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Asthma Is Associated With Subsequent Development of Inflammatory Bowel Disease: A Population-based Case–Control Study

  • M. Ellen Kuenzig
    Affiliations
    Department of Medicine, University of Calgary, Calgary, Alberta, Canada

    Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada

    Synder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada

    O’Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada
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  • Cheryl Barnabe
    Affiliations
    Department of Medicine, University of Calgary, Calgary, Alberta, Canada

    Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada

    O’Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada
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  • Cynthia H. Seow
    Affiliations
    Department of Medicine, University of Calgary, Calgary, Alberta, Canada

    Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
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  • Bertus Eksteen
    Affiliations
    Department of Medicine, University of Calgary, Calgary, Alberta, Canada

    Synder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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  • Maria E. Negron
    Affiliations
    Department of Production Animal Health, University of Calgary Faculty of Veterinary Medicine, Calgary Alberta, Canada
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  • Ali Rezaie
    Affiliations
    Division of Gastroenterology, Department of Medicine, Cedars-Sinai, Los Angeles, California
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  • Remo Panaccione
    Affiliations
    Department of Medicine, University of Calgary, Calgary, Alberta, Canada
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  • Eric I. Benchimol
    Affiliations
    CHEO Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Eastern Ontario, Ottawa, Canada

    Department of Pediatrics and School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada
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  • Mohsen Sadatsafavi
    Affiliations
    Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada
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  • J. Antonio Aviña-Zubieta
    Affiliations
    Arthritis Research Canada, Division of Rheumatology, University of British Columbia, BC, Canada
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  • Gilaad G. Kaplan
    Correspondence
    Reprint requests Address requests for reprints to: Gilaad G. Kaplan, MD, MPH, Teaching Research and Wellness Center, 3280 Hospital Drive NW, 6D56, Calgary, AB, T2N 4N1 Canada. fax: (403) 592-5090.
    Affiliations
    Department of Medicine, University of Calgary, Calgary, Alberta, Canada

    Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada

    Synder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada

    O’Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada
    Search for articles by this author
Open AccessPublished:March 23, 2017DOI:https://doi.org/10.1016/j.cgh.2017.02.042

      Background & Aims

      Asthma and the inflammatory bowel diseases (IBD) each arise through complex interactions between genetic and environmental factors, and share many environmental risk factors. We examined the association between asthma and Crohn’s disease or ulcerative colitis.

      Methods

      We performed a population-based case–control study using health administrative data from the province of Alberta, Canada. The odds of a diagnosis of asthma preceding the diagnosis of either Crohn’s disease (N = 3087) or ulcerative colitis (N = 2377) were compared with the odds of diagnosis of asthma among persons without IBD (N = 402,800) using logistic regression. Effect measure modification by age at diagnosis of IBD (16 years or less, 17–40 years, or older than 40 years) was tested using a likelihood ratio test.

      Results

      A diagnosis of asthma was associated with increased odds of incident Crohn’s disease (adjusted odds ratio [OR], 1.45; 95% confidence interval [CI], 1.31–1.60). No effect measure modification was observed for age at diagnosis for Crohn's disease (P = .42). However, we observed effect measure modification by age at diagnosis for ulcerative colitis (P = .0103), with an adjusted OR of 1.49 (95% CI, 1.08–2.07) among individuals diagnosed at an age of 16 years or less (OR) and an adjusted OR of 1.57 (95% CI, 1.31–1.89) among individuals diagnosed at an age older than 40 years. However, there was no association between asthma and ulcerative colitis among individuals diagnosed between ages 17 and 40 (adjusted OR, 1.05; 95% CI, 0.86–1.26).

      Conclusions

      In a population-based case–control study, we associated asthma with Crohn’s disease, and with early and late-onset ulcerative colitis.

      Keywords

      Abbreviations used in this paper:

      AHCIP (Alberta Health Care Insurance Plan), CI (confidence interval), IBD (inflammatory bowel disease), ICD (International Classification of Diseases), OR (odds ratio)
      See editorial on page 1353.
      Asthma and the inflammatory bowel diseases (IBD) (Crohn’s disease and ulcerative colitis) are chronic immune-mediated inflammatory diseases of the respiratory and gastrointestinal tracts, respectively. Both impose substantial morbidity and a heavy economic burden on individuals, populations, and health care systems. The incidence and prevalence of both diseases has increased in developed countries over the past several decades and are continuing to increase in developing countries.
      • Molodecky N.A.
      • Soon I.S.
      • Rabi D.M.
      • et al.
      Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.
      • Masoli M.
      • Fabian D.
      • Holt S.
      • et al.
      The global burden of asthma: executive summary of the GINA Dissemination Committee Report.
      • Kaplan G.G.
      The global burden of IBD: from 2015 to 2025.
      Although the etiology of asthma and IBD are not well understood, they share common features, including being rooted in a complex interaction between genetics, environmental factors, and the microbiome.
      • Knights D.
      • Lassen K.G.
      • Xavier R.J.
      Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome.
      • Xavier R.J.
      • Podolsky D.K.
      Unravelling the pathogenesis of inflammatory bowel disease.
      • Bønnelykke K.
      • Ober C.
      Leveraging gene-environment interactions and endotypes for asthma gene discovery.
      • Huang Y.J.
      • Boushey H.A.
      The respiratory microbiome and innate immunity in asthma.
      • Frolkis A.D.
      • Dieleman L.A.
      • Barkema H.W.
      • et al.
      Environment and the inflammatory bowel diseases.
      Many of these risk factors are common to both IBD and asthma. For example, both occur more commonly among children who are not breastfed and who are exposed to antibiotics as infants.
      • Frolkis A.D.
      • Dieleman L.A.
      • Barkema H.W.
      • et al.
      Environment and the inflammatory bowel diseases.
      • Noutsios G.T.
      • Floros J.
      Childhood asthma: causes, risks, and protective factors; a role of innate immunity.
      Furthermore, the relationship between asthma and IBD may be explained through the hygiene hypothesis, which postulates that immune-mediated diseases stem from increased sanitation that reduces childhood exposure to enteric pathogens beneficial to priming the immune system.
      • Daley D.
      The evolution of the hygiene hypothesis.
      • Stiemsma L.
      • Reynolds L.
      • Turvey S.
      • et al.
      The hygiene hypothesis: current perspectives and future therapies.
      Additionally, shared common genetic factors (eg, SMAD3) are involved in the signaling of proinflammatory pathways.
      • Lees C.W.
      • Barrett J.C.
      • Parkes M.
      • et al.
      New IBD genetics: common pathways with other diseases.
      • Zhong Y.
      • Kinio A.
      • Saleh M.
      Functions of NOD-like receptors in human diseases.
      Some patients with IBD exhibit bronchiectasis or bronchitis.
      • Papanikolaou I.
      • Kagouridis K.
      • Papiris S.A.
      Patterns of airway involvement in inflammatory bowel diseases.
      Studies have also shown that IBD is associated with respiratory disorders, including asthma and chronic obstructive pulmonary disease.
      • Papanikolaou I.
      • Kagouridis K.
      • Papiris S.A.
      Patterns of airway involvement in inflammatory bowel diseases.
      • Peng Y.-H.
      • Liao W.-C.
      • Su C.-H.
      • et al.
      Association of inflammatory bowel disease with asthma risk: a nationwide cohort study.
      • Haapamäki J.
      • Roine R.P.
      • Turunen U.
      • et al.
      Increased risk for coronary heart disease, asthma, and connective tissue diseases in inflammatory bowel disease.
      • Weng X.
      • Liu L.
      • Barcellos L.F.
      • et al.
      Clustering of inflammatory bowel disease with immune mediated diseases among members of a northern California-managed care organization.
      • Bernstein C.N.
      • Wajda A.
      • Blanchard J.F.
      The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study.
      • Brassard P.
      • Vutcovici M.
      • Ernst P.
      • et al.
      Increased incidence of inflammatory bowel disease in Québec residents with airway diseases.
      • Raj A.A.
      • Birring S.S.
      • Green R.
      • et al.
      Prevalence of inflammatory bowel disease in patients with airways disease.
      • Fenta Y.A.
      • Tello N.
      • Jung J.A.
      • et al.
      Inflammatory bowel disease and asthma: a population-based, case-control study.
      Because asthma is more commonly diagnosed in early childhood than IBD, we hypothesized that individuals diagnosed with asthma were more likely to be subsequently diagnosed with IBD compared with those without asthma. Thus, the aim of our study was to assess the effect of asthma on the development of Crohn’s disease and ulcerative colitis.

      Methods

       Study Design and Data Sources

      We performed a case-control study using administrative health databases in the province of Alberta, Canada, to examine the association between asthma and IBD. All study participants were enrolled in the Alberta Health Care Insurance Plan (AHCIP). The AHCIP is a publicly funded universal health care plan providing comprehensive health services to more than 99% of the approximately 4 million residents of Alberta, Canada. These data sources have been described previously.
      • Negrón M.E.
      • Rezaie A.
      • Barkema H.W.
      • et al.
      Ulcerative colitis patients with Clostridium difficile are at increased risk of death, colectomy, and postoperative complications: a population-based inception cohort study.
      • Rezaie A.
      • Quan H.
      • Fedorak R.N.
      • et al.
      Development and validation of an administrative case definition for inflammatory bowel diseases.
      Briefly, they include (1) a Registry database with patient demographic and geographic information; (2) the Physicians’ Claims database, containing outpatient claims made by all Alberta physicians in the delivery of health care; (3) the Alberta Inpatient Hospital Discharge Abstract Database, containing information on all hospitalizations; and (4) the Ambulatory Care Classification System, containing data on hospital-based ambulatory care, such as emergency department encounters and outpatient procedures (eg, colonoscopy).
      A unique personal health identification number is used to track patients through time and to perform deterministic linkage between data sources. The Ambulatory Care Classification System database was available from April 1, 1997, to March 31, 2010. All other databases were available from April 1, 1994, until March 31, 2010.

