Eosinophilic Granulomatous Polyangitis with Renal Granulomatous Angitis and Interstitial Eosinophilic Infiltration without Lung Granuloma

Eosinophilic granulomatous with polyangiitis (EGPA) is systemic vasculitis characterized by concomitant symptoms of asthma, allergic rhinitis, and marked increase in peripheral eosinophilia. It was previously known as Churg-Strauss syndrome. EGPA incidence in Japan is very low, with only approximately 1,800 cases reported. Renal involvement occurs in approximately 20-25% of EGPA patients, and the most typical expression is pauciimmune crescentic glomerulonephritis. We herein report a case of 69-year-old Japanese woman with fever and high titer of myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCA) and eosinophilia. Her renal biopsy showed massive interstitial nephritis with granulomatous vasculitis like lesion without apparent active crescent formation in glomeruli. Immediately after steroid treatment (prednisolone [PSL] 30 mg/day), she had symptomatic relief and was discharged with a reduction in MPO-ANCA.


Introduction
Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disorder involving small vessel antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which is defined as an eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels, which is associated with asthma and eosinophilia. Formerly known as Churg-Strauss syndrome, this eponym was replaced during the 2012 Revised International Chapel Hill consensus conference (CHCC) with the aim of focusing on the histopathology of the disease [1,2]. Unlike the 1990 American College of Rheumatology classification criteria and the former CHCC classification criteria, the 2012 CHCC reported for the first time that ANCA is found in EGPA, especially in patients with glomerulonephritis.
EGPA incidence in Japan is reported to be approximately 100 new cases annually, and the total number of EGPA patients was approximately 1,886 cases in 2008 [3]. EGPA incidence in Europe is 0.5-6.8 new cases per year per 1 million of the population, whereas its prevalence is 10.7-13 cases per 1 million of the population. It mostly affects individuals between 40 and 60 years old, and the mean age at diagnosis is 48 years [4].
We report one case of EGPA with renal granulomatous lesion, which is less frequent than EGPA with crescentic glomerulonephritis.

Case Report
A 69-year-old woman had a more than 40-year history of chronic sinusitis, allergic rhinitis, and diabetes mellitus, a 14-year history of bronchiectasis, and a history of autoimmune hemolytic anemia treated with corticosteroids 10 years previously that remained in remission with 5 mg of prednisolone. She had no family history of renal disease or dialysis.
She had a fever 1 month previously and was treated with antibiotics (clarithromycin [CAM]) for infectious disease). However, her symptoms did not show any improvement with CAM, and she developed fever, arthralgia, and myalgia within 2 weeks prior to admission despite a change in antibiotics to levofloxacin (LVFX).
Test results for myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCA) (288 U/ml), proteinuria, and urine occult blood were positive, and LVFX did not result in improvement; therefore, she was referred to our hospital for further evaluation and treatment. On physical examination, her temperature was 37.5°C and her blood pressure was 141/74 mmHg. Lower extremity edema without dyspnea was evident. She was prescribed bed rest without activity.
Fibrinoid necrosis of the interlobular artery was observed in the center of the granulomatous lesion.
There were no remarkable glomerular changes except for global sclerosis. Immuno-deposits of IgG, IgA, IgM, C1q, C3, and fibrinogen were absent.
Our patient was diagnosed as having definite EGPA because of the three main clinical findings (allergic rhinitis, eosinophilia and fever, myalgia and muscle weakness) and the histological finding (granulomatosis with eosinophilic infiltration around arteriole with fibrinoid necrosis) according to the diagnostic criteria of EGPA by Ministry of health and welfare in Japan.
She was treated with corticosteroids (PSL 30 mg/day) (Figure 3). Figure 3: Clinical course. 6 weeks prior to admission, her examination showed normal range of CRP, urinary protein (+), urinary occult blood (±). One month prior to admission, she showed antibiotics resistant fever and muscle weakness with gradually elevated CRP and anemia. After admission, she was diagnosed as EGPA by real biopsy and treated by corticosteroid therapy. After treatment with oral predonisolone at initial dose of 30 mg, hematuria, vasculitic symptoms were dramatically improved. She was discharged after PSL tapered.
Immediately after PSL administration, she had a normalized serum CRP level and showed dramatic symptomatic relief of her fever, arthralgia, muscle weakness, and myalgia. Anemia, proteinuria, and urine occult blood improved. PSL was tapered to 25 mg/day after 4 weeks, and she was discharged with a reduction in MPO-ANCA (17.3 U/ml).

Discussion
EGPA typically develops into three sequential phases marked by a progression of the main symptoms. The first phase, also called allergic, is most common during the second or third decade of life and is distinguished by asthma, allergic rhinitis, and sinusitis. Subsequently, the eosinophilic phase develops. The main pathological findings of this phase are increased peripheral eosinophilic count and eosinophilic organ infiltrations, especially in the lungs, heart, and gastrointestinal system. The third phase is vasculitic. During this last phase, the patient experiences the consequences of necrotizing vasculitis (e.g., peripheral neuropathy, crescentic glomerulonephritis), which is generally associated with vascular or extravascular granulomatosis, and constitutional symptoms like fever, malaise, and weight loss [5]. In this case, the woman had a history of allergic rhinitis since her second decade of life, which is a symptom of the first (allergic) phase.
ANCA is present in approximately 40-60% of patients; perinuclear ANCA is the prevalent pattern with antibody specificity for anti-MPO [5,6,7]. and granulomatosis with polyangiitis), renal involvement occurs in approximately 25% of EGPA patients; the most typical expression is pauci-immune crescentic glomerulonephritis, which has clinical features ranging from isolated urinary abnormalities (proteinuria, hematuria) to rapidly progressive glomerulonephritis [6]. Moosig also reported that renal involvement occurred in 18% of 150 monocentric cases in Germany [10]. It is suspected that MPO-ANCA induces abundant proinflammatory cytokines in EGPA as well as in mPA [11]. Our patient had an extremely high P-ANCA titer (> 300 U/ml) and renal involvement, which is consistent with previous reports. Her renal involvement included urinary abnormalities (proteinuria, hematuria) without Cr level elevation (0.8 mg/dl). Renal biopsy results revealed granulomatous changes, histiocytes and lymphocytes around the necrotizing interlobular artery, and massive interstitial infiltration of eosinophils and lymphocytes without apparent active crescent formation in glomeruli, which could be explained by renal involvement. Regarding renal granulomatous changes in EGPA, these are less commonly accompanied by crescent formation. Bajema reported that only 16 out of 157 systemic vasculitis patients showed renal granulomatous lesions; among these 16 patients, only two had EGPA [12]. We found only one case report of renal granulomatous lesions in EGPA [13]. In EGPA, lung granuloma is well known, but it may be accompanied by granulomatous lesions in the kidney.
We report a rare case of EGPA with renal granulomatous lesions and eosinophilic infiltration without crescent formation, respiratory symptoms, or lung granuloma. Necrotizing vasculitis as the renal involvement and lung granuloma as the respiratory involvement in EGPA are well known, but EGPA may be accompanied by granulomatous lesions in the kidney.

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