Wegener granulomatosis – an atypical case

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  • Abstract An unusual sequence of the clinical manifesta-tions of microvascular disease is described in a 15 year-old girl. She initially presented with acute renal failurecaused by a crescentic glomerulonephritis associatedwith positive tests for MPO-ANCA. Eighteen monthslater she had pulmonary hemorrhage and respiratory fail-ure. An open lung biopsy showed granulomas that werediagnostic for Wegener granulomatosis. We discuss thediagnostic dilemmas faced in attempts to distinguish in-fective causes of pulmonary granulomas, such as tuber-culosis or fungi, from granulomas associated with vascu-litis, in a patient previously treated with immunosuppres-sive therapy.

    Key words Wegener granulomatosis Anti-neutrophiliccytoplasmic antibodies Small-vessel vasculitis

    Case presentation

    A 15-year-old girl presented to the emergency room of another hospital with abdominal pain, vomiting, andrespiratory distress. She had been well until 2 weeksprior to this, when she developed fatigue and facial edema. There was no history of rash, arthritis, fever, hematuria, or oliguria. She had not taken any medica-tions/drugs and did not smoke. The family history was

    negative for renal diseases. Growth and developmentwere normal.

    Physical examination revealed pallor, facial and pedaledema, hypertension (150/100 mmHg), tachypnea, dif-fuse rales bilaterally, and a 2/6 precordial ejection sys-tolic murmur. There were no rashes, arthritis, adenopa-thy, fever, or hepatosplenomegaly.

    Laboratory investigation revealed: blood urea nitrogen140 mg/dl, and serum potassium 6.8 mEq/l, creatinine10.5 mg/dl, calcium 7.5 mg/dl, and albumin 2.2 g/dl. Thehemoglobin concentration was 3.1 g/dl, the sedimentationrate 46 mm/h, and platelet count 200,000/mm3. Urinaly-sis revealed: 3+ protein, hematuria, red blood cell casts,and tubular epithelial casts.

    Chest X-ray revealed cardiomegaly, pulmonary ede-ma, and a small pleural effusion. An echocardiogramshowed normal cardiac function and a small pericardialeffusion. Renal ultrasonography demonstrated normal-sized kidneys with increased echogenicity. She was ad-mitted to the intensive care unit and treated with hemo-dialysis for acute renal failure and intravenous solumed-rol for presumed rapidly progressive glomerulonephri-tis. A renal biopsy was performed on the 2nd hospitalday.

    Histopathological findings (Marta Guttenberg, M.D.,Pathologist, The Childrens Hospital of Philadelphia)

    Light microscopy of the renal biopsy showed a majorityof the glomeruli with a pattern of proliferative glomeru-lonephritis with cellular and fibrous crescent formation.There was tubular atrophy and an interstitial inflammato-ry infiltrate. Some blood vessels had thickened walls(Figs. 1, 2). Immunofluorescence showed strong mesan-gial and capillary loop staining with IgM and C3 anti-bodies. Extraglomerular blood vessels also stained withC3 antibodies. Electron microscopy showed epithelialand mesangial electron-dense deposits and effacement ofepithelial foot processes. The findings were consistentwith an immune-mediated crescentic glomerulonephritis.

    M. Pradhan K.E.C. Meyers B.S. KaplanDivision of Nephrology and Department of Pediatrics, The Childrens Hospital of Philadelphia,Pennsylvania, USAM. GuttenbergDepartment of Pathology, The Childrens Hospital of Philadelphia,Pennsylvania, USAB.S. Kaplan ()Department of Nephrology, The Childrens Hospital of Philadelphia, University of Pennsylvania, 34th Street and Civic Center Boulevard,Philadelphia, PA19104, USAe-mail: kaplanb@email.chop.eduTel.: +1-215-5902451, Fax: +1-215-5903705

    Pediatr Nephrol (2000) 14:862871 IPNA 2000

    G R A N D R O U N D S

    Madhura Pradhan Kevin E.C. Meyers Marta Guttenberg Bernard S. Kaplan

    Wegener granulomatosis an atypical case

    Received: 4 August 1999 / Revised: 28 October 1999 / Accepted: 3 January 2000

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    After the biopsy results were obtained, additionaltests were performed. The anti-neutrophil cytoplasmicantibody (ANCA) titer was >1:5,000 (perinuclear type).Anti-nuclear antibody was 1: 64, double-stranded DNAantibody was negative, and complement levels were nor-mal. Serum anti-glomerular basement membrane (GBM)antibodies and serological studies for hepatitis B andhepatitis C were negative. She was treated with cyclo-phosphamide (one intravenous dose of 1 g) and oral ste-roids (prednisone 20 mg every other day). She pro-gressed to end-stage renal disease (ESRD) while she wason steroids, and was then maintained on chronic hemodi-alysis. Eleven months later she began to cough andwheeze, and a chest X-ray showed an infiltrate in bothlower lobes. She was treated with bronchodilators andantibiotics.

