Health problems following Campylobacter jejuni enteritis in a Lancashire population
S. Zia,
D. Wareing1,
C. Sutton,
E. Bolton1,
D. Mitchell2 and
J. A. Goodacre
Consortium for Campylobacter Clinical and Molecular Research, Lancashire Postgraduate School of Medicine and Health, University of Central Lancashire,
1 Public Health Laboratory, Royal Preston Hospital and
2 Department of Neurology, Lancashire Teaching Hospitals NHS Trust, Preston, UK
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Abstract
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Objectives. Campylobacter jejuni enteritis can lead to musculoskeletal, neuropathic or other health sequelae. We investigated the coexistence, seasonal occurrence, strain-type associations and impact on work capacity of different health problems following C. jejuni enteritis in a Lancashire population during 1999 and 2001.
Methods. A semistructured questionnaire was used to characterize health problems that occurred in the community after laboratory-confirmed episodes of C. jejuni enteritis. The questionnaire was posted to all adults in the Preston and Chorley area who developed C. jejuni enteritis in 1999 or 2001. All Campylobacter isolates from this population were serotyped.
Results. Several types of sequelae occurred consistently in both years, including the coexistence of musculoskeletal and neuropathic problems. There was no evidence of C. jejuni strain-type associations or seasonal preponderance for any type of sequela. The overall health impact of C. jejuni enteritis, as measured by workdays lost, was high in this population.
Conclusions. A variety of health problems occur consistently following C. jejuni enteritis and substantially increase morbidity due to campylobacteriosis in the community.
KEY WORDS: Campylobacter jejuni, Enteritis, Health sequelae.
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Introduction
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Campylobacter jejuni is a major cause of enteritis worldwide. It is the most common known bacterial aetiology of infectious enteritis in the UK [1], and numbers of verified cases of human campylobacteriosis are increasing in the USA [2]. Most cases are sporadic, although outbreaks can occur. Campylobacter jejuni can be isolated from poultry, livestock and their derived food products [3], wild birds [4], water [5] and sand [6]. The peak incidence of human campylobacteriosis occurs in early summer and the disease is more common rurally [7].
There is strong circumstantial evidence that C. jejuni enteritis can lead to GuillainBarré syndrome (GBS) [812] or to reactive arthritis (ReA) [1321], which is also a known consequence of Salmonella, Shigella or Yersinia enteritis [22]. Campylobacter jejuni enteritis has also been implicated in meningitis, carditis, pancreatitis and skin and urinary problems. However, the extent to which different types of sequelae coexist in individual patients is unknown. For example, it is unclear whether musculoskeletal and neuropathic sequelae can occur in the same person, and, if so, whether their coexistence leads to different outcomes. This issue is relevant for studying the mechanisms of post-Campylobacter sequelae. Furthermore, it is unknown whether different sequelae show seasonal variability in parallel with the occurrence of acute enteritis, and whether the same sequelae occur consistently from year to year within a population. In order to investigate these issues, we characterized the health problems that occurred in adults following laboratory-proven C. jejuni enteritis in the same Lancashire subpopulation in 1999 and 2001.
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Methods
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Study design
Ethical approval was obtained from the Public Health Laboratory Service's Ethics Committee and from the Preston, Chorley and South Ribble Local Research Ethics Committee. All people aged over 16 yr living in an area within Lancashire centred around Preston and Chorley who had an episode of C. jejuni enteritis during 1999 or 2001 were identified by the Public Health Laboratory at Royal Preston Hospital. Permission was obtained from general practitioners to approach subjects for consent to participate.
Questionnaire
A 47-item semistructured questionnaire was developed and tested for comprehensibility among a total of 10 members of administrative and academic staff at the University of Central Lancashire. The questionnaire collected information on demography (seven questions, 15%), medical history and current medication (five, 11%), duration and severity of the diarrhoeal illness (eight, 17%), and subsequent musculoskeletal (nine, 19%), neuropathic (nine, 19%) and other (nine, 19%) health problems occurring up to 4 months after the diarrhoeal illness. This included information on the duration of symptoms and consequent days lost from work. Regarding musculoskeletal problems, people were asked to locate symptoms of pain, stiffness, swelling or functional impairment, guided by a detailed anatomical template of central and peripheral joints. To detect neuropathic problems, participants were asked to report and locate symptoms of muscle weakness, numbness, tingling or other sensory disturbance. Other health problems were sought by asking whether participants had experienced any of a panel of generic symptoms, such as chest pain, breathing difficulties, headaches and visual disturbance. All questionnaires were completed within 10 months of the episode of acute enteritis. Respondents who reported significant pre-existing chronic conditions, causing disability at work and/or at home and/or requiring regular therapy, were excluded from the study. Statistical analysis was performed using SPSS for Windows (release 10.0.5; SPSS, Chicago, IL, USA). Associations among different susceptibility factors and dependent variables were tested using Fisher's exact test.
