Infectious Gastroenteritis and Risk of Developing Inflammatory Bowel Disease

Article Outline

• Abstract
• Materials and Methods
  • Database Information
  • Exposure
  • Outcome
  • Potential Confounders
  • Analysis
• Results
• Discussion
• References
• Copyright

Background & Aims: Infectious gastroenteritis (IGE) is known to exacerbate previously diagnosed inflammatory bowel disease (IBD). However, limited data are available describing a causal link between IGE and incident IBD. Methods: By using a medical encounter data repository of active duty military personnel, a study was conducted to assess IBD risk in subjects with an antecedent case of IGE. Results: Between 1999 and 2006, there were 3019 incident IBD cases and 11,646 matched controls who were evaluated in a conditional logistic regression model. To control for potential misclassification, IGE episodes within 6 months of IBD diagnosis were excluded as exposures. After adjusting for potential confounders, an episode of IGE increased the risk of IBD (odds ratio, 1.40; 95% confidence interval, 1.19–1.66). The risk was slightly higher for Crohn's disease compared with ulcerative colitis. In addition, there was an approximate 5-fold increase in IBD risk for persons with a previous irritable bowel syndrome diagnosis. Conclusions: These data support theories that the initiation of IBD is a multifactorial process that might include the disruption of normal gut homeostatic mechanisms. Further studies are warranted to evaluate the pathogen-specific risks, identify susceptible populations, and better understand the pathophysiologic relationship between IGE and IBD.

Abbreviations used in this paper: IBS, irritable bowel syndrome, ICD-9-CM, International Classification of Diseases 9th revision Clinical Modification, IGE, infectious gastroenteritis, OR, odds ratio

Although infectious gastroenteritis (IGE) in most cases is a short-lived acute illness, the infections responsible for IGE have been linked to the development of several secondary or chronic health conditions, such as Guillain–Barré syndrome, Reiter's syndrome,¹ irritable bowel syndrome (IBS);², ³ and, most recently, a case is being made for infectious intestinal illness associated with the onset of inflammatory bowel disease (IBD).⁴, ⁵

Given the strong association between IGE and IBS and the hypothesis that subclinical inflammation and immune activation preceding IBD result in symptoms associated with IBS, a hypothesis naturally follows that IGE may be associated with increased IBD risk.³, ⁶, ⁷ We conducted a nested case-control study to assess the risk of IBD in subjects with documented antecedent IGE.

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Materials and Methods 

Database Information 

Data for this study were obtained from the Defense Medical Surveillance System, the main data repository for US Armed Forces medical data.⁸ All subjects were active duty US military personnel who served between 1999 and 2006. Medical information was derived from ambulatory and inpatient claims data for care provided both within the Military Health Service and from the Tri-Service Reportable Events System data. Demographic information was derived from personnel data. Deployment data were derived from deployment rosters and deployment health assessments. Included data were linked at the individual level, compiled into a dataset, and stripped of identifiers. The de-identified dataset then was provided to the study investigators by Defense Medical Surveillance System personnel. The study was reviewed and approved by the Naval Medical Research Center Institutional Review Board in compliance with all applicable federal regulations governing the protection of human subjects.

Exposure 

The primary exposure variable for this study was IGE based on International Classification of Diseases, Clinical Modification, 9th revision (ICD-9-CM) codes for specific pathogens or nonspecific infectious enteritis (Table 1). We included nonspecific infectious diagnosis codes because of the lack of cultures performed on subjects presenting with symptoms of IGE.⁹

Table 1. IGE Diagnoses Included as Exposures With Corresponding ICD-9-CM Codes

To ensure an initial medical encounter for IGE was not the first presentation of IBD undiagnosed at the time of the visit, a 6-month time period before first IBD diagnoses (for cases) or censoring (for controls) was established. This exposure window was developed using 266 (8%) cases randomly selected from the available dataset, evaluated to estimate the average time from initial presentation to IBD diagnosis. Exposures occurring within the 6-month time frame before IBD diagnosis (or censoring for controls) were excluded.

