Longitudinal study of infectious intestinal disease in the UK (IID2 study): incidence in the community and presenting to general practice
Clarence C Tam Laura C Rodrigues Laura Viviani Julie P Dodds Meirion R Evans Paul R Hunter Jim J Gray Louise H Letley Greta Rait David S Tompkins
Objectives To estimate, overall and by organism, the incidence of infectious intestinal disease (IID) in the community, presenting to general practice (GP) and reported to national surveillance.

Design Prospective, community cohort study and prospective study of GP presentation conducted between April 2008 and August 2009.

Setting Eighty-eight GPs across the UK recruited from the Medical Research Council General Practice Research Framework and the Primary Care Research Networks.

Participants 6836 participants registered with the 88 participating practices in the community study; 991 patients with UK-acquired IID presenting to one of 37 practices taking part in the GP presentation study.

Main outcome measures IID rates in the community, presenting to GP and reported to national surveillance, overall and by organism; annual IID cases and GP consultations by organism.

Results The overall rate of IID in the community was 274 cases per 1000 person-years (95% CI 254 to 296); the rate of GP consultations was 17.7 per 1000 person-years (95% CI 14.4 to 21.8). There were 147 community cases and 10 GP consultations for every case reported to national surveillance. Norovirus was the most common organism, with incidence rates of 47 community cases per 1000 person-years and 2.1 GP consultations per 1000 person-years. Campylobacter was the most common bacterial pathogen, with a rate of 9.3 cases per 1000 person-years in the community, and 1.3 GP consultations per 1000 person-years. We estimate that there are up to 17 million sporadic, community cases of IID and 1 million GP consultations annually in the UK. Of these, norovirus accounts for 3 million cases and 130 000 GP consultations, and Campylobacter is responsible for 500 000 cases and 80 000 GP consultations.

Conclusions IID poses a substantial community and healthcare burden in the UK. Control efforts must focus particularly on reducing the burden due to Campylobacter and enteric viruses.
https://gut.bmj.com/sites/default/themes/bmjj/favicon.ico
Gut
Microbiological analysis

First, all stool samples were cultured for Campylobacter jejuni/coli, E coli O157, Listeria monocytogenes, Salmonella spp., Shigella spp. and Yersinia spp. They were also examined by ELISA for Clostridium perfringens enterotoxin, C difficile cytotoxins A and B, Cryptosporidium and Giardia, by a commercial PCR test (Cepheid) for C difficile, and by light microscopic examination of a stained smear for Cyclospora and Cryptosporidium. Samples that were immunoassay positive for C difficile toxin or PCR-positive were cultured using National Standard Method BSOP 10, and all isolates were ribotyped.13 Samples from children under 5 years were examined for rotavirus and adenovirus 40/41 by immunoassay.

Next, two nucleic acid extracts were prepared from each stool sample.14–16 Each extract was examined by real-time PCR for C jejuni, C coli, L monocytogenes, Salmonella spp., rotavirus, norovirus, sapovirus, adenovirus, astrovirus, Cryptosporidium, Giardia and E coli (enteroaggregative and VTEC (genes encoding VT1 and VT2)).

Further information on microbiological methods has been published elsewhere.10 For quantitative PCR assays, a cycle threshold value <40 was considered positive for most organisms, with two exceptions: a cycle threshold cut-off value <30 was used to define clinically significant norovirus and rotavirus infection.17 18

In this study, C difficile-associated diarrhoea (CDAD) was defined as symptoms of diarrhoea not attributable to another cause (ie, in the absence of other enteropathogens), but with a positive C difficile toxin assay, in a patient aged >2 years.19

Rate of overall IID

There were 4658 person-years of follow-up and 1201 definite IID cases in the cohort. The crude IID incidence rate was 258 cases per 1000 person-years. The age- and sex-standardised rate was 274 cases per 1000 person-years (95% CI 254 to 296). When both definite and possible cases were considered, this rose to 523 cases per 1000 person-years (95% CI 497 to 551). There was little evidence that rates varied by socioeconomic characteristics or between urban and rural areas (data not shown).

