Inflammatory Bowel Disease

Published on 23/05/2015 by admin

Last modified 22/04/2025

Print this page

This article have been viewed 1305 times

Chapter 79 Inflammatory Bowel Disease

Thoracic involvement by Crohn disease (CD) and ulcerative colitis (UC) is part of the spectrum of extraintestinal manifestations of inflammatory bowel disease (IBD). The distinctive pathologic changes associated with IBD can involve the upper respiratory tract, the large and small airways, the interstitium of the lung, the pleura, and the heart and pericardium. It is often difficult to prove with certainty that a particular lung disease is causally related to an IBD. The presentation is not always temporally related to the bowel disease, and the pathologic findings can overlap with those seen in other inflammatory lung diseases. However, the correlation of pulmonary function with IBD severity and the striking response to corticosteroid therapy by many of the lesions suggests a common mechanism.

Anatomically, the gastrointestinal and respiratory systems have some common features. The cephalad end of the respiratory tract (larynx and trachea) is intimately associated with the foregut until their separation by the mesodermal tracheoesophageal folds. Both epithelia are of endodermal origin, and both mucosal surfaces contain mucosa-associated lymphoid tissue (MALT), columnar epithelium with surface differentiations (villi and cilia), goblet cells, and submucosal glands. The pathogenesis of extraintestinal manifestations is poorly understood. The emerging theme of the proposed mechanisms for bowel damage in IBD is an intricate interplay among innate and acquired immunologic factors, intraluminal microbial flora, and the mucosal barrier separating both. Several studies found a limited repertoire of T cell specificity in IBD patients, suggesting that a cellular immune response is elicited by only a small number of antigens. Autoantibodies, including atypical antinuclear antibodies (ANAs), found in some patients suggest an aberrant B cell functionality. The diapedesis (migration) of inflammatory cells into areas of inflammation suggests abnormalities in the homing of leukocytes. Lastly, increased levels of cytokines (e.g., interferon, tumor necrosis factor) suggest a dysregulation of inflammatory mediators in patients with IBD. Evidence has been found supporting all these mechanisms in sites other than the respiratory tract.

In addition, genetic linkage studies of affected kindred have identified several genes associated with IBD. The first susceptibility gene discovered (IBD1, also known as NOD2) encodes a protein that activates transcription in macrophages on encountering bacterial lipopolysaccharides. Another, more recent, example is the discovery of nonfunctional variants of the interleukin-23 (IL-23) receptor or some of its downstream effectors. IL-23 helps generate Th17 helper cells that play a central role in immune response regulation. Genetic factors are associated not only with the development of IBD but also with its extraintestinal manifestations. A study of more than 250 parent-child and sibling pairs showed concordance of extraintestinal involvement in 70% and over 80% of the pairs, respectively. Other studies more specifically sought associations with certain genes. IBD1 and IL-23 are associated with sacroiliitis and ankylosing spondylitis, respectively. CD patients carrying major histocompatibility complex (MHC) genes HLA-A2, HLA-DR1, HLA-DQw5, HLA-DRB1*0103 (DR103), or HLA-B*27 are more likely to develop extraintestinal manifestations. UC patients with HLA-B*58 have been found to have more joint, skin, and eye manifestations. HLA-B8 is more common in UC patients with primary sclerosing cholangitis than those without. No specific genetic link has been established between IBD and respiratory tract involvement. However, some genetic alterations may also be involved in other lung diseases; abnormalities of NOD2, for example, have been found in early-onset and advanced pulmonary sarcoidosis.

Thoracic conditions seen in IBD can conceptually be grouped into four categories: (1) nonspecific conditions (e.g., infection), (2) anatomic complications (e.g., fistulas); (3) therapy-related complications (e.g., drug toxicity); and (4) distinctive pathologic changes that statistically show a more-than-incidental association with IBD. This chapter focuses on the fourth category.