       Identification of Cases of Crohn’s Disease and Ulcerative Colitis

      Cases were derived from data provided by Alberta Health and Wellness that included all individuals enrolled in AHCIP with at least 1 diagnostic code for IBD (Crohn’s disease International Classification of Diseases [ICD]-9 555 or ICD-10 K50; ulcerative colitis ICD-9 556 or ICD-10 K51) in either the Physicians’ Claims database, Discharge Abstract Database, and Ambulatory Care Classification System database (Figure 1). Validated case definitions for Crohn’s disease and ulcerative colitis were then applied: (1) ≥2 IBD codes in the Discharge Abstract Database within 2 years; (2) ≥2 codes in the Ambulatory Care Classification System database within 2 years; and/or (3) ≥4 codes in the Physicians’ Claims database within 2 years.
      • Rezaie A.
      • Quan H.
      • Fedorak R.N.
      • et al.
      Development and validation of an administrative case definition for inflammatory bowel diseases.
      This algorithm has a sensitivity of 83.4%, specificity of 99.8%, positive predictive value of 97.4%, and negative predictive value of 98.5%.
      • Rezaie A.
      • Quan H.
      • Fedorak R.N.
      • et al.
      Development and validation of an administrative case definition for inflammatory bowel diseases.
      Figure thumbnail gr1
      Figure 1Flow diagram depicting the identification of cases of Crohn’s disease and ulcerative colitis for inclusion in the statistical analysis.
      Crohn’s disease was differentiated from ulcerative colitis using a validated scoring system based with a specificity of >99% for both Crohn’s disease and ulcerative colitis; the sensitivity of the score for ulcerative colitis is 86% and 94% for Crohn’s disease.
      • Rezaie A.
      • Quan H.
      • Fedorak R.N.
      • et al.
      Development and validation of an administrative case definition for inflammatory bowel diseases.
      Undifferentiated patients were excluded from analysis (Figure 1).
      Individuals diagnosed with IBD younger than the age of 3 were excluded to allow a diagnosis of asthma to precede the diagnosis of IBD among children with very early onset IBD and decrease potential misclassification of asthma because of challenges associated with its diagnosis in very young children. Next, we applied previously validated backward washout periods to exclude prevalent cases of IBD. For individuals 10 years and older, an 8-year washout period was used; for cases younger than the age of 10 at diagnosis, a 3-year washout period was used.
      • Rezaie A.
      • Quan H.
      • Fedorak R.N.
      • et al.
      Development and validation of an administrative case definition for inflammatory bowel diseases.
      • Benchimol E.I.
      • Guttmann A.
      • Griffiths A.M.
      • et al.
      Increasing incidence of paediatric inflammatory bowel disease in Ontario, Canada: evidence from health administrative data.
      The date of the first health care contact associated with a diagnosis of IBD was used as the date of IBD diagnosis.

       Control Subjects

      An age-stratified random sample of the individuals enrolled in AHCIP (n = 586,705) was obtained from Alberta Health and Wellness (Figure 2). Individuals with at least 1 code for IBD were excluded. Each control subject was assigned a random index date. The control population was oversampled to allow us to apply the same exclusion criteria and washout periods that applied to cases of IBD. This ensured the length of follow-up, from enrolment in AHCIP to index date, was similar for cases and control subjects.
      Figure thumbnail gr2
      Figure 2Flow diagram depicting the selectin of control subjects for inclusion in the statistical analysis.

       Asthma Diagnosis and Covariates

      IBD cases and their control subjects were determined to have a previous diagnosis of asthma based on a validated algorithm requiring ≥2 asthma codes within 2 years (ICD-9: 493; ICD-10: J45) in the Physicians’ Claims database, ≥2 asthma codes within 2 years in the Ambulatory Care Classification System database, or ≥1 asthma code in the Discharge Abstract Database. This algorithm was developed in a validation study using similarly structured administrative health databases in Ontario, Canada (sensitivity, 83.8%; specificity, 76.5%; positive predictive value, 61.5%; negative predictive value, 91.3%).
      • Gershon A.S.
      • Wang C.
      • Guan J.
      • et al.
      Identifying patients with physician-diagnosed asthma in health administrative databases.
      The first health care interaction with an asthma code was considered the date of asthma diagnosis.
      The dissemination area at the time of IBD diagnosis (cases) or randomly assigned index date (control subjects) was linked to 2006 Canadian census data to assign each individual a location of residence and socioeconomic status. Living in a major metropolitan city was defined as living in Calgary or Edmonton, Alberta’s 2 major cities. As previously evaluated in IBD studies, we assessed socioeconomic based on the median income for individuals living in a dissemination area.
      • Benchimol E.I.
      • To T.
      • Griffiths A.M.
      • et al.
      Outcomes of pediatric inflammatory bowel disease: socioeconomic status disparity in a universal-access healthcare system.

