Minireviews
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 14, 2016; 22(34): 7735-7741
Published online Sep 14, 2016. doi: 10.3748/wjg.v22.i34.7735
Inflammatory bowel disease and airway diseases
Maria Vutcovici, Paul Brassard, Alain Bitton
Maria Vutcovici, Alain Bitton, Division of Gastroenterology, McGill University Health Centre, Montreal General Hospital, Montreal, Québec H3G 1A4, Canada
Paul Brassard, Division of Clinical Epidemiology, McGill University Health Centre, Montreal, Québec H3A 1A1, Canada
Paul Brassard, Alain Bitton, Department of Medicine, McGill University, Montreal, Québec H3G 1Y6, Canada
Author contributions: Vutcovici M, Brassard P and Bitton A contributed equally to the conception and design of the manuscript; Vutcovici M conducted the literature review and drafted the manuscript; Bitton A and Brassard P contributed to the critical revision and editing; all authors approved the final version.
Supported by Financial support for this study was provided through internal funding from the McGill University Health Centre.
Conflict-of-interest statement: None of the authors has any conflict of interest to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Maria Vutcovici, MD, MSc, Division of Gastroenterology, McGill University Health Centre, Montreal General Hospital, 1650 Cedar Avenue D16-125, Montreal, Québec H3G 1A4, Canada. maria.vutcovici@mail.mcgill.ca
Telephone: +514-340-8222-3678 Fax: +514-843-2891
Received: March 24, 2016
Peer-review started: March 25, 2016
First decision: May 12, 2016
Revised: June 14, 2016
Accepted: July 6, 2016
Article in press: July 6, 2016
Published online: September 14, 2016

Abstract

Airway diseases are the most commonly described lung manifestations of inflammatory bowel disease (IBD). However, the similarities in disease pathogenesis and the sharing of important environmental risk factors and genetic susceptibility suggest that there is a complex interplay between IBD and airway diseases. Recent evidence of IBD occurrence among patients with airway diseases and the higher than estimated prevalence of subclinical airway injuries among IBD patients support the hypothesis of a two-way association. Future research efforts should be directed toward further exploration of this association, as airway diseases are highly prevalent conditions with a substantial public health impact.

Key Words: Inflammatory bowel disease, Ulcerative colitis, Asthma, Chronic obstructive pulmonary disease, Crohn's disease

Core tip: Recent evidence of inflammatory bowel disease (IBD) occurrence among patients with airway diseases and the higher than estimated prevalence of subclinical airway injuries among IBD patients support the hypothesis of a two-way association between these conditions. Future research efforts should be directed toward further exploration of this association, as airway diseases are highly prevalent conditions with a substantial public health impact.


Citation: Vutcovici M, Brassard P, Bitton A. Inflammatory bowel disease and airway diseases. World J Gastroenterol 2016; 22(34): 7735-7741
INTRODUCTION

An association between inflammatory bowel disease (IBD) and airway diseases has long been described in the literature. The majority of studies have addressed the topic from the perspective of airway diseases as an extraintestinal manifestation of IBD[1-7]. However, there is growing evidence regarding an increased risk of IBD occurrence among patients with airway diseases such as asthma[8-11], chronic obstructive pulmonary disease (COPD)[12,13] and bronchiectasis[13]. There are several similarities between these conditions, ranging from the multifactorial complex etiology to the chronic remitting-relapsing disease course and the presence of low-grade systemic inflammation. It is, therefore, likely that the complex relationship between IBD and airway diseases is not merely unidirectional, and the new evidence from population-based studies supports this hypothesis.

In this paper we review the similarities between airway diseases and IBD and address the epidemiological evidence for the association, focusing on IBD occurrence in patients with airway diseases.

SIMILARITIES IN PATHOGENESIS AND RISK FACTORS
Genetic factors

Genome-wide association studies have shown an overlap of regions of genetic linkage for asthma, IBD, and other autoimmune disorders[14]. Several gene loci, such as DENND1B, SMAD3 and SLC22A4/5 (5q31/IBD5), were found to be associated with both asthma and Crohn’s disease (CD), while the ORMDL3 gene variants present in CD and ulcerative colitis (UC) were also found in childhood-onset asthma[15]. The association between NOD2 gene polymorphism and the development of both CD[16] and COPD[17] supports the hypothesis of a shared genetic susceptibility. NOD2 proteins recognize peptidoglycan components of the bacterial wall, contributing thus to bacterial recognition and the activation of immune defense pathways[17].

