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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 3  |  Page : 639-644
An overlap of granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis

Department of Nephrology, Government Stanley Medical College and Hospital, Chennai, Tamil Nadu, India

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Date of Web Publication18-May-2017


We present a case report of overlap of granulomatosis with polyangiitis (GPA; formerly known as Wegener’s granulomatosis) and eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome). We report a 45-year-old female who presented with rapidly progressive renal failure associated with fever, polyarthralgia, and respiratory symptoms with cytoplasmic antineutrophilic cytoplasmic antibody (ANCA) and proteinase (PR-3) antigen positivity. Computerized tomography scan of the chest showed diffuse alveolar hemorrhage with renal biopsy revealing pauci-immune necrotizing crescentic glomerulonephritis with intense eosinophilic infiltration suggestive of eosinophilic GPA (EGPA). Our patient had ANCA-associated vasculitis (AAV) with features suggestive of both GPA and EGPA. She was treated with methylprednisolone and cyclophosphamide and attained remission after 2 weeks of therapy. This is a rare report of a patient with AAV having features of both EGPA and GPA.

How to cite this article:
Surendran S, Gundappa C, Gandhi A, Kurien AA, Fernando E. An overlap of granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. Saudi J Kidney Dis Transpl 2017;28:639-44

How to cite this URL:
Surendran S, Gundappa C, Gandhi A, Kurien AA, Fernando E. An overlap of granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 Nov 19];28:639-44. Available from: http://www.sjkdt.org/text.asp?2017/28/3/639/206450

   Introduction Top

Polyangiitis overlap syndrome is defined as systemic vasculitis that cannot be classified into any of the well-defined vasculitic syndromes. Establishing a proper diagnosis and introduction of appropriate treatment in patients with this rare and serious pathology is crucial to prevent irreversible organ damage.

   Case Report Top

A 45-year-old female with a history of symmetrical small and large joint arthralgia with early morning stiffness for three months, followed by respiratory symptoms in the form of cough with expectoration, epistaxis, and hemoptysis for one month, presented to our department with sudden onset of facial puffi- ness, pedal edema, and oliguria.

General physical examination revealed pallor, facial puffiness, bilateral pitting pedal edema, proptosis of right eye, and saddle nose deformity. She was dyspneic and her blood pressure was 150/100 mm Hg. Examination of the cardiovascular, abdomen, and neurological systems was normal. Respiratory system examination revealed bilateral rhonchi and crepitations. Urine analysis revealed proteinuria with microscopic hematuria. Her serum crea- tinine was 5.2 mg/dL and blood urea nitrogen was 120 mg/dL. Hematological evaluation showed hemoglobin of 5.8 g/dL, total leukocyte count of 10,000 cells/mm3, and platelet count of 4.56 lakhs/mm3. Peripheral smear showed normocytic normochromic anemia and the erythrocyte sedimentation rate was 95 mm/h. Her random blood sugar was 109 mg/ dL. Antineutrophilic antibody and rheumatoid factor were negative. Complement levels were normal. Computerized tomography (CT) scan of the chest was suggestive of diffuse alveolar hemorrhage involving upper and middle lobes of the right lung with sparing of peripheries. Ultrasonography of the abdomen showed normal sized kidneys. Serological tests for human immunodeficiency virus and hepatitis B and C virus were negative. She was diagnosed as having rapidly progressive glomerulonephritis and renal biopsy was performed.

The biopsy revealed 23 glomeruli, of which two were globally sclerotic, and there was rupture of Bowman’s capsule in 10 glomeruli. Fibrinoid necrosis of the capillary tuft was noted in four glomeruli. In the remaining glomeruli, crescents compressed and distorted the capillary tuft architecture [Figure 1]. No capillary proliferation was seen. A dense inflammatory infiltrate consisting of large number of eosinophils with plasma cells was seen in the interstitium along with ill-defined granulomas [Figure 2]. These findings were suggestive of pauci-immune necrotizing cre- scentic glomerulonephritis and eosinophilic granulomatosis with polyangiitis (EGPA).
Figure 1: Cellular crescents (arrows) encircling and destroying the capillary tuft in all 3 glomeruli. All viable glomeruli showing cellular crescents (PAS, ×200).

