animals [25–28, 31] Recreational water activity (particularly swimming pools) Living or working on a farm (dairy) Rural areas with high ruminant livestock density Salmonellosis Living or working on a farm [38–41] Farm contact (sheep and dairy) Working in a veterinary clinic VTEC (including O157) Living or working on a farm (sheep and dairy) [6, 8, 10–13] Rural residency or farm contact (particularly with animal faeces) Visiting agricultural fairs and petting zoos Meat processors and abattoir workers

VTEC, Verocytotoxin-producing Escherichia coli.

syndrome from Campylobacter infection. Although them working directly with domesticated or wild many cases of human salmonellosis, campylobacterio- animals. sis, cryptosporidiosis and E. coli O157 infections are Despite the lack of clinical symptoms, individuals foodborne or waterborne, both outbreak and sporadic with apparent immunity can still be colonized by infections have been linked with the veterinary sur- zoonotic pathogens [6], and could inadvertently facili- geries and the farming environment and a number tate disease transmission. A recent study from India of associated risk exposures have been identified demonstrated that children excreting viruses asympto- (Table 1). Here we consider the environmental path- matically served as a significant source of infection ways associated with prolonged antigenic exposure because they were not restricted by illness [7]. The and assess the role of occupational exposure in suscep- public health significance of this should not be under- tibility to zoonotic pathogens. We discuss the signifi- estimated as asymptomatically colonized individuals cance of asymptomatic carriage in disease outbreaks, involved in the food supply chain will not necessarily and explore the epidemiological implications of alter their behaviour (e.g. due to diarrhoea) and could asymptomatic carriage on disease management. be responsible for the prolonged cycling and trans- Zoonoses are infectious diseases that are transmissi- mission of infectious diseases. The costs of illness to ble from vertebrate animals to humans. In many local health services and the wider economy associ- countries, the reporting of most zoonotic illness has ated with asymptomatic carriage are currently traditionally been voluntary and therefore laboratory- unknown. A better understanding of the scale of the confirmed zoonotic cases probably account for only a role of asymptomatic carriage in disease burden small fraction of those occurring in the community. would inform policy makers and allow a more accu- Farm workers, veterinarians and abattoir workers, rate assessment of the value and cost-effectiveness of who have more repeated contact with animals than intervention strategies which would address it. almost any other occupational group, have a higher potential risk of contracting zoonotic illnesses. Seroprevalence studies have shown that these groups Recurrent occupational animal exposure and fi and their families are at risk of exposure to a signi - subclinical infection cant number of zoonoses [3–5]. However, frequent E. coli and recurrent occupational exposure to zoonoses can O157 result in reduced occurrence of clinical illness due to Circumstantial evidence suggests that occupational a build-up of immunity; consequently it has been exposure to domesticated livestock can result in sub- suggested that asymptomatic carriage of zoonoses is clinical infection with VTEC. For example, a study more likely in people whose occupation involves in Canada found that 12% of dairy farm families