Embryologic origin, anatomical structure and function

The epithelia of the intestine and airways derive from the same embryological structure, the foregut region of the endoderm[18]. Their anatomical structure is, therefore, very similar, with a columnar type epithelium, goblet cells and mucous glands[4,19,20]. The lymphoid tissue in the submucosal layer is composed of antigen-presenting cells and lymphocytes capable of releasing pro-inflammatory cytokines[21], and plays an important role in both innate and adaptive immune defense as part of the barrier organ function of the respiratory and gastrointestinal tracts[4].

Pathogenesis

Several similarities in the underlying pathological mechanisms have been described and may explain the association between IBD and airway diseases[1,2,22-24]. Dysbiosis and an inappropriate immune response to intestinal microbiota are considered key components of the pathophysiological process in IBD[25]. Similarly, an immune response to lung microbiota seems to occur in airway diseases such as bronchiectasis[26]. A dysregulation of protease activity is present in both IBD[27] and COPD[28], and is associated with the breakdown of connective tissue components and the ensuing remodeling process[1,29]. Alterations in immune cell homing function[1,22] may explain the low grade chronic systemic inflammation that is present in IBD[30], COPD[31], asthma[32-34] and bronchiectasis[35-38]. The hygiene hypothesis, proposing that a lack of exposure to microorganisms during childhood contributes to abnormal immune reactions later in life, may also constitute a common factor linking asthma, IBD and a variety of other conditions[39].

Environmental factors

Tobacco smoking is an important risk factor associated with the development of both airway diseases[40,41] and CD[42]. In asthmatic patients, smoking is associated with a decline in lung function[43] and increased morbidity rates[41,44]. A relative resistance to corticosteroid therapy was reported in smoking asthmatic and COPD patients[41], and the hospitalizations and mortality rates were higher than in non-smoking asthma and COPD controls[40,45]. Smoking has been associated with a poor response to treatment and a more severe disease course in CD patients[42,46,47]. In contrast, ulcerative colitis seems to be a disease of non-smokers or former smokers[48], and a more benign disease course was observed in UC smokers compared to non-smokers[49]. This suggests that the association between UC and airway diseases goes beyond the confounding effect of smoking. Several potential underlying mechanisms that may explain the effect of cigarette smoke in IBD have been advanced, including alterations in cellular and humoral immunity, alterations in mucosal blood flow, gut permeability and motility, as well as a pro-thrombotic and a reduced anti-oxidant effect[42], but the relationship with the dichotomous impact on CD and UC is still unclear.

Air pollution is another environmental risk factor associated with both airway diseases and IBD. Air pollutants such as particulate matter, ozone or nitrous oxides were associated with an increase in number of hospitalizations for asthma[50], COPD[51-53] and IBD[54], and with an increased risk of mortality in COPD patients[55]. The gastrointestinal tract is exposed to air pollutants through contaminated food and water[56]. There appears to be a dose-response association between long term exposure to air pollutants, such as nitrous oxides and particulate matter, and the risk of early onset CD[57]. Exposure to sulfur oxides was associated with an increased risk of early onset UC, but no dose-response effect could be demonstrated[57]. Gastrointestinal injury may be the result of alterations in gut microbiota induced by exposure to air pollutants, as demonstrated in animal models[58], of an increased intestinal permeability, or of a pro-inflammatory effect[56].

Vitamin D is an environmental factor with a pleiotropic role in immune regulation[59], from inhibiting cytokine production to enhancing innate immunity by facilitating the transcription of peptides with antimicrobial effects[60]. Low serum levels of Vitamin D in asthmatic patients were associated with impairments in lung function, a poor response to corticosteroid therapy and an increased airway hyper-reactivity[61]. In children with mild to moderate asthma, vitamin D deficiency is relatively common and associated with an increased risk of severe exacerbations[62]. Vitamin D deficiency in IBD patients may be a consequence of malabsorption, low dietary intake or reduced bioavailability[63], but the suboptimal serum levels observed in newly diagnosed patients[64] suggest that the deficiency may also be associated with IBD development[59,63]. A randomized control trial of Vitamin D supplementation in CD patients showed a reduced number of relapses compared to the placebo group[65]. Further studies are needed to confirm this effect.

AIRWAY DISEASE IN IBD

Airway diseases were first described in IBD patients four decades ago in the case series of Kraft et al[66]. There is an extensive literature documenting airway diseases as an extraintestinal manifestation of IBD. Approximately 6%-47% of patients develop at least one extraintestinal manifestation[67-69] during the course of IBD, but the true prevalence of lung involvement is unknown due to the presence of subclinical pulmonary injury. It is estimated that 40%-60% of IBD patients have some degree of subclinical lung involvement evidenced through alterations in pulmonary function tests and high resolution tomographic imaging (HRCT)[70-73].

