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doi:10.1378/chest.06-1074
(Chest. 2007; 131:524-532)
© 2007 American College of Chest Physicians
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Thoracic Manifestations of Inflammatory Bowel Disease*

Hugh Black, MD; Mark Mendoza, MD and Susan Murin, MD, MSc, FCCP

* From the Division of Pulmonary and Critical Care Medicine, University of California at Davis School of Medicine, Davis, CA.

Correspondence to: Susan Murin, MD, MSc, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of California at Davis School of Medicine, 4150 V St, Suite 3400, Sacramento, CA 95817; e-mail: sxmurin{at}ucdavis.edu

Abstract

Background: A growing number of case reports suggest that pulmonary disease occurs in association with inflammatory bowel disease (IBD) more frequently than previously recognized. Screening studies have also identified pulmonary abnormalities in a significant proportion of IBD patients.

Methods: A focused literature review of respiratory abnormalities in IBD patients and 55 English-language case series documenting 171 instances of respiratory pathology in 155 patients with known IBD.

Results: Screening studies using respiratory symptoms, high-resolution CT, and pulmonary function testing support a high prevalence of respiratory abnormalities among patients with IBD. Case reports and series document a spectrum of respiratory system involvement that spans from larynx to pleura, with bronchiectasis as the single most common disorder. IBD patients have a threefold risk of venous thromboembolism, and recent investigations have also revealed possible ties between IBD and other diseases involving the respiratory system, including sarcoidosis, asthma, and {alpha}1-antitrypsin deficiency.

Conclusion: Respiratory symptoms and diagnosed respiratory system disorders are more common among patients with IBD than generally appreciated. The spectrum of respiratory disorders occurring among patients with IBD is very broad. Diseases of the large airways are the most common form of involvement, with bronchiectasis being the most frequently reported form of IBD-associated lung disease.

Key Words: bronchiectasis • bronchiolitis obliterans • bronchiolitis obliterans organizing pneumonia • Crohn disease • inflammatory bowel disease • sarcoidosis • tracheitis • ulcerative colitis

The inflammatory bowel diseases (IBDs), Crohn disease (CD) and ulcerative colitis (UC), are widely recognized disorders of the GI tract that may have a variety of extraintestinal manifestations. These include pyoderma gangrenosum, erythema nodosum, uveitis, episcleritis, cholestatic liver disease, hemolytic anemia, arthritis, and pulmonary disease of various types.1 A link between pulmonary disease and IBD was suggested nearly 40 years ago.2 Both screening studies and the cumulative volume of case reports suggest that the respiratory system may be involved in IBD more frequently than is generally appreciated. Thoracic pathology in this population is extremely varied, and individual patients may manifest pulmonary abnormalities at multiple sites.

Commonality between the GI and respiratory systems provides some pathophysiologic basis for respiratory involvement in IBD. Both the colonic and respiratory epithelia share embryonic origin from the primitive foregut. Both possess goblet cells and submucosal glands as part of their lumenal structure. In addition, both lung and GI tract contain submucosal lymphoid tissue and play crucial roles in host mucosal defense. The aberrations in both innate and acquired immunity that are involved in the pathogenesis of IBD are complex and still incompletely understood.3 In addition, many of the reported pulmonary diseases associated with IBD have cryptic etiologies. Thus, at this time the causes or mechanisms of various forms of respiratory tract involvement in IBD remain poorly understood.

In this article, we review the thoracic manifestations of IBD. First, various approaches to the identification of pulmonary disease in IBD patients are discussed. Next, thoracic findings culled from > 50 case series identified via a focused literature review are summarized and organized according to the anatomic location of respiratory involvement. The relationships between IBD and sarcoidosis, {alpha}1-antitrypsin deficiency, and venous thromboembolism (VTE) are discussed. Pulmonary effects of pharmacologic therapies for IBD have been examined elsewhere4 and are beyond the scope of this review.