       Statistical Analysis

      All statistical analyses were conducted using SAS version 9.4 (Cary, NC). Chi-square tests were used to assess for differences between control subjects and cases of Crohn’s disease or ulcerative colitis for the following categorical variables: age categories at diagnosis or index date, as defined a priori by the Montreal Classification (A1, ≤16 years; A2, 17–40 years; A3, >40 years of age),
      • Silverberg M.S.
      • Satsangi J.
      • Ahmad T.
      • et al.
      Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 Montreal World Congress of Gastroenterology.
      sex, quintiles of median income of all individuals living in a census dissemination area, asthma before the index date, and living in a metropolitan city. Medians (Q1, Q3) were presented for continuous variables. Differences between cases and control subjects for the following continuous variables were tested using a Wilcoxon rank sum test: age at diagnosis or index date, length of follow-up, and median income of individuals living in a dissemination area.
      Logistic regression was used to examine the association between asthma and incident Crohn’s disease or ulcerative colitis. We a priori assessed for effect measure modification by age at diagnosis by including an interaction term between an asthma diagnosis and age categories (≤16 years; 17–40 years; >40 years). A likelihood ratio test was used to assess all interaction terms simultaneously. If the interaction was significant, regression models were constructed separately for each age group. Models were adjusted for the following confounding variables: age categories (in the absence of effect measure modification), sex, quintile of median income, and living in Calgary or Edmonton versus outside these 2 metropolitan cities.
      The median income for all individuals in a neighborhood was not available for dissemination areas with a small population or census nonresponse rate greater than 5%, corresponding to 1.7% (91 of 5464) of individuals with IBD and 2.2% (8995 of 402,800) of control subjects). Individuals living in these areas were excluded from the logistic regression analyses.
      For our primary analysis, the diagnosis of asthma preceded the diagnosis of IBD (cases) or index date (control subjects). In a sensitivity analysis, we assessed the association between having a diagnosis of asthma at any point in time (ie, not restricting to a diagnosis of asthma before the diagnosis of IBD or index date). We performed an indirect adjustment to evaluate the effect of an unmeasured confounder, such as cigarette smoking on the relationship between asthma and IBD (Supplementary Methods and Results, Supplementary Figures 1 and 2).
      • Lash T.L.
      • Fox M.P.
      • Fink A.K.
      Applying quantitative bias analysis to epidemiologic data.
      This study was approved by the Conjoint Research Ethics Board at the University of Calgary.