The most frequently observed alterations in pulmonary function tests are decreases in forced expiratory volume in 1 s (FEV1)[72,73] and FEV1/forced vital capacity (FVC) ratio, in forced expiratory flow 25%-75%[72,73] as well as in the transfer coefficient for carbon monoxide (DLCO)[73]. The severity of the observed alterations in pulmonary function tests was found to be in correlation with the endoscopic and clinical activity in UC patients[73,74] and independent of the effect of smoking[73].

HRCT imaging techniques allow the detection of lung involvement in IBD patients without overt respiratory symptoms. The most common findings are an enlarged bronchial internal diameter, peribronchial wall thickening, air trapping or the identification of airways in the extreme lung periphery[6,75]. The imaging appearance of small airway involvement in UC patients, with the “tree in bud” aspect and cellular bronchiolitis, was described as indistinguishable from the imaging findings in patients with rheumatoid arthritis or in transplant recipients, indicating thus an immunological mechanism of small airway injury[75].

In IBD patients with respiratory symptoms, airway diseases are the most commonly reported respiratory condition[4,11,73,76]. Bronchiectasis was found to occur in 22% of symptomatic cases[4,5], followed by chronic bronchitis in 20% of cases[5] and suppurative airway disease without bronchiectasis[4]. Furthermore, evidence from population-based epidemiologic studies indicates an association with asthma, bronchitis and COPD. A large matched-cohort study involving more than 8000 IBD patients found asthma to be the second most common comorbidity after arthritis in both CD and UC[11]. The prevalence of bronchitis was also significantly increased in IBD patients compared to healthy controls[11]. Studies of survival and cause of death reported a significant increase in mortality due to COPD among IBD patients[77,78].

Lung involvement in IBD can also result from the effect of IBD-specific medications. The most commonly reported associations were with interstitial lung diseases, such as interstitial pneumonitis (for Mesalamine, thiopurines and biologics) or diffuse interstitial lung disease (for Methotrexate)[3], or with diseases affecting the lung parenchyma, such as eosinophilic pneumonia (for Mesalamine and biologics)[79,80], but not with airway diseases.

IBD OCCURRENCE IN AIRWAY DISEASES

Despite the substantial evidence of an IBD-airway disease association and of the complex interplay between the two groups of conditions, an interest toward the possibility of IBD occurrence in patients with pre-existing airway diseases has only recently emerged. In the last decade, a handful of population-based studies have addressed the risk of developing IBD, its incidence or prevalence in patients with asthma, bronchitis, bronchiectasis and COPD (Table 1).

Table 1 Population-based studies of inflammatory bowel disease occurrence in patients with airway diseases.
Ref.CountryAirway diseaseCohort sizeResults
Crohn’s diseaseUlcerative colitisIBD
Bernstein et al[11]CanadaAsthma12397PRR = 1.38 (95%CI: 1.23-1.53)PRR = 1.56 (95%CI: 1.4-1.74)
Bronchitis3092PRR = 1.72 (95%CI: 1.15-2.58)PRR = 1.92 (95%CI: 1.35-2.73)
Ekbom et al[12]SwedenCOPD180239HR = 2.72 (95%CI: 2.33-3.18)HR = 1.83 (95%CI: 1.61-2.09)
Raj et al[13]United KingdomCOPD588OR = 5.26 (95%CI: 1.71-16.19)OR = 3.57 (95%CI: 1.3-9.38)OR = 3.87 (95%CI: 1.19-12.62)
Bronchiectasis215OR = 7.21 (95%CI: 1.62-32.2)OR = 7.88 (95%CI: 2.71-22.91)OR = 8.38 (95%CI: 2.43-28.89)
Asthma893OR = 1.74 (95%CI: 0.39-7.65)OR = 2.81 (95%CI: 1.15-6.90)OR = 2.54 (95%CI: 0.78-8.26)
Airway disease, total2192OR = 5.96 (95%CI: 1.94-18.31)OR = 4.21 (95%CI: 1.71-10.41)OR = 4.26 (95%CI: 1.48-11.71)
Virta et al[9]FinlandAsthma185OR = 2.33 (95%CI: 1.41-3.86)OR = 1.11 (95%CI: 0.68-1.80)
Hemminki et al[8]SwedenAsthma148295SIR = 1.64 (95%CI: 1.42-1.87)SIR = 1.54 (95%CI: 1.36-1.73)
Brassard et al[10]CanadaCOPD143904IRR = 1.55 (95%CI: 1.49-1.62)IRR = 1.30 (95%CI: 1.24-1.37)
Asthma136178IRR = 1.27 (95%CI: 1.22-1.31)IRR = 0.99 (95%CI: 0.94-1.04)