Campylobacter isolation and identification
All faecal specimens submitted to the Preston Public Health Laboratory between January and December 1999 and 2001 were tested for Campylobacter species by a standard direct culture method [23]. Isolates were identified according to the methods of Bolton et al. [24]. Cultures were subtyped by serotyping at the Campylobacter Reference Unit (CRU), Central Public Health Laboratory, Colindale, London, using established methods [25].
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Results
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Characteristics of the 1999 group
Distribution of 363 questionnaires to the 1999 group resulted in 155 participants, of whom 136 (88%) cases were sporadic whilst in 19 (12%) cases the acute enteritis occurred concurrently with one or more other family member. Eighty-seven (56%) participants were female and 68 (44%) male, with a mean age of 48 (S.D. 15.8) yr. Episodes of acute enteritis lasted on average 14.7 (5.6) days. One hundred and one of the 155 participants reported significant new health problems following C. jejuni enteritis, all of which developed within 4 weeks of the diarrhoeal illness. The seasonal distribution of enteritis in the group is shown in Fig. 1A
. Fifty-three per cent developed enteritis between April and June, with a second minor peak between October and December. Sequelae occurred proportionately throughout the year and were not over-represented among those who developed enteritis during the peak period, as exemplified for the musculoskeletal sequelae in Fig. 1B
. Overall, 26 different C. jejuni serotypes were found, of which serotype 50 was by far the most frequent (44% of isolates), with serotypes 11, 16 or 18 found in 10% of isolates. Serotype 50 is the most prevalent serotype in England and Wales [25, 26] including Lancashire [27]. However, there was no evidence of Campylobacter serotype associations, either with the peak AprilJune period of enteritis or with any form of reactive sequela (data not shown), although 25% of the Campylobacter isolates could not be serotyped using the method employed.

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FIG. 1. Seasonal distribution of enteritis in the 1999 group. (A) Graph showing the number of the 1999 group (n=155) who developed enteritis in each quarter of the year. (B) Graph showing the distribution of enteritis by month in the 1999 group and in subgroups of musculoskeletal sequelae. Data are shown as percentages of the total group.
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Health sequelae in the 1999 group
Fifty seven (37%) participants reported musculoskeletal problems in previously asymptomatic sites, and significantly more of these were female (n=38, 67%, P=0.04; Fisher's exact test). Musculoskeletal symptoms developed on average 10 days after resolution of the enteritis, with minimum and maximum periods of 1 and 30 days, respectively, and lasted for a mean of 8.4 (S.D. 7.0) days. Musculoskeletal and other sequelae developed more commonly following more severe enteritis, although the severity of neither the acute enteritis nor any of its sequelae led to hospital referral for any participant. Clinical features of the musculoskeletal sequelae are summarized in Table 1
. The most commonly affected anatomical site was the lower back, with 47 participants reporting pain and/or stiffness in this area. Among those with low back and coexistent limb involvement (n=39), lower limbs (n=38) were more commonly affected than upper limbs (n=20), and knees were the most frequently involved peripheral site. All people with upper limb involvement (n=27) had coexistent lower limb problems. There was no gender difference regarding the site of involvement. Six people reported joint swelling, suggesting that the proportion of ReA in this group may have been similar to that reported in the recent Finnish population study (7%) [28] and higher than that reported in cohort outbreak studies [18, 21].