Outcome 

The primary outcome variable for this study was IBD, which can be categorized into 2 separate disease phenotypes: ulcerative colitis (UC) and Crohn's disease (CD). For purposes of this study, IBD was defined as a person with at least 2 medical encounters with any of the following ICD-9-CM codes: 555.0 (noninfectious enteritis and colitis of the small intestine), 555.1 (noninfectious enteritis and colitis of the large intestine), 555.9 (noninfectious enteritis and colitis of an unspecified site), and UC 556 (including all subgroup codes). A diagnosis of pseudopolyposis colon (ICD-9-CM code 556.4) was included in the overall IBD analyses, but was not included in the analyses of UC and CD separately because it can be typified as either disease subtype. The outcome of IBD included subjects with nonspecific diagnoses, a potential limitation previously described.⁴, ¹⁰ Subjects diagnosed with IBD were time- (a medical encounter during the same calendar year), sex-, and age-matched (within 1 year) to 4 subjects with an unrelated diagnosis (controls). These controls were selected randomly from the same population that produced the cases (ie, US armed forces personnel) with a myriad of medical encounter visit types such as vaccinations, procedures, or other unrelated diagnoses. Date of IBD onset was defined as the first documented ambulatory or inpatient medical encounter with an ICD-9-CM code listed previously. However, later diagnostic codes were evaluated to ensure no change in classification. Cases whose diagnostic codes changed from one IBD subtype to the other, or who were coded as having diseases classified as both CD and UC, were included in the overall IBD analysis, but were excluded from the UC and CD subanalyses.

Potential Confounders 

In addition to IGE, other demographic variables available in the data were evaluated including race, military rank, educational attainment, marital status, branch of service, and previous diagnosed IBS (ICD-9-CM code 564.1). Similar to the concern of IBD being misdiagnosed as IGE, IBD also may be misdiagnosed as IBS in the early course of disease. Therefore, we excluded any IBS diagnoses occurring in the 6 months before IBD onset (for cases) or censoring (for matched controls).

Analysis 

The associations between IBD, IGE, and covariates initially were explored by univariate methods. Analyses evaluated all IBD diagnoses as well as UC and CD separately. Univariate and multivariate conditional logistic regression models were used to evaluate the relationship between IGE and UC, CD, and all IBD. For the multivariate models, a backwards elimination approach was used, whereby all variables initially were added to the models. The variable with the largest insignificant P value was removed, and the models were re-fit. This process was continued iteratively until all variables retained in the models were significant at an α value of .15 level. The use of an α value of .15 has been recommended by several investigators in the development of logistic regression models.¹¹

Statistical analyses were performed using SAS version 8.2 for Windows (SAS Institute, Cary, NC). Two-tailed statistical significance was evaluated using an α value of .05.

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Results 

A total of 3285 cases of IBD were identified in active duty US military personnel between 1999 and 2006 for an estimated IBD incidence of 29.2 cases/100,000 person-years. A subset of 266 cases was analyzed to calculate a 6-month diagnostic delay window used for exposure classification, and was excluded from additional analyses. Ninety-three percent of the remaining cases were matched with 4 controls, with fewer controls identified for the other 7%. The demographic information on the cases and the matched controls is outlined in Table 2. The majority of cases and controls were Caucasian (72% and 64%, respectively) and married (both 60%), and most reported a high school education or less (65% and 68%, respectively). The 3 major branches of the US military armed forces (Army, Navy, and Air Force) comprised the majority of the study population, with most classified as enlisted personnel.