Four studies have reported an increased prevalence of IBD in patients with airway diseases. In the study of Bernstein et al[11], the prevalence of CD and UC among patients with asthma and bronchitis was significantly increased compared to the prevalence in the general population of Manitoba, Canada. A four-fold increase in IBD prevalence was observed in a cohort of patients with airway diseases in the United Kingdom. The prevalence of UC was significantly increased in all types of airway disease investigated; CD prevalence was increased in patients with COPD and bronchiectasis[13]. A study of COPD patients and their first degree relatives identified from the Swedish Multigeneration Register showed an increased prevalence of both CD and UC among the patients and their siblings compared to IBD prevalence in controls[12]. Younger age at COPD diagnosis was found to be associated with a higher prevalence of UC. A case-control study of Finnish children with IBD showed that the risk of developing CD was significantly higher in children with asthma and with both asthma and cow milk allergy than in healthy controls[9].

Unfortunately, prevalence studies are informative only from the point of view of disease coexistence, and cannot provide an insight into the temporal sequence of developing these conditions. Two population-based studies assessed IBD occurrence during the course of airway diseases, one in asthmatic patients only and the other in asthma and COPD.

A study of Swedish inpatients discharged with a diagnosis of asthma showed an increased incidence of CD and UC hospitalizations during the follow up period[8]. To ensure incident IBD cases were captured, all subjects in which the diagnosis of CD and UC preceded that of asthma were excluded from the analyses. The standardized incidence rates for CD were significantly increased in all age groups, while the incidence increase of UC was only significant in subjects diagnosed with asthma after the age of 20 years.

More recently, a large retrospective cohort study of Québec patients with asthma and COPD showed a significantly increased incidence of both CD and UC in COPD patients and an increased incidence of CD in asthmatic patients compared to the IBD incidence in the general population[10]. Similar to the results of Hemminki et al[8], in asthmatic patients the incidence of CD was significantly increased in all age groups; the incidence of UC, although not significantly increased when all age groups were considered, was significantly increased in patients diagnosed with asthma after the age of 10 years. In COPD patients, the incidences of both CD and UC were significantly increased compared to the general population for all age groups. A follow up study of the same COPD cohort revealed that new onset IBD was associated with an increased risk of all-cause mortality as well as from respiratory and digestive causes[81].

FUTURE DIRECTIONS FOR RESEARCH

The existing evidence of IBD occurrence in patients with airway diseases is supported by population based studies. In clinical settings, the true prevalence of IBD or of digestive symptoms indicative of IBD is still unknown. If clinical studies confirm the association, it would be of importance to assess whether exacerbations in airway diseases are impacted by IBD disease activity.

Inversely, in IBD patients with lung manifestations, further assessment of prevalence of subclinical airway injuries is warranted, as recent evidence suggests it is much higher than previously expected. Such an assessment could shed more light into the temporal sequence of IBD-airway disease development.

CONCLUSION

There is a complex inter-relation between IBD and airway diseases and new evidence suggests that not only can airway diseases occur as an extraintestinal manifestation of IBD, but that IBD, in turn, can have a high occurrence in patients with airway diseases. This occurrence seems to also impact on key outcomes, such as mortality in COPD patients. While the importance of airway involvement as extraintestinal manifestation of IBD is amplified by the evidence of an increased prevalence of subclinical airway injuries, the impact of IBD occurrence in patients with airway diseases raises a substantially greater public health concern due to the worldwide high prevalence of airway diseases. Early detection of IBD may improve the treatment management and prognosis of airway disease patients.

ACKNOWLEDGMENTS

We thank librarian Tara Landry from the Montreal General Hospital branch of MUHC Libraries for assistance with the literature search.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Canada

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B, B

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): 0

P- Reviewer: Maharshak N, Soares RLS, Vecchi M S- Editor: Ma YJ L- Editor: A E- Editor: Ma S