Seventeen (11%) people reported sensory problems of numbness and/or paraesthesiae and 14 (9%) reported weakness, all involving the distal areas of upper and/or lower limbs. Among this group, 11 (7%) reported both sensory and motor disturbances together with musculoskeletal symptoms, suggesting that musculoskeletal and neuropathic sequelae can coexist. Furthermore, significantly more of this subgroup of 11 reported chest pain (n=6, P=0.0002), breathlessness (n=3, P=0.02), visual disturbance (n=5, P=0.001), headache (n=6, P=0.03) and dizziness (n=6, P=0.049) compared with the rest of the group (Table 2
), although several other symptoms, such as vomiting and loss of appetite, were not reported more commonly by this subgroup. Overall, 83 (53%) people reported sequelae other than musculoskeletal or neuropathic sequelae, although these did not include skin rashes, suggesting that neither erythema nodosum nor keratoderma, which have been documented in other postenteric syndromes, occurred. Similarly, no uveitis occurred, although visual disturbance (9.7%) and eye pain (8.4%) were reported.
The substantial health impact of both the acute diarrhoeal illness and its sequelae was reflected by the number of workdays lost. For those in either full- or part-time employment (n=101), a total of 1040 workdays were lost due to the acute enteritis and a further 275 due to sequelae. These figures show the minimum impact of campylobacteriosis on work capacity in this population, because more workdays may have been lost among those who did not participate in the study.
Comparisons between 1999 and 2001
In order to identify sequelae that occurred consistently within this population, the 1999 and 2001 groups were compared by focusing on the months between April and August, which encompass the peak period for human campylobacteriosis (Table 3
). The AprilAugust 1999 group comprised 106 people from a total of 195 questionnaires posted, whilst the 2001 group comprised 132 from a total of 188 questionnaires posted. Analysis of the 2001 group confirmed the existence of a subgroup (n=21) with both musculoskeletal and neuropathic sequelae and also confirmed that this subgroup contained significantly more people with chest pain (n=8, P=0.001), breathlessness (n=4, P=0.03), eye pain (n=10, P=0.01) and headache (n=13, P=0.03). In 2001, knees were the most commonly involved peripheral joint (n=37), as was also the case in 1999, whilst 34 people reported problems in one or both ankles and 15 reported problems in one or both hips. Among these, seven people reported swelling in one or more lower limb joints. The percentages of participants reporting each of the sequelae were remarkably similar in 1999 and 2001, although sensory and motor problems were reported by proportionately more than twice as many participants in 2001 compared with 1999, and the percentage who reported combined musculoskeletal and neuropathic problems together with other sequelae in 2001 (15%) was more than twice that in 1999 (7%). Furthermore, relative to the percentages who reported low back pain and/or stiffness (20% in 2001, 31% in 1999), lower limb problems were reported by proportionately more in 2001 (39%) compared with 1999 (30%). The number of workdays lost due to campylobacteriosis was also very similar between years. In 1999, 63 people were in employment, among whom 976 days were lost, whilst in 2001 the number in employment was 87, among whom 997 days were lost, the proportion attributable to sequelae being 22 and 33% respectively.
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Discussion
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This is the first study to use a cross-speciality approach for investigating post-Campylobacter sequelae, including both musculoskeletal and neurological problems, and to investigate the extent to which sequelae occur consistently from year to year in the same UK population. By studying a community subpopulation, we obtained a more comprehensive profile than would have been possible using a hospital-based approach. The main purpose of our study was to characterize the features and outcomes of different health problems following episodes of laboratory-proven C. jejuni enteritis in the community. We did not set out to ascertain the incidence of post-C. jejuni sequelae or to compare it with other types of enteritis or control groups, as this has been done by others. For example, cohort follow-up studies after Campylobacter outbreaks have suggested that ReA occurs in approximately 0.7 or 1.8% of cases [18, 21] whilst a recent population study in southern Finland, which included children as well as adults, found that 45 (7%) of the 610 participants developed ReA and 1% developed reactive tendinitis, enthesopathy or bursitis [28], giving an incidence of musculoskeletal sequelae of 5.1 per 100 000 population and an incidence of ReA of 4.3 per 100 000. Instead, we focused on characterizing the health problems reported by people with laboratory-proven C. jejuni enteritis. We used a retrospective approach, involving a questionnaire similar to that used by Hannu et al. [28], and therefore cannot assume that all the sequelae reported were causally related to the episode of enteritis in all cases. However, this limitation is inherent in the study of post-infective reactive diseases, in that whilst the development of health problems following recent infection implies a causal association, there is no objective means of verifying this in individual patients.
