Granulomatous bronchiolitis with necrobiotic pulmonary nodules in Crohn’s disease

1Department of Medicine, Division of Gastroenterology and 2Department of Laboratory Medicine, Division of Anatomical Pathology, University of British Columbia, Vancouver; and Department of Medicine, Divisions of 3Gastroenterology and 4Respiratory Medicine, Surrey Memorial Hospital, Surrey, British Columbia Correspondence: Dr Hugh Freeman, Gastroenterology, University of British Columbia Hospital, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5. Telephone 604-822-7216, fax 604-822-7236, e-mail hugfree@shaw.ca Received for publication April 29, 2004. Accepted August 10, 2004 HJ Freeman, JE Davis, ME Prest, EJ Lawson. Granulomatous bronchiolitis with necrobiotic pulmonary nodules in Crohn’s disease. Can J Gastroenterol 2004;18(11):687-690.

T he pulmonary changes in patients with chronic inflamma- tory bowel diseases have been well described in the past two decades, and were recently reviewed (1)(2)(3)(4).Most often, these have been associated with ulcerative colitis (3,4), although significant pulmonary changes have also been rarely recorded in Crohn's disease (3,4).
In Crohn's disease, changes usually develop after the intestinal disease is well established, but in some patients, the pulmonary disease preceded the intestinal changes (5)(6)(7).Earlier reports also suggested overlap between pulmonary granulomatous disease in Crohn's disease and sarcoidosis (8)(9)(10)(11), but newer classifications have categorized the pulmonary changes in Crohn's disease as either airway or interstitial disease (3,4).In some patients, mesalamine or other medications may be responsible, and differentiation of drug-induced versus diseaserelated changes may be difficult (12).
Cavitary lung lesions may also occur in Crohn's disease.Opportunistic infections with tuberculosis, Pneumocystis carinii and fungal infections should be considered, and aggressive immunosuppression may also predispose to cavitating malignancies, including lymphoma.In addition, vasculitis or metastatic Crohn's disease may cause cavitary lung lesions (13).Finally, necrobiotic pulmonary nodules may occur in patients with ulcerative colitis or predominantly Crohn's colitis (14,15).

CASE PRESENTATION
A 37-year-old man was referred in August 1993 for investigation of diarrhea, which had been present for over 10 years.In June 1993, an ischiorectal abscess was drained at his community hospital.Later, periumbilical abdominal pain developed, associated with a 15 kg weight loss.An examination revealed a fatigued man with a weight of 69 kg.There was no fever but tenderness was present in the right lower quadrant.Laboratory studies revealed anemia (hemoglobin 110 g/L), a normal white blood cell count and thrombocytosis of 493,000.Sedimentation rate was 48 mm/h.Serum iron studies showed 2% saturation while serum albumin was reduced to 30 g/L.Red cell folate, serum vitamin B 12 , liver chemistry tests and renal function tests were normal.Fecal bacteriology and parasite studies were negative.Chest radiographs were normal but barium studies showed aphthoid ulcerations in the stomach with narrowing of the antrum and pylorus, thickened duodenal folds with diminished distensibility of the bulb, and irregular narrowing of the descending duodenum.Extensive ulceration and narrowing were present in the proximal jejunum and the distal 20 cm of the ileum, as well as the cecum and the ascending and transverse colon, which is consistent with multifocal involvement due to Crohn's disease.Endoscopy revealed a normal esophagus but gastric antral erosions were present along with linear and serpiginous duodenal ulceration; biopsies showed focally active gastritis with a gastric mucosal granuloma and a single focus of duodenal granulomatous inflammation.A flexible sigmoidoscopy and rectal biopsy were normal.
Initial treatment included a lactose-free diet, oral iron, omeprazole and oral mesalamine followed by an eight-week course of tapering prednisone.
By May 1994, his diarrhea and abdominal pain had resolved.His weight had increased by 6 kg.His hemogram was normal but his serum iron studies still showed only 7% saturation and serum albumin was 31 g/L.
Diarrhea reappeared in June 1995 and a flexible sigmoidscopy showed scattered aphthoid ulcers in the rectum and sigmoid colon; a further course of oral prednisone was administered.
In March 1996, a colonoscopy showed ileal and cecal ulceration only.Biopsies showed nonspecific inflammatory changes but no granulomas.
In March 1997, diarrhea recurred with abdominal pain, vomiting and weight loss to 61 kg.Endoscopic studies of the upper and lower gastrointestinal tract showed gastric, duodenal and ileocecal ulceration.Instead of oral prednisone, budesonide controlled ileal release 3 mg twice a day was obtained through a compassionate release program (Astra Pharma, Canada), but it appeared to be ineffective in controlling symptoms over a period of six months.
From October 1997 to February 1998, a prolonged course of oral prednisone was provided.Repeated barium radiographic studies of his upper gastrointestinal tract showed a normal stomach but persistent strictures were present in the duodenum and ileum.Surgical treatment was refused and so metronidazole was initiated.
In early March 2000, cough, fever and further weight loss developed.Chest radiographs showed changes consistent with pneumonitis and his family physician prescribed azithromycin.
In June 2000, a helical computed tomography (CT) scan of the chest with contrast showed innumerable small nodular opacities in both lungs; the opacities were more numerous in the right upper and left lower lobes than elsewhere, and ranged in size up to 1 cm.Small areas of cavitation were seen in these opacities and an infectious etiology including fungal or tuberculous pulmonary disease was suggested.Serological studies for rheumatoid factor, antinuclear antibodies, antineutrophil cytoplasmic antibodies (ANCA, including ANCA with a cytoplasmic staining pattern [c-ANCA]) and HIV were negative.A purified protein derivative test was negative.There was no known exposure to tuberculosis or histoplasmosis and no history of foreign travel or occupational exposure.There were no clinical features or familial history to suggest an underlying or concomitant connective tissue disorder such as rheumatoid arthritis.Bronchoscopy revealed nonspecific findings and a transbronchial biopsy was negative.Pulmonary function studies showed changes of severe obstructive lung disease in a pattern consistent with advanced emphysema.Open lung biopsy showed granulomatous bronchiolitis and necrobiotic nodules (Figures 1 to 6).Acid fast and silver stains were negative.Cultures for mycobacteria and fungi were negative.During hospitalization, his intestinal disease worsened with recurrent abdominal pain and diarrhea.An ischiorectal abscess developed, necessitating surgical drainage.There was a persistent bronchopleural fistula from the biopsy site and chest tube drainage persisted for over two months.
Eventually, his chest tube was spontaneously expelled with a coughing episode and his fistula closed.His respiratory symptoms improved with a course of prednisone, and a follow-up CT scan showed resolution of the bronchiolitis and nodular changes.Subsequent treatment for his intestinal disease has included oral metronidazole, ciprofloxacin and azathioprine.

