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Granulomatous diseases in a patient with cystic fibrosis
Journal of Cystic Fibrosis 2 (2003) 35–37
Case report
Granulomatous diseases in a patient with cystic fibrosis Catherine J. Dobbin, Carmel Moriarty, Peter T.P. Bye* Department of Respiratory Medicine, E 11 South, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia
Abstract We report the case of an adult with Crohn’s disease and pulmonary sarcoidosis on the background of cystic fibrosis (CF). There is a recognized association between Crohn’s colitis and CF, but cases of pulmonary sarcoidosis in CF are rare. There may be a pathogenic link between the two granulomatous disorders and CF with chronic immune stimulation leading to hyperimmunoglobulinemia, circulating immune complexes and subsequent granuloma formation. 䊚 2003 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. Keywords: Cystic fibrosis; Crohn’s disease; Sarcoidosis
1. Introduction Although there is an association between Crohn’s disease and cystic fibrosis (CF), there are very few reports of pulmonary sarcoidosis in CF. We present the unique case of an adult patient who developed both these granulomatous disorders on the background of CF complicated by multiorgan involvement, pregnancy and Burkholderia cepacia (B. cepacia) colonization. 2. Case report The 31-year-old woman was homozygous delta F 508 and chronically colonized with Pseudomonas aeruginosa (P. aeruginosa). Five of her eight siblings also had CF. Extrapulmonary manifestations included sinusitis, diabetes and pancreatic insufficiency requiring standard enzyme supplementation. She experienced multiple adverse drug reactions including arthritis of small and large joints with ciprofloxacin. In 1992 she presented with persistent anorexia and nausea. Gastroscopy revealed esophagitis and she commenced ranitidine. Symptoms persisted and by 1994 she was experiencing frequent vomiting, weight loss and right iliac fossa pain with a palpable mass. Symptoms and signs were attributed to distal intestinal obstruction *Corresponding author. Tel.: q61-2-9515-7427; fax: q61-2-95158196. E-mail address: [email protected] (P.T. Bye).
syndrome (DIOS) and she was treated with cisapride and paraffin oil. After failing to improve mucosal biopsies confirmed Crohn’s disease (Fig. 1). Initial symptom control was achieved with intravenous corticosteroids, however, following relapse, mesalazine was added to her regimen. She continued to lose weight and in 1994 underwent an ileocolectomy. At surgery a chronic abscess extending into the retroperitoneum, right psoas and ureter was found. There was an ileocolic fistula. She had an uneventful acute post-operative course and put on 13 kg weight. Symptoms were subsequently well controlled on mesalazine alone. She had a term pregnancy in 1995 complicated only by gestational diabetes. Lung function was well maintained (FEV1s2.05 L 74% predicted). A prominent left hilum was noted on chest radiograph post delivery. In 1996 she was colonized with B. cepacia genomovar III sensitive to ceftazidime and meropenem. She remained well but serial chest radiographs showed persistent left hilar prominence. Chest CT revealed hilar and mediastinal lymphadenopathy and mediastinal node biopsy showed epithelioid cell non-caseating granulomas consistent with sarcoidosis (Fig. 2). The tissue was negative for acid-fast bacilli and fungi on stains and in culture. No B. cepacia was isolated either from the nodal specimens or the bloodstream and the onset of her hilar adenopathy preceded the isolation of B. cepacia from her sputum. Although not diagnostic, her serum angiotensin converting enzyme (ACE) was elevated,
1569-1993/03/$30.00 䊚 2003 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. doi:10.1016/S1569-1993(02)00140-6
C.J. Dobbin et al. / Journal of Cystic Fibrosis 2 (2003) 35–37
36
Fig. 1. Pathology from the terminal ileum showing a deep-fissured ulcer and erosion of the epithelial mucosa consistent with Crohn’s disease. Ulcers were typically narrow and some extended transmurally with fistula formation.