possessed serum antibodies to the E. coli O157 lipo- unpasteurized milk, which in previous studies has polysaccharide (LPS), although none of these subjects also been associated with elevated levels of antibodies reported gastrointestinal symptoms at the time of and immunity to Campylobacter symptomatic infec- sampling or a history of bloody diarrhoea or renal tion [23, 24]. However, while frequent farm-related problems [8]. Further evidence of asymptomatic car- antigenic stimulation may offer a degree of protective riage of VTEC in farm workers has led to the sugges- immunity, this type of acquired immunity is often tion that a degree of immunity to clinical infection incomplete, dose-respondent, and can be overcome by E. coli O157 develops as a result of prolonged low- by exposure to novel antigenic serotypes. level exposure to less virulent VTEC strains [6]. This was supported by a retrospective serosurvey of healthy adult farm workers from the UK, which provided evidence of persisting antibodies to E. coli O157, Cryptosporidium particularly of the IgG class, suggesting long-term or Infection with the protozoan parasite Cryptosporidium repeated exposure to VTEC [9]. Further studies have (Cr.) can cause gastrointestinal disease of clinical and shown elevated levels of antibodies to E. coli O157 economic significance in both humans and young LPS in dairy farm residents compared to urban resi- farmed animals, with most human cases being caused dents [10], and in farm-resident rural children com- by either Cr. hominis,orCr. parvum. Several UK pared to non-farm-resident children [11]. Although studies have provided evidence for the anthroponotic the phenomenon of seropositivity and asymptomatic spread of Cr. hominis and the mainly zoonotic spread carriage of VTEC in farm workers has been well docu- of Cr. parvum, with short visits to farms, handling mented, the risk factors associated with carriage are cattle and touching farm animals being identified as still poorly understood [12, 13]. independent risk factors [25–27]. Furthermore, a quar- ter of all reported sporadic annual cases of Cr. parvum in England and Wales can be attributed to direct con- Campylobacter tact with farm animals [28]. Several seroepidemiologi- While increased anti-Campylobacter jejuni antibodies cal studies have found more positive subjects in rural are often detected in the sera of individuals who settings than urban groups [e.g. 29, 30] and increased work with poultry [14, 15], the risk of developing seroprevalence has been detected in dairy farmers Campylobacter infection is much greater in inexperi- compared to control subjects [31]. However, in a series enced or temporary poultry farm workers [16, 17]. of 790 sporadic cases in the UK between 2004 and In a serological study of poultry abattoir workers, 2006, only three cases were adults who had occu- long-term occupational exposure was accompanied pational farm contact (two farmers and one veterinary by high levels of C. jejuni-specific IgG antibodies student), suggesting potential immunity in those fre- [18]. Eight of these abattoir workers tested positive quently and historically exposed to animals and their for faecal excretion of C. jejuni, with seven of faeces [28]. This contrasts with cryptosporidiosis out- them apparently asymptomatic, despite evidence for breaks that regularly occur at swimming pools, day- persistent excretion for up to 6 weeks. Occupational care nurseries, open farms and similar settings which exposure to farm animals (e.g. cattle, sheep, poultry) frequently involve children, and have been reported and farm residency have also been identified as signifi- in veterinary students who have had limited prior cant risk factors for Campylobacter infection [19–21]. exposure [32, 33]. Frequent exposure through inter- However, it has also been suggested that occupational mittent low-level contamination may lead to subclini- contact with livestock or their faeces can provide cal infection and some herd immunity [34]. This is protection against Campylobacter disease [22]. This supported by evidence from a seroepidemiologi- is supported by a study in rural Wisconsin, which cal study, which showed that people with high showed that 59% of children possessed antibodies to anti-cryptosporidial antibody levels were much less C. jejuni, with farm-residency and increasing age inde- likely to self-report diarrhoeal disease than those pendently associated with seropositivity, despite no with low levels of antibody [35]. Human infectivity corresponding increase in clinically recognized diar- studies have shown that although prior exposure rhoeal illness compared to non-farm-resident children does not provide complete protection against further [11]. Other factors associated with seropositivity infection, clinical symptoms are less severe [36, 37] included contact with cattle and sheep and drinking and age-related increases in seroprevalence appear to