Materials and Methods

Medline searches using the terms "inflammatory bowel disease," "ulcerative colitis," and "Crohn’s disease," in conjunction with the terms "lung," "pulmonary," "bronchiectasis," "bronchitis," "sarcoidosis," "bronchiolitis obliterans organizing pneumonia," "venous thromboembolism," "pulmonary embolism," "pericarditis," "interstitial lung disease," "alpha-1 anti-trypsin deficiency," and "asthma" were performed. Articles focused on infections, pathologies attributable to coexistent disease, and complications of therapy were excluded, as were those that were not in English. All applicable, retrievable manuscripts were reviewed by the authors, and data were abstracted. Articles not available in the University of California, Davis Library or UC Digital Library were requested through interlibrary loan services; > 95% of all citations were retrievable. The references of the various articles retrieved from the above process were themselves reviewed for additional citations. Relevant data were abstracted and entered into an Excel file (Microsoft; Redmond, WA) for summary and analysis. References for case reports not included have been placed in the Appendix at the end of this article.

Pulmonary Disease in IBD Patients

Respiratory Symptoms
The prevalence of respiratory symptoms in IBD patients without pulmonary pathology has been examined in a number of small studies. Among 44 randomly selected IBD patients, Douglas et al5 found that 48% had unspecified respiratory symptoms. Songur et al6 found that 16 of 36 IBD patients (44%) in a gastroenterology clinic had symptoms of wheeze, cough, sputum production, or breathlessness. Finally, Ceyhan and others7 found 15 of 30 consecutively surveyed IBD patients had symptoms of dyspnea, cough, sputum, or wheeze for > 1 month. These investigations, while limited in scope, suggest that patients with IBD have pulmonary symptoms with greater frequency than the general population (Table 1 ).5678910111213141516171819202122232425


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  		Table 1.. Evidence of Pulmonary Involvement in IBD Patients

 
High-Resolution CT Findings
High-resolution CT (HRCT) scanning has been used to screen for latent pulmonary disease in IBD patients. A single-center study8 of 15 asymptomatic patients with UC identified subtle HRCT abnormalities in 25% of patients. A subsequent case control study6 found subtle HRCT abnormalities in a majority of screened IBD patients but none among control subjects (n = 14; 53% vs 0%, respectively). The spectrum of reported HRCT abnormalities in these patients includes air-trapping, ground-glass opacification, peripheral reticular opacities, and cysts.

Pulmonary Function
A number of investigations have focused on results of pulmonary function testing (PFT) among patients with IBD. Case-control studies designed to investigate the hypothesis that IBD is associated with abnormal pulmonary function have been limited by low numbers of patients and poor choice of control subjects. An early investigation26 found no difference in pulmonary function between IBD patients and control subjects, but it may have lacked adequate statistical power. Subsequent studies have consistently found subtle abnormalities in pulmonary function in IBD patients.

A number of reports6910111213 have demonstrated a decrease in diffusion capacity of the lung for carbon monoxide (DLCO) between asymptomatic IBD patients and control subjects. The first large study to illustrate this was that of Heatley and colleagues,25 and those findings have since been corroborated.6910111213 Interestingly, two studies by Tzanakis et al1127 have shown that DLCO is significantly lower among IBD patients with active GI disease than those in remission. Marvisi et al12 reported a similar finding in a smaller cohort with UC. This suggests that degree of GI inflammation may correlate with the severity of lung disease in these patients, but this hypothesis has yet to be confirmed in a longitudinal cohort study.

A number of studies have been performed to assess airflow obstruction in patients with IBD, with conflicting results. Herrlinger and colleagues13 found decrements in FEV1 in IBD patients compared to control subjects, but the magnitude of difference was small and the absolute value of FEV1 in both groups was normal. More UC patients than control subjects were found to have obstruction during PFT in a series of 100 subjects,28 but cases and control subjects were not matched for age or smoking status. Most studies have not found evidence of obstruction using conventional spirometric parameters.