References
1.  Rodriguez-Roisin R, Bartolome SD, Huchon G, Krowka MJ. Inflammatory bowel diseases, chronic liver diseases and the lung. Eur Respir J. 2016;47:638-650.  [PubMed]  [DOI]
2.  Papanikolaou I, Kagouridis K, Papiris SA. Patterns of airway involvement in inflammatory bowel diseases. World J Gastrointest Pathophysiol. 2014;5:560-569.  [PubMed]  [DOI]
3.  Casella G, Villanacci V, Di Bella C, Antonelli E, Baldini V, Bassotti G. Pulmonary diseases associated with inflammatory bowel diseases. J Crohns Colitis. 2010;4:384-389.  [PubMed]  [DOI]
4.  Black H, Mendoza M, Murin S. Thoracic manifestations of inflammatory bowel disease. Chest. 2007;131:524-532.  [PubMed]  [DOI]
5.  Ott C, Schölmerich J. Extraintestinal manifestations and complications in IBD. Nat Rev Gastroenterol Hepatol. 2013;10:585-595.  [PubMed]  [DOI]
6.  Larsen S, Bendtzen K, Nielsen OH. Extraintestinal manifestations of inflammatory bowel disease: epidemiology, diagnosis, and management. Ann Med. 2010;42:97-114.  [PubMed]  [DOI]
7.  Jose FA, Heyman MB. Extraintestinal manifestations of inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2008;46:124-133.  [PubMed]  [DOI]
8.  Hemminki K, Li X, Sundquist J, Sundquist K. Subsequent autoimmune or related disease in asthma patients: clustering of diseases or medical care? Ann Epidemiol. 2010;20:217-222.  [PubMed]  [DOI]
9.  Virta LJ, Ashorn M, Kolho KL. Cow’s milk allergy, asthma, and pediatric IBD. J Pediatr Gastroenterol Nutr. 2013;56:649-651.  [PubMed]  [DOI]
10.  Brassard P, Vutcovici M, Ernst P, Patenaude V, Sewitch M, Suissa S, Bitton A. Increased incidence of inflammatory bowel disease in Québec residents with airway diseases. Eur Respir J. 2015;45:962-968.  [PubMed]  [DOI]
11.  Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study. Gastroenterology. 2005;129:827-836.  [PubMed]  [DOI]
12.  Ekbom A, Brandt L, Granath F, Löfdahl CG, Egesten A. Increased risk of both ulcerative colitis and Crohn’s disease in a population suffering from COPD. Lung. 2008;186:167-172.  [PubMed]  [DOI]
13.  Raj AA, Birring SS, Green R, Grant A, de Caestecker J, Pavord ID. Prevalence of inflammatory bowel disease in patients with airways disease. Respir Med. 2008;102:780-785.  [PubMed]  [DOI]
14.  Becker KG, Simon RM, Bailey-Wilson JE, Freidlin B, Biddison WE, McFarland HF, Trent JM. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc Natl Acad Sci USA. 1998;95:9979-9984.  [PubMed]  [DOI]
15.  Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Gut. 2011;60:1739-1753.  [PubMed]  [DOI]
16.  Adler J, Rangwalla SC, Dwamena BA, Higgins PD. The prognostic power of the NOD2 genotype for complicated Crohn’s disease: a meta-analysis. Am J Gastroenterol. 2011;106:699-712.  [PubMed]  [DOI]
17.  Kinose D, Ogawa E, Hirota T, Ito I, Kudo M, Haruna A, Marumo S, Hoshino Y, Muro S, Hirai T. A NOD2 gene polymorphism is associated with the prevalence and severity of chronic obstructive pulmonary disease in a Japanese population. Respirology. 2012;17:164-171.  [PubMed]  [DOI]
18.  Sadler TW.  Langman’s Medical Embryology. Philadelphia: Wolters Kluwer LWW; 2011;400.  [PubMed]  [DOI]
19.  Tzanakis NE, Tsiligianni IG, Siafakas NM. Pulmonary involvement and allergic disorders in inflammatory bowel disease. World J Gastroenterol. 2010;16:299-305.  [PubMed]  [DOI]
20.  Sostegni R, Daperno M, Pera A. Pulmonary manifestations of inflammatory bowel disease. Dig Liver Dis. 2007;39:239-241.  [PubMed]  [DOI]
21.  Actis GC, Rosina F. Inflammatory bowel disease: An archetype disorder of outer environment sensor systems. World J Gastrointest Pharmacol Ther. 2013;4:41-46.  [PubMed]  [DOI]
22.  Keely S, Talley NJ, Hansbro PM. Pulmonary-intestinal cross-talk in mucosal inflammatory disease. Mucosal Immunol. 2012;5:7-18.  [PubMed]  [DOI]