correlate well with the decline in incidence of clinical phenomenon in the abattoir industry where new cryptosporidiosis [37]. employees with a lack of previous exposure to a range of zoonotic pathogens, almost inevitably report fi Salmonella gastrointestinal illness in the rst few days of employ- ment, with far fewer cases occurring in longer-term The routes of zoonotic transfer of Salmonella spp. employees [18, 47]. Although the implications of abat- include direct contact with farm animals or their toir workers asymptomatically carrying gastrointesti- faeces and exposure to a number of companion nal zoonotic pathogens is not as immediately serious animals, particularly reptiles. Consequently, occu- as subclinical infection in other types of food handlers, pational exposure has been demonstrated in farm e.g. during the preparation of ready-to-eat products, workers [38, 39] and veterinarians [40, 41], although asymptomatic individuals may well be significantly the type of practice, i.e. small or large animal practice, facilitating the transmission of zoonotic pathogens will determine the Salmonella serotypes personnel are into the food chain. exposed to. Although secondary transmission of While few studies directly compare the prevalence Salmonella is a recurrent problem in animals at veter- of zoonoses within populations of developing and inary clinics, there have been no direct studies on the developed countries, there is evidence for increased levels of immunity in veterinary personnel; however, asymptomatic carriage of gastrointestinal pathogens a stool sample from an asymptomatic employee in developing nations [48, 49]. Environmental path- during one outbreak of salmonellosis at a veterinary ways associated with prolonged antigenic exposure clinic in the USA was found to be positive for include the recurring consumption of contaminated S. Typhimurium [41]. Clearly the risks for zoonotic drinking water and lower levels of hygiene during transfer are high in veterinary workers, although a food preparation together with an increased environ- recent report indicated that veterinarians rarely use mental burden. This makes recurring cycles of infec- personal protective equipment or adopt infection con- tion with a range of zoonoses in the developing trol practices to protect themselves against zoonotic world more likely, with many reports ascribing the disease transmission [42]. It remains unclear whether asymptomatic carriage of particular zoonotic patho- the occupational exposure to zoonoses experienced gens (e.g. Campylobacter) to this constant antigenic by veterinary workers results in a form of protection; exposure [45]. Although microbial stimulation plays and although several studies have linked the zoonotic an important role in modulating and improving the spread of Salmonella from farm animals to farm immune response against future challenges by infec- workers, intriguingly there are as yet no reports of tive agents, the levels of immunity to zoonoses in asymptomatic carriage in farm workers. Whether the developing world are acquired at the expense of this is due to a lack of cumulative exposure, through considerable infant and child mortality, often due to common antigens from the range of different diarrhoeal diseases. Salmonella serotypes present in animals (as suggested Asymptomatic Campylobacter infections are con- for acquired immunity to E. coli O157 [6]), or whether sidered endemic in developing countries, with sympto- this is simply because there is a paucity of studies matic infection limited to children aged <2 years. A clearly needs further epidemiological investigation. considerable number of studies have reported that breastfeeding can induce basal immunity against certain zoonotic pathogens, e.g. Campylobacter [50], Acquired immunity and environmental exposure and as breastfeeding is widespread in the developing Exposure to potentially ‘unhygienic’ environments world, this may play an important role in the level and the onset of protective immunity has been dis- of subclinical infection in children and asymptomatic cussed in the context of many diseases. For example, carriage within a community. Conversely, evidence evidence of acquired, exposure-related, immunity suggests that asymptomatic breastfeeding mothers comes from travellers from Western countries who can transfer certain zoonoses to their baby either often suffer from ‘traveller’s diarrhoea’ on arrival directly, e.g. brucellosis [51, 52] or indirectly, e.g. in a developing country [43–45]; however, their dur- Helicobacter pylori [53]. ation of stay is linearly correlated with protection A large Iranian study conducted on faecal samples from infection, indicating a build-up of immunity from children revealed that a significant proportion over time [46]. This supports a widely reported (7·2%) were asymptomatically shedding strains of

enterotoxigenic E. coli (ETEC) known to cause diar- other than environmental exposure can also affect rhoea [54]. A systematic review on the aetiological susceptibility, e.g. socioeconomic status, which is an role of ETEC in children with diarrhoea in the devel- important co-factor for the prevalence of H. pylori oping world found that colonization in the 0–4 years in the US adult population [60]. The available age group was a significant risk factor for contracting evidence for the occurrence of subclinical infections diarrhoea [44]. There also existed high rates of ETEC demonstrates that they can be multifactorial and in children aged >5 years; however, these children may be related to the type or level of exposure, the were asymptomatic with a notable decrease in the presence of potential immunity in the host, or frequency of diarrhoea. Enterohaemorrhagic E. coli agent-specific factors, such as genotypic variation in O157, which has recently become a serious zoonotic virulence. Whatever the mechanism, the presence of pathogen in industrialized nations, appears to be a subclinical zoonotic infections in human populations, relatively uncommon causative agent of illness in together with associated asymptomatic carriage, gives developing countries. Whether this is due to this rise to a number of important issues for the epidemiol- particular strain of E. coli being relatively new, or ogy and control of these diseases. whether people in developing countries have already acquired a significant amount of immunity to it clearly warrants further investigation. Community epidemiology and the public health fi Genetic variation in human populations also signi cance of subclinical zoonotic infections in humans plays an important role in susceptibility to infectious The emergence of several zoonotic diseases of diseases, with several genetically determined factors major public health significance, e.g. swine influenza influencing susceptibility to specific infections, e.g. A(H1N1), E. coli O157, vCJD, and SARS, have high- Norwalk virus [55]. However, the role of genetic vari- lighted the importance of early surveillance. Essential ation in determining resistance to infection by zoono- to mitigating the spread of communicable diseases tic pathogens remains unclear, although evidence is the implementation of control measures, which from genetic epidemiological studies has demon- includes horizon-scanning and risk assessment. How- strated that immunity to disease usually arises from ever, the presence of subclinical cases can present a a complex interaction of environmental, pathogen barrier to effective disease control as infections often and host genetic factors [56]. Genetically controlled escape detection. Subsequently, under-ascertainment host defence factors can affect the susceptibility of of cases may underestimate the extent of an outbreak, individuals to zoonotic challenge, e.g. individuals and facilitate continued transmission, or lead to bias unable to produce or respond to interferon-gamma in an epidemiological investigation, e.g. by the [57]. Genetic factors can also alter innate immunity, misclassification of controls in case-control studies. e.g. the heterogeneous condition hypogammaglobuli- Further, the presence of subclinical or mild infection naemia can lead to repeated infection and prolonged in a proportion of hosts may provide an evolutionary symptoms from a range of pathogens, including zoo- advantage to an emerging pathogen, facilitating noses [58]. onward transmission within animal and/or human Comparing the incidence of zoonoses in immigrant populations. Asymptomatic carriers can still excrete and resident populations may help to understand infective organisms, and may pass the infection on acquired immunity, although these studies need to to others, although for gastrointestinal infections, be treated with caution as they can often be influenced transmission is more likely from clinical cases, by confounding factors. An example of this occurred especially where cases exhibit diarrhoea (Fig. 1). during the largest ever outbreak of Q fever in the Person-to-person spread of zoonoses is most usually UK, where no cases were reported in the local considered in the control of gastrointestinal infections Asian community despite there being many cases in such as Salmonella and E. coli O157. Horizontal the same area in the non-Asian community [59]. transmission of E. coli O157 spread via the faecal– Although it was hypothesized that cultural factors oral route can occur in families and in the wider partially explained this observation, serosurvey data community. However, secondary transmission of provided evidence for an underlying immunity as salmonellosis during outbreaks may vary depending many members of the Asian community had origi- on the outbreak setting and the strain of pathogen, nated from areas of Pakistan with high rates of and is often dependent on the population at risk. In Coxiella burnetii infection in sheep [59]. Factors a large outbreak on the Navajo Nation Indian