Other reports have employed less conventional measures of airflow obstruction to identify subclinical pulmonary disease. Utilizing a measurement of the volume at which flow of oxygen and helium became equal as a indication of small airways function, Tzanakis et al27 have shown an increased prevalence of small airway dysfunction among IBD patients. In addition, patients with active UC had increased airway obstruction compared with patients with inactive UC. Pasquis et al14 found an increase in functional residual capacity among a small number of patients with CD. Two other investigations56 have also found evidence of hyperinflation, as assessed by functional residual capacity and residual volume, among patients with IBD. Furthermore, there was an association between hyperinflation and active IBD in this cohort. Muscle weakness and steroid myopathy may be confounders of this variable, given the frequent use of steroid treatment for IBD. Two groups, Mansi and colleagues17 and Louis et al1516 have documented increased bronchial response to methacholine, a measure of airway hyperactivity, among patients with both CD and UC15 and CD,1617 but this was not confirmed in another study7 of similar design.

Bronchoscopy
The presence of chronic inflammation in the lungs of IBD patients has also been documented by cellular analysis of BAL fluid from IBD patients. Investigators at the University of Lille found increased alveolar lymphocytosis on BAL in a cohort of 18 asymptomatic subjects with CD compared to 25 control subjects,18 and in another case-control study19 with 22 asymptomatic subjects with CD and 25 control subjects.

Survey of Case Report Literature

A search using the PubMed database identified 55 English-language articles documenting thoracic findings in 155 patients with known IBD. These are organized according to site of involvement within the respiratory system and are presented in Table 2 .


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  		Table 2.. Summary of Reported Cases of Thoracic Involvement in IBD*

 
Airway Disease
The large airways are the most common location of IBD involvement, accounting for 39% of all cases reviewed.2930314041424344454647484950515253 Respiratory disease tends to occur in the fifth decade of life, although a there is a wide range of ages of onset. Most patients are female, and nearly all patients have UC. In only four cases has large airway disease been reported to predate GI disease, and the age of disease onset in these patients is notably younger (13 ± 7.5 years [± SD]). Patients with large airways disease may also have coincident nonthoracic extraintestinal manifestations, including microangiopathic hemolytic anemia, pyoderma gangrenosum, primary sclerosing cholangitis, episcleritis, and peripheral and axial arthritis.

Bronchiectasis is the classic pulmonary manifestation of IBD, noted in 66% of instances of IBD involving the large airways (Fig 1 ). Other abnormalities of the large airways include chronic bronchitis, suppurative large airway disease without airway dilation, and acute bronchitis. A surprisingly high proportion of these patients are nonsmokers (81%).


Figure 1
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  		Figure 1.. CT showing bronchiectasis and inflammatory nodules in a 72-year-old woman with UC.

 
Interestingly, nine patients, mostly with UC, presented with or had a recrudescence of bronchiectasis within 1 year of colectomy. In one case, bronchiectasis presented within weeks of colectomy. This temporal link between colonic resection and onset or worsening of pulmonary disease has fueled speculation that colectomy may actually induce pulmonary disease in these patients.88 Alternatively, this phenomenon may be related to the discontinuation of immunosuppressive therapies after presumed surgical cure of the disease.

Clinically, small airways are rarely affected in IBD. However, the recent advent of HRCT has increased the detection small airway involvement in these patients. HRCT abnormalities consistent with small airways abnormalities have been described in symptomatic IBD patients, some with normal PFT findings.52

Small airway involvement in IBD tends to present at a younger age and at an earlier point in the disease course than abnormalities of the large airways.3246505455565758596061 In contrast to other airway manifestations, diseases of the small airways more commonly occur before symptomatic GI disease (29% of surveyed cases). Pathologically, bronchiolitis is the most commonly reported disease involving the small airways in patients with IBD. Pathology frequently shows peribronchiolar granuloma formation (58.8%). Less frequent findings include peribronchiolar inflammation with either neutrophils or lymphocytes and plasma cells, concentric small airway fibrosis, and diffuse panbronchiolitis.

