Epidemiological states and state movements

The disease transmission path proposed for CA-CDI contains eight epidemiological states, labelling populations as susceptible, gastrointestinal exposed, colonized, diseased, deceased, clinically resolved colonized, relapse diseased or cleared. Figure 1 shows the directional movements through the model. The states are defined in Table 1, excluding the deceased state which includes those with C. difficile listed as the cause of death. Several of the states are clinically indistinguishable, as only three clinical states exist (healthy, infected, deceased); but eight states exist in the proposed pathway because the course a person takes to arrive in a clinical state is of relevance to the study of CA-CDI.

Fig. 1.

Transmission model of community-associated C. difficile, infection states and state transfers.

Table 1.

Clinical definitions of seven states within the community-associated C. difficile infection model of Figure 1

+, Must be present; −, must not be present; +/−, may or may not be present.

C. difficile is transferred through the faecal–oral route [Reference Kelly, Pothoulakis and LaMont17]; once exposed, an incubation period is accounted for by time spent in the gastrointestinal exposed state before a tertiary state. A CDI study review lead to the concept that C. difficile exposure may result in one of three outcomes: development of CDI, or colonization following an incubation of a few days, or no infection [Reference Johnson and Gerding3, Reference Shim4]. To account for this, the tertiary states from the exposed state are diseased, colonized and susceptible. Individuals in the colonized state may still transfer from the colonized to the diseased state, as observed for both adult and infant patients [Reference Shim4, Reference Kim12].

Individuals experiencing intermittent symptoms may be experiencing relapse or re-infection. These two events may be distinguished by typing isolates to compare CDI strains, with a new strain indicating re-infection; however, re-infection with an indistinguishable strain can also occur. With this technique, two separate studies found 5/10 and 12/27 patients may have experienced relapse, as they were excreting the same strain during their previous CDI episode [Reference O'Neill, Beaman and Riley18, Reference Wilcox19]. Relapse of CDI occurs from the diseased state of infection and is proposed as a pathway first taking the individual to a state of clinically resolved colonization. In this state no symptoms are apparent, but C. difficile is still present in the individual's intestinal tract. The individual may then move to the relapse diseased state to account for subsequent periods of infection. Relapse may occur indefinitely by moving between the clinically resolved colonized and relapse diseased states, or an individual may leave the relapse pathway by clearing C. difficile, or dying as a result of their symptoms.

Rather than relapse, persons may leave the colonized and diseased states to enter the cleared state, when symptoms resolve and C. difficile vegetative cells and spores are expelled. The transition of patients to the cleared state, a loss of symptoms without later relapse, has been observed by both spontaneous resolving of symptoms and through antimicrobial treatment [Reference Teasley10, Reference Johnson20].

Persons may remain in the cleared state due to protective factors or return to a susceptible state with the possibility of re-infection. Of recurrences recently observed, 10% of hospital-associated C. difficile infection (HA-CDI) cases followed were due to re-infection [Reference Norén5]. Even greater, at least 56% of recurrent cases were attributed to re-infection in an earlier HA-CDI study [Reference Wilcox19].

Death may occur due to CDI, movement from diseased or relapse diseased to deceased. Deaths of C. difficile-infected patients have been reported at rates of 4%, 13% and 15·2% in Canadian, American and Swedish studies, respectively [Reference Norén5–Reference Olson7]; but those with C. difficile listed as the cause of death had lower rates of 0·6%, 0·7% and 1·5%, respectively.

Exposure routes

To fully account for CA-CDI exposure risks, community C. difficile sources are separated into four broad categories: consumption, person-to-person contact, animal-to-person contact, and environment-to-person (Fig. 2). Sources of C. difficile in the community may be placed in one of these four categories and must have the potential to result in ingestion of toxigenic C. difficile spores or vegetative cells.

Fig. 2.

Transmission model of community-associated C. difficile, with infection source categories.

The dashed lines in Figure 2 link general reservoirs of C. difficile to infection sources; for example, infected individuals may be a source of infection within the community, and therefore, the number of persons in the colonized and diseased states affect the influence of the human infection reservoir on the person-to-person and environmental exposure risks. The change in risk depends on both the number of infected people shedding C. difficile and the amount each individual sheds. Non-human infection reservoirs may exist as well, affecting the risk of C. difficile exposure through consumption, or direct contact with animals and the environment. The relative risks of each exposure in the community are unknown at this time, but both documented and presumed routes are included in the transmission pathway.