Gastrointestinal zoonotic Acquired immunity/ infection occupational exposure

Subclinical Clinical infection infection

Limited by No behavioural behavioural change change Secondary infection

Presentation to GP No presentation to GP

Treatment Undetected reservoir in the community

Fig. 1. Infection pathways and potential for the maintenance of asymptomatic carriage of gastrointestinal zoonotic pathogens.

Reserve in the USA, which involved 3400 cases, no exclusion from work, school and other institutional secondary infections were reported [61], whereas in settings, and identifying population groups at greater hospital outbreaks in the UK during the 1980s risk of spreading infection, e.g. children aged person-to-person transmission was a significant factor <5 years attending pre-school facilities, people work- [62]. Secondary transmission of E. coli O157 is rela- ing with ready-to-eat food and health and social tively common [63], and of 157 cases identified in a care staff who have direct contact with individuals, school outbreak in Wales, UK, 48 cases were attribu- for whom a gastrointestinal infection could have ted to secondary transmission [64]. By contrast, serious consequences. Outbreaks in children’s nur- person-to-person spread of Campylobacter is rare series in which an explicit link between human asymp- and family clusters are seldom seen [65], and although tomatic carriers of E. coli O157 and person-to-person secondary transmission following point-source out- infection have been reported [71]. Given the frequency breaks does occur, it is uncommon [66]. In a recent of secondary transmission by E. coli O157, and the outbreak of E. coli O157 on a petting farm in the potential severity of outcomes of infection, the UK, of 93 cases of illness, 65 were attributed to pri- prompt separation of primary cases of E. coli O157 mary infection, 13 to secondary infection and 15 from young household contacts has been rec- were asymptomatic cases [67]. While it is theoretically ommended [72]. possible that some of the secondary cases of infection The theoretical possibility of person-to-person could be linked to direct person-to-person spread from infection from asymptomatic carriers poses a signifi- some of the asymptomatic cases, quantifying this risk cant demand on the monitoring and control of disease during an outbreak scenario would prove very diffi- outbreaks. Methicillin-resistant Staphylococcus aureus cult. However, the potential for asymptomatic (MRSA) is an example of a disease with evidence of human carriage as an epidemiological variable should asymptomatic person-to-person infection, e.g. health- not be discounted [68]. care workers [73], and recent reports also suggest a Guidelines exist in the UK for the prevention of zoonotic pathway through professional contact with person-to-person spread of gastrointestinal infections animals [74–76]. Asymptomatically colonized individ- in general [69], and E. coli O157 in particular [70]. uals can transmit MRSA to others [77], and in These guidelines consider the public health manage- so doing can unknowingly act as reservoirs for the ment of cases and contacts and the control of second- disease [73], particularly in nosocomial situations ary transmission. Special attention is given to hygiene [78–81]. Although the infection pathways for zoonotic precautions, such as hand washing, decontamination, MRSA transmission are different to E. coli O157,

