Necrotizing Granulomatous Inflammation with Organizing Fibrinous Pneumonia Associated with Focal Tissue Eosinophilia Henry D. Tazelaar Mayo Clinic Phoenix, AZ

History: A 29 year old female tri-athlete who frequently travels to South America presented with a 2 week history of shortness of breath and chest pain. She was treated with antibiotics, but remained symptomatic. Imaging studies showed multiple bilateral nodules, some cavitated. Her past medical history included Crohn disease which was currently inactive. ANCA and connective tissue disease serologies were negative. She underwent lung biopsy. Flow cytometry on the tissue was negative for a monoclonal population. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Diagnosis: Necrotizing granulomatous inflammation with organizing fibrinous pneumonia associated with focal tissue eosinophilia. Special stains (and cultures) for organisms were negative. The features are, therefore, consistent with non-infectious pulmonary pathology associated with Crohn Disease. Discussion: Patients with inflammatory bowel disease (IBD) may have a variety of extra intestinal manifestations, including arthritis, ankylosing spondylitis, erythema nodosum, pyoderma gangrenosum, dermatitis, aphthous stomatitis, conjunctivitis, episcleritis, uveitis, hepatitis, pericholangitis, sclerosing cholangitis, primary biliary cirrhosis, pancreatitis, thyroiditis, pyelitis, and pericarditis. Pulmonary complications also occur and although more common in ulcerative colitis, have also been reported in Crohn disease [1]. The landmark article was published by Camus, et. al., in 1993 [2]. They summarized the results of 33 patients with IBD, predominantly ulcerative colitis (n=27). A number of features emerged from this study. Most patients (84%) developed respiratory involvement following the onset of IBD by nine years (range one week to 36 years). The bowel disease activity at the time of the respiratory illness was variable, many having inactive disease or being post-colectomy. In only 10% of patients was the inflammatory bowel disease active. In a few patients, severe bronchopulmonary involvement developed suddenly and unexpectedly a few days or weeks following proctocolectomy. Rarely, the bowel disease and lung symptoms developed concurrently and in four patients the bronchopulmonary disease developed prior to the IBD. The patterns of pulmonary involvement can be divided into those which consisted predominately of airway disease (60%), interstitial lung disease (35%), and parenchymal nodules (5%, see Table 1). Large airway involvement usually includes the presence of chronic bronchitis and bronchiectasis, and a recent series found the prevalence of IBD in patients with large airways disease to be 4 times higher than the local prevalence of IBD [3], emphazing this association. Airways in these cases usually contain a dense submucosal cuff of lymphocytes and plasma cells similar in appearance to the infiltrate seen in the bowel. Occasionally, neutrophils may be present. The mucosa sometimes shows squamous metaplasia. In lobectomy specimens, where large airway involvement can be better appreciated, the inflammatory infiltrate often involves bronchial submucosal glands as well. Usually, germinal centers are absent from the lymphoid aggregates, an overall pattern unusual for ordinary bronchiectasis. Mucous stasis and a distal endogenous lipoid pneumonia may also be prominent as a manifestation of an inability to adequately clear secretions. In biopsies lacking bronchi, similar changes may be identified in bronchioles. While some may show simply a chronic bronchiolitis without fibrosis, luminal, and mural fibrosis have also been reported. Such cases could be classified as showing bronchiolitis obliterans (without the organizing pneumonia). In our review of patients with noninfectious pulmonary complications associated with Crohn disease [4], the bronchiolitis took two forms; one, a chronic bronchiolitis with non- necrotizing granulomatous inflammation within bronchiolar walls and second, a more acute bronchiolitis with bronchopneumonia-like features in the surrounding pulmonary parenchyma. The interstitial changes associated with IBD have been variable and have been classified as organizing pneumonia (OP, a.k.a. bronchiolitis obliterans organizing pneumonia), with or without giant cells and non-necrotizing granulomas, nonspecific interstitial pneumonia (NSIP), and eosinophilic pneumonia. Camus, et. al., have commented that the OP associated with IBD may be associated with a distinctive septal edema which is infiltrated by chronic inflammatory cells and modest numbers of eosinophils, not characteristic of cryptogenic OP. Table 1: Patterns of thoracic involvement in inflammatory bowel disease* Pattern of involvement Camus 1993 % of total Lit review % total Subglottic stenosis 3 9.4 3 5.3 Chronic bronchitis 6 18.8 12 21.0 Chronic bronchial suppuration 3 9.4 4 7.0 Bronchiectasis 6 18.8 14 24.6 Chronic bronchiolitis 2 6.3 1 1.8 Bronchiolitis obliterans organizing pneumonia 6 18.8 5 8.8 Interstitial lung disease 1 3.1 15 26.3 Pulmonary infiltrates and eosinophilia 3 9.4 0 --- Necrobiotic nodules - neutrophilic