supporting a diagnosis of sarcoidosis. Apart from intermittent knee arthritis she had no extrapulmonary features. She did not receive treatment for sarcoidosis and her lymphadenopathy spontaneously regressed. Both her granulomatous disorders are currently quiescent without therapy. 3. Discussion Colitis in CF can occur for a number of different reasons including Crohn’s disease, pseudomembranous colitis and fibrosing colonopathy. Colitis due to Crohn’s disease has a predilection for the ileocolic region, possibly due to CF-related defects in the enterohepatic circulation w1x. The case for a pathogenic link between CF and Crohn’s disease is strong given that its prevalence in CF is approximately 17 times higher than in controls. There appears to be an association between Crohn’s colitis, meconium ileus at birth and the delta F
508 mutation w1x. In a series of 12 CF patients with Crohn’s disease, 50–67% also had DIOS, 33% had arthritis, 75% had ileocolic involvement with fistula formation and 83% required surgical treatment w1x. Active Crohn’s disease is likely to remain active during pregnancy. Likewise, as in our patient, quiescent disease should remain quiescent w2x. Our case highlights the fact that although DIOS is the most common cause of abdominal pain with a mass in CF, other possibilities including appendicitis, Crohn’s disease, or colonic strictures need consideration if symptoms persist. There have been very few cases of pulmonary sarcoidosis described in CF w3x. However, there have been a number of cases of non-pulmonary sarcoid reported including granulomatous arthritis, erythema nodosum and iritis w3,4x. Diagnosis of pulmonary sarcoid in CF is challenging given that most adult patients already have extensive lung disease. There are also important differential diagnoses to consider. Our patient had a history of treatment with corticosteroids, a pregnancy and the development of diabetes, all of which predisposed her to fungal or mycobacterial infection. We carefully excluded bacterial, fungal and atypical and typical mycobacterial infection as causes of her granulomatous hilar adenopathy. Although studies from European and North American centers quote the prevalence of non-tuberculous mycobacteria in patients with CF as 13% w5x, prevalence in Australia is much lower at 0.3% w6x. Similarly Histoplasma capsulatum, a common cause of granulomatous lung disease in the US, is rarely found in Australia w7x. Our patient’s mediastinal adenopathy occurred prior to infection with B. cepacia and regressed spontaneously despite persistent B. cepacia colonization. The necrotizing granulomas typically seen with B. cepacia w8x were not present and B. cepacia was not isolated from the nodal specimens. An elevated serum ACE level has a specificity of 90% for sarcoidosis w9x, strongly supporting our patient’s diagnosis of pulmonary sarcoid. Although Crohn’s disease can manifest as granuloma-
Fig. 2. A section of lymph node obtained at biopsy showing multiple epithelioid granulomas composed of histiocytes.
C.J. Dobbin et al. / Journal of Cystic Fibrosis 2 (2003) 35–37
tous pulmonary disease, neither mediastinal adenopathy nor elevated ACE levels are typically seen w9x. Sarcoidosis has no known adverse effects on pregnancy, but it typically worsens within 6 months of parturition w10x. In keeping with this, our patient’s hilar adenopathy first became prominent post partum. Cystic fibrosis aside, there have only been a few cases of co-existing sarcoidosis and Crohn’s disease described in the literature w11x. As in our patient, in most cases the Crohn’s disease has preceded the sarcoidosis, in one case by up to 16 years w11x. Certain pathological and immunological similarities between Crohn’s disease and sarcoidosis such as similar CD4y CD8 lymphocyte ratios on bronchoalveolar lavage and abnormalities of intestinal permeability suggest a possible etiological link w12x. Both conditions are characterized by higher than normal IgG antibodies to mycobacterial species w13x. There may also be a pathogenic link between the two granulomatous conditions and CF. The most likely pathogenic mechanism is an altered immune response in CF secondary to chronic infection w3x. Chronic immune stimulation in CF leads to hyperimmunoglobulinemia and circulating immune complexes similar to those seen in sarcoidosis. Progressive tissue damage and defective bronchial mucosal surfaces may potentiate antigen presentation in CF w3x. In the presence of excessive antibody, large antigen–antibody complexes may form that are resistant to digestion by phagocytic cells. These complexes are known to cause granulomas in animals w14x. 4. Conclusion This is a unique case of a patient with two different granulomatous disorders in addition to CF. Her sarcoidosis spontaneously regressed and her Crohn’s disease, despite the need for surgery, subsequently remained stable and quiescent. In other ways, however, she typified the resilient older CF patient. She had multisystem involvement and major complications, including P. aeruginosa colonization, asymptomatic carriage of B. cepacia, and diabetes. Despite all this she was married,