Epidemiology

The true incidence of thoracic complications in IBD patients is unknown. There have been no screening tests performed on large populations of IBD patients. The proportion of IBD patients with subjective respiratory symptoms such as cough, sputum production, wheezing, or shortness of breath has been reported to be as high as 50%. One or more pulmonary function tests (PFTs) are abnormal in approximately 40% of IBD patients, with forced expiratory volume in 1 second (FEV₁), inspiratory vital capacity (IVC), or diffusion capacity (DLCO) showing a 10% to 30% reduction. Between 25% and 50% of asymptomatic IBD patients show abnormalities on high-resolution computed tomography (HRCT) scans. Often, the findings are subtle and include ground-glass opacities, mosaicism suggestive of air trapping, peripheral opacities, and cysts. At the other end of the spectrum are case reports and small series of patients with distinctive manifestations of thoracic involvement. These reports, accounting for 155 patients, were recently reviewed (see Suggested Readings). Although nothing is offered to calculate incidence or prevalence, significant symptomatic thoracic involvement by IBD probably is not a common event. However, it is common enough that physicians need to be cognizant of IBD to recognize it and prevent the potentially debilitating consequences of some of its forms.

The temporal relation of the thoracic manifestation to the bowel disease varies. Approximately 80% of patients have an established history of IBD, whereas in about 10% each, the thoracic symptoms precede the bowel disease or develop concomitantly. About one half of patients with airway disease have had a colectomy, and occasionally the onset of airway disease follows the colectomy by days or weeks, suggesting a shift of the inflammatory reaction from the gut to the bronchial tree.

In ulcerative colitis and Crohn disease, the most common anatomic structures involved are the large airways (39%), followed by infiltrative lung disease (23%) and involvement of the serosa (13%). Small airways inflammation (10%), upper airways inflammation (9%), and involvement of the pulmonary vasculature (6%) are slightly less common. In general, respiratory tract involvement is more common in UC than CD patients. In both diseases, however, all compartments of the respiratory tract can be affected, although with slight differences in incidence.

Severity of thoracic involvement in many cases parallels disease activity in the bowel. Patients with active IBD have a greater chance of exhibiting airway obstruction. Inflammation of the bowel also correlates inversely with diffusion capacity. Serosal disease is more common among those with active IBD, while parenchymal disease is often seen in patients with quiescent bowel disease.

Women appear to be more frequently affected (~2 : 1). When considering only airway disease, this ratio increases up to 4 : 1. However, pleural involvement is about equally distributed between women and men.

Two thirds of patients with thoracic complications also have other extraintestinal manifestations at the same time, such as involvement of the skin, eyes, joints, or the biliary tract. Smoking does not appear to be a risk factor for developing airway inflammation in IBD, because most patients with this manifestation are nonsmokers.

Interestingly, two recent analyses found that CD patients appear to have a slightly increased risk of lung cancer, whereas the risk appears to be decreased in UC patients (standardized incidence ratios of 1.82 vs. 0.39 and 0.72, respectively).

Clinical and Pathologic Features

The diagnostic workup should include chest radiograph and CT scan. PFTs should be obtained, if possible, because they can provide a baseline in the course of treatment. Endoscopy complements imaging studies in the detection of upper airway obstruction or stenosis and in obtaining material for microbiology and histologic studies. A complete blood count with differential as well as a metabolic panel should be performed. Erythrocyte sedimentation rate and C-reactive protein may be helpful in following disease activity during treatment. Between 50% and 70% of patients with ulcerative colitis and 10% to 30% of patients with Crohn disease (predominantly those with colonic involvement) show atypical antineutrophil cytoplasmic antibodies (ANCAs), characterized by a fine granular and perinuclear (“snowdrift”) pattern. Serologic testing for ANCAs may be helpful in patients with suspected underlying IBD. ANAs can help identify drug-induced lupus syndrome in patients with serositis. Since thromboembolic disease is a known cause of morbidity and mortality in IBD patients, the physician should maintain a low threshold to consider and exclude pulmonary embolism in this population.