23.  Wang H, Liu JS, Peng SH, Deng XY, Zhu DM, Javidiparsijani S, Wang GR, Li DQ, Li LX, Wang YC. Gut-lung crosstalk in pulmonary involvement with inflammatory bowel diseases. World J Gastroenterol. 2013;19:6794-6804.  [PubMed]  [DOI]
24.  Mateer SW, Maltby S, Marks E, Foster PS, Horvat JC, Hansbro PM, Keely S. Potential mechanisms regulating pulmonary pathology in inflammatory bowel disease. J Leukoc Biol. 2015;98:727-737.  [PubMed]  [DOI]
25.  Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640.  [PubMed]  [DOI]
26.  Hurst JR. Microbial dysbiosis in bronchiectasis. Lancet Respir Med. 2014;2:945-947.  [PubMed]  [DOI]
27.  Garg P, Vijay-Kumar M, Wang L, Gewirtz AT, Merlin D, Sitaraman SV. Matrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrix metalloproteinase-2 during colitis. Am J Physiol Gastrointest Liver Physiol. 2009;296:G175-G184.  [PubMed]  [DOI]
28.  Vernooy JH, Lindeman JH, Jacobs JA, Hanemaaijer R, Wouters EF. Increased activity of matrix metalloproteinase-8 and matrix metalloproteinase-9 in induced sputum from patients with COPD. Chest. 2004;126:1802-1810.  [PubMed]  [DOI]
29.  Keely S, Hansbro PM. Lung-gut cross talk: a potential mechanism for intestinal dysfunction in patients with COPD. Chest. 2014;145:199-200.  [PubMed]  [DOI]
30.  Lochhead P, Khalili H, Ananthakrishnan AN, Richter JM, Chan AT. Association Between Circulating Levels of C-Reactive Protein and Interleukin-6 and Risk of Inflammatory Bowel Disease. Clin Gastroenterol Hepatol. 2016;14:818-824.e6.  [PubMed]  [DOI]
31.  Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004;59:574-580.  [PubMed]  [DOI]
32.  Fu JJ, McDonald VM, Baines KJ, Gibson PG. Airway IL-1β and Systemic Inflammation as Predictors of Future Exacerbation Risk in Asthma and COPD. Chest. 2015;148:618-629.  [PubMed]  [DOI]
33.  Wood LG, Baines KJ, Fu J, Scott HA, Gibson PG. The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma. Chest. 2012;142:86-93.  [PubMed]  [DOI]
34.  Karthikeyan R, Krishnamoorthy S, Maamidi S, Kaza AM, Balasubramanian N. Effect of inhaled corticosteroids on systemic inflammation in asthma. Perspect Clin Res. 2014;5:75-79.  [PubMed]  [DOI]
35.  Martínez-García MA, Soler-Cataluña JJ, Perpiñá-Tordera M, Román-Sánchez P, Soriano J. Factors associated with lung function decline in adult patients with stable non-cystic fibrosis bronchiectasis. Chest. 2007;132:1565-1572.  [PubMed]  [DOI]
36.  Hemminki K, Li X, Sundquist K, Sundquist J. Familial association of inflammatory bowel diseases with other autoimmune and related diseases. Am J Gastroenterol. 2010;105:139-147.  [PubMed]  [DOI]
37.  Agustí A, MacNee W, Donaldson K, Cosio M. Hypothesis: does COPD have an autoimmune component? Thorax. 2003;58:832-834.  [PubMed]  [DOI]
38.  Birring SS, Pavord ID. COPD: an autoimmune disease? Eur Respir J. 2011;38:484.  [PubMed]  [DOI]
39.  Springmann V, Brassard P, Krupoves A, Amre D. Timing, frequency and type of physician-diagnosed infections in childhood and risk for Crohn’s disease in children and young adults. Inflamm Bowel Dis. 2014;20:1346-1352.  [PubMed]  [DOI]
40.  Forey BA, Thornton AJ, Lee PN. Systematic review with meta-analysis of the epidemiological evidence relating smoking to COPD, chronic bronchitis and emphysema. BMC Pulm Med. 2011;11:36.  [PubMed]  [DOI]
41.  Tamimi A, Serdarevic D, Hanania NA. The effects of cigarette smoke on airway inflammation in asthma and COPD: therapeutic implications. Respir Med. 2012;106:319-328.  [PubMed]  [DOI]
42.  Birrenbach T, Böcker U. Inflammatory bowel disease and smoking: a review of epidemiology, pathophysiology, and therapeutic implications. Inflamm Bowel Dis. 2004;10:848-859.  [PubMed]  [DOI]
43.  Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med. 1998;339:1194-1200.  [PubMed]  [DOI]
