CASE REPORT

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A 43-yr-old woman was admitted to the emergency room with a history of acute left-sided chest pain in January 1997. Crohn's disease had been diagnosed 20 years ago, and the patient had initially been treated with sulfasalazine for approximately 2 yr. In 1983, she experienced intense cramping abdominal pain and bloody stools. Small bowel follow-through examination and colonoscopy disclosed extensive ileocolorectal involvement with marked stricture of the terminal ileum. The patient underwent resection of the terminal ileum and cecum, which resolved her abdominal symptoms. The macroscopic and microscopic features of the surgical specimen were considered typical for Crohn's disease. In 1988, a relapse of her abdominal symptomatology was controlled with salazopyrine.

On her admission (January 1997), the patient's physical examination was unremarkable with the exception of marked obesity (weight, 114 kg; height, 163 cm). She had spontaneously discontinued maintenance therapy with sulfasalazine about 8 yr earlier. She noted three to four liquid stools per day, and she took only loperamide chlorhydrate on an as-needed basis. On close questioning, the patient reported that she had experienced mild dyspnea on exertion and nonproductive cough for about 3 mo. She was a lifelong non-smoker and had no history of occupational or environmental exposure relevant to lung disease. The electrocardiogram and chest radiographs were normal. Arterial blood-gas analysis revealed mild hypoxemia (Pa_O2 , 10.2 kilopascals (kPa); Pa_CO2 , 4.5 kPa). Laboratory investigations showed a moderate increase of erythrocyte sedimentation rate (49 mm in the first hour) and C-reactive protein level (41 mg·L⁻¹). Radioisotope lung scanning indicated matched ventilation/perfusion defects in the lingula and lower lobes. Contrast-enhanced spiral computed tomography (CT) showed no evidence of pulmonary embolism but did disclose areas of variable attenuation in both lungs. There was no mediastinal lymphadenopathy. A high-resolution CT (HRCT) demonstrated a mosaic pattern of lung attenuation composed of sharply demarcated areas of decreased attenuation associated with areas of normal attenuation (Figure 1, top panel). Expiratory CT scans revealed air trapping in the areas of decreased attenuation consistent with bronchiolar narrowing (Figure 1, bottom panel).

Fig. 1. High-resolution computed tomography (HRCT) of the chest on admission. Inspiratory CT scan (top panel ) shows a mosaic pattern of lung attenuation characterized by localized areas of decreased attenuation (white arrows) and areas of normal attenuation. Note that the number and caliber of pulmonary vessels are decreased in low attenuation areas. Expiratory CT scan (bottom panel ) at the same level demonstrates air trapping in the areas of low attenuation.

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Chest pain remained unexplained but resolved spontaneously within 12 h after admission. Pulmonary function testing showed mild airway obstruction with hyperinflation and normal diffusion indices (Table 1). Fiberoptic bronchoscopy revealed normal macroscopic appearance of the bronchi. Multiple bronchial biopsy samples demonstrated mild infiltration of the epithelium and lamina propria by mononuclear cells as well as thickening of the basement membrane. BAL showed 353,846 cells · ml⁻¹, 78.5% macrophages, 0.5% neutrophils, and 21% lymphocytes with CD4+ to CD8+ lymphocytes ratio of 3.1. Bacteriologic studies of BAL fluid, including cultures for mycobacteria and fungi, were negative. Transbronchial biopsies failed to provide suitable material. Assessments of anti-nuclear antibodies, anti-DNA antibodies, anti-neutrophil cytoplasmic antibodies (ANCA), circulating immune complexes, serum angiotensin-converting enzyme, complement, and precipitins against avian and fungal antigens were normal. Serologic tests for Mycoplasma pneumoniae, Chlamydia pneumoniae, respiratory syncytial virus, adenovirus, and influenza and parainfluenza viruses were all negative. Tuberculin skin test was negative.

Four months later (May 1997), repeat assessment of the patient demonstrated persistence of impaired lung function tests (Table 1) and abnormal HRCT (findings not illustrated). Thoracoscopic lung biopsy revealed a mononuclear cell infiltrate associated with non-necrotizing epithelioid granulomas and giant multinucleated cells in the bronchiolar walls (Figure 2). The biopsy specimen contained bronchioles with a diameter less than 300 μm, of which 80% showed inflammatory changes. Granulomas were found in 15% of bronchiolar sections. The granulomas did not contain collagen deposit nor birefringent material. There was virtually no inflammatory infiltrate of the interalveolar septa. Examination of 12 biopsy sections disclosed only one granuloma away from the bronchioles, in the alveolar interstitium. Gomori's methenamine silver and Ziehl-Neelsen stains, as well as cultures of lung biopsy specimens for fungi and mycobacteria, were negative. Oral methylprednisolone at 0.4 mg · kg⁻¹ a day was started for 1 mo, followed by progressive tapering of the dose over a period of 3 mo. This treatment led to resolution of respiratory symptoms and improvement in pulmonary function tests (Table 1). HRCT demonstrated improvement of air trapping, which, however, persisted.