This section discusses the different compartments of the respiratory tract involved by IBD, including unique considerations of the particular location, clinical presentation, and its pathologic features (Table 79-1).

Table 79-1 Thoracic Involvement in Inflammatory Bowel Disease (IBD)

Airway Disease

Inflammatory bowel disease can affect the entire tracheobronchial tree, including larynx, trachea, and large and small airways, in the form of airway inflammation. Most common is inflammation of the large airways, seen in about 40% of IBD patients. Approximately 10% of patients show involvement of the upper respiratory tract or small airways. Extent and location of involvement are unpredictable; some patients have involvement restricted to a small area, some have patchy disease involving different anatomic levels of the conducting airways, and others show involvement of the entire tracheobronchial tree. The vast majority of patients with airway disease have UC, and only 10% CD. About two thirds of patients are female, with a median age at presentation of 42 years. In about 5% of patients the airway disease predates the diagnosis of IBD, and these patients tend to be much younger (median age, 13 years).

Clinically, laryngeal inflammation affecting the glottis and epiglottis produces narrowing and stenosis. Corresponding symptoms include dry, deep-toned cough with stridor. Severe cases may result in asphyxia, which is why laryngeal inflammation in IBD is one of the three conditions that require emergency treatment. Large airways inflammation in the form of tracheobronchitis manifests with chronic, otherwise unexplained cough that can be dry or productive of copious amounts of mucopurulent sputum. It is this purulent material that led to the historical designation for this condition, “chronic bronchial suppuration.” It is also the condition that established the link between IBD and lung disease in 1976. Long-standing chronic inflammation and suppuration lead to bronchiectasis, often with basilar distribution. Small airways disease manifests as airflow obstruction with or without sputum production. Although unlikely to be the dominant feature, microscopic involvement is often found distally from affected large airways.

Radiographically, airway walls appear thickened with a “tram line” pattern. Larger airways show mucus plugging, smaller airways a tree-in-bud appearance. These changes tend to occur in a basilar-predominant distribution, occasionally with associated volume loss. Small airways disease can be associated with a tree-in-bud pattern, diffuse reticular shadows, or mosaic pattern due to air trapping (Figure 79-1). Bronchiectasis after long-standing disease can range from prominent thick-walled bronchi to subtle increases in airway caliber (Figure 79-2).

Figure 79-1 Involvement of large and small airways in ulcerative colitis. A, Plain chest radiograph of chronic bronchiolitis shows overall increase in nonspecific lung markings (“dirty lung”) and occasional “tram tracks” related to bronchial wall thickening (arrows). B, Chest CT scan of cellular bronchiolitis with tree-in-bud pattern.

(Courtesy Dr. Carl Fuhrman, University of Pittsburgh Medical Center.)

Figure 79-2 Bronchiectasis in patient with inflammatory bowel disease as a result of long-standing chronic bronchitis. The chest CT scan shows increased airway caliber (arrows) compared with adjacent pulmonary arteries.

(Courtesy Dr. Carl Fuhrman, University of Pittsburgh Medical Center.)

Bronchoscopically, the large airways show variable, but often severe, inflammation. Scarred bronchial granulomas are sometimes seen in patients with CD.

Histologically, large airways inflammation in IBD is characterized by a mucosal mononuclear inflammatory infiltrate, which is often bandlike and resembles that seen in the bowel mucosa in IBD (Figure 79-3, A). A luminal exudate containing neutrophils is common (Figure 79-3, B). Granulomas are frequently but not always seen in lung biopsies from patients with CD. On the other hand, the presence of a granuloma in a biopsy does not exclude UC as the underlying bowel disease. Small airways inflammation is similarly suppurative, with chronic inflammation of the bronchiolar wall. Occasionally, interstitial foamy macrophages are present in a centrilobular distribution, morphologically resembling diffuse panbronchiolitis. Late-stage small airways involvement may histologically present as constrictive bronchiolitis, which can be patchy throughout the lung and therefore may be missed by the biopsy sampling. An expiratory chest CT scan showing air trapping may support a clinical impression of obliterative small airways disease in these patients.

