Granulomatous diseases in a patient with cystic fibrosis

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 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 (FEV1=2.05 L 74% predicted). A prominent left hilum was noted on chest radiograph post delivery.

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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.

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, 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.

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Fig. 2. A section of lymph node obtained at biopsy showing multiple epithelioid granulomas composed of histiocytes.

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 [1]. 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 [1]. 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 [1]. Active Crohn's disease is likely to remain active during pregnancy. Likewise, as in our patient, quiescent disease should remain quiescent [2]. 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 [3]. However, there have been a number of cases of non-pulmonary sarcoid reported including granulomatous arthritis, erythema nodosum and iritis [3], [4]. 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% [5], prevalence in Australia is much lower at 0.3% [6]. Similarly Histoplasma capsulatum, a common cause of granulomatous lung disease in the US, is rarely found in Australia [7]. 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 [8] 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 [9], strongly supporting our patient's diagnosis of pulmonary sarcoid. Although Crohn's disease can manifest as granulomatous pulmonary disease, neither mediastinal adenopathy nor elevated ACE levels are typically seen [9]. Sarcoidosis has no known adverse effects on pregnancy, but it typically worsens within 6 months of parturition [10]. 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 [11]. As in our patient, in most cases the Crohn's disease has preceded the sarcoidosis, in one case by up to 16 years [11]. Certain pathological and immunological similarities between Crohn's disease and sarcoidosis such as similar CD4/CD8 lymphocyte ratios on bronchoalveolar lavage and abnormalities of intestinal permeability suggest a possible etiological link [12]. Both conditions are characterized by higher than normal IgG antibodies to mycobacterial species [13].

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 [3]. 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 [3]. 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 [14].

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, caring for her child, and coping well with a good quality of life.