Radhakrishnan, Kadakkal R. MD*; Kay, Marsha MD*; Wyllie, Robert MD*; Hashkes, Philip J. MD, MSc†
*Department of Pediatric Gastroenterology and Nutrition; and †Department of Rheumatology, Cleveland Clinic Foundation, Cleveland, OH
Address correspondence and reprint requests to Marsha Kay, MD, Department of Pediatric Gastroenterology and Nutrition, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.
Wegener granulomatosis (WG) is an idiopathic granulomatous vasculitis, usually involving the respiratory tract and kidneys. WG presenting primarily with GI symptoms without extraintestinal manifestations is very rare, especially in children. We present a case of a teenager with WG who presented initially with clinical and histopathological findings indistinguishable from Crohn disease.
The patient was a 14-year-old male, who presented with intermittent abdominal pain and weight loss, and had previously undergone an appendectomy. Physical examination was unremarkable. He had an elevated ESR, and microscopic hematuria with a normal complete blood count, was anti-Saccharomyces cerevisiae (ASCA) positive and perinuclear anti-neutrophilic cytoplasmic antibody (p-ANCA) negative. Esophago-gastro-duodenoscopy (EGD) and colonoscopy revealed gastric, duodenal and rectosigmoid erosions consistent with Crohn disease. Biopsy demonstrated focal active gastritis and focal active colitis. He was started on corticosteroids and a 5-ASA product with immediate resolution of his symptoms. Three weeks later he developed hemoptysis and exercise intolerance. CT scan showed multifocal alveolar and interstitial lung infiltrates. His prior appendectomy slides showed active necrotizing vasculitis with a transmural eosinophilic infiltrate consistent with WG. Renal biopsy demonstrated pauci-immune crescentic glomerulonephritis. His c-ANCA Protease 3 was significantly elevated. Oral cyclophosphamide was added with significant improvement. Although our patient s initial symptoms, labs, biopsies and response to therapy were suggestive of Crohn disease, WG may mimic Crohn disease in patients without extraintestinal symptoms. Sinopulmonary or renal findings in a patient with suspected or known IBD should raise the possibility of WG. A positive C-ANCA PR3 and characteristic histological findings are diagnostic.
Wegener granulomatosis is a chronic idiopathic granulomatous vasculitis, which occurs infrequently in children compared to adults. Both inflammatory bowel disease (IBD) and WG may involve multiple organ systems, including the alimentary tract, oropharynx and respiratory tract. WG most commonly presents with sinopulmonary or renal disease (1). WG presenting primarily with GI symptoms without extraintestinal involvement is very rare in adults and even rarer in pediatric patients. We present a case of a teenager who ultimately was diagnosed as having WG who initially presented with clinical and histopathological findings indistinguishable from Crohn disease.
The patient is a 14-year-old white male who presented with 2-month history of right lower quadrant abdominal pain, intermittent hip pain and a 4-kg involuntary weight loss. His prior history was significant for an appendectomy 6 months before the onset of his symptoms at an outside institution performed for severe right-lower quadrant abdominal pain. The appendix was not found to be grossly inflamed at surgery. He had a history of microscopic hematuria of unknown etiology. His physical examination was remarkable only for a weight loss of 10% of baseline. His abdominal examination including rectal exam was unremarkable. Laboratory evaluation revealed an elevated Westergren sedimentation rate of 39 mm/hr, hemoglobin of 13.8 g/dL, white cell count of 9.7 kg/μL with 8% eosinophils. Hisserum electrolytes were normal including an albumin of 3.8 g/dL and a serum creatinine of 0.6 mg/dL; he was ASCA positive and negative for p-ANCA. An upper gastrointestinal x-ray and small bowel follow through (UGI SBFT) to rule out Crohn disease was normal. He subsequently underwent an upper endoscopy and colonoscopy, which demonstrated gastric and duodenal erosions and erosions in the recto-sigmoid colon consistent with Crohn disease. The terminal ileum was normal in appearance. Histologic evaluation demonstrated focal active gastritis, focal active colitis with a normal terminal ileal biopsy and was otherwise normal.
