Van der Woude syndrome

Christine Lenclud, M.D.;(*1) Paul De Vuyst, M.D.;(*1) Etienne Dupont, M.D.;([unkeyable]) Michel Depierreux, M.D.;([unkeyable]) Paulette Ketelbant, M.D.;([unkeyable]) Michel Goldman, M.D.; Section

Anti-neutrophil-cytoplasm antibodies recently have been reported as serologic markers of Wegener's granulomatosis. We describe two cases in which this test appeared to be of great value in the diagnosis of Wegener's granulomatosis presenting as acute respiratory failure, a clinical setting in which it may be the only diagnostic test that can be safely and easily performed.

Wegener's granulomatosis is an uncommon disease characterized by necrotizing granulomatous lesions of the upper and lower respiratory tract, glomerulonephritis, and small vessel vasculitis.[1,2] Classically, the diagnosis requires evidence of both necrotizing vasculitis and granulomas in one or more of the affected organs,[3] the lung tissue being the best site for histologic diagnosis.

Recently, ANCA have been demonstrated in the sera of patients presenting with Wegener's granulomatosis. It has been suggested that the titer of these antibodies could reflect disease activity.[4] In this article, we report two cases of Wegener's disease presenting as acute respiratory failure with circulating ANCA.

CASE REPORTS

CASE 1

A 69-year-old woman was admitted to the hospital with a one-month history of fever, productive cough with blood-streaked sputum, asthenia and anorexia. A few days before admission, she had conjunctivitis, which was treated with locally applied corticosteroids. For one year, she had complained of vertigo and headache. Physical examination showed a dullness and inspiratory crackles at the right lung base. Initial laboratory studies were as follows: WBC, 18,500/cu mm, with 70 percent neutrophils; ESR, 105 mm/L h; fibrinogen, 750 mg/100 ml; LDH, 322 U/L. Other routine laboratory tests were normal. The chest x-ray film showed an infiltrate at the right lung base. A diagnosis of infectious pneumonitis was made and erythromycin was given, 3 g daily. Cultures of blood, sputum and urine were negative. Serologic tests for Mycoplasma, Legionella, Chlamydia, Psittaci and respiratory viruses were also negative. Fiberoptic bronchoscopy revealed a diffuse inflammatory mucosa with abundant mucopurulent and bloody secretions. The sputum cultures remained negative for acid-fast bacilli. Fever persisted and the chest x-ray film showed extension of the infiltrate to the entire right lung field. On the seventh hospital day, erythromycin was replaced by gentamicin and cefotaxime without clinical improvement. On the 14th hospital day, she developed acute respiratory failure calling for intubation and ventilation, and acute renal failure for which iterative hemodialysis was started. Urinalysis showed microscopic hematuria and proteinuria (0.8 g/L). Serum electrophoresis, complement studies for [C.sub.3], [C.sub.4] fractions and [CH.sub.50] were normal. Circulating immune complexes, antinuclear antibodies and antiglomerular basement membrane antibodies were absent. On day 21, she developed a coma without focal neurologic signs. The cerebral CAT scan showed significant hydrocephaly requiring ventriculoperitoneal derivation. An open-lung biopsy was done at the same time. Microscopic examination of the lung tissue showed characteristic lesions of Wegener's granulomatosis with granulomas and necrotizing vasculitis (Fig 1). At the same time the immunofluorescence test for autoantibodies against neutrophil cytoplasmic antigens (ANCA) was positive. This test was performed on granulocytes prepared from healthy blood donors by sedimentation of heparinized blood on dextran followed by Ficoll-Hypaque gradient centrifugation. They were adjusted at 1.5 [10.sup.6]/ml in RPMI 1640 (Gibco) supplemented with 20 percent fetal calf serum. Cells were centrifuged on glass slides by a Shandon Cytospin 2 at 1,000 rpm and fixed in ethanol. After incubation with the patient's serum, flourescein-conjugated goat antihuman IgG (Nordic, Tilburg, The Netherlands) was added. The serum titer, defined as the highest serum dilution giving an intracytoplasmic fluorescence, was 1:512.

