A case of cryptogenic organizing pneumonia occurring in Crohn’s disease

1Institute of Respiratory Disease, Department of Clinical Methodology and Medical Surgery Technology; 2Institute of Pathological Anatomy, University of Bari, Bari, Italy Correspondence: Dr Onofrio Resta, Department of Clinical Methodology and Medical Surgery Technology, University of Bari, Piazza G Cesare, 11-70124 Bari, Italy. Telephone/fax 39-080-5592907, e-mail oresta@pneumol.uniba.it P Carratù, S Dragonieri, MC Nocerino, et al. A case of cryptogenic organizing pneumonia occurring in Crohn’s disease. Can Respir J 2005;12(8):437-439.

Est examiné un homme de 29 ans atteint de la maladie de Crohn qui a développé des infiltrats pulmonaire diffus et une hypoxémie deux mois après l'administration orale de mésalazine.Les observations cliniques et la tomodensitométrie laissaient supposer une bronchiolite oblitérante avec organisation pneumonique, également désignée pneumopathie organisée cryptogénique, diagnostiquée par une histologie pulmonaire.Bien que les données n'aient pas permis de tirer des conclusions définitives, elles indiquaient que la maladie pulmonaire constituait une manifestation extraintestinale de la maladie de Crohn plutôt qu'une réaction indésirable à la mésalazine.En fait, le patient a présenté des améliorations cliniques, radiologiques et fonctionnelles malgré le traitement à la mésalazine et l'abandon de la stéroïdothérapie.P ulmonary involvement is uncommon in Crohn's disease (CD) and has been evaluated to occur in 0.4% of cases (1), a frequency less than that in ulcerative colitis (2).Cases of lung manifestations have been reported in CD, such as granulomatous edema of the upper airways, bronchiectasis, bronchiolitis obliterans organizing pneumonia (BOOP) and lung infiltrates with peripheral eosinophilia (3).Drug therapy for inflammatory bowel disease, such as mesalazine (4), may also cause adverse reactions in the lung and, thus, may present a diagnostic dilemma.
The present report describes the case of a patient with CD who developed diffuse pulmonary infiltrates with hypoxemia two months after administration of oral mesalazine.

CASE PRESENTATION
A 29-year-old nonsmoking man, who had no history of extraintestinal diseases, was diagnosed with CD by ileocolonoscopy with biopsy in 2001.On October 16, 2002, a relapse of the disease was treated with oral mesalazine (3 g/day).On December 14, 2002, the patient suddenly showed dyspnea, a dry cough and fever.Chest x-rays showed the presence of subpleural opacities, predominantly found in the upper right lobe, which were believed to be consistent with infective pneumonia; thus, the patient was treated by his physician with clarithromycin.Because the fever continued, the patient underwent a thoracic computed tomography (CT) scan, which showed the presence of peripheral subpleural opacities in the upper and middle lobes, and less in the left lung.A new trial of antibiotic therapy (levofloxacin 500 mg/day) was initiated.Despite treatment, clinical worsening occurred, and on February 2, 2003, the patient was admitted to hospital with severe pleuritic chest pain, dyspnea at rest, fever (higher than 39°C), abdominal pain and acute bloody diarrhea.
A physical examination of the chest revealed only a respiratory rate of 30 breaths/min and inspiratory crackles at both lung bases.The patient did not present a rash, icterus, hypopigmentation, clubbing, oronasal lesions or eye signs.
Laboratory findings revealed a white blood cell count of 8×10 9 /L (57% neutrophils, 26% lymphocytes and 8.1% eosinophils), an erythrocyte sedimentation rate of 38 mm/h (normal range 0 mm/h to 20 mm/h) and a C-reactive protein level of 1.5 mg/dL (normal range 0 mg/dL to 0.33 mg/dL).Anti-DNA antibodies, circulating immune complexes, antinuclear antibodies and complement levels were all in the normal range.Serology for Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia pneumoniae, Aspergillus fumigatus and Candida albicans were negative.A tuberculin skin test was nonreactive, and sputum stains for Mycobacterium tuberculosis were negative.Arterial blood gas analysis revealed a partial pressure of oxygen of 72 mmHg (9.5 kPa) and a partial pressure of carbon dioxide of 36 mmHg (4.7 kPa) while resting on 2 L/min of oxygen.Pulmonary function tests showed a restrictive pattern ©2005 Pulsus Group Inc.All rights reserved

