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Pulmonary complications of inflammatory bowel disease

Pulmonary complications of inflammatory bowel disease
Authors:
Steven E Weinberger, MD
Mark A Peppercorn, MD
Section Editors:
Kevin R Flaherty, MD, MS
Sunanda V Kane, MD, MSPH
Deputy Editor:
Paul Dieffenbach, MD
Literature review current through: Dec 2022. | This topic last updated: Dec 03, 2021.

INTRODUCTION — Inflammatory bowel disease (IBD) is associated with a variety of conditions outside of the gastrointestinal tract, termed extraintestinal manifestations of IBD (table 1). Since the original report in 1976 of six patients with unexplained chronic purulent sputum production, involvement of the respiratory tract, although relatively rare, has been increasingly recognized in patients with IBD [1].

The pulmonary complications of IBD including those related to the medications used to treat IBD are discussed here. An approach to the evaluation and diagnosis of interstitial pneumonia and discussions of the clinical manifestations of Crohn disease and ulcerative colitis are provided separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults" and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults".)

EPIDEMIOLOGY — Case series vary in terms of the proportions of patients with ulcerative colitis and Crohn disease who have associated lung disease [2-4]. In a series of 52 patients with IBD, abnormal pulmonary function tests were more common in patients with Crohn disease than ulcerative colitis (25 versus 6 percent), but abnormal computed tomography was seen in approximately 50 percent of patients with ulcerative colitis or Crohn disease [3]. In a separate series of 33 patients with IBD-associated lung involvement, 27 had ulcerative colitis and six had Crohn disease [2].

PATHOGENESIS — The pathogenesis of pulmonary parenchymal and pleural disease associated with IBD is unknown. However, the more common airway inflammatory changes are thought to represent the same type of inflammatory changes that occur in the bowel [5]. (See "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease".)

PRIMARY RESPIRATORY INVOLVEMENT — Pulmonary complications of IBD include inflammation of small and large airways, pulmonary parenchymal disease, serositis, and pulmonary embolism [6-9]. These abnormalities are generally related to the underlying bowel disease, although interstitial lung disease can also be induced by administration of certain drugs, such as sulfasalazine, 5-aminosalicylic acid, methotrexate, azathioprine, anti-TNF agents, and ustekinumab [10-14]. Patients with IBD may present with cough, dyspnea, chest pain, or an abnormal chest radiograph obtained for another reason. Often the initial history (including current medications) and physical examination will focus attention on a given type of lung involvement (eg, airway versus parenchymal).

The three main patterns of presentation (airway disease, parenchymal disease, and pleural disease with serositis) have somewhat different characteristics in terms of sex preponderance and activity of the bowel disease [2]:

A female preponderance of almost 2:1 is reported for bronchopulmonary complications as a whole and approximately 3:1 for bronchial complications. In contrast, serositis occurs with roughly equal frequency in men and women.

Bronchopulmonary complications follow the onset of inflammatory bowel disease in 80 to 85 percent of patients, precede bowel disease in 10 to 15 percent, and develop concomitantly in 5 to 10 percent. Almost one-half the patients with airway disease have undergone colectomy; in some cases, development of airway symptoms follows colectomy by days to weeks.

The majority of patients with serositis have active inflammatory bowel disease, while parenchymal lung disease often develops in the setting of inactive bowel disease.

Airway involvement — Inflammatory bowel disease is associated with inflammation of the trachea, bronchi, and bronchioles [2,5,15-17]. In a review of 131 cases of respiratory involvement in IBD, approximately 41 percent presented with some form of airway inflammation (table 2) [2]. The types of airway involvement in IBD include bronchiectasis, which is the most common, acute and chronic tracheobronchitis, bronchiolitis, subglottic stenosis, and fistula formation [2,14].

Bronchitis or bronchiectasis – Patients with IBD-associated bronchitis or bronchiectasis typically present with cough and variable amounts of mucopurulent sputum production [18]. Cultures of bronchial secretions are unrevealing, and the symptoms unresponsive to antibiotics. Chest radiographs are frequently normal or show nonspecific changes resulting from bronchial wall thickening or bronchiectasis. High resolution chest computed tomography (HRCT) scanning is more sensitive than conventional chest radiographs, often demonstrating findings of bronchial wall thickening, dilated airways with thickened walls, or branched opacities suggestive of mucoid impaction [19,20].

On pulmonary function testing, an obstructive impairment with a reduced or normal forced vital capacity (FVC), a low forced expiratory volume (FEV1), and a low FEV1/FVC is the most frequent finding. In contrast to asthma, however, airflow obstruction does not show significant reversibility following inhaled bronchodilator, and bronchoprovocation challenge (eg, histamine, methacholine) does not reveal airway hyperresponsiveness. (See "Clinical manifestations and diagnosis of bronchiectasis in adults", section on 'Diagnostic evaluation'.)

Bronchiolitis – Small airway involvement (bronchiolitis) can cause cough, variable sputum production, wheezing, and airflow obstruction. Pathologic findings include nonspecific inflammation, narrowing, and fibrosis of the small airways; granulomatous bronchiolitis has also been reported [12,21]. Small airway involvement with IBD is associated with abnormalities in pulmonary function (eg, airflow obstruction and reduced diffusing capacity). The clinical manifestations of bronchiolitis are discussed separately. (See "Overview of bronchiolar disorders in adults".)