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Figure 2: A large number of eosinophils in the interstitium (H and E, ×1000) (Inlet showing an eosinophil).

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Her further evaluation revealed positivity for cytoplasmic antineutrophilic cytoplasmic antibody (C-ANCA) by indirect immunofluore- scence (IFA) method. Proteinase-3 (PR-3) antigen was positive by enzyme-linked immune sorbent assay (ELISA). Absolute eosinophil count was in the upper limit of normal (460 cells). Serum IgE level was elevated (110 IU/mL).

CT scan of the paranasal sinuses revealed nasal septal perforation with pansinusitis. Endoscopic maxillary sinus biopsy revealed diffuse sheets of inflammatory cells with occasional eosinophils. No eosinophils were noted on bronchioalveolar lavage (BAL). Smear from BAL had only inflammatory cells.

CT scan of the orbit revealed no retro-orbital soft tissue enhancement or mass lesion. Nerve conduction study showed bilateral lower limb sensory axonal neuropathy and right median sensory axonal neuropathy. Her echocardio- gram was normal.

With these findings, ANCA-associated vas- culitis with features overlapping both EGPA and GPA was diagnosed. Patient was initiated on hemodialysis immediately, and methyl- prednisolone 1 g was administered intravenously for three days followed by intravenous cyclophosphamide 750 mg as pulse therapy. She was subsequently switched over to oral prednisone 50 mg/day.

The patient improved symptomatically, her urine output increased, and the facial puffiness and pedal edema subsided. Thus, the patient attained clinical remission.

   Discussion Top

ANCA-associated vasculitis is a multisystem disorder involving mainly kidneys and respiratory system.

There is substantial overlap in many of the clinical features of the ANCA-associated vas- culitides. In some cases, distinguishing between two or more of these syndromes clinically is difficult. Some salient features of GPA and EGPA are showed in [Table 1]. We discuss the major organs involved.
Table 1: Clinical and laboratory findings in eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis.

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The kidneys are involved in 80% of patients with GPA (formerly known as Wegener’s granulomatosis) and 45% of patients with eosinophilic granulomatosis with polyangiitis [EGPA; formerly known as Churg-Strauss (CS syndrome)].[1] A variety of acute and chronic lesions can be observed in renal biopsies from patients with ANCA disease. The most common and most distinctive histopathologic features of ANCA pauci-immune crescentic glomerulonephritis are glomerular necrosis and crescents.[2],[3] In an analysis of 232 renal biopsy specimens with ANCA-positive pauci- immune renal disease who were evaluated at the University of North Carolina Nephropatho- logy Laboratory, 75% had both glomerular necrosis and crescent formation and this involved over 50% of glomeruli in 48% of specimens.[4] Comparatively mild, possibly early, acute disease with focal necrosis but no crescents was observed in only 3% of specimens. Extensive crescent formation involving more than 50% of glomeruli in the absence of active necrosis was seen in 4%. Either focal (4%) or diffuse (12%) sclerosing glome- rulonephritis with no necrosis and no cellular crescents was seen in 16% of specimens, presumably representing a chronic phase of disease. On light microscopy, no lesions or only tubulointerstitial inflammation was identified in 1% each.

In most cases, the glomerulonephritis is indistinguishable among the ANCA-associated vasculitides. Granulomas are observed only occasionally in the renal biopsies from patients with Wegener’s granulomatosis (WG). The presence of eosinophils on biopsy specimens, although characteristic of CS syndrome, may also be seen in WG and microscopic poly- angiitis. The presence of large numbers of eosinophils, however, is typical of the CS syndrome.[5]

Although patients with CS syndrome may experience substantial ear, nose, or sinus disease, this pattern of involvement is more characteristic of WG. More than 90% of patients with WG eventually develop upper airway or ear abnormalities.[6],[7]

Nasal inflammation may lead to septal erosions, septal perforation, or, in many cases, nasal bridge collapse and the “saddle-nose deformity.” Two principal categories of ear disease such as conductive and sensorineural hearing loss are typical of WG.[8],[9],[10]