      Results

      We identified 3087 individuals with incident Crohn’s disease and 2377 individuals with incident ulcerative colitis (Table 1). Control subjects (N = 402,800) were older at index date compared with cases of Crohn’s disease and ulcerative colitis (P < .0001 for both). Overall, 14.5% and 12.8% of individuals with Crohn’s disease and ulcerative colitis, respectively, had a diagnosis of asthma before the diagnosis of IBD. In contrast, 9.8% of control subjects were diagnosed with asthma before their randomly selected index date (P < .0001 for comparisons of control subjects with both Crohn’s disease and ulcerative colitis).
      Table 1Demographic Characteristics of Patients With Crohn’s Disease, with Ulcerative Colitis, and Control Subjects
      Crohn’s disease (N = 3087)Ulcerative colitis (N = 2377)Control subjects (N = 402,800)
      P value
      Characteristics of individuals with Crohn’s disease were compared with control subjects.
      P value
      Characteristics of individuals with ulcerative colitis were compared with control subjects.
      Age at diagnosis
      Age at randomly assigned index date for control subjects.
       Median (Q1–Q3)36 (22–51)<.000139 (25–54)<.000144 (28–59)
       A1 (3–16 years), n (%)358 (11.6)<.0001210 (8.8)<.000125,939 (6.4)
       A2 (17–40 years), n (%)1422 (46.1)1038 (43.7)148,911 (37.0)
       A3 (>40 years), n (%)1307 (42.3)1129 (47.5)227,950 (56.6)
      Sex, n (%)
       Male1401 (45.4)<.00011203 (50.6).11197,266 (49.0)
       Female1686 (54.6)1174 (49.4)205,534 (51.0)
      Asthma, n (%)
       Before IBD Diagnosis or index date, n (%)446 (14.5)<.0001305 (12.8)<.000139,344 (9.8)
       Before or after IBD diagnosis or index date, n (%)505 (16.4)<.0001348 (14.6)<.000146,620 (11.6)
      Length of look-back period, Median (Q1–Q3)
       <10 years at IBD diagnosis
      Age at randomly assigned index date for control subjects.
      6 (4–8).147 (4–8).716 (4–7)
       ≥10 years at IBD diagnosis
      Age at randomly assigned index date for control subjects.
      11 (10–13)<.000111 (10–13)<.000111 (10–13)
      Quintile of median income, n (%)
      Median income was missing for the dissemination areas in which 9086 individuals were living at the time of diagnosis with IBD or randomly assigned index date for control subjects (47 Crohn’s disease; 44 ulcerative colitis; 8995 control subjects).
       <$22,935564 (18.6).01401 (17.2)<.000178,684 (20.0)
       $22,936–$26,888567 (18.7)433 (18.6)78,966 (20.1)
       $26,889–$30,841606 (19.9)418 (17.9)78,823 (20.0)
       $30,842–$36,302660 (21.7)534 (22.9)78,638 (20.0)
       ≥$36,303643 (21.2)547 (23.5)78,694 (20.0)
       Median (Q1–Q3)$29,514 (24,377–35,143).0007$30,059 (24,645–35,948)<.0001$28,790 (23,974–34,830)
      Living in a metropolitan city, n (%)
       In Calgary or Edmonton, Alberta1480 (47.9).00021253 (52.7).18206,816 (51.3)
       Outside Calgary or Edmonton, Alberta1607 (52.1)1124 (47.3)195,984 (48.7)
      a Characteristics of individuals with Crohn’s disease were compared with control subjects.
      b Characteristics of individuals with ulcerative colitis were compared with control subjects.
      c Age at randomly assigned index date for control subjects.
      d Median income was missing for the dissemination areas in which 9086 individuals were living at the time of diagnosis with IBD or randomly assigned index date for control subjects (47 Crohn’s disease; 44 ulcerative colitis; 8995 control subjects).
      The odds of having Crohn’s disease were significantly increased in those with pre-existing asthma (crude odds ratio [OR], 1.56; 95% confidence interval [CI], 1.41–1.73). Age group at diagnosis did not modify the association between asthma and Crohn’s disease (P = .32 for the crude model; P = .42 for the adjusted model). The association between asthma and Crohn’s disease (adjusted OR, 1.45; 95% CI, 1.31–1.60) persisted after adjusting for age at diagnosis, income quintile, sex, and living in a metropolitan city (Table 2).
      Table 2Logistic Regression Analysis Examining the Association Between Crohn’s Disease and Asthma Diagnosed Before the Onset of Crohn’s Disease or Index Date in Control Subjects
      OR (95% CI)
      Asthma
       Yes1.45 (1.31–1.60)
       No
      Reference group.
      Age at diagnosis
       A1 (3–16)
      Reference group.
       A2 (17–40)0.71 (0.63–0.80)
       A3 (>40)0.43 (0.38–0.48)
      Sex
       Male
      Reference group.
       Female1.16 (1.08–1.25)
      Quintile of median income
       <$22,935
      Reference group.
       $22,936–$26,8881.01 (0.90–1.14)
       $26,889–$30,8411.09 (0.97–1.22)
       $30,842–$36,3021.19 (1.06–1.33)
       ≥$36,3031.15 (1.03–1.29)
      Living in a metropolitan city
       In Calgary or Edmonton, Alberta0.85 (0.79–0.92)
       Outside Calgary or Edmonton, Alberta
      Reference group.
      a Reference group.
      Age at IBD diagnosis modified the association between asthma and ulcerative colitis (P = .01 for both the crude and adjusted models). Asthma was associated with incident ulcerative colitis among individuals diagnosed with ulcerative colitis at ≤16 years of age (crude OR, 1.45; 95% CI, 1.05–2.01; adjusted OR, 1.49; 95% CI, 1.08–2.07) and among those diagnosed after the age of 40 (crude OR, 1.56; 95% CI, 1.30–1.87; adjusted OR, 1.57; 95% CI, 1.31–1.89) (Table 3). Asthma was not associated with incident ulcerative colitis among individuals diagnosed between the ages of 17 and 40 (crude OR, 1.06; 95% CI, 0.88–1.28; adjusted OR, 1.05; 95% CI, 0.86–1.26).
      Table 3Logistic Regression Analysis Examining the Association Between Ulcerative Colitis and Asthma Diagnosed Before the Onset of Ulcerative Colitis or Index Date in Control Subjects
      OR (95% CI)
      A1 (≤16 years)A2 (17–40 years)A3 (>40 years)
      Asthma
       Yes1.49 (1.08–2.07)1.05 (0.86–1.26)1.57 (1.31–1.89)
       No
      Reference group.
      Sex
       Male
      Reference group.
       Female1.03 (0.78–1.46)0.99 (0.87–1.11)0.87 (0.77–0.98)
      Quintile of median income
       <$22,935
      Reference group.
       $22,936–$26,8881.23 (0.77–1.96)1.00 (0.81–1.23)1.12 (0.92–1.35)
       $26,889–$30,8410.89 (0.54–1.49)1.10 (0.90–1.36)1.00 (0.82–1.22)
       $30,842–$36,3021.80 (1.17–2.79)1.22 (0.99–1.49)1.35 (1.12–1.63)
       ≥$36,3031.52 (0.97–2.37)1.45 (1.19–1.76)1.22 (1.01–1.48)
      Living in a metropolitan city
       In Calgary or Edmonton, Alberta0.96 (0.73–1.26)1.07 (0.95–1.22)1.00 (0.89–1.13)
       Outside Calgary or Edmonton, Alberta
      Reference group.
      a Reference group.
      The sensitivity analysis in which the diagnosis of asthma could occur either before or after the diagnosis of IBD (or randomly assigned index date for control subjects) demonstrated a similar association for both Crohn’s disease and ulcerative colitis (Supplementary Tables 1 and 2, respectively). Results were consistent after indirectly adjusting for smoking as an unmeasured confounder (Supplementary Methods and Results, Supplementary Figures 1 and 2).