Subglottic stenosis – Subglottic stenosis is associated with inflammation, friability, and inflammatory pseudotumors in the trachea [22-24]. The primary symptoms are cough and dysphonia, although some patients develop upper airway obstruction with resulting stridor and severe dyspnea [25]. A flow-volume loop may show variable extrathoracic obstruction. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults" and "Flow-volume loops", section on 'Variable extrathoracic obstruction'.)

Enteric-pulmonary fistulas – Enteric-pulmonary fistulas, such as colo-bronchial, ileo-bronchial, and esophago-bronchial, have been described in patients with Crohn disease [12,26]. In a series of over 400 patients with IBD, five patients with colobronchial fistulae were reported [12]. Four had left lower lobe pneumonia; clinical findings included fever, radiographic opacities, pleural effusion, and growth of enteric pathogens on culture. Esophageal Crohn disease is rare, but four cases of esophago-bronchial fistulae have been reported. These patients complained of dysphagia and had clinical evidence of pneumonia [12].

Asymptomatic abnormalities in pulmonary function tests — Several studies have identified abnormalities in pulmonary function tests among patients with IBD [3,13,27,28]. In a series of 82 patients with IBD and normal plain chest radiographs, 47 (57 percent) had abnormal findings on pulmonary function tests [13]. Most of these patients had findings consistent with restrictive lung disease and a reduced diffusing capacity. A separate series of 85 patients with ulcerative colitis and 47 patients with Crohn disease found that diffusing capacity was significantly lower during exacerbations of bowel disease than when gastrointestinal disease was quiescent [27]. No pulmonary symptoms were associated with these transient physiologic derangements. These results have been confirmed in other reports, suggesting that mild pulmonary inflammation commonly accompanies inflammation of the bowel [28]. (See "Overview of pulmonary function testing in adults" and "Diffusing capacity for carbon monoxide".)

Pulmonary parenchymal disease — Among patients with respiratory involvement with IBD, approximately 27 percent have parenchymal lung disease (table 2) [2]. Several patterns of parenchymal lung involvement have been described in IBD, with organizing pneumonia and interstitial lung disease (not otherwise specified) being most common [2,10,14,29]. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults" and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults".)

Lung infections should be considered in the differential diagnosis of pulmonary parenchymal disease in patients with IBD, particularly when patients present with fever, dyspnea, cough, and radiographic opacities. Information about community-acquired pneumonia and pneumonia in immunocompromised hosts is presented separately. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults" and "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults" and "Epidemiology of pulmonary infections in immunocompromised patients".)

Organizing pneumonia — Organizing pneumonia (OP) presents in an acute or subacute fashion with variable combinations of fever, dyspnea, cough, and pleuritic chest pain [2,30-32]. OP can also be a manifestation of drug-induced lung toxicity. (See 'Drug-induced complications' below and "Cryptogenic organizing pneumonia", section on 'Clinical features'.)

Chest radiographic findings range from patchy focal consolidation to diffuse opacities; HRCT scanning often demonstrates peripheral ground-glass opacities or areas of consolidation that may have an air bronchogram. (See "Cryptogenic organizing pneumonia", section on 'Chest imaging'.)

Interstitial lung disease — Interstitial lung disease (ILD) in IBD is thought to reflect a spectrum of diseases, such as organizing pneumonia, nonspecific interstitial pneumonia, desquamative interstitial pneumonia (typically in smokers), eosinophilic pneumonia, and usual interstitial pneumonia [14]. When mild or not progressive, it is often not evaluated histopathologically, so the exact type of ILD is not always identified. Drug-induced pulmonary toxicity is an important cause of ILD among patients with IBD. (See 'Drug-induced complications' below.)

The clinical presentation of ILD is generally characterized by a subacute onset of dyspnea, crackles on chest examination, and radiographic findings of diffuse ground glass or reticular opacities, most prominent at the lung bases. Patients may have a stable course or manifest progressive respiratory insufficiency. (See "Idiopathic interstitial pneumonias: Classification and pathology" and "Approach to the adult with interstitial lung disease: Clinical evaluation".)

The bronchoalveolar lavage (BAL) fluid in IBD-associated ILD is usually lymphocytic. An elevated CD4:CD8 ratio in the BAL, a finding often described in sarcoidosis, has also been documented in patients with Crohn disease [14,33,34].

Sarcoidosis — Several cases of sarcoidosis coexisting with ulcerative colitis or Crohn disease have been reported [12,33,35]. No clear etiologic association has been identified between inflammatory bowel disease and sarcoidosis. However, it has been suggested that there may be a pathogenetic relationship between sarcoidosis and Crohn disease, since bronchoalveolar lavage fluid lymphocytosis (with elevated CD4/CD8 ratios) and noncaseating granulomas in lung tissue can be seen in both disorders [33,34]. In addition, four reports of the coexistence of Crohn disease and sarcoidosis in siblings suggest a potential genetic overlap [12]. The clinical and radiographic manifestations of sarcoidosis are discussed separately. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis".)