Figure 79-3 A, Large airway inflammation in ulcerative colitis. This endobronchial biopsy shows a bandlike mononuclear cell infiltrate underlying metaplastic mucosal epithelium. B, Bronchiolitis in ulcerative colitis. A small airway is surrounded by circumferential inflammation and contains a luminal exudate of neutrophils.

Air Space Disease

Inflammatory bowel disease can involve the distal air spaces of the lung in the form of organizing pneumonia (OP) or eosinophilic pneumonia (EP). The main difficulty with these patterns of involvement is distinguishing them from infection and drug-related lung disease. Clinically, patients present with shortness of breath ranging from moderate dyspnea to acute respiratory failure, sometimes accompanied by fever. Radiographically, OP shows bilateral, ovoid, elongated subpleural opacities, which may contain air bronchograms (Figure 79-4, A and B). EP, similar to non-IBD cases, may assume a masslike appearance or manifest as migratory opacities. Bronchoalveolar lavage (BAL) findings are often nonspecific, but an increase in neutrophils or eosinophils suggests a diagnosis of infection or EP, respectively.

Figure 79-4 Air space disease in inflammatory bowel disease. A, Chest radiograph shows dense focal infiltrates. B, Chest CT image of different patient shows dense infiltrates with air bronchograms, corresponding histologically to organizing pneumonia (C).

(Courtesy Dr. Carl Fuhrman, University of Pittsburgh Medical Center.)

Histologically, OP is characterized by loose, fibroblastic plugs in air spaces (Figure 79-4, C), whereas EP shows numerous eosinophils within the interstitium and among fibrinous air space exudates. Both patterns are nonspecific and can also be seen in infections, drug reactions, connective tissue disease, airway obstruction, or cryptogenic (idiopathic) forms of OP and EP. Biopsies may still be helpful to rule out infection or other causes of air space disease.

Interstitial Lung Disease

Diffuse interstitial lung diseases described in IBD patients include nonspecific interstitial pneumonia (NSIP) and granulomatous interstitial pneumonia, the latter almost exclusively seen in CD. Rare cases with usual interstitial pneumonia (UIP) or desquamative interstitial pneumonia (DIP) patterns have been reported. In some patients, IBD-related interstitial lung disease has been found to coexist with sarcoidosis. The reason for this association is unknown, but the presence of granulomas and similar T cell subpopulations in both diseases may indicate a pathogenetic connection.

Patients with interstitial lung disease present with shortness of breath and crackles on auscultation. Radiographically, interstitial markings are increased, and often more prominent in the lower lung zones (Figure 79-5, A). Bronchoscopic examination is normal unless concomitant airway disease is present. Wedge biopsies are necessary for histologic confirmation of diffuse fibrosing lung disease, because transbronchial biopsies are usually too small for assessing the fibrosis pattern. Biopsies show interstitial collagen fibrosis with variable mononuclear inflammatory infiltrates with or without granulomas (Figure 79-5, B and C). The presence of granulomas should always prompt exclusion of infection with special histochemical stains or preferably by concomitantly submitted tissue culture.

Figure 79-5 Interstitial lung disease in patient with inflammatory bowel disease. A, Chest CT image shows prominent interstitial markings with superimposed ground-glass changes. B, Corresponding wedge biopsy shows parenchymal remodeling by fibrosis with interstitial inflammation in a usual interstitial pneumonia pattern. Fibroblastic foci are seen at bottom right. C, Biopsy of different patient with homogeneous interstitial thickening resembling nonspecific interstitial pneumonia. The air spaces are filled with numerous pigmented macrophages.