Table 2. Demographic Characteristics of US Military Service Members Diagnosed With IBD Between 1999 and 2006 and Their Matched Controls

Variable	Cases (n = 3019)			Controlsa (n = 11,646)
	CD (n = 1037)	UC (n = 1720)	All IBD (n = 3019)
Mean age, y (SD)	33(7.4)	35(8.1)	34(7.9)	34(7.8)
Sex
Male	852(82%)	1415(82%)	2488(82%)	9640(83%)
Female	185(18%)	305(18%)	531(18%)	2006(17%)
Race/ethnicityb
White	748(72%)	1230(72%)	2167(72%)	7463(64%)
Black	163(16%)	255(15%)	459(15%)	2228(19%)
Hispanic	74(7%)	130(8%)	218(7%)	1047(9%)
Asian	16(2%)	47(3%)	70(2%)	424(4%)
Other	35(3%)	55(3%)	101(3%)	471(4%)
Marital statusc
Married	604(58%)	1034(60%)	1800(60%)	6960(60%)
Single	383(37%)	596(35%)	1071(36%)	4168(36%)
Other	46(4%)	82(5%)	136(5%)	488(4%)
Unknown	1(0.1%)	3(0.2%)	4(0.1%)	11(0.1%)
Branch of service
Army	356(34%)	516(30%)	961(32%)	4002(34%)
Air Force	282(27%)	523(30%)	886(29%)	3283(28%)
Navy	277(27%)	423(2%)	756(25%)	2903(25%)
Marines	88(8%)	194(11%)	315(10%)	1138(10%)
Coast Guard	34(3%)	64(4%)	101(3%)	320(3%)
Rank
Enlisted	905(87%)	1338(78%)	2463(82%)	9729(84%)
Warrant officers	5(1%)	26(2%)	35(1%)	131(1%)
Officers	127(12.2)	356(21%)	521(17%)	1786(15%)
Education
≤ High school	738(71%)	1049(61%)	1974(65%)	7954(68%)
> High school	273(26%)	627(36%)	972(32%)	3415(29%)
Unknown	26(3%)	44(3%)	73(2%)	277(2%)
Prior IBS diagnosisd	52(5%)	70(4%)	131(4%)	94(1%)
Prior infectious diarrhea diagnosisd	88(8%)	115(7%)	225(7%)	603(5%)

In initial univariate analyses (Table 3), the following covariates were associated independently (P < .20) with IBD: self-classification as single (odds ratio [OR], 0.90; P = .002), having a high school education or less (OR, 1.05; P = .16), being of Caucasian race (OR, 1.23; P < .0001), and a previous diagnosis of IBS more than 6 months before IBD diagnosis (cases) or censoring (controls) (OR, 4.85; P < .0001). Previous IGE episodes were most commonly nonspecific pathogens and were distributed as follows: pathogen-specific (n = 8; 1%), pathogen not specified (n = 429; 46%), protozoal (n = 10; 1%), and viral (n = 494; 52%) with 150 having at least 2 IGE episodes.

Table 3. Unadjusted and Adjusted ORs (95% Confidence Intervals) for Exposure Variables and Included Covariates From a Conditional Logistic Regression Model Evaluating the Risk of IBD, CD, and UC Among Active Duty US Military Personnel From 1999 to 2006

Variable	Univariate model			Multivariatea model
	IBD	CD	UC	IBD	CD	UC
Prior exposureb	1.47(1.26–1.74)	1.68(1.29–2.19)	1.39(1.11–1.74)	1.40(1.19–1.66)	1.54(1.17–2.04)	1.36(1.08–1.72)
Single	0.98(0.89–1.01)	0.82(0.69–0.97)	1.13(0.99–1.29)	0.98(0.88–1.08)	0.82(0.69–0.97)	1.11(0.97–1.27)
More than high school education	1.21(1.09–1.34)	1.01(0.83–1.22)	1.38(1.21–1.58)	1.18(1.06–1.32)	1.00(0.82–1.21)	1.33(1.16–1.53)
Caucasian	1.45(1.32–1.59)	1.42(1.22–1.65)	1.47(1.31–1.66)	1.44(1.31–1.57)	1.38(1.17–1.61)	1.46(1.29–1.65)
Previous IBS diagnosisc	5.72(4.35–7.53)	7.30(4.58–11.64)	5.22(3.61–7.54)	5.60(4.22–7.42)	7.11(4.39–11.53)	5.15(3.53–7.53)