CASE REPORT
(forced vital capacity [FVC] 53% of predicted value, forced expiratory volume in 1 s [FEV 1 ] 42% of predicted, with a FEV 1 /FVC ratio of 80%) and a reduced diffusing capacity for carbon monoxide (54%), with a lung transfer factor for carbon monoxide corrected for hemoglobin to alveolar volume ratio of 99%.
A second CT scan (Figure 1) revealed multiple diffuse, patchy peripheral opacities, predominantly involving the upper lobes, similar to the previous CT scan, and compatible with cryptogenic organizing pneumonia (COP).Fibreoptic bronchoscopy was macroscopically normal.Bronchoalveolar lavage was highly cellular, with 30% of lymphocytes, an increased CD4 to CD8 ratio (1.8) and a low number of eosinophils (less than 4%), similar to previous reports on COP (5).The patient declined transbronchial biopsy and video-assisted thoracoscopy and, eventually, an open-lung biopsy of the right upper lobe was performed.On gross examination, pleurae appeared diffusely inflamed and thickened; a moderate pleural effusion was present and the involved lung was consolidated.
Microscopic examination of lung tissue showed the following findings: atelectasis; mild interstitial collagen fibrosis; isolated foci of nonspecific chronic inflammation bronchiolitis, with non-necrotizing granulomatous inflammation; aspects of myofibroblastic proliferation in the bronchiolar lumen; and the presence of peripheral endoalveolar foamy macrophages (Figure 2).Cultures of the pleural fluid and lung tissue were negative.Histological findings were diagnostic of BOOP, also known as COP.
Treatment was initiated with 40 mg/day intravenous methylprednisolone for two weeks while mesalazine was continued.Clinical, radiological and functional respiratory improvements were observed after eight days of steroid therapy; improvements observed included regression of fever and dyspnea, partial clearing of pulmonary infiltrates, increased partial pressure of oxygen (81 mmHg [10.68 kPa]), increased FVC (71%), increased FEV 1 (84%), an improved FEV 1 /FVC ratio (97.6%) and an increased diffusing capacity for carbon monoxide (75%).After two weeks, the patient was discharged and intravenous corticosteroids were switched to 25 mg/day oral prednisone for two months, and the patient subsequently continued the treatment at a dose of 10 mg/day.Four months later, in the absence of respiratory symptoms, oral prednisone was withdrawn, whereas treatment with oral mesalazine was continued until irritable bowel syndrome improved.Finally, after six months of therapy, the patient was asymptomatic.A third CT scan showed an almost complete clearing of pulmonary infiltrates (Figure 3).

DISCUSSION
In the present case of pulmonary involvement occurring in CD, the clinical findings, the CT scan abnormalities, the lung histology, the clinical course of pulmonary disease and the response to corticosteroid treatment were strongly suggestive of COP.To our knowledge, few cases of pulmonary parenchymal involvement in patients with CD have been reported in the literature (6,7), including few cases of BOOP in patients receiving sulfasalazine or mesalamine (3).Although pulmonary involvement may be considered an extraintestinal manifestation of CD, or may be related to treatment with oral  Sulfasalazine may cause fever, rash, arthralgia, hemolytic anemia (8), and rarely, bilateral patchy lung infiltrates, with or without peripheral eosinophilia (9).Mesalazine is a modified 5-aminosalicylic acid without a sulfonamide group and with less reported sulfonamide-related toxicity.Reactions such as acute interstitial nephritis (10) have been reported in patients taking oral or rectal mesalazine.Pulmonary reactions, including COP, have been reported in patients taking oral or rectal mesalazine (11); however, all cases of COP related to mesalazine were reported in patients affected by ulcerative colitis (12).
In our patient, the following findings were suggestive of pulmonary involvement not related to oral mesalazine: pulmonary manifestations developed in conjunction with the relapse of CD; the absence of pulmonary capillaritis, which is frequently associated with hypersensitivity to the drug; and the patient recovered despite the maintenance of treatment with mesalazine alone for two months.In contrast, other evidence suggests that pulmonary involvement may be related to mesalazine, ie, the development of respiratory manifestations during treatment with mesalazine and the presence of blood and bronchoalveolar lavage eosinophilia.

CONCLUSIONS
The present findings suggest that CD may be responsible for the development of COP, probably independent of mesalazine administration; however, further evidence is needed to clarify this pathophysiological mechanism.
COP occurring in Crohn's disease Carratù et al Can Respir J Vol 12 No 8 November/December 2005 438