37
caring for her child, and coping well with a good quality of life. Acknowledgments Dr Dobbin is supported by the National Health and Medical Research Council (NHMRC) of Australia. References w1x Lloyd-Still J. Crohn’s disease and cystic fibrosis. Digestive diseases and sciences. 1994. p. 880 –5. w2x Rogers R, Katz V. Course of Crohn’s disease during pregnancy and its effect on pregnancy outcome: a retrospective review. Am J Perinatol 1995;12:262. w3x Cooper T, Day A, Waller P, Geddes D. Sarcoidosis in two patients with cystic fibrosis: a fortuitous association? Thorax 1987;42:818 –20. w4x Soden M, Tempany E, Bresnihan B. Sarcoid arthropathy in cystic fibrosis. Br J Rheumatol 1989;28:341 –3. w5x Yankaskas JR, Knowles MR. Cystic fibrosis in adults. Lippincott-Raven, 1999. w6x Australian cystic fibrosis data registry annual data report 2002. North Ryde, NSW: Cystic Fibrosis Australia, 2002. w7x Hunt P, Harden T, Hibbins M, Pritchard R, Muir D, Gardner F. Histoplasma capsulatum. Isolation from an Australian cave environment and from a patient. Med J Australia 1984;141:280 –3. w8x Belchis D, Simpson E, Colby T. Histopathologic features of Burkholderia cepacia pneumonia in patients without cystic fibrosis. Modern Pathol 2000;13:369 –72. w9x Ainslie G, Benatar S. Serum angiotensin converting enzyme in sarcoidosis: sensitivity and specificity in diagnosis: correlations with disease activity, duration, extrathoracic involvement, radiographic type and therapy. Q J Med 1985;55:253 –70. w10x Selroos O. Sarcoidosis and pregnancy: a review with results of a retrospective survey. J Inter Med 1990;227:221. w11x Johard U, Berlin M, Eklund A. Sarcoidosis and regional enteritis in two patients. Sarcoidosis Vasculitis Diffuse Lung Dis 1996;13:50 –3. w12x Levine J, Lukawski-Trubbish D. Extraintestinal considerations in inflammatory bowel disease. Gastroenterol Clin North Am 1995;24:633 –46. w13x Reid J, Chiodini R. Serologic reactivity against Mycobacterium paratuberculosis antigens in patients with sarcoidosis. Sarcoidosis 1993;10:32 –5. w14x Spector W, Heesom N. The production of granulomata by antigen–antibody complexes. J Pathol 1969;98:31 –9.
Case report
Granulomatous diseases in a patient with cystic fibrosis Catherine J. Dobbin, Carmel Moriarty, Peter T.P. Bye* Department of Respiratory Medicine, E 11 South, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia
Abstract We report the case of an adult with Crohn’s disease and pulmonary sarcoidosis on the background of cystic fibrosis (CF). There is a recognized association between Crohn’s colitis and CF, but cases of pulmonary sarcoidosis in CF are rare. There may be a pathogenic link between the two granulomatous disorders and CF with chronic immune stimulation leading to hyperimmunoglobulinemia, circulating immune complexes and subsequent granuloma formation. 䊚 2003 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. Keywords: Cystic fibrosis; Crohn’s disease; Sarcoidosis
1. Introduction Although there is an association between Crohn’s disease and cystic fibrosis (CF), there are very few reports of pulmonary sarcoidosis in CF. We present the unique case of an adult patient who developed both these granulomatous disorders on the background of CF complicated by multiorgan involvement, pregnancy and Burkholderia cepacia (B. cepacia) colonization. 2. Case report The 31-year-old woman was homozygous delta F 508 and chronically colonized with Pseudomonas aeruginosa (P. aeruginosa). Five of her eight siblings also had CF. Extrapulmonary manifestations included sinusitis, diabetes and pancreatic insufficiency requiring standard enzyme supplementation. She experienced multiple adverse drug reactions including arthritis of small and large joints with ciprofloxacin. In 1992 she presented with persistent anorexia and nausea. Gastroscopy revealed esophagitis and she commenced ranitidine. Symptoms persisted and by 1994 she was experiencing frequent vomiting, weight loss and right iliac fossa pain with a palpable mass. Symptoms and signs were attributed to distal intestinal obstruction *Corresponding author. Tel.: q61-2-9515-7427; fax: q61-2-95158196. E-mail address: [email protected] (P.T. Bye).
