What every physician needs to know:
The inflammatory bowel diseases (IBD), ulcerative colitis and Crohn’s disease, are immune-modulated disorders of the gastrointestinal (GI) tract that also have a number of manifestations outside the gut. Extraintestinal manifestations of IBD include pyoderma gangrenosum, erythema nodosum, uveitis, hemolysis, arthritis, and a broad variety of respiratory disorders. Respiratory disease in IBD patients can manifest anywhere from the larynx to the pleura. Bronchiectasis is the most common pulmonary manifestation of IBD.
Evidence of respiratory abnormalities in patients with IBD include more frequent symptoms of wheeze, cough, sputum production, and/or breathlessness than those in the general population; abnormalities of pulmonary function testing, including decreased DLCO and bronchial hyperreactivity; decrements in pulmonary function during IBD flares; more radiographic abnormalities, such as air trapping, peripheral reticular opacities, cysts, and ground glass opacification on high-resolution (CT) scans compared to non-IBD controls (even in the absence of symptoms); increased frequency of asthma; increased (3-4 fold) incidence of venous thromboembolic disease with even higher risk during IBD exacerbations; bronchoalveolar lavage (BAL) fluid lymphocytosis and inflammatory changes in the submucosa of airways as occurs in regions of the GI tract affected by IBD.
Pulmonary disease has been encountered and documented in all portions of the respiratory tract of IBD patients although the dominant sites of involvement are the airways. It is not uncommon to find disease in multiple sites in the same patient. Respiratory abnormalities are discussed by location below:
Upper airway disease – rare manifestations that include tracheal and subglottic stenosis.
Large airway disease – Bronchiectasis is by far the most commonly reported form of respiratory disease found in IBD patients. Most patients have ulcerative colitis (UC), concomitant extraintestinal manifestations are common, and most patients are non-smokers in their 5th decade of life. Colobronchial and esophagobronchial fistulas have been reported, leading to recurrent pneumonia with enteric bacteria.
Small airway disease – Bronchiolitis is the most commonly reported disease of the small airways in IBD patients. Granulomatous bronchiolitis is the most common pathologic pattern among patients with small airways disease. Affected patients tend to be in their forties or fifties and are as likely to have Crohn’s Disease (CD) as UC. Small airways disease may manifest before GI symptoms.
Asthma occurs with increased frequency in the IBD population. IBD patients with asthma have greater decrement in pulmonary function than do asthmatics without IBD. IBD patients with asthma may also have a more severe respiratory course and an increased risk of fatal asthma.
Parenchymal disease – This is an uncommon manifestation of IBD. Organizing pneumonia represents about half of the reported parenchymal abnormalities in IBD patients, most reported cases have UC, and necrobiotic nodules are rarely seen.
Sarcoidosis – There have been more than fifty reported cases of coexisting IBD and sarcoidosis, which suggests a link between the two disorders.
Pulmonary vasculature – Venous thromboembolic disease (VTE) occurs with increased frequency in the IBD population, but pulmonary vasculitis is rare.
Serosal disease – Pleural and pericardial disease is rarely reported in IBD patients. Unilateral exudative pleural effusion is the most commonly reported form of serosal involvement.
Are you sure your patient has pulmonary involvement in inflammatory bowel disease? What should you expect to find?
The most common respiratory manifestation of IBD is bronchiectasis, which often presents with cough. Bronchiectasis should be considered among patients with IBD who present with chronic cough and/or sputum production. Isolation of Staphylococcus aureus or Pseudomonas species from the sputum also suggests bronchiectasis. CT imaging of the chest can confirm the clinical suspicion of bronchiectasis.
Beware: there are other diseases that can mimic pulmonary involvement in inflammatory bowel disease:
Much of the association between IBD and respiratory disease is confounded by the fact that many of the drugs used to treat IBD may themselves cause pulmonary abnormalities. However, while numerous case reports exist, especially with methotrexate and sulfasalazine, the overall incidence of pulmonary adverse drug effect appears to be low. Below is a list of drugs used in the treatment of IBD and the pulmonary disorders with which these medications have been associated.
Sulfasalazine: pneumonitis, pulmonary infiltrates with eosinophilia (PIE) syndromes, DIP, vasculitis, necrobiotic nodules, 5-ASA: PIE syndromes, organizing pneumonia
Methotrexate: acute and subacute pneumonitis, organizing pneumonia, diffuse alveolar damage (DAD), granulomatous inflammation, reactive airway disease, and pulmonary fibrosis
Azathioprine: pneumonitis, organizing pneumonia, vasculitis, angioedema
6-mercaptopurine: pneumonitis, DAD
Anti-tumor necrosis factor (TNF) alpha therapy: acute and subacute pneumonitis, PIE syndromes, increased risk for reactivation tuberculosis as well as non-tuberculous mycobacterial disease and invasive fungal disease.
There are also infectious consequences to immunosuppression that may mimic respiratory manifestations of inflammatory bowel disease, including suppurative airways disease, bronchiectasis, and bronchiolitis.
How and/or why did the patient develop pulmonary involvement in inflammatory bowel disease?
Mechanisms underlying pulmonary involvement among patients with IBD are unknown. This is not surprising given that there remain significant gaps in our knowledge about the pathogenesis of IBD itself.
Which individuals are at greatest risk of developing pulmonary involvement in inflammatory bowel disease?