44.  Silverman RA, Boudreaux ED, Woodruff PG, Clark S, Camargo CA. Cigarette smoking among asthmatic adults presenting to 64 emergency departments. Chest. 2003;123:1472-1479.  [PubMed]  [DOI]
45.  Marquette CH, Saulnier F, Leroy O, Wallaert B, Chopin C, Demarcq JM, Durocher A, Tonnel AB. Long-term prognosis of near-fatal asthma. A 6-year follow-up study of 145 asthmatic patients who underwent mechanical ventilation for a near-fatal attack of asthma. Am Rev Respir Dis. 1992;146:76-81.  [PubMed]  [DOI]
46.  Cosnes J, Carbonnel F, Beaugerie L, Le Quintrec Y, Gendre JP. Effects of cigarette smoking on the long-term course of Crohn’s disease. Gastroenterology. 1996;110:424-431.  [PubMed]  [DOI]
47.  Breuer-Katschinski BD, Holländer N, Goebell H. Effect of cigarette smoking on the course of Crohn’s disease. Eur J Gastroenterol Hepatol. 1996;8:225-228.  [PubMed]  [DOI]
48.  Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci. 1989;34:1841-1854.  [PubMed]  [DOI]
49.  Cosnes J. Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice. Best Pract Res Clin Gastroenterol. 2004;18:481-496.  [PubMed]  [DOI]
50.  Halonen JI, Lanki T, Yli-Tuomi T, Kulmala M, Tiittanen P, Pekkanen J. Urban air pollution, and asthma and COPD hospital emergency room visits. Thorax. 2008;63:635-641.  [PubMed]  [DOI]
51.  Medina-Ramón M, Zanobetti A, Schwartz J. The effect of ozone and PM10 on hospital admissions for pneumonia and chronic obstructive pulmonary disease: a national multicity study. Am J Epidemiol. 2006;163:579-588.  [PubMed]  [DOI]
52.  Ko FW, Tam W, Wong TW, Chan DP, Tung AH, Lai CK, Hui DS. Temporal relationship between air pollutants and hospital admissions for chronic obstructive pulmonary disease in Hong Kong. Thorax. 2007;62:780-785.  [PubMed]  [DOI]
53.  Anderson HR, Spix C, Medina S, Schouten JP, Castellsague J, Rossi G, Zmirou D, Touloumi G, Wojtyniak B, Ponka A. Air pollution and daily admissions for chronic obstructive pulmonary disease in 6 European cities: results from the APHEA project. Eur Respir J. 1997;10:1064-1071.  [PubMed]  [DOI]
54.  Ananthakrishnan AN, McGinley EL, Binion DG, Saeian K. Ambient air pollution correlates with hospitalizations for inflammatory bowel disease: an ecologic analysis. Inflamm Bowel Dis. 2011;17:1138-1145.  [PubMed]  [DOI]
55.  Zanobetti A, Bind MA, Schwartz J. Particulate air pollution and survival in a COPD cohort. Environ Health. 2008;7:48.  [PubMed]  [DOI]
56.  Salim SY, Kaplan GG, Madsen KL. Air pollution effects on the gut microbiota: a link between exposure and inflammatory disease. Gut Microbes. 2014;5:215-219.  [PubMed]  [DOI]
57.  Kaplan GG, Hubbard J, Korzenik J, Sands BE, Panaccione R, Ghosh S, Wheeler AJ, Villeneuve PJ. The inflammatory bowel diseases and ambient air pollution: a novel association. Am J Gastroenterol. 2010;105:2412-2419.  [PubMed]  [DOI]
58.  Kish L, Hotte N, Kaplan GG, Vincent R, Tso R, Gänzle M, Rioux KP, Thiesen A, Barkema HW, Wine E. Environmental particulate matter induces murine intestinal inflammatory responses and alters the gut microbiome. PLoS One. 2013;8:e62220.  [PubMed]  [DOI]
59.  Mouli VP, Ananthakrishnan AN. Review article: vitamin D and inflammatory bowel diseases. Aliment Pharmacol Ther. 2014;39:125-136.  [PubMed]  [DOI]
60.  Székely JI, Pataki Á. Effects of vitamin D on immune disorders with special regard to asthma, COPD and autoimmune diseases: a short review. Expert Rev Respir Med. 2012;6:683-704.  [PubMed]  [DOI]
61.  Sutherland ER, Goleva E, Jackson LP, Stevens AD, Leung DY. Vitamin D levels, lung function, and steroid response in adult asthma. Am J Respir Crit Care Med. 2010;181:699-704.  [PubMed]  [DOI]
62.  Brehm JM, Schuemann B, Fuhlbrigge AL, Hollis BW, Strunk RC, Zeiger RS, Weiss ST, Litonjua AA. Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol. 2010;126:52-58.e5.  [PubMed]  [DOI]