    Subsequent course

    Eighteen months after the initial presentation she de-veloped cough, dyspnea, and hemoptysis. A chest film

    showed diffuse bilateral infiltrates (Fig. 3) which on com-puted tomographic (CT) scan appeared nodular (Fig. 4).On admission for the above symptoms she developed hyp-oxemia and was given one dose of intravenous methyl-prednisolone (1 g) before further tests were performed. Abronchoscopy and broncho-alveolar lavage (BAL) per-formed on the 2nd hospital day demonstrated inflamed

    Fig. 2 The renal interstitium shows tubular atrophy, mixed in-flammatory infiltrate, and thick-walled blood vessel (center), he-matoxylin and eosin (H&E), 30

    Fig. 3 The chest X-ray shows diffuse bilateral infiltrates, whichappear more prominent peripherally

    Fig. 4 The computed tomographic scan of the chest shows diffusebilateral nodular lesions

    Fig. 1 The glomerulus demonstrates crescentic glomerulonephri-tis with a fibrous crescent, compressed capillary loops, with me-sangial cell and matrix increase, periodic acid-Schiff, 30

  • ued. Three months later while the corticosteroids werebeing tapered, she again began to cough up blood, and achest X-ray showed increasing pulmonary infiltrates. Arepeat bronchoscopic study revealed acute pulmonaryhemorrhage. Three doses of intravenous methylprednis-olone (1 g) were given and oral cyclophosphamide (1 mg/kg per day) and prednisone (2 mg/kg per day)were started. She remained asymptomatic while on cy-clophosphamide and tapering doses of steroids for 6months. She has subsequently received a cadaver renalallograft and has no evidence of systemic vasculitis.


    This patient had atypical features of a vasculitic syn-drome, which raise important diagnostic and therapeuticquestions. She was initially thought to have microscopicpolyangiitis based on the crescentic glomerulonephritisand the presence of perinuclear staining (p-ANCA). How-ever she later developed pulmonary hemorrhage withgranulomas in her lung, typical of Wegener granulomato-sis. This case is instructive from several standpoints. First,Wegener granulomatosis is uncommon in children and ad-olescents. Second, this presentation with isolated renaldisease with ANCA-positive glomerulonephritis and a re-lapse with pulmonary symptoms 18 months later is atypi-cal. Third, the patient had evidence for Mycobacteriumavium intracellulare in the BAL performed at the time ofthe pulmonary relapse before institution of chronic immu-nosuppression. The patient subsequently had a recurrenceof pulmonary hemorrhage after having received anti-tu-berculous therapy for 2 months, while the corticosteroidswere being tapered, suggesting that the lung disease wasmost likely due to Wegener granulomatosis.

    The therapeutic dilemma in this patient when she de-veloped respiratory symptoms with evidence of pulmo-nary hemorrhage was whether to administer corticoste-roids without waiting for the diagnostic tests for infec-tion or whether to treat her for pulmonary infection. Al-though she had a history of ANCA-positive crescenticglomerulonephritis, her disease had been inactive for 18months while she was on hemodialysis, and therefore anew infectious process had to be considered as a possiblecause of her symptoms.

    Classification of vasculitis

    Wegener granulomatosis is classified as a small-vesselvasculitis (SVV) that includes microscopic polyangiitisand Churg-Strauss syndrome. In 1993 the Chapel HillConsensus Conference for the nomenclature of systemicvasculitis agreed on the names and definitions of many ofthe vasculitides that affect the kidney (Table 1). Patientswith SVV have a high frequency of ANCA that react withcytoplasmic constituents of neutrophils and monocytes [14]. Approximately 90% of cytoplasmic staining ANCA(c-ANCA) react with the serine proteinase called protein-


    mucosa, and microscopy revealed hemosiderin-ladenmacrophages. An open lung biopsy was performed on the3rd hospital day.

    Histopathological findings (Marta Guttenberg, M.D.)A wedge biopsy of the lung showed multiple necrotizingand non-necrotizing granulomas, and evidence of vasculitiswith irregular endothelial cell proliferation (Figs. 5, 6). Spe-cial stains for fungi and acid-fast organisms were negative.

    Cultures from the lung biopsy were negative for bac-teria, fungi, viruses, and Pneumocystis carinii. TheANCA titer was 1:80. A CT scan of the sinuses was nor-mal. She was treated with oral corticosteroids (1.5 mg/kgper day) as well as isoniazid, rifampicin, pyrazinamide,and ethambutol for possible pulmonary tuberculosis. Amonth later a specimen of respiratory secretions from theBAL performed on the 2nd hospital day (at that time shehad received a single dose of methylprednisolone) grewMycobacterium avium intracellulare, and the treatmentwas modified for atypical mycobacteria (azithromycinand rifampicin) but corticosteroid treatment was contin-

    Fig. 5 A distal airway that shows a non-caseating granuloma,H&E, 15

    Fig. 6 The small pulmonary artery shows cellular proliferation ofan endothelial cushion, consistent with healing vasculitis, tri-chrome, 15