      Discussion

      Our findings indicate that asthma is associated with an increased risk of developing Crohn’s disease or ulcerative colitis. These findings are consistent with previous studies examining the association between asthma and IBD.
      • Peng Y.-H.
      • Liao W.-C.
      • Su C.-H.
      • et al.
      Association of inflammatory bowel disease with asthma risk: a nationwide cohort study.
      • Haapamäki J.
      • Roine R.P.
      • Turunen U.
      • et al.
      Increased risk for coronary heart disease, asthma, and connective tissue diseases in inflammatory bowel disease.
      • Weng X.
      • Liu L.
      • Barcellos L.F.
      • et al.
      Clustering of inflammatory bowel disease with immune mediated diseases among members of a northern California-managed care organization.
      • Bernstein C.N.
      • Wajda A.
      • Blanchard J.F.
      The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study.
      • Brassard P.
      • Vutcovici M.
      • Ernst P.
      • et al.
      Increased incidence of inflammatory bowel disease in Québec residents with airway diseases.
      • Raj A.A.
      • Birring S.S.
      • Green R.
      • et al.
      Prevalence of inflammatory bowel disease in patients with airways disease.
      Thus, the totality of evidence suggests that patients with asthma are at higher risk of developing IBD. This may serve as a red flag to help identify patients presenting with chronic gastrointestinal symptoms that may benefit from priority referrals to gastroenterologists.
      Intestines and lungs are both derived from the primitive foregut and have similar underlying structures, including a mucous-coated epithelial layer.
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      • Shaheen F.
      • et al.
      Intrinsic phenotypic differences of asthmatic epithelium and its inflammatory responses to respiratory syncytial virus and air pollution.
      • Wark P.A.B.
      • Johnston S.L.
      • Bucchieri F.
      • et al.
      Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus.
      • Geremia A.
      • Biancheri P.
      • Allan P.
      • et al.
      Innate and adaptive immunity in inflammatory bowel disease.
      • Wildenberg M.E.
      • van den Brink G.R.
      House dust mite: a new player in intestinal inflammation?.
      • Williams C.I.
      • Karayev D.
      • Learch T.
      • et al.
      Clinical, serologic, and genetic associations among patients with both inflammatory bowel disease and ankylosing spondylitis.
      Although the underlying pathology linking asthma and IBD is unknown, the commonalities suggest that these diseases may in fact be linked.
      Alternatively, this association may result from methodological factors, including ascertainment bias or residual confounding. For example, individuals being actively followed for IBD may visit physicians more often than control subjects. As a result, these individuals may be more likely to meet our case definition of asthma
      • Gershon A.S.
      • Wang C.
      • Guan J.
      • et al.
      Identifying patients with physician-diagnosed asthma in health administrative databases.
      than those not seeking health care on a regular basis. Also, individuals of higher socioeconomic status may have greater access to health care, although the association between asthma and IBD persisted after adjusting for median household income. Unmeasured confounders (eg, smoking) may have influenced the association. However, our results were consistent after indirectly adjusting for smoking as an unmeasured confounder.
      The association between asthma and Crohn’s disease was not modified by age at diagnosis. However, the association between asthma and ulcerative colitis was dependent on the age at which ulcerative colitis was diagnosed. Specifically, a significant association between asthma and ulcerative colitis was only observed in individuals diagnosed before age 17 or after age 40. A study limited to individuals diagnosed with IBD before age 20 observed no association between asthma and either Crohn’s disease or ulcerative colitis.
      • Kappelman M.D.
      • Galanko J.A.
      • Porter C.Q.
      • et al.
      Association of paediatric inflammatory bowel disease with other immune-mediated diseases.
      Another study found that the incidence of ulcerative colitis was only elevated among individuals with asthma when ulcerative colitis was diagnosed between 30 and 49 years of age.
      • Brassard P.
      • Vutcovici M.
      • Ernst P.
      • et al.
      Increased incidence of inflammatory bowel disease in Québec residents with airway diseases.
      This same study observed a consistently elevated risk of Crohn’s disease among individuals with asthma across all ages.
      • Brassard P.
      • Vutcovici M.
      • Ernst P.
      • et al.
      Increased incidence of inflammatory bowel disease in Québec residents with airway diseases.
      Age-specific associations between other risk factors and IBD including air pollution,
      • Kaplan G.G.
      • Hubbard J.
      • Korzenik J.
      • et al.
      The inflammatory bowel diseases and ambient air pollution: a novel association.
      appendicitis,
      • Andersson R.E.
      • Olaison G.
      • Tysk C.
      • et al.
      Appendectomy and protection against ulcerative colitis.
      and cigarette smoking
      • Frolkis A.D.
      • de Bruyn J.
      • Jette N.
      • et al.
      The association of smoking and surgery in inflammatory bowel disease is modified by age at diagnosis.
      have been observed. Together with findings that individuals with pediatric-onset IBD are enriched for IBD-susceptibility genes,
      • Imielinski M.
      • Baldassano R.N.
      • Griffiths A.
      • et al.
      Common variants at five new loci associated with early-onset inflammatory bowel disease.
      • Okou D.T.
      • Kugathasan S.
      Role of genetics in pediatric inflammatory bowel disease.
      • McGovern D.P.B.
      • Kugathasan S.
      • Cho J.H.
      Genetics of inflammatory bowel diseases.
      our findings point to important differences in the pathogenesis of IBD across the spectrum of ages. Furthermore, the potential for an incorrect diagnosis of asthma varies across age. Young children with viral wheezing and older individuals with chronic obstructive pulmonary disease may both be incorrectly identified as having asthma based on the diagnostic codes available in administrative databases.
      In our study women were more likely to be diagnosed with Crohn’s disease as compared with men. In contrast, women older than the age of 40 had lower odds of developing ulcerative colitis compared with men of the same age. Although we did not a priori evaluate effect modification by sex, these findings highlight the multiphenotypic nature of Crohn’s disease and ulcerative colitis that may explain heterogeneity in prior studies evaluating the association between asthma and IBD.
      Several additional limitations should also be considered. First, administrative databases include limited information on important unmeasured confounders, such as smoking. Second, we were unable to account for asthma severity. Third, administrative databases were only available from 1994. Younger individuals diagnosed with childhood asthma are more likely to have their diagnosis captured in the period of time captured by the look-back period compared with adults with childhood asthma. Furthermore, older individuals being treated for asthma may not have had a sufficient number of encounters for asthma treatment within the time frame required by the validated case definition of asthma.
      • Gershon A.S.
      • Wang C.
      • Guan J.
      • et al.
      Identifying patients with physician-diagnosed asthma in health administrative databases.
      In addition, we were unable to evaluate the effect of IBD on the risk of developing of asthma.
      Also, because we did not exactly match cases and control subjects by age, our random sample of control subjects were slightly older than patients with IBD. Finally, control subjects had a 1-year longer look-back period than cases. A longer look-back period in control subjects would allow for a greater period of time in which to detect a diagnosis of asthma and would bias the association between asthma and IBD toward the null.