As shown in Table 3, after controlling for potential confounders, a previous diagnosis of IGE was associated significantly with an increased odds of IBD (OR, 1.40; 95% confidence interval, 1.19–1.66). When subdivided into the 2 component diseases of IBD, the OR associated with CD was slightly higher than UC (ORs, 1.54 and 1.36, respectively). The conditional logistic regression model did not show a significant effect of marital status on the risk of UC. However, being single was associated with a significantly decreased risk of CD (0.82; 95% confidence interval 0.69–0.97). Similarly, although receipt of some college education had no effect on CD in either model, it significantly increased the odds of UC. Being of Caucasian race was associated significantly with an increased risk of UC and CD, although the effect estimate was consistently greater for UC. Risk of IBD in persons with a prior diagnosis of IBS was approximately 5 times that of persons without a prior IBS diagnosis. This effect was consistent across IBD subtypes. When the analysis was restricted to only subjects without a prior IBS diagnosis, previous IGE remained associated significantly with both CD (OR, 1.48; 95% confidence interval, 1.09–2.00) and UC (OR, 1.39; 95% confidence interval, 1.09–1.77).

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Discussion 

Similar to Garcia Rodriguez et al,⁴ we found that the risk of IBD was greater in those with a prior episode of infectious diarrhea. We also noted a similar finding in that the risk for CD was slightly higher than UC (OR, 1.54 vs 1.36). The pathogenesis of IBD represents the evolving understanding of a complex interaction between environmental factors (eg, geography, cigarette smoking, sanitation, and hygiene), microbial insults, ethnicity, genetic susceptibility, and a dysregulated immune system; whereby among genetically susceptible individuals, IBD may arise subsequent to an enteric infection owing to an alteration of the gut epithelial barrier resulting in exposure to commensal and/or pathogenic microflora and disturbed adaptive and innate immune responses leading to disease.¹², ¹³, ¹⁴, ¹⁵

The emerging understanding of differential genetic predisposition and immunopathologic triggers associated with the CD subtype may explain the slight differences in risk associated with antecedent enteric infection among IBD subtypes found in a recent twin study,¹⁶ and shown by Garcia Rodriguez et al⁴ and reflected in these results. Restricted to the small intestine, the anatomic site of CD, a specialized type of secretory cell called Paneth cells are found to produce high quantities of defensins and several other antibiotic peptides and proteins.¹⁷, ¹⁸ Paneth cell defensins play a pivotal role in defense from enteric pathogens and may be a key susceptibility factor in CD.¹⁹, ²⁰, ²¹, ²² It also is hypothesized that recently discovered or as of yet undiscovered susceptibility loci may contribute to increased risk of CD after enteric infection compared with UC. For example, genetic variants in CARD15 and the IBD5 haplotype have been associated differentially with CD.²³, ²⁴ In addition, a recently discovered genetic variant associated with altered autophagy, ATG16L1, may explain the association between CD and enteric infection, particularly those caused by invasive pathogens.²⁵ In addition to being required for cellular homeostasis and organelle turnover, autophagy also plays a role in innate and adaptive immune responses to pathogens.²⁶, ²⁷

Taken together, these results suggest that individuals with altered autophagy might modify either bacterial replication and immune control or delivery of antigens to adaptive immune pathways in different ways, the results of which may cause disruption of immune response homeostasis. Limited information on specific pathogen etiology in our dataset precluded an assessment of associations between invasive and noninvasive pathogens in CD or UC. However, the previous study by Garcia Rodriguez et al⁴ did identify differential risk for CD associated with invasive enteric infections caused by Campylobacter and Salmonella (slightly higher in the Salmonella group), providing epidemiologic evidence for the role of intracellular microbial infections in the pathogenesis of CD owing to an altered autophagy genetic susceptibility pathway. Clearly, our understanding of the complex interrelationship between enteric infection, genetic susceptibility, and disease pathogenesis is growing and future genetic, epidemiologic, and animal model studies are needed to evaluate these hypothetical pathways.