Orbital masses termed pseudotumors, which are characteristic of WG, typically occur in retrobulbar location, causing proptosis, diplo- pia, or visual loss. In WG, the pulmonary manifestations range from asymptomatic lung nodules and fleeting (or fixed) pulmonary infiltrates to fulminant alveolar hemorrhage. The nodules are usually multiple and bilateral and often cavitary. Obstructive airway disease and fleeting pulmonary infiltrates are the hallmarks of CS syndrome. In majority of patients, there is an onset of asthma followed by the onset of overt vasculitis months to years later. Chest radiographs are abnormal, however, in only one-third of patients.[11]

Our patient had septal perforation; the saddle nose deformity and proptosis of eyes which is characteristic of granulomatosis with poly- angiitis, the GPA only.

Mononeuritis multiplex occurs more commonly in CS syndrome (up to 78%) of pa- tients[12] and microscopic polyangiitis (up to 58%)[11] than in WG.

Eosinophilia (before treatment) is a sine qua non of CS syndrome. Mild eosinophilia (up to 15% of the total white blood cell count) may also occur in WG.

As a screening assay, indirect immunofluo- rescence (IIF) using ethanol-fixed human neu- trophils reveals two major staining patterns of antibody binding to neutrophils comprising a cytoplasmic pattern (cANCA) and a perinuclear pattern (pANCA). Detection of proteinase-3 (PR-3) and myeloperoxidase (MPO) ANCA is made by antigen-specific ELISA. The c- ANCA pattern usually equates to specificity for PR3-ANCA, and pANCA usually equates to MPO-ANCA.[1]

Proteinase-3, usually c-ANCA, positivity occurs in 70% of patients with granulomatosis with polyangiitis and in 5% of patients with eosinophilic granulomatosis with polyangiitis. MPO, usually p-ANCA, positivity occurs in 25% of patients with granulomatosis with polyangiitis and in 40% of patients with eosi- nophilic granulomatosis with polyangiitis.[1]

Our patient had c-ANCA positive by IIF and PR-3 positivity by ELISA. The American College of Rheumatology criteria are used for diagnosing vasculitis.

Four criteria were selected for GPA: (a) abnormal urinary sediment (red cell casts or greater than five red blood cells per high- power field), (b) abnormal findings on chest radiograph (nodules, cavities, or fixed infiltrates), (c) oral ulcers or nasal discharge, and (d) granulomatous inflammation on biopsy.[13]

The presence of two or more of these four criteria was associated with a sensitivity of 88.2% and a specificity of 92%.

Our patient had abnormal urinary sediment and granulomatous inflammation on renal biopsy.

Six criteria were selected for EGPA: (a) asthma, (b) eosinophilia greater than 10% on differential blood cell count, (c) mononeuro- pathy (including multiplex) or polyneuropathy, (d) nonfixed pulmonary infiltrates on chest radiograph, (e) paranasal sinus abnormality, and (f) biopsy containing a blood vessel with extravascular eosinophils.[14]

The presence of four or more of these six criteria gave a sensitivity of 85% and a specificity of 99.7%.

Our patient is an asthmatic, had mononeuritis multiplex, nonfixed pulmonary infiltrates on chest radiograph, and paranasal sinus radiography. Thus, she fulfilled the American College of Rheumatology diagnostic criteria for GPA and EGPA.

In our case, the presence of polyarthritis, pan- sinusitis, C-ANCA positivity, the clinical presentation of rapidly progressive glomerulo- nephritis, and mononeuritis multiplex favors both EGPA and GPA. The presence of a history of asthma and tissue eosinophilia favors EGPA. The presence of nasal septal perforation and proptosis of eye favors GPA.

Polyangiitis overlap syndrome is defined as systemic vasculitis that cannot be classified into one of the well-defined vasculitic syndromes. To our knowledge, this is the second case report of overlap of GPA and EGPA. There is another case report about this overlap.[15] In this report, a female patient who presented with vasculitis-like and asthmatic symptoms was diagnosed as having poly- angiitis overlap syndrome with GPA and EGPA.