syndrome (DIOS) and she was treated with cisapride and paraffin oil. After failing to improve mucosal biopsies confirmed Crohn’s disease (Fig. 1). Initial symptom control was achieved with intravenous corticosteroids, however, following relapse, mesalazine was added to her regimen. She continued to lose weight and in 1994 underwent an ileocolectomy. At surgery a chronic abscess extending into the retroperitoneum, right psoas and ureter was found. There was an ileocolic fistula. She had an uneventful acute post-operative course and put on 13 kg weight. Symptoms were subsequently well controlled on mesalazine alone. She had a term pregnancy in 1995 complicated only by gestational diabetes. Lung function was well maintained (FEV1s2.05 L 74% predicted). A prominent left hilum was noted on chest radiograph post delivery. In 1996 she was colonized with B. cepacia genomovar III sensitive to ceftazidime and meropenem. She remained well but serial chest radiographs showed persistent left hilar prominence. Chest CT revealed hilar and mediastinal lymphadenopathy and mediastinal node biopsy showed epithelioid cell non-caseating granulomas consistent with sarcoidosis (Fig. 2). The tissue was negative for acid-fast bacilli and fungi on stains and in culture. No B. cepacia was isolated either from the nodal specimens or the bloodstream and the onset of her hilar adenopathy preceded the isolation of B. cepacia from her sputum. Although not diagnostic, her serum angiotensin converting enzyme (ACE) was elevated,
1569-1993/03/$30.00 䊚 2003 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved. doi:10.1016/S1569-1993(02)00140-6
C.J. Dobbin et al. / Journal of Cystic Fibrosis 2 (2003) 35–37
36
Fig. 1. Pathology from the terminal ileum showing a deep-fissured ulcer and erosion of the epithelial mucosa consistent with Crohn’s disease. Ulcers were typically narrow and some extended transmurally with fistula formation.
supporting a diagnosis of sarcoidosis. Apart from intermittent knee arthritis she had no extrapulmonary features. She did not receive treatment for sarcoidosis and her lymphadenopathy spontaneously regressed. Both her granulomatous disorders are currently quiescent without therapy. 3. Discussion Colitis in CF can occur for a number of different reasons including Crohn’s disease, pseudomembranous colitis and fibrosing colonopathy. Colitis due to Crohn’s disease has a predilection for the ileocolic region, possibly due to CF-related defects in the enterohepatic circulation w1x. The case for a pathogenic link between CF and Crohn’s disease is strong given that its prevalence in CF is approximately 17 times higher than in controls. There appears to be an association between Crohn’s colitis, meconium ileus at birth and the delta F
508 mutation w1x. In a series of 12 CF patients with Crohn’s disease, 50–67% also had DIOS, 33% had arthritis, 75% had ileocolic involvement with fistula formation and 83% required surgical treatment w1x. Active Crohn’s disease is likely to remain active during pregnancy. Likewise, as in our patient, quiescent disease should remain quiescent w2x. Our case highlights the fact that although DIOS is the most common cause of abdominal pain with a mass in CF, other possibilities including appendicitis, Crohn’s disease, or colonic strictures need consideration if symptoms persist. There have been very few cases of pulmonary sarcoidosis described in CF w3x. However, there have been a number of cases of non-pulmonary sarcoid reported including granulomatous arthritis, erythema nodosum and iritis w3,4x. Diagnosis of pulmonary sarcoid in CF is challenging given that most adult patients already have extensive lung disease. There are also important differential diagnoses to consider. Our patient had a history of treatment with corticosteroids, a pregnancy and the development of diabetes, all of which predisposed her to fungal or mycobacterial infection. We carefully excluded bacterial, fungal and atypical and typical mycobacterial infection as causes of her granulomatous hilar adenopathy. Although studies from European and North American centers quote the prevalence of non-tuberculous mycobacteria in patients with CF as 13% w5x, prevalence in Australia is much lower at 0.3% w6x. Similarly Histoplasma capsulatum, a common cause of granulomatous lung disease in the US, is rarely found in Australia w7x. Our patient’s mediastinal adenopathy occurred prior to infection with B. cepacia and regressed spontaneously despite persistent B. cepacia colonization. The necrotizing granulomas typically seen with B. cepacia w8x were not present and B. cepacia was not isolated from the nodal specimens. An elevated serum ACE level has a specificity of 90% for sarcoidosis w9x, strongly supporting our patient’s diagnosis of pulmonary sarcoid. Although Crohn’s disease can manifest as granuloma-
Fig. 2. A section of lymph node obtained at biopsy showing multiple epithelioid granulomas composed of histiocytes.