63.  Ananthakrishnan AN. Environmental triggers for inflammatory bowel disease. Curr Gastroenterol Rep. 2013;15:302.  [PubMed]  [DOI]
64.  Leslie WD, Miller N, Rogala L, Bernstein CN. Vitamin D status and bone density in recently diagnosed inflammatory bowel disease: the Manitoba IBD Cohort Study. Am J Gastroenterol. 2008;103:1451-1459.  [PubMed]  [DOI]
65.  Jørgensen SP, Agnholt J, Glerup H, Lyhne S, Villadsen GE, Hvas CL, Bartels LE, Kelsen J, Christensen LA, Dahlerup JF. Clinical trial: vitamin D3 treatment in Crohn’s disease - a randomized double-blind placebo-controlled study. Aliment Pharmacol Ther. 2010;32:377-383.  [PubMed]  [DOI]
66.  Kraft SC, Earle RH, Roesler M, Esterly JR. Unexplained bronchopulmonary disease with inflammatory bowel disease. Arch Intern Med. 1976;136:454-459.  [PubMed]  [DOI]
67.  Bernstein CN, Blanchard JF, Rawsthorne P, Yu N. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol. 2001;96:1116-1122.  [PubMed]  [DOI]
68.  Mendoza JL, Lana R, Taxonera C, Alba C, Izquierdo S, Díaz-Rubio M. [Extraintestinal manifestations in inflammatory bowel disease: differences between Crohn’s disease and ulcerative colitis]. Med Clin (Barc). 2005;125:297-300.  [PubMed]  [DOI]
69.  Ricart E, Panaccione R, Loftus EV, Tremaine WJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. Autoimmune disorders and extraintestinal manifestations in first-degree familial and sporadic inflammatory bowel disease: a case-control study. Inflamm Bowel Dis. 2004;10:207-214.  [PubMed]  [DOI]
70.  Hoffmann RM, Kruis W. Rare extraintestinal manifestations of inflammatory bowel disease. Inflamm Bowel Dis. 2004;10:140-147.  [PubMed]  [DOI]
71.  Kelly MG, Frizelle FA, Thornley PT, Beckert L, Epton M, Lynch AC. Inflammatory bowel disease and the lung: is there a link between surgery and bronchiectasis? Int J Colorectal Dis. 2006;21:754-757.  [PubMed]  [DOI]
72.  Mohamed-Hussein AA, Mohamed NA, Ibrahim ME. Changes in pulmonary function in patients with ulcerative colitis. Respir Med. 2007;101:977-982.  [PubMed]  [DOI]
73.  Yilmaz A, Yilmaz Demirci N, Hoşgün D, Uner E, Erdoğan Y, Gökçek A, Cağlar A. Pulmonary involvement in inflammatory bowel disease. World J Gastroenterol. 2010;16:4952-4957.  [PubMed]  [DOI]
74.  Herrlinger KR, Noftz MK, Dalhoff K, Ludwig D, Stange EF, Fellermann K. Alterations in pulmonary function in inflammatory bowel disease are frequent and persist during remission. Am J Gastroenterol. 2002;97:377-381.  [PubMed]  [DOI]
75.  Mahadeva R, Walsh G, Flower CD, Shneerson JM. Clinical and radiological characteristics of lung disease in inflammatory bowel disease. Eur Respir J. 2000;15:41-48.  [PubMed]  [DOI]
76.  Betancourt SL, Palacio D, Jimenez CA, Martinez S, Marom EM. Thoracic manifestations of inflammatory bowel disease. AJR Am J Roentgenol. 2011;197:W452-W456.  [PubMed]  [DOI]
77.  Jess T, Loftus EV, Harmsen WS, Zinsmeister AR, Tremaine WJ, Melton LJ, Munkholm P, Sandborn WJ. Survival and cause specific mortality in patients with inflammatory bowel disease: a long term outcome study in Olmsted County, Minnesota, 1940-2004. Gut. 2006;55:1248-1254.  [PubMed]  [DOI]
78.  Jussila A, Virta LJ, Pukkala E, Färkkilä MA. Mortality and causes of death in patients with inflammatory bowel disease: a nationwide register study in Finland. J Crohns Colitis. 2014;8:1088-1096.  [PubMed]  [DOI]
79.  Parry SD, Barbatzas C, Peel ET, Barton JR. Sulphasalazine and lung toxicity. Eur Respir J. 2002;19:756-764.  [PubMed]  [DOI]
80.  Peters FP, Engels LG, Moers AM. Pneumonitis induced by sulphasalazine. Postgrad Med J. 1997;73:99-100.  [PubMed]  [DOI]
81.  Vutcovici M, Bitton A, Ernst P, Kezouh A, Suissa S, Brassard P. Inflammatory bowel disease and risk of mortality in COPD. Eur Respir J. 2016;47:1357-1364.  [PubMed]  [DOI]