infiltrates 2 6.3 3 5.3 Serositis 32 100 57 100 Myocarditis 0 --- 10 24.4 Pericarditis 0 --- 15 36.6 Pleural effusion 0 --- 4 9.6 Pleuropericarditis 1 --- 12 29.3 Total 1 --- 41 100 * from Camus P et al, 1993 [2] Cases associated with eosinophilic pneumonia show airspace, septal, and pleural involvement. The septae may also show marked edematous thickening similar to that seen in cases of OP described above. Nonspecific interstitial pneumonia (NSIP) has been associated with rare granulomas and giant cells in cases associated with Crohn disease [4]. Necrobiotic nodules have been described as resembling necrotic granulomas. Early nodules appear to consist of dense airspace accumulations of neutrophils and a fibrinous exudate. These nodules may then undergo central necrosis and cavitation. There is some resemblance of these nodules to infectious and noninfectious granulomas, particularly lesions seen in Wegener granulomatosis and dermal pyoderma gangrenosum. Table 2 summarizes our recent experience and the published literature on pulmonary involvement with Crohn disease. Although there is some overlap, respiratory involvement may differ in patients with ulcerative colitis and Crohn disease. For instance, disease reported to occur in conjunction with Crohn disease, such as granulomatous involvement of the larynx, trachea, and bronchi have not been reported in patients with ulcerative colitis. Interestingly, both have been reported to be associated with pulmonary sarcoidosis. Whether the pulmonary granuloma seen in patients with inflammatory bowel disease is true sarcoid or a distinct granulomatous process remains unclear. Table 2. Spectrum of Pulmonary Changes Associated with Crohn Disease Chronic Bronchiolitis with Granulomas Acute bronchiolitis with Bronchopneumonia-like features Non-specific interstitial pneumonia (± giant cells) OP with rare granulomas and/or giant cells Necrobiotic nodules/Granulomas In the current case, necrotizing granulomatous inflammation was the dominant finding, associated with a fibrinous eosinophilic pneumonia-like reaction. The differential diagnosis includes infection first and foremost, but all cultures and special stains were negative. For this reason, the patient was treated with steroids and 5 months later, her nodules and symptoms have resolved, making it highly likely that the nodules were a non-infectious complication of her inflammatory bowel disease. This case, therefore, represents an example of two histologies described in patients with inflammatory bowel disease. The differential diagnosis for lung disease associated with IBD is fairly lengthy depending on the exact pattern of involvement. In all cases, including this one, as emphasized above, infection needs to be excluded with special stains and cultures, particularly because many patients may be on immunosuppressive therapy. Although not a factor in this case, because the patient was not on any therapy, a drug reaction should also be considered. Drugs used to treat IBD, particularly sulfasalazine and 5-ASA, have been associated with a variety of histologic patterns. Sulfasalazine can cause eosinophilic pneumonia, or chronic interstitial pneumonia not otherwise specified i.e. nonspecific interstitial pneumonia; desquamative interstitial pneumonia, OP, diffuse alveolar damage, and hypersensitivity pneumonitis. Finally, the character of the pathology in this case raises two additional possibilities, Wegener granulomatosis and Churg Strauss Syndrome. While the histology in this case could be consistent with either disease in the right clinical setting, there was no evidence of systemic disease at the time of her presentation and she did not have asthma. Additionally, serologies were negative (it is worth noting that patients with IBD can have a positive pANCA). It could, of course, be argued nonetheless, that her disease actually does represent the eosinophilic variant of Wegener granulomatosis occurring in a patient with Crohn disease. The prognosis for patients with pulmonary disease is generally favorable [5], with most patients responding well to steroids. In some patients, the disease appears self limited [6] while in others, infliximab has been used successfully [7]. References Black, H., M. Mendoza, and S. Murin, Thoracic manifestations of inflammatory bowel disease. Chest, 2007. 131(2): p. 524-32. Camus, P., et al., The lung in inflammatory bowel disease. Medicine (Baltimore), 1993. 72(3): p. 151-83. Raj, A.A., et al., Prevalence of inflammatory bowel disease in patients with airways disease. Respir Med, 2008. 102(5): p. 780-5. Casey, M.B., et al., Non-infectious lung pathology in Crohn's disease Am J Surg Pathol, 2003. 27(2): p. 213-9. Camus, P. and T.V. Colby, The lung in inflammatory bowel disease. Eur Respir J, 2000. 15(1): p. 5-10. Kasuga, A., et al., Pulmonary complications resembling Wegener's granulomatosis in ulcerative colitis with elevated proteinase-3 anti-neutrophil cytoplasmic antibody. Intern Med, 2008. 47(13): p. 1211-4. Krishnan, S., et al., Lung lesions in children with Crohn's disease presenting as nonresolving pneumonias and response to infliximab therapy. Pediatrics, 2006. 117(4): p. 1440-3.