C.J. Dobbin et al. / Journal of Cystic Fibrosis 2 (2003) 35–37
tous pulmonary disease, neither mediastinal adenopathy nor elevated ACE levels are typically seen w9x. Sarcoidosis has no known adverse effects on pregnancy, but it typically worsens within 6 months of parturition w10x. In keeping with this, our patient’s hilar adenopathy first became prominent post partum. Cystic fibrosis aside, there have only been a few cases of co-existing sarcoidosis and Crohn’s disease described in the literature w11x. As in our patient, in most cases the Crohn’s disease has preceded the sarcoidosis, in one case by up to 16 years w11x. Certain pathological and immunological similarities between Crohn’s disease and sarcoidosis such as similar CD4y CD8 lymphocyte ratios on bronchoalveolar lavage and abnormalities of intestinal permeability suggest a possible etiological link w12x. Both conditions are characterized by higher than normal IgG antibodies to mycobacterial species w13x. There may also be a pathogenic link between the two granulomatous conditions and CF. The most likely pathogenic mechanism is an altered immune response in CF secondary to chronic infection w3x. Chronic immune stimulation in CF leads to hyperimmunoglobulinemia and circulating immune complexes similar to those seen in sarcoidosis. Progressive tissue damage and defective bronchial mucosal surfaces may potentiate antigen presentation in CF w3x. In the presence of excessive antibody, large antigen–antibody complexes may form that are resistant to digestion by phagocytic cells. These complexes are known to cause granulomas in animals w14x. 4. Conclusion This is a unique case of a patient with two different granulomatous disorders in addition to CF. Her sarcoidosis spontaneously regressed and her Crohn’s disease, despite the need for surgery, subsequently remained stable and quiescent. In other ways, however, she typified the resilient older CF patient. She had multisystem involvement and major complications, including P. aeruginosa colonization, asymptomatic carriage of B. cepacia, and diabetes. Despite all this she was married,
37
caring for her child, and coping well with a good quality of life. Acknowledgments Dr Dobbin is supported by the National Health and Medical Research Council (NHMRC) of Australia. References w1x Lloyd-Still J. Crohn’s disease and cystic fibrosis. Digestive diseases and sciences. 1994. p. 880 –5. w2x Rogers R, Katz V. Course of Crohn’s disease during pregnancy and its effect on pregnancy outcome: a retrospective review. Am J Perinatol 1995;12:262. w3x Cooper T, Day A, Waller P, Geddes D. Sarcoidosis in two patients with cystic fibrosis: a fortuitous association? Thorax 1987;42:818 –20. w4x Soden M, Tempany E, Bresnihan B. Sarcoid arthropathy in cystic fibrosis. Br J Rheumatol 1989;28:341 –3. w5x Yankaskas JR, Knowles MR. Cystic fibrosis in adults. Lippincott-Raven, 1999. w6x Australian cystic fibrosis data registry annual data report 2002. North Ryde, NSW: Cystic Fibrosis Australia, 2002. w7x Hunt P, Harden T, Hibbins M, Pritchard R, Muir D, Gardner F. Histoplasma capsulatum. Isolation from an Australian cave environment and from a patient. Med J Australia 1984;141:280 –3. w8x Belchis D, Simpson E, Colby T. Histopathologic features of Burkholderia cepacia pneumonia in patients without cystic fibrosis. Modern Pathol 2000;13:369 –72. w9x Ainslie G, Benatar S. Serum angiotensin converting enzyme in sarcoidosis: sensitivity and specificity in diagnosis: correlations with disease activity, duration, extrathoracic involvement, radiographic type and therapy. Q J Med 1985;55:253 –70. w10x Selroos O. Sarcoidosis and pregnancy: a review with results of a retrospective survey. J Inter Med 1990;227:221. w11x Johard U, Berlin M, Eklund A. Sarcoidosis and regional enteritis in two patients. Sarcoidosis Vasculitis Diffuse Lung Dis 1996;13:50 –3. w12x Levine J, Lukawski-Trubbish D. Extraintestinal considerations in inflammatory bowel disease. Gastroenterol Clin North Am 1995;24:633 –46. w13x Reid J, Chiodini R. Serologic reactivity against Mycobacterium paratuberculosis antigens in patients with sarcoidosis. Sarcoidosis 1993;10:32 –5. w14x Spector W, Heesom N. The production of granulomata by antigen–antibody complexes. J Pathol 1969;98:31 –9.