In the under-ascertainment analysis, approximately one case was recruited into the GP presentation study for every six identified in the medical records, although this varied by age group, Read code category and practice. After adjustment for under-ascertainment, there were 5546 IID cases and 312 232 person-years of follow-up, yielding a consultation rate of 17.7 per 1000 person-years (95% CI 14.4 to 21.8). This was lower than that estimated from definite cases in the cohort who reported consulting their GP for their illness (25.3 cases per 1000 person-years, 95% CI 20.7 to 31.3). The age-specific rates of GP consultation in the two studies were similar except for young children and older adults (figure 3). Among children <5 years, the rate was 133 consultations per 1000 person-years in the cohort study (95% CI 92 to 199) and 85 consultations per 1000 person-years in the GP presentation study (95% CI 59 to 122), while among those aged 65 and over, the corresponding rates were 30 consultations per 1000 person-years (95% CI 22 to 42) and 20 consultations per 1000 person-years (95% CI 15 to 27), respectively.

Call rates to NHS Direct in England for diarrhoea and vomiting were 6.1 per 1000 person-years, similar to that estimated from cohort study patients in England who reported contacting NHS Direct for their illness (5.5 per 1000 person-years, 95% CI 3.4 to 9.5).

Ratios to national surveillance

Table 2 presents, by organism, the rates of IID in the community and presenting to GP, and the ratios of these rates to those estimated from national surveillance data. Figures 4 and 5 illustrate reporting patterns for all IID and for the four major pathogens, Campylobacter, Salmonella, norovirus and rotavirus. In each diagram, the rates in the community, presenting to GP and reported to national surveillance are represented as ellipses, with the area of each ellipse proportional to the rate.

The ratios of community and GP presentation rates to national surveillance rates were much higher for viruses than for bacteria and protozoa. For every national surveillance case of norovirus IID, there were 12.7 GP consultations (95% CI 8.8 to 18.3) and 288 community cases (95% CI 239 to 346). The corresponding ratios for rotavirus were one in five (95% CI 3 to 7) and one in 43 (95% CI 30 to 62). By contrast, for every national surveillance case of campylobacteriosis, there were 1.3 GP consultations (95% CI 0.9 to 1.8) and 9.3 community cases (95% CI 6.0 to 14.4). For Salmonella, the corresponding ratios were 1.4 GP consultations (95% CI 0.6 to 3.3) and approximately five community cases (95% CI 1.2 to 18.2). Among the protozoa, 2.3 GP consultations (95% CI 1.0 to 5.6) and 8.2 (95% CI 2.1 to 31.7) community cases occurred for every case of cryptosporidiosis reported to national surveillance. The corresponding figures for giardiasis were somewhat higher, although there was considerable uncertainty in the estimates.

Comparison with other studies

In a previous study,12 limited to England in the mid-1990s, using the same case definition and similar methods, the reported IID rates were 194 community cases and 33.1 GP consultations per 1000 person-years. In our study, the community incidence is ∼40% higher, but GP consultation rates for all the major pathogens have almost halved. This is consistent with data from the Royal College of General Practitioners Weekly Returns Service indicating a threefold decrease in IID-related consultations to its GP network between 1996 and 2008.25 A major change to primary care since the 1990s is the introduction of telephone information and advice services. However, use of services such as NHS Direct in England was low in our study and cannot account for the decline in GP consultations. Instead, increased self-management and perhaps a decrease in the severity of illness from certain pathogens may be responsible.

Our case definition was more sensitive than those used in other studies and may have resulted in milder illness being captured. The effect of varying case definitions will be the subject of more detailed investigation. The Dutch SENSOR Study, which used a definition for IID of three or more loose stools in a 24 h period,23 produced a similar estimate (283 per 1000 person-years) to ours. Approximately 20% of patients in our cohort experienced fewer than three loose stools in a 24 h period, implying that, using comparable definitions, our study would produce somewhat lower estimates of all-cause IID in the community. Nevertheless, using comparable diagnostic methods, rates in the community for Campylobacter, norovirus and rotavirus were similar to those in both the previous IID Study12 26 and the Dutch SENSOR Study.23 By contrast, the incidence of salmonellosis in our study was considerably lower than in those two studies. This reflects a decrease in contamination of poultry products, particularly from Salmonella Enteritidis phage type 4, following the introduction of vaccination of breeder and layer flocks in the mid-1990s.27

We estimate that there are up to 17 million cases of sporadic IID in the UK every year. Studies of IID burden in similar settings using telephone survey methods generally produce incidence estimates two to three times higher.28 The reasons are unclear, but may include differences in case definitions, telescoping of symptoms among telephone survey respondents, and reporting fatigue among cohort participants followed-up for long periods.28 In the IID2 Study, we conducted a parallel telephone survey to study these differences in detail (to be reported elsewhere).