Fig. 2. Lung biopsy specimen showing mononuclear cell infiltrate and non-necrotizing granulomas (white asterisks) containing multinucleated cells in the bronchiolar wall. The airway lumen (white arrows) is almost entirely occluded by the inflammatory changes (hematoxylin and eosin stain; original magnification: ×400).

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DISCUSSION

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This patient with long-standing Crohn's disease demonstrated pathologic evidence of a granulomatous inflammatory process that was almost exclusively limited to the bronchioles. Anecdotal cases of granulomatous interstitial lung disease have been reported in Crohn's disease (2-4, 11). Laryngeal and/or bronchial involvement have been documented in only two patients with Crohn's disease, who demonstrated normal chest radiographs and widespread whitish granulations at bronchoscopy (12). Biopsy specimens of these bronchial lesions revealed the presence of noncaseating granuloma in one patient and epithelioid-like cells in the other. The results of pulmonary function tests were not detailed, although one patient presented with asthma-like symptoms. In our patient, the bronchi showed normal macroscopic appearance at bronchoscopy, while bronchial biopsies demonstrated only minimal and nonspecific inflammatory changes.

Tuberculosis and atypical mycobacteria infection have been associated with granulomatous bronchiolitis (13). In our patient, mycobacterial infection could be excluded by the absence of caseating granuloma, negative tuberculin skin test, and failure to identify mycobacteria on culture of bronchoalveolar fluid and lung biopsy specimens. Bronchiolar granuloma are a common finding in hypersensitivity pneumonitis (14). In this condition, however, the granuloma are usually associated with alveolitis. In addition, our patient reported no history of exposure to occupational and domestic agents or to drugs causing hypersensitivity pneumonitis reactions. Serologic studies did not detect precipitating antibodies to fungal antigens. Pathologic studies have also documented the presence of granulomatous bronchiolitis in patients with sarcoidosis (15). Granulomatous inflammation of the airways could be responsible, at least in part, for the obstructive ventilatory defect seen in a substantial proportion of sarcoidosis patients (16). Granulomatous enterocolitis has been reported in patients with long-standing sarcoidosis (17-19). Conversely, granulomatous lung disease has been described in patients with Crohn's disease (2-4, 11). In some of these cases, the presence of mediastinal lymphadenopathy suggested the development of true sarcoidosis (2, 11). It is, however, almost impossible to determine whether bronchopulmonary granulomatosis seen in patients with Crohn's disease should be considered concurrent sarcoidosis or extraintestinal involvement of Crohn's disease. Sarcoidosis and Crohn's disease share pathologic and immunologic features, since both conditions are of unknown etiology and are characterized by the presence of noncaseating epithelioid granulomas and the accumulation of CD4+ T lymphocytes at sites of disease activity. In addition, sarcoidosis and Crohn's disease may occur in different members of the same family (20). These observations suggest that Crohn's disease and sarcoidosis could be related to a common disorder of the mucosal immune system, leading to different clinical manifestations in response to exogenous agents.

Abnormalities of pulmonary function tests have been described in patients with Crohn's disease in the absence of clinical and radiographic evidence of lung disease (6-9). Reduced transfer factor for carbon monoxide has been identified most frequently (7-9, 21), although several studies have documented airway obstruction and/or lung hyperinflation (6-8). A recent study has demonstrated small airways dysfunction in patients with Crohn's disease using methods based on the density dependence of air flow (21). Our patient experienced only slight respiratory symptoms and showed a mild obstructive defect, which improved on steroid treatment. Chest radiographs were normal, while HRCT scan showed evidence of bronchiolar disorder. These findings raise the hypothesis that granulomatous bronchiolitis could be involved in the development of airway obstruction recorded in some patients with Crohn's disease. HRCT scan could be a sensitive tool to identify bronchiolar involvement in patients with Crohn's disease who demonstrate physiologic evidence of hyperinflation or airway obstruction.

To our knowledge, this is the first account of an exclusively bronchiolar granulomatous process in a patient with Crohn's disease. Further studies are needed to determine whether granulomatous inflammation of the bronchioles can lead to the development of obstructive pulmonary disease in Crohn's disease and whether such bronchiolar inflammatory disorder warrants early steroid treatment.