Upper airway involvement comprises the remainder of IBD-related airways disease. We review 15 cases of this rare entity.2930313233343536373839 All cases of upper airway involvement involve the trachea, although two cases of laryngeal and glottic disease occurring concomitantly with tracheal lesions have been reported. One patient required tracheal dilation but eventually succumbed to barotrauma after repeated dilations.32

Steroids are the major therapy involved in the treatment of airways disease in patients with IBD (65%), although some of these patients do not require systemic therapy. Clinical improvement with inhaled steroids alone or in combination with systemic steroids has been reported. Rarely, other forms of immune modulation have been used to treat IBD-related airway disease.5053

Asthma: Recent data suggest that IBD may be associated with asthma to a far greater extent than had previously been considered. A population-based cohort study22 at the University of Manitoba documented an increased prevalence of asthma among 8,072 UC patients compared with 41,815 control subjects matched for age, sex, and postal location. Furthermore, a number of studies document an association between IBD and various allergic diseases. D’Arienzo and colleagues89 showed an increased propensity for allergic disease identified by family history, skin-prick testing, and prior diagnosis of allergic disease among 45 patients with UC compared to 37 control subjects. Increased levels of tumor necrosis factor-{alpha} and increased mast cell activity are common to both atopy and IBD, and have been suggested as the link between them.90

Other investigations have focused on the intersection between allergic and airway disease in IBD patients. Ceyhan and colleagues7 found increased allergic symptoms, increased prevalence of positive skin-prick test results, higher IgE levels, and more abnormal pulmonary function among 30 IBD patients compared with control subjects. Louis and colleagues16 also documented increased response to methacholine and sputum eosinophils among CD patients. Increased bronchial hyperresponsiveness on methacholine challenge was also documented in 14 children with CD compared to control subjects, although the provocative dose causing a 20% fall in FEV1 in CD patients was greater than in the 10 asthmatics also tested in the study.17

There is evidence that asthma has a more severe course in IBD patients. A population-based cohort study in Stockholm found a sixfold increase in the number of deaths caused by asthma among 1,547 patients with UC compared with sex-specific death rates from the National Cause-of-Death Register.91 Finally, patients with UC and asthma have increased airway obstruction and a lower provocative concentration causing a 20% fall in FEV1 on methacholine challenge compared to asthmatics without UC.92 This same cohort of patients also demonstrated increased sputum concentration of vascular endothelial growth factor, leading the authors to propose a more pronounced inflammatory cascade, increased vascular endothelial growth factor activity, and vascular permeability in UC patients with asthma. Further investigation is needed to better elucidate this connection.

Parenchymal Disease
Lung disease involving the pulmonary parenchyma is relatively uncommon among IBD patients. Those cases that have been reported reveal a wide range of pathologies. Analysis of diffuse lung disease in IBD patients is further confounded by documented pulmonary sequelae to various medical therapies used to treat IBD. Findings discussed below were attributed by their authors to IBD and not to medications used in its treatment.304546535661626364656667686970717273747576

UC is the underlying form of IBD in the majority of reported cases of IBD-associated parenchymal lung disease. Age of onset varies, and there is a slight female predominance. Bronchiolitis obliterans organizing pneumonia (BOOP) is the most commonly reported parenchymal manifestation of IBD. As with non-IBD-related BOOP, resolution with systemic steroids is the norm, although disease may remit without treatment in a minority of cases (21%). A single report76 documented resolution of BOOP with infliximab after a failure of steroid therapy. Other forms of diffuse lung disease reported among patients with IBD include pulmonary interstitial emphysema syndrome, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, fibrosing alveolitis, and eosinophilic pneumonitis. Pulmonary nodules have been infrequently reported in patients with IBD. Histologically, these lesions have been reported to be necrobiotic (25%), granulomatous (12.5%), or otherwise.