Pulmonary infiltrates with eosinophilia — The pulmonary infiltrates with eosinophilia (PIE) syndrome is a recognized complication of sulfasalazine, which is commonly used in the therapy of ulcerative colitis. There are also case reports of eosinophilic pneumonia in patients taking mesalamine and methotrexate for IBD [11,36-38]. However, the PIE syndrome can occur in patients with inflammatory bowel disease who have no history of using these medications [7]. Eosinophilia is frequently present in the peripheral blood, and chest radiographs often show patchy peripheral opacities typical of chronic eosinophilic pneumonia. BAL eosinophilia is frequently present. (See "Overview of pulmonary eosinophilia" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Eosinophilic BAL'.)

Necrobiotic nodules — Rarely, necrobiotic lung nodules are described in patients with IBD [39-43]. The nodules have a radiographic resemblance to the cavitating nodules seen with septic pulmonary emboli or granulomatosis with polyangiitis (image 1). Histologically, the nodules are composed of sterile aggregates of neutrophils with necrosis, findings that are similar to those of pyoderma gangrenosum, a cutaneous complication of inflammatory bowel disease (picture 1) [40]. In isolated case reports, the clinical presentation has included fever, cough, weight loss, and a flare of intestinal Crohn disease; in one patient concomitant cutaneous pyoderma gangrenosum was noted [40,41].

A separate case report described development of pulmonary necrobiotic nodules, associated with dyspnea, fever, pleuritic chest pain, and pleural effusion, four months after initiation of vedolizumab, a monoclonal antibody to alpha-4beta-7 integrin [42]. Discontinuation of vedolizumab and initiation of prednisone led to resolution of the pleuropulmonary findings. (See "Dermatologic and ocular manifestations of inflammatory bowel disease".)

Pleural disease — As a rare complication of inflammatory bowel disease, serositis involving intrathoracic structures has occurred in the form of pleural effusions, pericarditis, pleuropericarditis, and myopericarditis (table 2) [2,12,44]. Patients typically present with chest pain. The serosal fluid is exudative, with a cellular content generally composed primarily of neutrophils.

Drugs are another potential cause of serositis [45]. Sulfasalazine and methotrexate, commonly used medications for IBD, have been associated with pleural effusions, although not particularly in patients with IBD. A lupus-like syndrome sometimes with serositis has been reported in 10 patients receiving infliximab for Crohn disease [46]. All of the patients had a positive antinuclear antibody, some had a positive anti-double stranded DNA antibody, and three had a positive antihistone antibody, although it was not clear whether antihistone antibody testing was done in other patients. Symptoms and autoantibodies improved with discontinuation of the medication. (See 'Drug-induced complications' below.)

A very rare but reported complication of Crohn disease is a colopleural fistula, which can lead to development of a fecopneumothorax [47].

Pulmonary embolism — Patients with IBD are at increased risk for venous thromboembolism (VTE) [14,48-59]. In a meta-analysis of 11 case-control and cohort studies, which included hospitalized and nonhospitalized patients, the relative risk for VTE among patients with IBD was estimated to be 2.20 (95% CI 1.83-2.65) [60]. The risk of VTE appears to be further increased during IBD flares, as suggested by a cohort study in which the hazard ratio for VTE during disease flares was 8.4 (95% CI 5.5-12.8) [56]. It is thought that patients with IBD have several risk factors for hypercoagulability, although no particular laboratory test has sufficient predictive value to identify patients at increased risk (table 3). (See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults", section on 'Extraintestinal manifestations' and "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults", section on 'Extraintestinal manifestations' and "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)

DRUG-INDUCED COMPLICATIONS — A broad spectrum of pulmonary disease has been described associated with drugs used to treat IBD. The drugs implicated include sulfasalazine, 5-aminosalicylic acid (5-ASA), methotrexate, azathioprine, 6-mercaptopurine, anti-tumor necrosis factor (TNF) agents, ustekinumab, and tofacitinib [11,36,61].

The Groupes d'Etudes de la Pathologie Pulmonaire Iatrogène maintains a frequently updated website listing drugs that have been associated with pneumonitis and a list of references (www.pneumotox.com) [62].

Sulfasalazine — Pneumonitis, commonly in conjunction with fever and rash, is a recognized complication of sulfasalazine therapy. Nearly half of affected patients present with the clinical syndrome of pulmonary infiltrates with eosinophilia [11]. Cough and crackles on lung examination were commonly reported. Eosinophil counts in the peripheral blood ranged from 432 to 7500/mm3. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease".)

Other pulmonary disorders associated with sulfasalazine include nonspecific interstitial pneumonia, organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia), granulomatous lung disease, and rarely pleural effusion [2,63]. A pulmonary picture consistent with granulomatosis with polyangiitis has also been attributed to sulfasalazine [64].

5-aminosalicylic acid — Pulmonary toxicity attributable to 5-aminosalicylic acid (5-ASA or mesalamine) is less common than with sulfasalazine. Affected patients may have diffuse or patchy basilar opacities on high resolution computed tomography (HRCT) [61,65]. Histopathologic patterns of inflammation include pulmonary eosinophilia [36], organizing pneumonia, and bronchiolitis obliterans [38,61]. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease".)