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    ase 3 (PR3-ANCA) and 90% of the p-ANCA react withmyeloperoxidase (MPO-ANCA). c-ANCA are detectedmost commonly in patients with Wegener granulomatosisbut are not specific for this disease; 65% of patients withWegener granulomatosis have c-ANCA and 20% have p-ANCA [5]. p-ANCA are more commonly seen in micro-scopic polyangiitis. ANCA positivity in a patient with thesigns and symptoms of SVV confirms the presence ofsome form of ANCA-associated SVV. The characteristicpathological lesion of ANCA-associated vasculitis is focalfibrinoid necrosis of vessels with associated leukocyte in-filtration and necrotizing crescentic glomerulonephritis.Wegener granulomatosis is distinguished by the presenceof necrotizing granulomatous inflammation, Churg-Strauss by the presence of asthma and eosinophilia, andmicroscopic polyangiitis by the absence of granulomatousinflammation and asthma. ANCA-SVV is typically pauci-immune. However, in half the patients, variable degrees ofmesangial and/or parietal deposition of C3 and IgG areseen without features of any of the well-classified primaryimmune complex-mediated glomerulonephritides [6]. Falkand Jennette [5] evaluated 213 patients with glomerulone-phritis and crescent formation. They concluded that to beat least 80% predictive of ANCA disease, pauci-im-mune should be defined as 2+ or less staining for any im-munoglobulin and the absence of immune complex-typeelectron-dense deposits by electron microscopy [5, Fig. 7].

    Table 1 Names and definitions of vasculitis adopted by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitisa

    Large-vessel vasculitsGiant-cell (temporal) arteritis Granulomatous arteritis of the aorta and its major branches, with a predilection for the extra-

    cranial branches of the carotid artery. Often involves the temporal artery. Usually occursin patients over 50 years and is often associated with polymyalgia rheumatica

    Takayasu arteritis Granulomatous inflammation of the aorta and its major branches. Usually occurs in patientsunder 50 years

    Medium vessel vasculitisPolyarteritis nodosa Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis

    or vasculitis in arterioles, capillaries, or venulesKawasaki disease Arteritis involving large, medium-sized, and small arteries, and associated with mucocutaneous

    lymph node syndrome. Coronary arteries are often involved. Aorta and veins may be involved.Usually occurs in children

    Small-vessel vasculitisWegener granulomatosis Granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting

    small- to medium-sized vessels, e.g., capillaries, venules, arterioles, and arteries. Necrotizingglomerulonephritis is common

    Churg-Strauss syndrome Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizingvasculitis affecting small- to medium-sized vessels, and associated with asthma and blood eosinophilia

    Microscopic polyangiitis Necrotizing vasculitis with a few or no immune deposits, affecting small vessels, i.e., capillaries, venules, or arterioles. Necrotizing arteritis involving small- to medium-sized arteriesmay be present. Necrotizing glomerulonephritis is very common. Pulmonary capilllaritis oftenoccurs

    Henoch-Schnlein purpura Vasculitis with immunoglobulin A-dominant immune deposits, affecting small vessels, i.e., capillaries, venules, or arterioles. Typically involves skin, gut, and glomeruli, and is associatedwith arthralgias or arthritis

    Essential cryoglobulinemic vasculitis Vasculitis with cryoglobulin immune deposits, affecting small vessels, i.e., capillaries, venules,or arterioles, and associated with cryoglobulins in serum. Skin and glomeruli are often involved

    Cutaneous leukocytoclastic angiitis Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis

    a Printed with permission from reference [1]

    Fig. 7 Graph showing the frequency of anti-neutrophil cytoplas-mic antibody (ANCA) positivity as a function of the intensity ofglomerular staining for immunoglobulin. The data were obtainedfrom 213 patients with glomerular crescent formation. Patientswith anti-glomerular basement membrane antibodies and lupusglomerulonephritis patients were excluded (IF immunofluores-cence, ELISA enzyme-linked immunosorbent assay). Printed withpermission from reference [5]

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    Patients with anti-GBM glomerulonephritis and immunecomplex crescentic glomerulonephritis have a higher fre-quency of ANCA positivity than healthy controls [7, 8].ANCA, by acting in a synergistic manner with localizedimmune complex deposition, induce more severe inflam-mation in those patients with anti-GBM disease [7, 8].

    Clinical manifestations of Wegener granulomatosis in childrenWegener granulomatosis is a necrotizing granulomatousvasculitis of the upper and lower respiratory tract that isassociated with variable degrees of SVV that can involvejoints, skin, eyes, and ears [9]. Glomerulonephritis isseen in 77% of patients and completes the triad of upperand lower airway disease and kidney involvement; how-ever, renal disease is not a pre-requisite for the diagnosis[10]. The mean age of presentation is in the 4th to 5thdecade and presentation in childhood is uncommon. Ananalysis of 23 child...