Sarcoidosis: IBD and sarcoidosis are usually considered to be distinct entities. However, the cumulative volume of case reports documenting coexistence of these two entities suggests a link between them. Storch et al93 documented 46 cases of IBD and concomitant sarcoidosis in a review of the literature in 2003. We have identified seven more reports769495969798 of this association, bringing the total reported cases of coexisting disease to 53.

The pathophysiologic basis of a relationship between IBD and sarcoidosis is unclear. Genetic susceptibility and derangements of cellular immunity play important roles in the development of both. Barr et al99 reported that human leukocyte antigen (HLA)-B8 and HLA-DR3 haplotypes were present in three of eight patients with UC and sarcoidosis, a higher proportion than expected. Papadopoulos et al100 reported a greater incidence of a variety of autoimmune diseases in patients with sarcoidosis, and suggested that HLA-linked genetic susceptibility (HLA-B8/DR3) predisposes sarcoidosis patients to a variety of autoimmune diseases. Finally, IBD and sarcoidosis share comparable dermatologic, ocular, and joint manifestations, further suggesting a pathogenic link.

Nontuberculous Mycobacterium species have been postulated as an infectious cause of, and have been detected in tissues from patients with, both IBD and sarcoid.101 Elevated CD4:CD8 ratios on BAL, a characteristic but not diagnostic finding in sarcoidosis, have also been documented in patients with CD.2021 Serum angiotensin-converting enzyme levels, while often increased in several granulomatous diseases such as sarcoidosis, leprosy, Gaucher disease, histoplasmosis, and extrinsic allergic alveolitis, remain low in CD.102

{alpha}1-Antitrypsin Deficiency: A single case report103 of colitis and coincident emphysema noted in the 1980s has led to the recent hypothesis that, like emphysema, disregulation of protease activity may be involved in the pathogenesis of IBD. Fecal clearance of {alpha}1-antitrypsin has been used as an indicator of severity of disease in IBD. A number of studies104105106 have investigated the prevalence of abnormal {alpha}1-antitrypsin alleles in patients with IBD, with mixed results. In the only study with positive results of its kind, Elzouki and colleagues105 documented a greater prevalence of PiZ carriers among patients with IBD vs that expected in the general population (8.5% vs 4.7%), and an increased extent and severity of colitis in association with PiZ carrier status. Subsequently, a group at the Mayo Clinic have identified an additional 10 patients, 7 with emphysema, who had concomitant {alpha}1-antitrypsen deficiency and IBD.107 Combined with the complex effects of smoking on the prevalence and course of UC and CD, this observation has lead the authors to propose that, as in the lung, imbalances in neutrophil elastase regulation exhibited in {alpha}1-antitrypsin deficiency may enhance potential local tissue damage in the gastroenterological tract from smoking. Further investigation is needed to better elucidate this connection.

Pulmonary Vascular Disease
Vascular disease rarely occurs with IBD.30607374757778798081 Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, and pulmonary vasculitis have been reported. Nearly all cases have coexisting cholangitis or arthritis. Systemic steroids are the mainstay of therapy, although a patient with Churg-Strauss syndrome also received cytoxan.81

VTE: Patients with inflammatory bowel disease are at increased risk of thromboembolic disease. The incidence of thromboembolic events appears to be three to four times higher for patients with IBD compared with age-matched control subjects.2324 The majority of thromboembolic events among IBD patients are VTE, manifested as either deep venous thrombosis or pulmonary embolism, but arterial thromboembolism and venous thrombosis at unusual sites have also been reported.108

The pathogenesis of increased thrombotic risk among patients with IBD is unclear. The prevalence of inherited prothrombotic disorders is no higher among patients with IBD than in the general population. While laboratory markers of activation of the coagulation system have been found in some patients with IBD,109110111112113 the significance of this finding is unclear. IBD patients often have acquired thrombosis risk factors in conjunction with their disease or its treatment, including immobility, surgery, and central venous catheters. However, up to one third of thrombotic events among IBD patients occur while their disease is quiescent, suggesting ongoing thrombotic risk unrelated to disease activity or therapy.110