Masses and Nodules

Necrobiotic nodules are an uncommon manifestation in ulcerative colitis and Crohn disease. Nodules may occur synchronously with pyoderma gangrenosum lesions in the skin, with common histologic features. One study found that necrobiotic nodules precede the diagnosis of IBD in one third of patients. Patients present with a rapid onset of fever, dyspnea, and chest pain. Imaging studies show multiple rounded lung nodules that may cavitate over time (Figure 79-6, A). Without intervention, nodules may eventually disappear, leaving a scar. The histologic picture is distinctive, showing aggregates of neutrophils and necrosis without granulomatous features or identifiable infectious organisms (Figure 79-6, B). Although drug-induced lung injury can present with lung nodules, these nodules tend not to show cavitation radiographically or sterile abscesses histologically.

Figure 79-6 Necrobiotic lung nodules in inflammatory bowel disease. A, Chest CT scan shows multiple rounded lung nodules, which later may develop cavities. B, Corresponding histology reveals a core of blue necrosis with neutrophils (left) surrounded by fibrosis and organizing pneumonia.

Serosal Disease

Serosal membranes may be involved in the form of pleural or pericardial inflammation and thickening or effusions. Patients complain of pleuritic or anterior, sometimes position-dependent, chest pain and sometimes fever. Radiographs or echocardiography may be able to demonstrate an effusion, which if sampled is characteristically exudative and rich in neutrophils. Complications to consider are the possibility of tamponade and associated myocarditis. Electrocardiographic (ECG) changes such as arrhythmias or conduction blocks may indicate myocarditis. Serositis or effusions associated with drug-induced lupus can be identified by the presence of ANAs.

Mediastinal Disease

Pneumomediastinum of uncertain pathogenesis has been described in a few UC patients. Because it seems to correlate with disease flares, it could be a result of acute airway obstruction, analogous to the pneumomediastinum seen in asthma attacks. Another possibility is the development of small fistula tracts between colon and mediastinum.

Rare Manifestations

Some conditions have only been described in reports of a single or few cases, and the strength of association with IBD is uncertain. These include eosinophilic pneumonia (to be distinguished from drug effect), Langerhans cell histiocytosis (to be distinguished from reactivation by therapy), and Wegener granulomatosis (to be distinguished from primary Wegener granulomatosis which can present with colitis).

Drug-Induced Lung Disease

A major difficulty when encountering patients with apparent lung involvement by IBD is excluding drug-related toxicity. A causal role of drugs in airway inflammation is unlikely for two reasons. First, airway inflammation is common among IBD patients after colectomy and no longer receiving culprit drugs such as sulfasalazine or mesalamine. Second, airway inflammation does not improve on withdrawal of these drugs in patients with no history of colectomy. Infiltrative (air space or interstitial) lung disease, on the other hand, is a pattern associated with several drugs used in IBD patients. Unfortunately, withdrawal of the drug does not always result in stabilization or reversal of the lung disease. Decisions regarding discontinuation of drug therapy must consider the relative severity of the lung disease and the IBD, because drug discontinuation may result in a flare of IBD. Table 79-2 summarizes toxicity patterns associated with common IBD drugs. An excellent resource for drug-associated pulmonary disease can be found online at Pneumotox.com.

Table 79-2 Biopsy-Proven Lung Changes Related to Drugs Used in Inflammatory Bowel Disease (Other than Infection)

Drugs	Lung Conditions
Mesalazine Sulfasalazine Balsalazide Olsalazine (5-aminosalicylic acid derivatives)	DAD, EP, OP, HP, chronic interstitial pneumonia
Azathioprine	DAD
6-Mercaptopurine	ND
Methotrexate	DAD, OP, HP, chronic interstitial pneumonia, pulmonary edema, granulomatous inflammation
Infliximab Adalimumab	DAD, EP, OP, chronic interstitial pneumonia
Certolizumab Natalizumab	ND
Cyclosporine	Pulmonary edema
Mycophenolate	Chronic interstitial pneumonia

DAD, diffuse alveolar damage (adult respiratory distress syndrome); EP, eosinophilic pneumonia; HP, hypersensitivity pneumonitis; ND, none documented; OP, organizing pneumonia.