Our results demonstrate that a broad range of health problems can occur following C. jejuni enteritis in the community. Among these, musculoskeletal sequelae affected predominantly the low back and lower limbs, particularly the knees. This is consistent with the common impression that reactive joint disease is usually mono- or oligo-articular, although some studies have documented a polyarticular pattern involving the proximal interphalangeal and metacarpophalangeal joints [13, 1517, 30, 31], as has also been described following infection with Salmonella [32, 33] and Yersinia [34]. The reason for such differences in the expression of polyarticular problems is unclear. Possibly, awareness or recall of musculoskeletal problems may depend in part upon their impact on function at work or leisure, which might lead to differences between communities in reporting involvement of different joints. Alternatively, these findings might reflect different biological mechanisms, but it would be important to verify that these features occurred consistently within these populations before investigating such a possibility. A possible relationship between polyarticular involvement and rheumatoid arthritis (RA) was considered by Hannu et al. [28], but although five out of 45 of people with ReA in their study were seropositive for rheumatoid factor, there were no other features suggestive of RA.
Our findings suggest that musculoskeletal and neuropathic sequelae can coexist, and also raise the possibility that these features may form part of a systemic syndrome. To our knowledge, coexistence of musculoskeletal and neuropathic post-Campylobacter reactive features has not been documented in hospital-based studies. This would have important implications for future mechanistic studies; for example, different host or bacterial factors might determine susceptibility to different types of sequelae, in which case it would be important to distinguish carefully between the different clinical phenotypes. This issue might also be influenced by whether cases are ascertained by population, outbreak or hospital clinic routes, as applies to the HLA B27 association with ReA [22, 28]. Further studies involving groups of patients ascertained both through outbreaks and through hospital clinics, together with longer follow-up of the population cases, would be needed to determine the extent to which the phenotypes that we have identified are clinically distinct.
Interpretation of previous studies implicating particular C. jejuni strain types in reactive pathogenesis is difficult because such work has been entirely hospital-based, and it therefore remains uncertain whether some strains are predisposed towards inducing reactive sequelae and, if so, whether arthritogenic strains differ from neuropathogenic or other strains. Furthermore, C. jejuni typing is complex, involving serotyping, phage-typing and genetic typing. In the context of GBS, heat-labile strains or flagellin types have been implicated [35, 36] although a recent study found no evidence of GBS strain associations [37]. Ours is the first population study to investigate whether sequelae are associated either with particular C. jejuni serotypes or with seasonal onset. However, no evidence for either of these effects was obtained. Sequelae occurred throughout the year in close proportion to the overall seasonal incidence of enteritis. Of 26 different serotypes found, serotype 50, which is known to be the most prevalent in England and Wales, was by far the most frequent. However, as about 25% of the Campylobacter isolates could not be serotyped it remains possible that improved typing methods may yet reveal associations with different clinical phenotypes.
We compared the peak period of human campylobacteriosis in 1999 and 2001 in order to identify features that were consistent from year to year. The existence of a subgroup with combined musculoskeletal and neuropathic features and other systemic features was confirmed. The systemic features reported by this subgroup were relatively selective, suggesting that this profile cannot simply be explained by a tendency by some people to non-specifically over-report health problems. Although the occurrence of problems was broadly similar each year, there was an approximate doubling in 2001 of the proportion with neuropathic sequelae, and also of the proportion who developed lower limb problems relative to low back problems. However, these results are based on percentages within the two groups of participants and do not indicate overall incidence within the population. Further work is needed to quantify this more reliably and to investigate the possibility that, whilst the overall profile of sequelae may remain constant from year to year within a population, variation in the relative proportions of some of the health problems may occur. However, the considerable health impact of C. jejuni enteritis, as measured by work days lost, was highly consistent between the two years. Our figures show the minimum effect on work capacity within this population, as additional days may have been lost from work among those who did not participate in the study.
In summary, this study demonstrates the existence of different types of post-C. jejuni health sequelae in the community, including a subgroup in which musculoskeletal and neuropathic sequelae coexist. One application of our findings relevant to clinical practice is that the possibility of C. jejuni enteritis should be considered as a candidate trigger in people presenting with unexplained musculoskeletal, neuropathic and/or systemic symptoms.
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Conflict of interest
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The authors have declared no conflict of interests.
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Acknowledgments
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The project was supported by funding from the Arthritis Research Campaign, the Lancashire Teaching Hospitals NHS Trust and the Preston Public Health Laboratory.
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Notes
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Correspondence to: J. Goodacre. E-mail: jagoodacre{at}uclan.ac.uk 
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Submitted 2 September 2002;
Accepted 5 February 2003