      Conclusions

      Asthma is associated with an increased risk of Crohn’s disease and ulcerative colitis. This observation was consistent across all ages at Crohn’s disease diagnosis, but only for those diagnosed before age 17 or after age 40 with ulcerative colitis. Future studies are necessary to determine the mechanisms through which asthma and IBD are related. Important areas of research include shared genetic susceptibility, environmental exposures, and microbial influences. Studies exploring mechanisms connecting asthma to ulcerative colitis should be age-specific.

      Acknowledgments

      This study is based in part on data provided by Alberta Health. The interpretation and conclusions contained herein are those of the researchers and do not necessarily represent the views of the Government of Alberta. Neither the Government nor Alberta Health express any opinion in relation to this study.

      Methods and Results of a Sensitivity Analysis Evaluating the Impact of Smoking as an Unmeasured Confounder on the Association Between Asthma and IBD

       Methods

      A potential limitation of our study is the inability to adjust for important confounding variables that are not available in health administrative databases, such as cigarette smoking. We conducted a bias analysis to estimate what the OR for the association between asthma and Crohn’s disease or ulcerative colitis may have been if we were able to adjust for smoking.
      • Lash T.L.
      • Fox M.P.
      • Fink A.K.
      Applying quantitative bias analysis to epidemiologic data.
      This approach allows us to indirectly adjust for residual confounding caused by smoking.
      Because of important differences between current and former smokers with regard to the risk of IBD, particularly among those with ulcerative colitis, the approach allowing for a 3-level confounding variable was used. Indirect adjustment requires a raw contingency table (ie, the number of individuals with and without asthma and IBD); thus, the crude estimates were adjusted for smoking.
      To estimate an adjusted OR, we need to estimate the following parameters:
      • 1.
        The OR for the association between current smoking and the risk of Crohn’s disease or ulcerative colitis;
      • 2.
        The OR for the association between former smoking and the risk of ulcerative colitis;
      • 3.
        The proportion of individuals with asthma who currently smoke;
      • 4.
        The proportion of individuals without asthma who currently smoke;
      • 5.
        The proportion of individuals with asthma who are former smokers; and
      • 6.
        The proportion of individuals without asthma who are former smokers.
      We used the association between cigarette smoking and Crohn’s disease or ulcerative colitis as described in a meta-analysis.
      • Mahid S.S.
      • Minor K.S.
      • Soto R.E.
      • et al.
      Smoking and inflammatory bowel disease: a meta-analysis.
      The associations between smoking and IBD are listed below:
      • For patients with Crohn’s disease:
        • Current smoking, compared with never smoking: OR 1.76
        • Former smoking, compared with never smoking: OR 1.30
      • For patients with ulcerative colitis:
        • Current smoking, compared with never smoking: OR 0.58
        • Former smoking, compared with never smoking: OR 1.79
      We then used the public-use data file for the 2005 Canadian Community Health Survey to estimate the proportion of individuals in Alberta without asthma who smoked. All proportions were weighted to ensure the proportions were representative of all Albertans. Approximately 57% of Albertans without asthma are never smokers; 18% are current smokers and 25% are former smokers.
      The proportion of individuals with asthma who are current and former smokers was allowed to vary. We estimated the possible adjusted ORs, allowing between 10% and 50% of individuals with asthma to be current smokers; we allowed the prevalence of former smoking to be 15%, 25%, or 35%.
      We conducted a single analysis for Crohn’s disease. In ulcerative colitis, this analysis was conducted separately for individuals diagnosed between 17 and 40 and diagnosed after 40 because of the observation that age is an effect measure modifier of the association between asthma and ulcerative colitis.