Food and water consumption

Individuals in the community may be exposed to C. difficile through consumption of contaminated food and water, creating the potential for developing CDI. One of the largest studies of community C. difficile contamination was performed in South Wales in the 1990s, with 5·5% of tap water and 2·3% of raw vegetables tested carrying C. difficile. Animal products were not directly tested, but the faecal samples of cattle, sheep, pigs, poultry and horses tested positive at a level of <1% [Reference Al Safi and Brazier2]. In 2005, 20% of ground meat samples collected from Ontario and Quebec stores were C. difficile positive [Reference Rodriguez-Palacios21]; and a subsequent 2006 study, with more nationally comprehensive sampling, found 6·1% prevalence of C. difficile in beef and veal [Reference Rodriguez-Palacios22]. C. difficile prevalence in raw and ready-to-eat retail meat in Arizona, purchased over 3 months in 2007, was 42% [Reference Songer23]. These differences may be due to geographical or seasonal differences or method of testing; and while produce, animal products and water may be potential reservoirs of C. difficile, none have been proven to transmit disease.

As well as contamination during processing, the possibility of food contamination during final preparation could be included to account for food preparation by an infected family member or food handler. Although this route has not been investigated, it is believed to be a potentially important route which requires study. Of relevance is the finding that spores of C. difficile may survive at the recommended cooking temperature of 71°C for ground beef, even if held for 120 minutes (A. Rodriguez-Palacios, unpublished data).

Person-to-person transmission

Direct contact with family members may be significant in C. difficile exposure as both diseased and colonized persons are considered potential sources of infection, with diseased individuals shedding more C. difficile due to diarrhoeal symptoms [Reference McFarland13, Reference Fekety24]. Close proximity with a diseased or colonized individual increases the exposure risk in the hospital; it is therefore assumed that this is also true in the home and community setting. Hospital studies have linked C. difficile cases to the admittance of an infected patient with the identical strain, or ended an outbreak by isolating C. difficile-positive patients, implicating these carriers as the disease reservoir for others [Reference Johnson and Gerding3, Reference Heard14, Reference Clabots25]. Additional hospital investigations implicated person-to-person transmission as indistinguishable strains isolated from infected patients were not isolated from the environment [Reference Cohen11, Reference Fawley and Wilcox26]; however, infection strains have been found in the hospital environment during other studies, creating uncertainty as to whether infection is resulting from person-to-person or environmental contacts, or both [Reference McFarland13, Reference Fekety24, Reference Mulligan27]. Proximity to patients with C. difficile in the hospital has been shown to influence infection rates of susceptible patients; 21·7% of those roomed near an infected patient acquired C. difficile in a HA-CDI study [Reference McFarland13]. Of 10 peripartum and 23 CA-CDI cases recorded within the USA, from early 2003 to mid-2005, five resulted after close contacts with other diagnosed CA-CDI cases, implying person-to-person transmission [Reference Chernak15].

A study of community person-to-person transmission considered a class of university students and university employees over a 1-year period, with positives typed for comparison. While similar types were not seen in the students, employees were infected with the same strain [Reference Ozaki28]; however, environmental testing was not conducted so an environmental source cannot be ruled out. Community transmission was also documented when an infant treated for CDI returned home and developed a recurrent case outside the hospital setting. Testing of the home resulted in 12·2% positive swabs, as well as the discovery of a colonized sibling [Reference Kim12]. While infection of the siblings from a common environmental source cannot be discounted, person-to-person transmission is plausible.

Another important component of person-to-person spread is the potential for a family member employed in a high C. difficile-risk environment to bring C. difficile home on clothing or hands. Transfer of C. difficile to the uniforms of healthcare workers has been documented, with 19% of uniforms testing positive after a shift. Uniforms at the study hospital were cleaned through home laundering [Reference Perry, Marshall and Jones29]. The common practice of taking uniforms out into the community may make healthcare workers a reservoir for community infection [Reference Stirling, Littlejohn and Willbond30]. American researchers found 25/27 patients hospitalized with CDI had at least one of five skin sites positive for C. difficile when swabbed; and a ten-patient subset of the study showed a 30–70% transmission rate for C. difficile from the patients to a gloved hand, depending on the skin site tested, only 1 hour after showering [Reference Bobulsky31]. While gloves were used to control variables in the study, this supports the concept of transfer from patient to healthcare worker, even during contact possibly considered as low risk, e.g. touching the forearm or chest.

Those working at veterinary clinics and daycare centres may also be at risk of carrying home the organism to family members from infected animals or children. An Ontario veterinary teaching hospital found 19% of 360 dogs to be positive for toxigenic C. difficile over an 8-month period in 2001; including both CA and HA colonizations [Reference Clooten32]. While the possibility of transfer to staff was not included in the study, animal-to-person transfer is plausible. Day-care workers may also become contaminated with C. difficile due to the high incidence of infant colonization; a 48% colonization rate of children in three Japanese day-care centres as well as environmental contamination in the facilities was found by researchers [Reference Matsuki33]. Agricultural workers exposed to contaminated soil or farm animals may pose a risk, as soil samples positive for C. difficile have been reported from South Wales at a prevalence of 21% [Reference Al Safi and Brazier2].