Methotrexate — Lung toxicity from methotrexate may have an acute, subacute, or chronic presentation; typical symptoms include nonproductive cough, dyspnea, fever, and malaise [38,66]. Chest HRCT patterns associated with methotrexate toxicity include patchy ground glass or consolidative opacities, diffuse ground glass with or without reticulation, micronodules, and bilateral basilar reticular opacities. In one patient, lymphocytic bronchoalveolar lavage fluid was noted [67]. Histopathologic findings include organizing pneumonia, diffuse alveolar damage, pulmonary fibrosis, granulomatous inflammation, eosinophilic pneumonitis, and nonspecific interstitial pneumonia. Methotrexate-induced pulmonary injury is discussed separately. (See "Methotrexate-induced lung injury".)

Methotrexate has also been associated with drug-induced pleural effusion. (See 'Pleural disease' above.)

Azathioprine and 6-mercaptopurine — Immunomodulatory drugs, such as azathioprine (AZA) and 6-mercaptopurine (6-MP), can potentiate the therapeutic effect of glucocorticoids and exert a glucocorticoid-sparing effect in patients with glucocorticoid-dependent ulcerative colitis. Drug-induced hypersensitivity pneumonitis is a rare but potentially serious complication of therapy with these agents, although it is more commonly reported in patients taking AZA for renal transplant immunosuppression than for IBD [26,68,69]. Clinical manifestations include dyspnea, cough, and fever [68]. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease", section on 'Adverse effects'.)

Other pathologic patterns, such as usual interstitial pneumonia and organizing pneumonia (formerly known as bronchiolitis obliterans with organizing pneumonia), have rarely been reported in patients with inflammatory bowel disease treated with AZA or 6-MP [68].

Anti-TNF agents — Infliximab and adalimumab, used to treat patients with Crohn disease and ulcerative colitis, and certolizumab, used in patients with Crohn disease, have been reported to cause interstitial pneumonitis in patients with rheumatoid arthritis and IBD, in addition to causing infectious complications, most notably tuberculosis [70-76]. In some patients the pattern was consistent with drug-induced lupus and in others with usual interstitial pneumonia, nonspecific interstitial pneumonia, or organizing pneumonia [72,73]. The risk of infliximab-associated pneumonitis appears greater among patients of older age or with a history of preexisting lung disease, although these risk factors are not always present [77]. (See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Idiopathic interstitial pneumonias: Classification and pathology" and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Pulmonary disease' and "Drug-induced lupus", section on 'Drug-induced lupus'.)

Infliximab has also been associated with development of serositis. (See 'Pleural disease' above.)

Ustekinumab — Ustekinumab is an interleukin (IL)-12/23 antagonist used to treat Crohn disease and ulcerative colitis. Noninfectious pneumonitis has been reported with the use of this agent [78].

Tofacitinib — Tofacitinib, a Janus kinase inhibitor, is used to treat active ulcerative colitis. Reports have suggested an increased risk of thromboembolic events including pulmonary emboli in patients taking a dose of 10 mg twice daily [79].

DIAGNOSIS — The evaluation and diagnosis of pulmonary complications of inflammatory bowel disease usually starts with an assessment of the severity of dyspnea, rapidity of onset of symptoms, and presence of medications that are known to cause lung toxicity or immunosuppression. For patients with a rapid onset of dyspnea, fever, or respiratory distress, pulmonary embolism, pneumonia, and drug toxicity should be evaluated promptly. (See appropriate topic reviews.)

For patients with a more indolent onset of disease, the workup usually starts with a complete blood count and differential, antinuclear antibodies and antihistone antibodies if drug-induced lung disease is suspected, pulmonary function testing (PFT), and a conventional chest radiograph. Further studies depend on the results of the initial studies and the suspected site of involvement. The following are some examples:

Airway involvement — The diagnosis of airway involvement with inflammatory bowel disease is suspected based on the clinical presentation of cough and sputum production in a patient without evidence of an infectious tracheobronchitis or asthma. In patients with chronic bronchitis, bronchiectasis, or bronchiolitis, pulmonary function tests usually reveal airflow obstruction, but in contrast to asthma do not show significant reversibility following inhaled bronchodilator or methacholine hyperresponsiveness. Direct visualization via flexible bronchoscopy is generally not necessary unless airway compromise is suspected or the patient has hemoptysis. Irregular and erythematous mucosa, exuberant inflammatory tissue, ulcerations, and narrowing of the airways have been described [2,15]. (See 'Airway involvement' above and "Asthma in adolescents and adults: Evaluation and diagnosis", section on 'Pulmonary function testing'.)

Bronchiectasis – The diagnosis of bronchiectasis is usually based on the presence of typical chest high resolution computed tomography (HRCT) findings of airway dilation (ie, 1.5 times the diameter of the adjacent vessel or wider), often accompanied by bronchial wall thickening. (See 'Airway involvement' above and "Clinical manifestations and diagnosis of bronchiectasis in adults", section on 'Computed tomography'.)