IID-related GP consultation rates vary considerably by study: the SENSOR study rate was half that estimated by us,29 while the rate recently reported in Germany was double.30 These differences are difficult to interpret, but variations in primary care provision and usage between countries may explain them.

Study limitations

Adherence to weekly follow-up in the cohort study was high. Drop-outs accounted for losing <5% of total follow-up time. Nevertheless, ∼10% of those invited were recruited into the study. This is lower than previous studies in England (35%)12 and the Netherlands (42%),23 but similar to recent prospective, population-based UK studies.31 32 Study participants may differ from the general population in terms of IID risk or propensity to report symptoms. We standardised all rates to account for differences in the age and sex structure between the cohort and census populations, and we did not find important differences in IID rates by ethnicity, socioeconomic group, urban–rural residence or area-level deprivation (data not shown).

We based our estimates of community incidence on definite IID cases. These could be conservative, since some cohort participants reporting illness were classified as possible cases because of missing symptom information. If definite and possible cases were considered, the community rate nearly doubled. We used definite cases only because information from them on health service usage agrees with estimates from the GP presentation study and NHS Direct, suggesting that these estimates are more reliable than those based on all definite and possible cases. In addition, our results show a marked decline in community Salmonella incidence, but for Campylobacter, norovirus and rotavirus, for which control measures have not been implemented, our estimates are similar to those reported previously in England12 26 and the Netherlands.23

One in six patients presenting to GP with IID-compatible symptoms was recruited into the GP presentation study, with considerable variation by practice. Although we publicised the study widely in participating practices, some GPs may not have referred patients if they were too busy. To satisfy ethics requirements, invited patients were given a 24 h cooling-off period before providing consent. Some patients were unable or unwilling to return for an interview on another day, and others were no longer interested because their condition had improved. We corrected for under-ascertainment using adjustment factors to account for differences in ascertainment by age group, sex, diagnostic category and practice.

In the cohort study, a third of cases did not provide a stool specimen for microbiological examination, so we used multiple imputation methods to infer missing organism information. Our imputation models included variables most likely to predict the likelihood of infection with different organisms, namely age group and symptom profile, but may not have dealt adequately with missing data if other important factors related to positivity with specific organisms had been omitted.

We used both conventional and quantitative PCR methods for microbial diagnosis. PCR-based methods have greater sensitivity for enteric viruses. For norovirus and rotavirus, however, a substantial fraction of asymptomatic people have evidence of infection using PCR.33 We used previously validated PCR cut-off values to distinguish clinically significant from coincidental infection with norovirus and rotavirus. Similar data do not exist for other organisms, and we opted for a more sensitive threshold. We may have overestimated incidence, particularly for sapovirus, adenovirus and astrovirus, since, in some people, infection may have been coincidental rather than causative. Conversely, we may have underestimated Cryptosporidium and Giardia rates; these organisms often cause illness lasting over 2 weeks, so cases of longer duration may have been excluded.

Despite extensive microbiological testing, ∼50% and 60% of specimens tested in the GP presentation and cohort studies, respectively, were negative for all the organisms investigated. This is similar to previous studies23 34 and may reflect the role of other organisms for which we did not test, or hitherto unknown pathogens. We excluded patients with known non-infectious causes of IID, and required cases to be symptom-free for the preceding 3 weeks and have illness lasting less than 2 weeks. However, it is possible that a fraction of these stool-negative cases had non-infectious causes such as transient irritable bowel syndrome, either pre-existing or resulting from a prior episode of IID.

The reporting ratios should be interpreted in their epidemiological context. Norovirus cases in national statistics arise primarily from institutional outbreaks, which were not included in our study. We may therefore have overestimated the proportion of sporadic cases in the community captured by national surveillance. For organisms such as Campylobacter, which is uncommonly associated with large outbreaks, the reporting ratio reflects more accurately the ratio of community incidence to national statistics.