Person-to-person transmission through contact with non-family members may also transfer C. difficile from an infected individual, or from the hands or clothing of someone who works in a high-risk environment to susceptible persons in the community.

Animal-to-person transmission

Direct contact with colonized or diseased animals is a likely source of infection for humans, as animals may transfer the organisms in a close contact situation. The presence of CDI in animals is documented by several studies, but without proof of transmission to humans. CDI rates of 0–26% have been reported for domestic dogs [Reference Al Safi and Brazier2, Reference Erdemoglu34, Reference Struble35], with higher rates, 9–40%, reported for dogs in veterinary hospitals [Reference Erdemoglu34–Reference Riley37]. Similarly, CDI prevalence in domestic cats has been recorded from 2% to 32% [Reference Al Safi and Brazier2, Reference Erdemoglu34]; and 25–38% for those admitted to veterinary hospitals [Reference Erdemoglu34, Reference Boriello36, Reference Riley37]. A Canadian veterinary teaching hospital recently reported that upon admission, 11% of 366 dogs and cats presented with C. difficile colonization that could be linked to community onset [Reference Clooten32].

The possible connection of such infections to human infections was investigated by molecular typing of C. difficile from humans, dogs, horses, a cat, and a calf. Twenty-five percent of isolates from those species were indistinguishable from human isolates, supporting the theory of inter-species transmission [Reference Arroyo38]. A case of probable inter-species transmission, from humans to a dog, was recorded when a hospital visitation dog was confirmed to be infected with ribotype 027, while a hospital frequented by the dog was experiencing untyped CDI cases [Reference Lefebvre, Arroyo and Weese39].

Persons in contact with agricultural animals may also be at risk of CDI as it has been found at different prevalence levels; 11·2% of Canadian calves tested were infected with C. difficile [Reference Rodriguez-Palacious40]; and cattle, sheep, pigs, poultry and horses showed infection rates of 0%, 1%, 0%, 1·7% and 1%, respectively, in South Wales [Reference Al Safi and Brazier2]. The possibility of increased exposure risks to C. difficile due to animal contact must be more conclusively investigated.

Environment-to-person contamination

Infected persons and domestic animals may contaminate the home or community environment, leaving C. difficile spores on common contact surfaces. Environmental contamination has been shown to increase in proximity of colonized and diseased persons and animals. Hospital rooms of diseased, colonized and C. difficile-negative patients were positive at rates of 19·6%, 6·8% and 2·6%, respectively [Reference Fekety24]. Similarly, positive samples from diseased, colonized and C. difficile-negative patients' rooms at another facility were obtained at rates of 49%, 29%, and 8%, respectively [Reference McFarland13]. Both sets of results show the increased contamination due to a diseased individual; but that colonized persons still create contamination in their surroundings, to a greater extent than those that are C. difficile negative. Testing of hospital environments found samples from diseased and colonized patients' rooms ranged from 0% to 53·3% positive with an average of 32·5%, while control rooms ranged from 0% to 7% with an average of 1·3% [Reference Mulligan27]. Again, shedding by C. difficile patients created more contaminated environments. It was also observed that once patients were either removed from a room or treated for CDI, the number of positive samples as well as the concentration in positive samples decreased; evidence that the contamination was caused by the patient.

A community study of day-care centres found that the floors of two separate facilities were contaminated with strains indistinguishable from those infecting the children at each respective location [Reference Matsuki33]. The timeline of infections vs. environmental contamination was not available, so it cannot be stated which came first, but it is likely that the children themselves were contaminating their environment. With regards to contamination by animals, 11·4% of environmental samples at a veterinary hospital where infected animals were treated were positive for C. difficile. Subsequent sampling from an infected dog's home setting, however, failed to show C. difficile contamination in any of six sites tested [Reference Boriello36]. Recently, two environmental household studies have been conducted to examine C. difficile contamination at 10 sites within households in Ontario, Canada. The first study, considering households with dogs, found 31% of households had at least one site positive for C. difficile; however, the dog and environmental ribotypes did not match in any of the four households where concurrent positives were collected (J. S. Weese, unpublished data). The second study, consisting of randomly selected households, found 34% of households to have at least one site positive for C. difficile (R. Finley, personal communication).

Environmental contamination in soil and water may be encountered during activities such as gardening and swimming. Water samples taken from rivers, sea, lakes and drainage water in South Wales resulted in 87·5%, 43·7%, 46·7% and 27% positive samples, respectively. Four of eight swimming pools in the area were also positive for C. difficile. Soil taken from public places in the region showed C. difficile in 21% of sites [Reference Al Safi and Brazier2]. Both samples taken from the yard of a house where one child was colonized and another was diseased were positive for C. difficile [Reference Kim12]. Clearly, environmental contamination can be found in areas both with and without colonized and diseased human and animals, and may be a source of community infection in humans.