Bronchiolitis – The diagnosis of bronchiolitis is suggested when airflow limitation is irreversible and associated with a gas transfer abnormality in a nonsmoker. The most consistent abnormalities on HRCT are expiratory air trapping (mosaic or diffuse) and bronchiolar wall thickening (eg, centrilobular nodules and “tree-in-bud” opacities). In addition, a pattern of diffuse ground glass opacity with a mosaic pattern of attenuation is seen in some patients. A firm diagnosis of bronchiolitis requires an open or thoracoscopic lung biopsy. (See 'Airway involvement' above and "Overview of bronchiolar disorders in adults", section on 'Diagnosis'.)

Tracheal disease – Tracheal involvement, suggested by the combination of dyspnea on exertion and a clear conventional chest radiograph (with or without stridor), is evaluated with a flow-volume loop; flattening of the inspiratory loop suggests extrathoracic variable obstruction (figure 1). The expiratory loop may be normal. Computed tomography of the trachea with three-dimensional reconstruction can provide additional support with visualization of the degree and extent of airway narrowing. The diagnosis is confirmed by direct visualization. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults", section on 'Diagnostic evaluation and initial management' and "Flow-volume loops", section on 'Variable intrathoracic obstruction'.)

Interstitial lung disease — For patients with interstitial lung disease associated with IBD, several processes must be differentiated: interstitial lung disease, sarcoidosis, drug-induced disease, superimposed infection, and concomitant connective tissue disease (eg, lupus). After a careful review of the history of medication use and potential exposures to infectious agents, the evaluation typically involves laboratory testing to assess for peripheral blood eosinophilia and antinuclear antibody positivity, pulmonary function testing to assess the severity of restrictive impairment, and HRCT of the lungs to determine the pattern and distribution of opacities. (See "Approach to the adult with interstitial lung disease: Diagnostic testing".)

The combination of diffuse pulmonary opacities and peripheral eosinophilia creates a high suspicion for drug-induced lung disease, although eosinophilic pneumonias are seen in patients with IBD without a drug association and fungal pneumonia, and tropical filarial infection can also cause eosinophilia, particularly in endemic areas. (See 'Drug-induced complications' above and 'Interstitial lung disease' above and "Overview of pulmonary eosinophilia" and "Tropical pulmonary eosinophilia" and "Nonresolving pneumonia", section on 'Fungi'.)

Flexible bronchoscopy with bronchoalveolar lavage (BAL) is typically performed to obtain samples for cell counts, microbiologic stains and cultures, and cytology. The BAL findings are more helpful in excluding processes such as infection or malignancy than in confirming a specific type of interstitial lung disease, although an eosinophilic BAL in a patient with IBD is more likely to be drug-induced. (See "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

For patients with significant respiratory impairment or evidence of progressive deterioration in lung function, further evaluation typically includes lung biopsy via thoracoscopy or thoracotomy. The main role for lung biopsy is to characterize the histopathologic pattern and to exclude other processes, such as tumor or infection. (See "Approach to the adult with interstitial lung disease: Diagnostic testing" and "High resolution computed tomography of the lungs" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Pleuritis — For patients with pleuritic type chest pain or radiographic evidence of pleural or other serosal involvement, it is important to exclude infection, particularly in patients taking immunosuppressive agents. Laboratory testing (eg, antinuclear antibodies, antihistone antibodies, antidouble-stranded DNA antibodies) may be indicated to look for drug-induced lupus or a concomitant connective tissue disease. A diagnostic thoracentesis is typically performed to exclude infection or malignancy if an adequate amount of free-flowing pleural fluid is present. (See "Ultrasound-guided thoracentesis" and "Diagnostic evaluation of a pleural effusion in adults: Initial testing" and "Drug-induced lupus".)

Pulmonary embolism — The evaluation for suspected thromboembolic disease typically includes computed tomography pulmonary angiography (CTPA) and is discussed separately. (See "Overview of acute pulmonary embolism in adults" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

Patients with an insidious onset of dyspnea, hypoxemia on exertion, a reduced diffusing capacity, and relative lung parenchymal sparing may have chronic thromboembolic pulmonary hypertension. Transthoracic echocardiography shows elevated pulmonary artery pressures, which can be confirmed with right heart catheterization. (See 'Pulmonary embolism' above and "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Diagnostic evaluation'.)

Drug-induced interstitial lung disease — The diagnosis of drug-induced interstitial lung disease (ILD) is supported by the presence of eosinophilia in the peripheral blood, bronchoalveolar lavage, or lung tissue, although eosinophilia is not always present and infectious and other inflammatory processes can also cause eosinophilia. In the absence of eosinophilia, the diagnosis of drug-induced lung toxicity is based on the clinical presentation (eg, clinical syndrome of drug-induced lupus versus atypical pneumonia), the likelihood of the drug in question causing lung toxicity, exclusion of other etiologies, and a trial of drug discontinuation (dechallenge). (See "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment", section on 'Diagnosis' and "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease", section on 'Side effects' and "Methotrexate-induced lung injury", section on 'Diagnostic evaluation'.)

Lung biopsy is occasionally necessary when the diagnosis is unclear. A variety of histopathologic patterns have been associated with agents used to treat IBD, including virtually all of the idiopathic interstitial lung diseases. Organizing pneumonia on histopathology can be drug-induced or associated with the underlying IBD. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Role of lung biopsy' and 'Organizing pneumonia' above.)