As has been described in other studies on the epidemiology of IBD, we found that race was associated with increased risk.²⁸, ²⁹, ³⁰ There was also a differential effect of education on CD compared with UC, with more high school education being protective for CD but a risk factor for UC. Although our data sources did not include any direct measurement of past or current tobacco use, data on education level, known to be associated inversely with education in military and nonmilitary populations,³¹, ³² could have the effect of a surrogate for tobacco use, which is well known to have a differential risk effect on these IBD subtypes.²⁸, ³³, ³⁴, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹ Future studies for which data on tobacco use and education level are collected would be needed to explore the differential effect of education on IBD subtype we observed.

In addition to these independent IBD risk associations, we noted that subjects with a previous diagnosis of IBS were at higher risk of developing IBD. Although controversial, some have argued that IBS and IBD represent clinical presentations on a pathophysiologic spectrum of disease given the considerable overlap between symptoms in patients with IBS and IBD, whereby IBS symptoms represent subclinical inflammation and immune activation that precede the expression of IBD.⁶, ⁷ It is known that patients with IBD often complain of having symptoms of IBS for several years before being diagnosed with IBD, and IBS-like symptoms are known to occur in IBD patients who are in remission.⁴⁰, ⁴¹ An IBD diagnosis later in life also has been associated with a prior history of IBS symptoms.⁴⁰ Therefore, it is possible that the association between IBS and IBD that we identified could be owing to IBS-like symptoms of undiagnosed CD, or that IBS actually predisposes individuals to the development of IBD. Importantly, when we restricted our analysis to cases and controls without a prior IBS diagnosis, the association between acute enteric infection and IBD persisted.

The results of this study should be interpreted with a complete understanding of the potential biases inherent in the database for which the study population was obtained as well as limitations in the study design. First, we were unable to appropriately evaluate potential confounding for variables known to be associated with disease (eg, tobacco use). However, there is no reason to assume differential distribution of the currently known risk factors by exposure status. In addition, the use of a medical encounter database is a potential source for case misclassification as a result of diagnoses codes being assigned in error before confirmatory diagnostic testing. We attempted to reduce the impact of this misclassification by requiring multiple medical encounters with the same diagnosis code as has been described previously by Bernstein et al.⁴²

Conversely, our use of nonspecific diagnosis codes may result in unconfirmed cases repeatedly diagnosed as IBD. This may be more common in this population because there is the potential for military personnel to be medically discharged as a result of an IBD diagnosis. In fact, one recent study showed that “digestive system” conditions were the reason for 3%–5% of all disability cases reviewed by medical evaluation boards in the mid-1990s.⁴³ Importantly, when we evaluated the association between IGE and IBD excluding the nonspecific diagnoses, the association remained, although was no longer statistically significant (data not shown).

We used a 6-month exposure exclusion period before initial IBD diagnosis (or control censoring) to prevent misclassification of initial IBD presentation as an episode of IGE. However, if the duration between exposure and disease onset is short, we may have under-represented the true association, biasing the results shown here toward the null. Although this is a less than ideal scenario, we believed it more conservative to decrease the likelihood of IBD misclassification as IGE than to increase the sensitivity of exposure identification.

Of particular concern in case-control studies is differential exposure misclassification. For this study, it is conceivable that persons with undiagnosed IBD may be more likely to seek medical care as a result of an IGE episode. This may be owing to an increase in disease severity among persons with undiagnosed IBD, or an increased susceptibility to infectious organisms in those persons owing to pathophysiologic changes associated with the concurrent undiagnosed IBD or an insufficient immune response in persons with IBD.² This was an inherent limitation in our study that may have artificially increased in the effect estimates. However, because of the invasiveness of the procedures required for IBD diagnosis, it is difficult to envision a study design that could adequately control for care-seeking behavior among undiagnosed IBD cases.

In summary, this study is in concordance with previous research supporting the notion that IGE might contribute to an initiation of IBD among susceptible individuals through disruption of normal gut homeostasis. Future studies using well-defined exposures should evaluate the pathogen-specific risks in an effort to better understand the pathophysiology between IGE and IBD.

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