The patient was started on mesalamine (Pentasa, Shire US Inc, Newport, KY) 50 mg/kg/day and prednisone 1 mg/kg/day, with rapid resolution of his abdominal pain and improved weight gain. Three weeks later he developed hemoptysis, consisting of a small amount of fresh blood in the sputum, and exercise intolerance while on a high-altitude skiing trip. His mesalamine was discontinued because of a possible adverse medication effect and after pulmonary consultation computerized tomography of his lungs was performed, which showed multifocal alveolar and interstitial infiltrates (Fig. 1). He underwent bronchoscopy, which was visually normal; cultures for bacteria, mycobacterium, fungus and virus were negative. Review of his prior outside appendectomy specimen, which had been requested at his initial consultation revealed active necrotizing vasculitis with transmural eosinophilic infiltrate consistent with Wegener granulomatosis. (Fig. 2) Urinalysis revealed microscopic hematuria; his serum creatinine had increased to 0.9 mg/dL. He underwent renal biopsy, which demonstrated pauci-immune cresenteric glomerulonephritis. He also was cytoplasmic antineutrophilic cytoplasmic antibody Proteinase-3 (c-ANCA PR-3) positive. Thepatient was subsequently transferred to the care of a pediatric rheumatologist. Remission was induced by administration of cyclophosphamide 2 mg/kg/day and prednisone. He has been weaned off prednisone and heis currently on maintenance therapy of azathioprine 100 mg/day (1.6 mg/kg/day) and enalapril 2.5 mg once per day.
Wegener granulomatosis is a necrotizing granulomatous small- and medium-vessel vasculitis predominantly affecting the upper airways, lungs and the kidneys. The disorder is rare in children and most publications are based on case reports and small patient series (1,2). The etiology of WG is unknown but existing evidence suggests an autoimmune process, with predominantly neutrophilic inflammation in early lesions and increasing titers of c-ANCA directed against proteinase-3 (3). Children with WG have similar sites of organ system involvement when compared to adults with a higher incidence of subglottic stenosis in children.
The most common manifestations of WG in children and adults are because of upper and lower respiratory tract involvement (3). Patients typically present with epistaxis, sinusitis, otitis, hearing loss, stridor, hoarseness and lower respiratory symptoms including cough, wheezing, dyspnea or hemoptysis. CT scanning is superior to chest x-ray in establishing the diagnosis and defining the extent of parenchymal disease (4). Multiple lung nodules or masses are the most common imaging findings, seen in 70% of patients. Other common findings include air space opacification, thickening of the airway walls and narrowing of the lumen. Less frequent findings include interstitial fibrosis, pleural disease and enlarged mediastinal lymph nodes (4).
Renal involvement is the second most common and often the most serious manifestation of WG. Patients may be asymptomatic despite the presence of significant renal disease. Necrotizing crescentic glomerulonephritis is frequently identified on biopsy. Ocular manifestations are common and include episcleritis, conjunctivitis, uveitis, optic neuritis and pseudotumor cerebri. Cutaneous manifestations range from erythematous or purpuric macules to necrotizing vasculitic ulcerations and gangrene.
Gastrointestinal involvement is rare in WG, and patients infrequently present primarily with GI symptoms. The literature is limited to case reports and to our knowledge there has only been 1 prior pediatric case report with isolated gastrointestinal symptoms as the initial manifestation (3,5). Patients with GI involvement may present with abdominal pain, rectal bleeding, diarrhea, and intestinal perforation mimicking IBD or infectious colitis. Other gastrointestinal manifestations include gastritis, colitis and perirectal abscess. The extraintestinal manifestations of Crohn disease and WG may overlap. Pulmonary complications of IBD include bronchiolitis obliterans, interstitial lung disease and granulomatous lung disease (6,7). IBD can also present with renal manifestations including hematuria because of renal calculi or rarely glomerulonephritis.