Salmonella, Campylobacter and Cryptosporidium, the The latter could involve payment for regular screening role of occupational exposure, asymptomatic carriage for high-risk asymptomatic carriage groups such as and person-to-person spread of MRSA gives rise to a veterinarians. However, surveillance of veterinarians number of important implications relating to the con- and farmers may prove to be controversial and a trol and surveillance of gastrointestinal zoonotic need to adhere to strict confidentiality guidelines essen- diseases. tial [84]. As a control measure the weekly voluntary Livestock farmers and veterinarians in this context screening of veterinarians appears to be technically are an occupational group analogous to healthcare feasible and coupled with an overall improvement in workers and should be considered at risk of becoming hygiene practices may provide sufficient protection asymptomatic carriers due to their regular handling from transmitting both clinical and subclinical infec- of potentially infected animals. Therefore, protective tions [42, 84]. Schemes which aim to reduce the risk measures for this group are important [82]; although posed by asymptomatic carriers in the food chain approaches proposed for healthcare workers in hospi- are mostly not predicated on the assumption that tal settings, e.g. regular screening and decolonization there is some intervention that will remove gastroin- of carriers [83], would be impractical for workers in testinal zoonotic pathogens from asymptomatic the livestock sector. Screening farmers for occupation- hosts. Rather, those hosts are removed from food ally acquired diseases would be logistically problema- handling until such time as the organism can no tical owing to the number of farms, their type and the longer be recovered from their stool. Such interven- practicality of regularly screening in geographically tions are not available for all zoonoses, and even if isolated locations. Veterinarians pose a potentially they were, they would need to be taken regularly in greater threat for the dispersal of these types of patho- order to counter host re-colonization. The imposition gen than farmers due to their multiple daily farm of any programme aimed at reducing the risk from visits, and subsequently have greater potential for asymptomatic carriers may be best focused on groups asymptomatic person-to-person contact within the with a higher risk of transmitting zoonoses to others more densely populated urban and semi-urban com- and lower probabilities of infection, e.g. farmers and munities. veterinarians. The importance of asymptomatic carriage in In theory, a prospective cohort study could be set causing secondary infection was highlighted during a up following a cohort of high-risk individuals (high retrospective cohort study following an outbreak risk of acquiring a zoonotic infection with a low risk of E. coli O157 in the UK [72]. Although it would of clinical symptoms, but a high risk of transmitting be fairly straightforward to set up a similar study to it on) and collecting detailed information about their quantify the spread of zoonoses from primary symp- contacts. In practice, this would probably need a tomatic cases to asymptomatic secondary cases, large number of people, as risk of secondary spread future epidemiological investigations need to focus would be low, and would therefore not be practical. on quantifying the spread from asymptomatic car- Another approach would be to simply screen a riers. However, identifying clinical cases that result healthy occupational cohort for markers of infection, from the secondary transmission from asymptomatic screen the contacts of both positives and negatives and primary cases would be chronologically difficult simply examine statistically whether contacts of posi- during an outbreak setting, as the investigation tives are more likely to be positive. However, this usually begins with the symptomatic case. would likely be confounded by the fact that contacts would have other common sources of infection, rather than linearly transmitting to each other. Potential mitigation strategies The effective management of such diseases is con- If asymptomatic carriers are a source of infection then tingent upon substantive empirical information under- there may be an economic case for identifying and pinning policy decisions. The nature of emerging treating asymptomatic carriage if the costs of screen- diseases often requires policy makers and scientists ing and treatment are less than the costs of identifying to make choices about disease control in the absence and treating those individuals infected by asympto- of hard empirical data. Although when the efficacy matic hosts. One strategy to encourage high-risk occu- of a large number of intervention strategies requires pational groups to seek tests and treatment would such thorough evaluation the task can be cognitively be to impose penalties and/or positive incentives. taxing. To overcome such obstacles, recent research

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