Any patient with IBD can develop respiratory manifestations. Until proven otherwise, patients with IBD who have persistent or unstable respiratory symptoms without identifiable cause should be considered to have a pulmonary manifestation of IBD or a complication of medical therapy for IBD. Patients with IBD with acute onset of breathlessness should be urgently evaluated for thromboembolic disease. Respiratory manifestations of IBD should be considered in patients with concomitant flares of pulmonary and intestinal symptoms.
What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
Start by evaluating for the presence of infection with sputum gram stain and bacterial culture, sputum AFB smear and mycobacterial culture for both typical and atypical mycobacterial disease, and sputum fungal culture. Consider serologic evaluation for endemic fungi based upon geographic location or exposure (e.g., coccidioidomycosis titers in California’s central valley). Interferon gamma release assay (i.e. QuantiFERON Gold ®) and purified protein derivative (PPD) skin testing for tuberculosis are difficult to interpret in the setting of immunosuppression.
Guide further evaluations by the distribution of pulmonary abnormalities on imaging studies. If VTE is suspected, an elevated d-dimer may be a nonspecific finding during flares of IBD. Consider an evaluation for autoimmune disease if there is diffuse parenchymal disease, organizing pneumonia, pulmonary vasculitis, bronchiolitis obliterans, or tracheal stenosis.
What imaging studies will be helpful in making or excluding the diagnosis of pulmonary involvement in inflammatory bowel disease?
HRCT of the chest allows the disease to be localized to large airways, small airways, pulmonary parenchyma, or the pleura. Lower extremity dopplers and a contrast CT angiogram of the chest should be considered if venous thromboembolism is in the differential.
What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of pulmonary involvement in inflammatory bowel disease?
Full pulmonary function testing with bronchodilator testing, lung volumes, and DLCO measurement should be performed in all IBD patients with respiratory symptoms. Numerous studies have demonstrated that PFT abnormalities are common in patients with IBD, even in those with no overt respiratory symptoms. The degree of DLCO impairment is strongly associated with the degree of IBD activity. Methacholine challenge testing should be considered in patients who have dyspnea or wheezing along with normal spirometry. Baseline six-minute pulmonary function testing may be useful in assessing cardiopulmonary function longitudinally.
What diagnostic procedures will be helpful in making or excluding the diagnosis of pulmonary involvement in inflammatory bowel disease?
Diagnostic procedures should be guided by the nature and location of disease that is discovered on previous testing.
Diagnostic bronchoscopy should be considered if there is suspicion of tracheal or glottic stenosis or suspicion of sarcoidosis or bronchiolar disease, as transbronchial biopsies may yield a diagnosis. Patients on pharmacologic immunosuppression for IBD should be considered for diagnostic bronchoscopy to evaluate for the presence of infection.
Open lung biopsy should be considered if there is symptomatic or unstable parenchymal disease that remains unexplained or in the presence of an efficacious IBD therapy that may be causing drug-related parenchymal disease.
What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of pulmonary involvement in inflammatory bowel disease?
More than one hundred genetic susceptibility loci for IBD have been identified. However, genetic testing does not currently play a role in making or excluding the diagnosis of pulmonary involvement in IBD. The histologic features of the pulmonary diseases associated with IBD are those of the pulmonary disorder and are not specific to IBD-associated disease. Lymphocytic inflammation may be seen in affected tissues.
If you decide the patient has pulmonary involvement in inflammatory bowel disease, how should the patient be managed?
Management options reflect the broad spectrum of pulmonary disease that can be encountered in IBD and may include observation, augmentation of immunomodulating therapy, steroids,inhaled bronchodilators, removal of a pulmonary toxic medication, or antimicrobial therapy.
Treatment of bronchiectasis involves sputum clearance maneuvers and treatment of exacerbations with antibiotics, as is the case for non-IBD-related disease. Systemic steroids are the main therapy for many other forms of IBD-related lung disease. IBD-associated bronchiolitis can improve with high-dose inhaled steroids. Acute breathlessness in a patient with an IBD flare should prompt early consideration for anticoagulation for VTE pending further diagnostic evaluation.
What is the prognosis for patients managed in the recommended ways?
Given that most of the literature on this topic is in the form of case reports and small case series, little is known specifically about the prognosis of pulmonary diseases associated with IBD. The course of pulmonary disease does tend to track with that of the underlying gastrointestinal disease.
What other considerations exist for patients with pulmonary involvement in inflammatory bowel disease?
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- What every physician needs to know:
- Are you sure your patient has pulmonary involvement in inflammatory bowel disease? What should you expect to find?
- Beware: there are other diseases that can mimic pulmonary involvement in inflammatory bowel disease:
- How and/or why did the patient develop pulmonary involvement in inflammatory bowel disease?
- Which individuals are at greatest risk of developing pulmonary involvement in inflammatory bowel disease?
- What imaging studies will be helpful in making or excluding the diagnosis of pulmonary involvement in inflammatory bowel disease?
- What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of pulmonary involvement in inflammatory bowel disease?
- What diagnostic procedures will be helpful in making or excluding the diagnosis of pulmonary involvement in inflammatory bowel disease?
- What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of pulmonary involvement in inflammatory bowel disease?
- If you decide the patient has pulmonary involvement in inflammatory bowel disease, how should the patient be managed?
- What is the prognosis for patients managed in the recommended ways?
- What other considerations exist for patients with pulmonary involvement in inflammatory bowel disease?