Our patient presented with abdominal pain and weight loss and had gastric, duodenal and colonic erosions at endoscopy. These findings in conjunction with the biopsy changes and a positive ASCA were highly suggestive of Crohn disease. In addition, he had a dramatic improvement with initiation of prednisone and 5-ASA therapy. The subsequent development of dyspnea, hemoptysis and review of his full-thickness appendectomy specimen led to the diagnosis of WG.
The diagnosis of WG is usually suggested by a typical pattern of organ involvement and confirmed by histopathological evidence of vasculitis, granulomatous inflammation and necrosis (8). Antineutrophilic cytoplasmic antibodies (ANCA), specifically c-ANCA, are elevated in up to 90% of patients with WG. The targeted antigen has been identified as PR-3. Proteinase-3 is a neutral serine protease localized in the azurophilic granules of the neutrophils and myeloperoxidase-positive monocytes. It is involved in the enzymatic degradation of elastin, hemoglobin, type IV collagen, fibronectin and laminin (9). The specificity of c-ANCA in WG varies from 80%-100% (10). Elevated levels of ANCA may be seen in other pediatric diseases including cystic fibrosis (c-ANCA) juvenile idiopathic arthritis, ulcerative colitis (p-ANCA) and Crohn disease (p-ANCA) (10-14). An elevated c-ANCA is suggestive of WG but is insufficient to establish the diagnosis and histopathological confirmation is required in patients with an atypical presentation (10). In our patient, the positive c-ANCA PR-3 helped establish the diagnosis of WG. This test was particularly helpful in a patient whose initial gastrointestinal symptoms were suggestive of IBD and who was ASCA positive. ASCA recognize mannose sequences inthe cell wall mannan of S. cerevisiae and is a non-autoantigen in IBD (15). Although the reason why patients with Crohn disease develop ASCA positivity is unknown, this antibody is thought to be highly specific for Crohn disease (13,15-17). Although WG has been associated with positive ANCA testing, to our knowledge it has not been associated with false positive ASCA testing. ASCA positivity is not 100% specific for Crohn disease with positive tests occurring in some patients with celiac disease, autoimmune hepatitis and in healthy relatives of patients with Crohn disease (15,16).
Initial therapy of WG includes steroids and cyclophosphamide in severe cases. Methotrexate is an alternative in patients with less severe disease and has been used with good results in pediatric patients (18,19). Originally WG in adults had a high mortality with an average survival of only 5 months. Treatment with glucocorticoids and cyclophosphamide has improved the mean survival to more than 80% at 5 years. A recent retrospective study in adults demonstrated that treatment with cyclophosphamide and corticosteroids resulted in a 10-year survival rate of 75%, but therapy did not prevent severe organ damage (20). Morbidity and mortality data in pediatric patients indicate that treatment with glucocorticoids and cyclophosphamide results in a 5-year survival rate of 94% (1). In pediatric patients chronic renal failure is the major cause of long-term morbidity (2,21). Permanent morbidity from nasal deformities and subglottic stenosis seems to be more frequent in children than in adults (1,21).
Wegener granulomatosis is an uncommon disorder in pediatric patients which may present primarily with gastrointestinal complaints mimicking IBD. The pathological findings may be similar to Crohn disease with patchy intestinal involvement and granulomas on biopsy. WG may initially respond to the medication used to treat IBD. Therefore, a high index of suspicion is required to diagnose WG. Sinopulmonary or renal symptoms in a patient with suspected IBD should raise the possibility of WG. An elevated c-ANCA proteinase-3 in an appropriate clinical setting is strongly suggestive ofWG. Examination of full-thickness biopsy specimens, if available, may also help to establish the diagnosis. It isimportant for pediatric gastroenterologists to differentiate these 2 conditions, as appropriate initiation of cyclophosphamide therapy appears to significantly improve long-term outcome in patients with WG.
The authors would like to thank Martha Yearsley, MD, for assistance in manuscript preparation.
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