TREATMENT — The treatment of the various pulmonary complications of IBD depends on the site, severity, and type of involvement. The activity of the underlying IBD does not always correlate with the activity of lung involvement, so lung involvement is often treated independently. If the IBD is flaring at the same time as the lung involvement, therapy is tailored to achieve a combination that will address both processes. If the patient has a drug-induced pulmonary toxicity, the treatment of the IBD will need to be changed to an alternate agent. (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease" and "Management of the hospitalized adult patient with severe ulcerative colitis".)

Smoking cessation should be strongly encouraged for those who smoke [80]. (See "Overview of smoking cessation management in adults" and "Pharmacotherapy for smoking cessation in adults".)

Airway involvement — Airway compromise due to subglottic stenosis requires urgent attention to secure the airway via endotracheal intubation and/or rigid bronchoscopy. Additional airway interventions such as dilation, laser therapy, or stenting depend on the assessment of the airway at the time of bronchoscopy. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".)

Patients with potentially life-threatening airway inflammation, such as subglottic stenosis, are typically treated with systemic glucocorticoids, based on clinical experience rather than clinical trial data [2]. We usually start with prednisone 1 mg/kg lean body weight per day to a maximum of 60 mg per day, given as a single oral dose in the morning. For patients who are unable to take oral medication, an intravenous preparation is substituted, such as methylprednisolone 60 to 80 mg in divided doses. As the airway inflammation improves, intravenous glucocorticoids are changed to oral and then inhaled preparations.

For patients who have IBD-associated airway involvement without immediate airway compromise, inhaled glucocorticoid therapy is frequently effective, although formal data are limited [2]. In a case series, among 12 patients treated with inhaled glucocorticoids, nine had a significant improvement, but three experienced progressive and disabling disease [2]. Relatively high doses (eg, beclomethasone 1500 to 2000 mcg/day) were needed in some patients. We typically start with the equivalent of fluticasone 500 mcg twice daily and adjust based on the response to therapy. Inflammation in the larger airways tends to be more responsive than bronchiolitis, possibly due to relatively poor delivery of the inhaled medication to the affected small airways. Patients with copious sputum production (greater than 50 mL/day) and those with bronchiectasis are less likely to respond to inhaled glucocorticoids. Antibiotics are indicated in the setting of an acute infectious exacerbation of bronchiectasis (see "Bronchiectasis in adults: Treatment of acute exacerbations and advanced disease"). After excluding an infectious cause for copious sputum production, we consider adding prednisone 0.5 to 1 mg/kg lean body weight per day to a maximum of 60 mg per day, given as a single oral dose in the morning.(See "Overview of bronchiolar disorders in adults", section on 'Treatment'.)

Enteric-bronchial fistulae typically require systemic antibiotics to treat associated pulmonary parenchymal infection and then surgical resection to prevent recurrence. The treatment of fistulae due to Crohn disease is discussed separately. (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease", section on 'Fistulizing disease' and "Surgical management of Crohn disease", section on 'Fistula'.)

Pulmonary parenchymal disease — Symptomatic patients with pulmonary parenchymal complications of IBD generally require oral glucocorticoid therapy, once infection and drug-induced disease have been excluded. Management is typically based on the underlying histopathology. Thus, treatment of organizing pneumonia, eosinophilic pneumonia, nonspecific interstitial pneumonia, or sarcoidosis would follow treatment recommendations for these diseases, most of which are treated with prednisone at an initial dose of 0.5 to 1.0 mg/kg per day, up to a daily dose of 60 mg. The higher initial doses are usually chosen for patients with more severe lung involvement and for noneosinophilic conditions; lower doses are usually adequate for eosinophilic lung diseases and sarcoidosis. (See "Idiopathic acute eosinophilic pneumonia", section on 'Treatment' and "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Overview of treatment' and "Treatment of pulmonary sarcoidosis: Initial approach to treatment" and "Treatment of pulmonary sarcoidosis refractory to initial therapy" and "Cryptogenic organizing pneumonia", section on 'Treatment'.)

The optimal duration of systemic glucocorticoid treatment has not been established, but generally is based on the response to therapy and the timing of tapering established for the underlying histopathology. In general, for patients who respond or stabilize with treatment, the prednisone dose is gradually tapered, aiming to reach 5 to 10 mg daily or on alternate days, by the end of 6 months, with attempted cessation after one year of therapy.

Most patients with parenchymal lung disease due to IBD have a good response to glucocorticoid therapy [2]. However, for those with progressive pulmonary dysfunction despite therapy with systemic glucocorticoids, immunomodulatory therapy is usually added. For patients with ongoing need for immunomodulatory therapy to control their IBD, the optimal agent to control their IBD is usually chosen. However, if the patient’s IBD is not active, the choice of a second-line agent is based on the specific underlying lung histopathology. (See "Management of moderate to severe ulcerative colitis in adults" and "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease".)