DISCUSSION
Pulmonary complications in patients with inflammatory bowel disease are becoming increasingly recognized.Even in the absence of symptoms or reported radiological changes, over 50% of Crohn's disease patients have been documented with altered lung function (16).Indeed, very recent studies in patients with Crohn's disease using high resolution CT scanning showed that all patients had one or more abnormalities detected with this modern imaging method (17).Pathological pulmonary changes in Crohn's disease may be categorized as airway or interstitial parenchymal disease, and include infectious, noninfectious and drug-induced causes.This patient had dramatic radiographic and helical CT scan findings of extensive cavitating pulmonary parenchymal disease confirmed histologically, with an open lung biopsy that showed granulomatous bronchiolitis and necrobiosis.The latter feature has been rarely recorded in Crohn's disease (14,15,18), usually with disease localized predominantly in the colon alone, or occasionally associated with pyoderma gangrenosum (19,20).In this patient, extensive multifocal involvement of the stomach, small intestine and colon with Crohn's disease was defined without other extraintestinal changes, including dermatological complications.
In this patient, the duration of the lung disease before its eventual recognition and diagnosis was unknown, but may have been occult and prolonged because of intermittent courses of oral corticosteroids used to treat his intestinal symptoms over many years.In some patients with noninfectious pulmonary pathology in Crohn's disease, treatment with corticosteroids has been associated with resolution of the lung disease, and in this patient, may have indirectly and unknowingly ameliorated pulmonary changes.Eventually, in the absence of ongoing corticosteroids, respiratory symptoms became clinically evident, which led to more detailed pulmonary investigations and a precise diagnosis.
Although there is evidence from case studies that use of corticosteroids or other forms of immunosuppression may be useful to manage the necrobiotic pulmonary lesions in Crohn's disease, definition of cavitating pulmonary nodules raises the possibility of underlying pulmonary tuberculosis or another ubiquitious infectious agent.In this setting, the decision to use immunosuppressive therapy is difficult.Here, infliximab therapy was also considered but it was thought not to be a safe option.There are a number of studies now documenting subsequent development of serious infections, including fatal tuberculous disease, histoplasmosis and other infections (21-23) as well as sterile pulmonary granulomas (24) following infliximab treatment.In contrast, there are also rare cases of resolution of noninfectious pulmonary disease (25,26) with infliximab therapy.These apparently contradictory reports serve as a reminder that our understanding of the effects and risks of Figure 2) Bronchiolitis with destruction of some of the wall (hematoxylin and eosin stain, original magnification ×160) Figure 3) Bronchiolitis obliterans organizing pneumonia with mixed inflammation (hematoxylin and eosin stain, original magnification ×40) Figure 4) Stellate scar with a collection of giant cells in the centre (hematoxylin and eosin stain, original magnification ×40) tumour necrosis factor-alpha inhibition remain limited and, despite recent reports of adverse events in large clinical experiences (27,28), still require further elucidation and longer term monitoring.

ACKNOWLEDGEMENTS:
The authors are grateful to the following physicians for their helpful input in the clinical management of this patient's pulmonary disorder: Dr R Blackmore, family physician, Langley, British Columbia; Dr D Grant, Department of Pathology and Dr A Valji, Department of Surgery, Surrey Memorial Hospital, Surrey, British Columbia; and Dr A Churg, Department of Pathology, University of British Columbia, Vancouver, British Columbia.