Our results provide evidence that the rate of IID recurrence varies by age. Although infants experience more episodes of IID, among older age groups recurrent IID clusters much more strongly in certain individuals. This effect was particularly pronounced in the elderly, in whom every additional IID episode increased the rate of a subsequent episode by three times. We are not aware of previous evidence from observational studies for such strong clustering effects in adult age groups. In an analysis of surveillance data on laboratory-confirmed campylobacteriosis in Québec, Canada, Arsenault et al. found that, over a period of 11 years, a second episode of Campylobacter IID was more likely to be reported among those aged 15 years and above compared with children under 5 years .
While our data demonstrate an age-dependent effect of recurrent IID, we have no direct evidence for the biological mechanisms involved. However, it is possible that this effect results from changes in immune development and host susceptibility with age. For many enteric pathogens, rates of disease are highest in infants and decrease markedly with age. In particular, rotavirus is the third most common pathogen among paediatric IID cases , accounting for a sixth of cases in children under five years in the IID2 Study for whom an aetiological agent could be identified. Infection with rotavirus is known to decrease the risk of clinical disease following subsequent rotavirus infection [16, 17]; by the age of five, most infections are asymptomatic. This would partly account for the decreased effect of previous episodes on recurrent disease in young children compared with other age groups. Infection with norovirus and sapovirus, the two commonest pathogens in this age group, results in short-term protection from re-infection with related strains, and could also explain the lower rate of recurrent disease in young children compared with older age groups over the relatively short follow-up period of our study.
Among older individuals, the increased rate of recurrent IID is likely due to a greater proportion of individuals with impaired immune function, or chronic or transient gastrointestinal conditions that increase susceptibility to infection with enteric pathogens. Alternatively, infection at older age groups could result in long-lasting changes to the gut flora that facilitate subsequent infection. In our study, we excluded individuals with known chronic gastrointestinal conditions, but it is possible that a fraction of individuals had undiagnosed bowel abnormalities. We did not have information on other conditions that affect immune function, such as diabetes and HIV, or on the use of medications that could influence susceptibility to infection, such as use of steroids, antibiotics, or proton pump inhibitors.
An alternative explanation for the higher rates of recurrent IID in older age groups is that enteric infections themselves increase the risk of bowel abnormalities; irritable bowel syndrome is commonly reported following infection with Campylobacter and other bacterial pathogens [18, 19]. This could suggest that infection with specific pathogens might lead to subsequent diarrhoea episodes in which no pathogen can be found. Our study was insufficiently powered to investigate the effect of specific pathogens on subsequent IID episodes; 60% of specimens in the IID2 Study were negative for any of the pathogens investigated , and the number of recurrent episodes was relatively small. However, we defined a recurrent episode as one that was preceded by a three-week symptom-free period, and our case definition excluded episodes of diarrhoea lasting more than 14 days. It is therefore unlikely that these recurrent episodes constituted persistent or pre-existing bowel abnormalities.
Ascertainment of diarrhoea cases in the IID2 Study relied on weekly, active follow-up of individuals and included negative reporting of symptoms. Nevertheless, it is possible that completeness of reporting, or the effects of reporting fatigue, differed between age groups. This could partly explain our results if reporting of symptoms was more complete in older age groups, but decreased over the follow-up period among younger individuals. In our data, this would manifest itself as a change in the relative rate of disease between different age groups over time, effectively a violation of the proportional hazards assumption required by the Cox model. We found no evidence of a violation of this assumption, and we think this explanation is unlikely.
A further limitation of our study is that we only had information on IID symptoms during the follow-up period. Our data on previous IID episodes is therefore limited to the period of observation. This is likely to underestimate individuals’ IID experience and would tend to limit our ability to observe an effect on recurrent IID, although it is unlikely to have resulted in spurious associations.
Our study indicates that certain subgroups in the population have a high propensity for recurrent IID, particularly among older age groups. The mechanisms for this are unclear, but prevention and control of IID is likely to require a better understanding of how underlying conditions affect both the risk and the outcomes of IID, especially among the elderly. More detailed studies among vulnerable populations, including those with underlying conditions or impaired immunity, should help to better establish the risks and pathogens associated with certain subgroups and inform adequate control policies. Clinicians should be aware of the increased risk of recurrent IID among the elderly and consider whether closer monitoring is required, particularly in the context of underlying conditions. Diarrhoea is a common condition in the elderly that can have profound consequences either owing to the effects of the causative organism itself or because of the associated dehydration [20, 21]. C. difficile is considered to be the most likely cause of persistent or relapsing diarrhoea in the elderly, but our analysis has shown that recurrent IID was common in an elderly population in which C. difficile was rare. With the advent of molecular methods that can be used to screen for multiple pathogens at the same time it is possible that the diversity of organisms causing recurrent gastroenteritis in the elderly will be better understood. This, in turn, might mean that unnecessary antibiotic treatment or invasive procedures can be avoided.