Serositis — After exclusion of infectious processes, patients who have symptoms caused by pleuritis, pericarditis, or myopericarditis due to IBD are typically treated with a nonsteroidal antiinflammatory drug (NSAID), such as ibuprofen 400 to 800 mg three times daily, unless the IBD is active and the patient is at risk for gastrointestinal bleeding. NSAIDs have been used successfully in other forms of inflammatory serositis, although the experience in patients with IBD is limited. Systemic glucocorticoid therapy is an alternative if the patient does not respond to NSAIDs or is unable to take them. Based on experience with recurrent pericarditis, we typically initiate therapy with prednisone (0.2 to 0.5mg/kg/day; ie, 25mg for the average patient) for four weeks and then taper as tolerated. As NSAID therapy can precipitate a flare of IBD, careful patient education and close follow up is needed during NSAID therapy. (See "Recurrent pericarditis", section on 'Glucocorticoids' and "Definitions, epidemiology, and risk factors for inflammatory bowel disease", section on 'NSAIDs'.)

Pulmonary thromboembolism — In patients with IBD, the choice of treatment of acute pulmonary thromboembolism depends on the expected risk of gastrointestinal bleeding. For patients with active IBD, especially with significant bleeding, an inferior vena cava filter is usually inserted and anticoagulation deferred until the bleeding is under control. If the patient is not deemed to be at increased risk for gastrointestinal bleeding, the usual guidelines for anticoagulation are followed. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults" and "Placement of vena cava filters and their complications" and "Venous thromboembolism: Initiation of anticoagulation".)

Drug-induced lung disease — For patients taking a medication for IBD that has been associated with pulmonary toxicity who present with fever, cough, and radiographic opacities, appropriate antimicrobial therapy is usually initiated. In addition, the implicated drug is empirically discontinued, while awaiting culture results and a response to drug discontinuation [2,11,12]. Drug-induced lung inflammation and peripheral blood eosinophilia, if present, usually resolve with drug discontinuation [11]. (See "Methotrexate-induced lung injury", section on 'Treatment'.)

For patients with severe respiratory insufficiency due to drug-induced pulmonary disease or lack of improvement with drug discontinuation, we initiate therapy with systemic glucocorticoids. This choice is based on clinical experience, as clinical data in support of this therapy are lacking. The initial dose of prednisone is usually 1 mg/kg per day in a single morning dose. For patients who have had an episode of drug-induced pulmonary toxicity, we avoid reintroduction of that agent.

When it is unclear whether a particular drug contributed to the lung injury, decisions concerning cessation of drug therapy should consider the availability of alternative agents and the relative severity of the pulmonary disease and the IBD, which could flare if the drug is withdrawn.

PROPHYLAXIS FOR VENOUS THROMBOEMBOLISM — Consensus guidelines from the Canadian Association of Gastroenterology recommend anticoagulant prophylaxis against venous thromboembolism (VTE) for patients over age 18 who are hospitalized for a flare of IBD without severe bleeding, independent of the reason for hospitalization, except for planned admissions <48 hours in duration for diagnostic testing or nonsurgical procedures [59]. Anticoagulant VTE prophylaxis is recommended for patients over 18 years of age hospitalized with a flare of IBD and non-severe gastrointestinal bleeding. For patients hospitalized with an IBD flare and severe gastrointestinal bleeding, mechanical rather than anticoagulant thromboprophylaxis is recommended. The prevention of VTE in medical patients is described separately. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Summary and recommendations'.)

For adult outpatients with a moderate-to-severe flare of IBD, the same guidelines suggest not initiating anticoagulant VTE prophylaxis in those without a prior history of VTE, but suggest that anticoagulant VTE prophylaxis be administered to those patients with a previous episode of VTE, unless all episodes of VTE occurred after major surgery [59].

Surgical patients with IBD are considered to be at increased risk for VTE. Anticoagulant prophylaxis is recommended for patients with IBD undergoing major abdominal-pelvic or other general surgical procedures [59]. For those patients who are actively bleeding or at increased risk for bleeding, mechanical methods of thromboprophylaxis are preferred. These choices are discussed in greater detail separately. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients", section on 'Summary and recommendations'.)

SUMMARY AND RECOMMENDATIONS

Pleuropulmonary complications – Pleuropulmonary complications of inflammatory bowel disease (IBD), although uncommon, include the following:

Airway inflammation – In patients with IBD, inflammation of the trachea, bronchi, and bronchioles may develop before or after bowel resection and rarely preceding the onset of IBD. Bronchiectasis is the most common form of airway involvement, but subglottic stenosis, airway-enteral fistulae, bronchitis, and bronchiolitis also occur. (See 'Airway involvement' above.)

Diffuse lung parenchymal disease – Several patterns of diffuse lung parenchymal involvement have been described in IBD, including organizing pneumonia, eosinophilic pneumonia, nonspecific interstitial lung disease, and sarcoidosis. (See 'Pulmonary parenchymal disease' above.)

Pleuropericarditis – IBD-associated pleuropericarditis may present with pleural effusions, pericarditis, pleuropericarditis, and/or myopericarditis. The pleural fluid is exudative, with a cellular content composed primarily of neutrophils. Rarely, pleural-enteric fistulas occur. (See 'Pleural disease' above.)

Drug-induced lung disease – Most of the drugs used to treat IBD have been implicated in drug-induced pulmonary disease. Drug-induced lung diseases associated with these agents include pulmonary infiltrates with eosinophilia (PIE) syndrome, organizing pneumonia, a hypersensitivity syndrome (fever, cough, dyspnea, radiographic opacities), interstitial pneumonitis, reactivation of Mycobacterium tuberculosis, and development of other opportunistic infections. (See 'Drug-induced complications' above and "Methotrexate-induced lung injury" and "Diagnosis of pulmonary tuberculosis in adults".)