Serositis
Pleural and pericardial manifestations of IBD are uncommon.3059656667737475828384858687 Most patients are young, male, and have UC. Pleural involvement is nearly always unilateral; when examined, pleural fluid tends to be exudative in nature.29 Direct inspection of pleural surfaces reveals thickening and inflammation.5975 In a single case in which pleural biopsy was reported, nonspecific inflammation without granulomas was found.65 The pericardium is uniquely involved in 45% of cases, and many of these patients also received systemic steroids, although two patients were treated with nonsteroidal antiinflammatory drugs (aspirin or indocin). A single case of cardiac tamponade requiring pericardial drainage has been reported. Coincident pleural and pericardial involvement has been documented in a minority of cases.

Conclusion

Screening studies using respiratory symptoms, HRCT, and PFT support a high prevalence of respiratory abnormalities among patients with IBD. The cumulative volume of published case reports suggests that respiratory manifestations of IBD are more common than generally appreciated and are quite varied. Bronchiectasis is the most common form of respiratory tract abnormality seen among patients with IBD, but the spectrum of involvement spans the entire respiratory system, from larynx to pleura. Most cases of respiratory tract disease occur years after the diagnosis of IBD, but occasionally the respiratory tract disease precedes the diagnosis. IBD patients have an increased risk for VTE. In addition, there may also be links between IBD and sarcoidosis, asthma, and {alpha}1-antitrypsin deficiency. Steroids are the most frequently reported treatment used for pulmonary disease associated with IBD, but controlled trials confirming their efficacy are lacking.

Appendix

Bar-Dayan Y, Ben-Zikrie S, Fraser G, et al. Pulmonary alveolar hemorrhage in a patient with ulcerative colitis and primary sclerosing cholangitis. Isr Med Assoc J 2002; 4:464–465

Baron FA, Hermanne JP, Dowlati A, et al. Bronchiolitis obliterans organizing pneumonia and ulcerative colitis after allogeneic bone marrow transplantation. Bone Marrow Transplant 1998; 21:951–954

Chikano S, Sawada K, Ohnishi K, et al. Interstitial pneumonia accompanying ulcerative colitis. Intern Med 2001; 40:883–886

Codish S, Abu-Shakra M, Depsames R, et al. Wegener’s granulomatosis in a patient with Crohn’s disease. Isr Med Assoc J 2000; 2:630–631

Dawson A, Gibbs AR, Anderson G. An unusual perilobular pattern of pulmonary interstitial fibrosis associated with Crohn’s disease. Histopathology 1993; 23:553–556

Kar PM, Aronoff G, Schuette P. Bronchopulmonary disease: an association with ulcerative colitis and pyoderma gangrenosum. J

Kedziora JA, Wolff M, Chang J. Limited form of Wegener’s granulomatosis in ulcerative colitis. Am J Roentgenol Radium Ther Nucl Med 1975; 125:127–133 Ky Med Assoc 1993; 91:320–323

Kuzela L, Vavrecka A, Prikazska M, et al. Pulmonary complications in patients with inflammatory bowel disease. Hepatogastroenterology 1999; 46:1714–1719

Footnotes

Abbreviations: BOOP = bronchiolitis obliterans organizing pneumonia; CD = Crohn disease; DLCO = diffusing capacity of the lung for carbon monoxide; HLA = human leukocyte antigen; HRCT = high-resolution CT; IBD = inflammatory bowel disease; PFT = pulmonary function testing; UC = ulcerative colitis; VTE = venous thromboembolism

None of the authors of this article have any conflicts of interest to disclose.

Received for publication April 21, 2006. Accepted for publication August 8, 2006.

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CARDIAC DISORDERS IN INFLAMMATORY BOWEL DISEASE PATIENTS
Ugo Cioffi, et al.
Chest Online, 21 Feb 2007 [Full text]
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