In the 2012 Chapel Hill Consensus Conference system, small-vessel vasculitis was subdivided into ANCA-associated vasculitis (AAV) and immune-complex small-vessel vasculitis. An AAV is defined as a group of necrotizing vasculitides with few or no immune deposits, predominantly affecting small vessels, associated with ANCA. AAV included MPA, GPA, and EGPA. Among the types of small- vessel vasculitis, MPA, WG, and EGPA have common characteristics; the affected vessels are arterioles, capillaries, and venules; the most common organs affected are the kidney and lung, and they involve ANCA as the common pathogenesis. Godman and Churg suggest that these three forms of vasculitis comprise “a continuous spectrum of tissue changes from pure necrosis and granuloma formation to pure angiitis with intermediated combinations,” and that these processes are related pathogenetically.[16]

Conflict of interest: None declared.

   References Top

Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997;337:1512-23.  Back to cited text no. 1
Vizjak A, Rott T, Koselj-Kajtna M, Rozman B, Kaplan-Pavlovcic S, Ferluga D. Histologic and immunohistologic study and clinical presentation of ANCA-associated glomerulo- nephritis with correlation to ANCA antigen specificity. Am J Kidney Dis 2003;41:539-49.  Back to cited text no. 2
Hauer HA, Bajema IM, van Houwelingen HC, et al. Renal histology in ANCA-associated vasculitis: Differences between diagnostic and serologic subgroups. Kidney Int 2002;61:80-9.  Back to cited text no. 3
D’Agati V, Jennette JC, Silva FG. Non- neoplastic renal disease. Washington: American Registry of Pathology, 2005:385.  Back to cited text no. 4
Seo P, Stone JH. The antineutrophil cyto- plasmic antibody-associated vasculitides. Am J Med 2004;117:39-50.  Back to cited text no. 5
Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: An analysis of 158 patients. Ann Intern Med 1992;116:488-98.  Back to cited text no. 6
Stone JH, Wegener’s Granulomatosis Etanercept Trial Research Group. Limited versus severe Wegener’s granulomatosis: Baseline data on patients in the Wegener’s granulomatosis etanercept trial. Arthritis Rheum 2003;48: 2299-309.  Back to cited text no. 7
Kornblut AD, Wolff SM, Fauci AS. Ear disease in patients with Wegener’s granulo- matosis. Laryngoscope 1982;92(7 Pt 1):713-7.  Back to cited text no. 8
Kempf HG. Ear involvement in Wegener’s granulomatosis. Clin Otolaryngol Allied Sci 1989;14:451-6.  Back to cited text no. 9
Bennett RW, Staker LV. Wegener’s granulo- matosis presenting as vertigo. West J Med 1987;146:359-61.  Back to cited text no. 10
Chumbley LC, Harrison EG Jr., DeRemee RA. Allergic granulomatosis and angiitis (Churg- Strauss syndrome). Report and analysis of 30 cases. Mayo Clin Proc 1977;52:477-84.  Back to cited text no. 11
Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, Casassus P. Churg-Strauss syndrome. Clinical study and long-term follow-up of 96 patients. Medicine (Baltimore) 1999;78: 26-37.  Back to cited text no. 12
Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’ s granulomatosis. Arthritis Rheum 1990;33: 1101-7.  Back to cited text no. 13
Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990;33:1094-100.  Back to cited text no. 14
Uematsu H, Takata S, Sueishi K, Inoue H. Polyangiitis overlap syndrome of granulo- matosis with polyangiitis (Wegener’s granulo-matosis) and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). BMJ Case Rep 2014;2014. pii: Bcr2013010195.  Back to cited text no. 15
Jennette JC, Falk RJ. Clinical and pathological classification of ANCA-associated vasculitis: What are the controversies? Clin Exp Immunol 1995;101 Suppl 1:18-22.  Back to cited text no. 16

Correspondence Address:
Chandramohan Gundappa
Department of Nephrology, Government Stanley Medical College and Hospital, Chennai - 600 001, Tamil Nadu
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DOI: 10.4103/1319-2442.206450

PMID: 28540906

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  [Figure 1], [Figure 2]

  [Table 1]


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