Evaluation and diagnosis – The evaluation and diagnosis of pulmonary complications of inflammatory bowel disease usually starts with an assessment of the severity of dyspnea, rapidity of onset of symptoms, and presence of medications that are known to cause lung toxicity or immunosuppression. (See 'Diagnosis' above.)

For patients with a more rapid onset of dyspnea, fever, or respiratory distress, pulmonary embolism, pneumonia, and subglottic stenosis should be evaluated promptly.

For patients with a more indolent onset of disease, the workup usually starts with a complete blood count and differential, antinuclear antibodies and antihistone antibodies if drug-induced lung disease is suspected, pulmonary function testing (PFT), and a conventional chest radiograph.

For patients with airflow limitation on PFTs, the key next steps are determining the severity of airway compromise, whether subglottic stenosis may be present, and whether reversible airflow obstruction is more suggestive of asthma than IBD-associated airway inflammation. (See 'Airway involvement' above.)

High resolution computed tomography is performed in patients suspected of having bronchiectasis, bronchiolitis, diffuse lung parenchymal disease, or drug-induced lung disease; computed tomography pulmonary angiography (CTPA) is used for suspected pulmonary embolism. (See 'Diagnosis' above.)

Drug(s) suspected of causing lung toxicity should be withheld; improvement following drug discontinuation supports a drug-induced process. (See 'Drug-induced interstitial lung disease' above.)

Treatment – The treatment of the various pulmonary complications of IBD depends on the site, severity, and type of involvement. The activity of the underlying IBD does not always correlate with the activity of lung involvement, so the lung involvement is often treated independently. If the IBD is flaring at the same time as the lung involvement, therapy is tailored to achieve a combination that will address both processes simultaneously. (See 'Treatment' above.)

Subglottic stenosis – Airway compromise due to subglottic stenosis requires urgent attention to secure the airway via endotracheal intubation and/or rigid bronchoscopy. Additional airway interventions such as dilation, laser therapy, or stenting depend on the assessment of the airway at the time of bronchoscopy. In addition, we suggest initiation of systemic glucocorticoids (Grade 2C). The usual dose is prednisone 1 mg/kg lean body weight per day to a maximum of 60 mg/day, given as a single oral dose in the morning. Systemic glucocorticoids are tapered and transitioned to inhaled glucocorticoids as the patient improves. (See 'Airway involvement' above and "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults", section on 'Follow-up'.)

Tracheobronchitis and bronchiolitis – For patients who have IBD-associated airway involvement without immediate airway compromise, we suggest initial administration of inhaled glucocorticoids (Grade 2C). Relatively high doses of an inhaled glucocorticoid (eg, beclomethasone 1500 to 2000 mcg/day or fluticasone 500 to 1000 mcg/day) may be needed. For patients who do not have an adequate response to inhaled glucocorticoid therapy, we suggest initiation of systemic glucocorticoids (Grade 2C). We usually start with prednisone 0.5 to 1 mg/kg lean body weight per day to a maximum of 60 mg/day, given as a single oral dose in the morning. (See 'Airway involvement' above.)

Pulmonary parenchymal disease – IBD-associated interstitial lung disease is generally treated according to the underlying histopathology. As an example, treatment of organizing pneumonia, eosinophilic pneumonia, nonspecific interstitial pneumonia, or sarcoidosis would follow treatment recommendations for these diseases as described separately. (See 'Pulmonary parenchymal disease' above.)

Serositis – For patients with IBD-associated serositis whose IBD does not place them at increased risk for gastrointestinal bleeding, we suggest initial therapy with a nonsteroidal anti-inflammatory drug (NSAID) (Grade 2C). A reasonable choice is ibuprofen 600 mg three times daily or the equivalent. However, NSAID therapy may exacerbate underlying IBD, so ongoing monitoring is needed. Systemic glucocorticoid therapy is an alternative if the patient does not respond to NSAIDs. (See 'Serositis' above.)

Drug-induced lung toxicity – For patients with IBD and suspected drug-induced lung toxicity (eg, due to sulfasalazine, 5-aminosalicylic acid, methotrexate, azathioprine, 6-mercaptopurine, anti-TNF agents, or ustekinumab), the first step is to discontinue the culprit drug (dechallenge). (See 'Drug-induced lung disease' above.)

For patients with drug-induced lung toxicity who present with severe respiratory insufficiency or have an incomplete response to drug discontinuation, we suggest initiation of oral glucocorticoids (Grade 2C). The initial dose of prednisone is usually 1 mg/kg per day up to 60 mg in a single morning dose. Rechallenge with a culprit drug is avoided, although data on the exact risk of recurrent lung disease are lacking. (See 'Drug-induced lung disease' above.)

ACKNOWLEDGMENT — We are saddened by the death of Paul Rutgeerts, MD, who passed away in September 2020. UpToDate gratefully acknowledges Dr. Rutgeerts' work as our Section Editor for Gastroenterology.

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