       Results

      As the prevalence of current smoking increased, the OR for the association between asthma and Crohn’s disease decreased toward the null (Supplementary Figure 1). In contrast, as the proportion of current smokers among those with asthma increases, the OR increases. These findings were consistent for those diagnosed with ulcerative colitis between 17 and 40 years of age (Supplementary Figure 2A) and after age 40 (Supplementary Figure 2B).
      These findings were most pronounced when we allowed 35% of individuals with asthma to be former smokers. However, the association between smoking and asthma is moderate and such a large difference in the proportion of smokers among those with and without asthma is not expected.
      • Williamson E.J.
      • Aitken Z.
      • Lawrie J.
      • et al.
      Introduction to causal diagrams for confounder selection.
      Thus, we would not expect adjusting for smoking status to have a substantial impact on our study findings.
      Figure thumbnail fx1
      Supplementary Figure 1Indirectly adjusted ORs for the association between asthma and Crohn’s disease corresponding to a spectrum of values corresponding to the percentage of people with asthma who are current and former smokers. The crude and adjusted ORs from the primary analyses are also included.
      Figure thumbnail fx2
      Supplementary Figure 2Indirectly adjusted ORs for the association between asthma and ulcerative colitis corresponding to a spectrum of values corresponding to the percentage of people with asthma who are current and former smokers. The crude and adjusted ORs from the primary analyses are also included. (A) For individuals diagnosed with ulcerative colitis between the ages of 17 and 40 years. (B) For individuals diagnosed with ulcerative colitis after 40 years of age.
      Supplementary Table 1Logistic Regression Analysis Examining the Association Between Crohn’s Disease and Asthma Diagnosed Either Before or After Diagnosis With Crohn’s Disease (Cases) or Index Date (Control Subjects)
      OR (95% CI)
      P value for effect measure modification by age at diagnosis of Crohn’s disease (cases) or index date (control subjects) was 0.1605.
      Asthma
       Yes1.39 (1.27–1.54)
       No
      Reference group.
      Age at diagnosis
       A1 (3–16)
      Reference group.
       A2 (17–40)0.71 (0.63–0.80)
       A3 (>40)0.43 (0.38–0.48)
      Sex
       Male
      Reference group.
       Female1.16 (1.08–1.25)
      Quintile of median income
       <$22,935
      Reference group.
       $22,936–$26,8881.01 (0.90–1.14)
       $26,889–$30,8411.09 (0.97–1.22)
       $30,842–$36,3021.19 (1.06–1.33)
       ≥$36,3031.15 (1.03–1.29)
      Rural/urban residence
       Urban (Calgary or Edmonton, Alberta)0.85 (0.79–0.92)
       Rural
      Reference group.
      a P value for effect measure modification by age at diagnosis of Crohn’s disease (cases) or index date (control subjects) was 0.1605.
      b Reference group.
      Supplementary Table 2Logistic Regression Analysis Examining the Association Between Asthma Diagnosed at Any Point in Time
      OR (95% CI)
      A1 (≤16 years)A2 (17–40 years)A3 (>40 years)
      Asthma
       Yes1.37 (1.00–1.88)1.04 (0.87–1.24)1.48 (1.25–1.76)
       No
      Reference group.
      Sex
       Male
      Reference group.
       Female1.02 (0.78–1.35)0.99 (0.87–1.11)0.87 (0.77–0.98)
      Quintile of median income
       <$22,935
      Reference group.
       $22,936–$26,8881.23 (0.77–1.96)1.00 (0.81–1.23)1.12 (0.92–1.35)
       $26,889–$30,8410.89 (0.54–1.49)1.10 (0.90–1.36)1.00 (0.82–1.22)
       $30,842–$36,3021.80 (1.17–2.79)1.22 (0.99–1.49)1.35 (1.12–1.63)
       ≥$36,3031.51 (0.97–2.37)1.45 (1.19–1.76)1.22 (1.01–1.48)
      Rural/urban residence
       Urban (Calgary or Edmonton, Alberta)0.96 (0.73–1.27)1.07 (0.95–1.22)1.00 (0.89–1.13)
       Rural
      Reference group.
      NOTE. Results for ulcerative colitis are stratified by age group because of the present of effect measure modification by age at diagnosis of IBD (cases) or index date (control subjects); P value for the interaction terms was 0.02.
      a Reference group.

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