The patient received prednisolone and cyclophosphamide but died a few days later from septic shock caused by a Staphylococcus aureus infection originating from a central venous catheter. Postmortem examination showed pulmonary lesions similar to those described at open-lung biopsy, as well as a focal proliferative necrotizing glomerulonephritis with crescent formation. Other findings included endocarditis on mitral and tricuspid valves and an important dilation of the brain's ventricular system, which was of unknown origin.

CASE 2

A 70-year-old man was admitted for increasingly severe dyspnea and recurrent hemoptysis. One month before admission, he began to experience exertional dyspnea without orthopnea, cough and mocous expectoration, asthenia, anorexia, headache, ottis and conjunctivitis, aqueous rhinorrhea, diffuse myalgia and arthralgia. Two weeks before admission, he developed spiking fever reaching 39 degrees C. Amoxicillin and cefazolin were given successively without clinical benefit. One week before admission, he presented several episodes of abundant hemoptysis. The patient was pale, tachypneic and looked acutely ill. Blood pressure was 130/70 mm Hg; heart rate, 88 beats per minute, regular; temperature, 38.3 [degrees] C; and respiratory rate, 28 breaths per minute. No rash or lymphadenopathy was found. Head and neck examination disclosed purulent conjunctivitis of the left eye, otitis media of the left ear, and aqueous rhinitis. Lung examination disclosed inspiratory crackles scattered over the whole lung fields. Arterial blood pH was 7.52; [PO.sub.2], 47 mm Hg; and [PCO.sub.2], 27 mm Hg. Laboratory tests were as follows: hemoglobin level, 7.5 g/100 ml with normal RBC indices; WBC count, 14,900/cu mm, with 83 percent neutrophils; platelet count, 451,000/cu mm; ESR, 32 mm/L h; fibrinogen, 551 mg/100 ml; CRP, 28 mg/100 ml; BUN, 32 mg/100 ml; creatinine, 1.3 mg/100 ml. Urinalysis showed 0.2 WBCs and 6.20 RBCs per high power field without significant albuminuria. Results of all other routine laboratory studies were normal. The chest x-ray film disclosed a diffuse bilateral interstitial infiltration with areas of airspace consolidation; the size of the heart was normal (Fig 2). Fiberoptic bronchoscopy showed fresh blood in the whole bronchial tree; no endobronchial lesion was observed. Bronchoalveolar fluid collected from the right middle lobe contained 527,000 RBC/cu mm. Immunofluorescence examinations and cultures for M pneumoniae, L pneumophila and cytomegalovirus were negative. Hemodynamic parameters were as follows: central venous pressure, 9 cm [H.sub.2]O; pulmonary arterial pressure, 35/17 mm Hg; mean, 23 mm Hg; pulmonary capillary wedge pressure, 15 mm Hg; right cardiac output, 5.78 L/min. The patient was increasingly dyspneic and hypoxemic ([PaO.sub.2]: 49 mm Hg with a [FIo.sub.2] of 40 percent) and was admitted to the intensive care ni t. A diagnosis of immune alveolar hemorrhage putatively due to Wegener's granulomatosis was made. Immunologic studies including the detection of antinuclear factor, anti-basement membrane antibodies and ANCA were immediately performed. The results of immunologic tests were negative except for ANCA present at high titer by indirect immunofluorescence (1/512) as well as by ELISA. The antigenic subtrate of this assay is made of [unkeyable] granule extracts obtained by cavitation with nitrogen bombs[5] and results are considered positive if above the mean [+ or - 3] SD of a panel of healthy controls.

After administration of methylprednisolone 1 g per day intravenously, and cyclophosphamide, 1 g/m[2] intravenously, the patient rapidly recovered a satisfactory pulmonary function. Chest x-ray films showed a decrease of the interstitial disease and consolidation after four days of therapy. A renal biopsy performed because of acute renal failure showed focal proliferative necrotizing glomerulonephritis. The patient transiently required hemodialysis but could be discharged from the hospital one month after admission with a moderate inflammatory syndrome and a mild impairment of his renal function (BUN, 54 mg/100 ml; creatinine, 1.9 mg/100 ml). At this time, treatment consisted of cyclophosphamide (150 mg/day) and prednisolone (45 mg/day). Four months later, he died in a marastic state after the development of pulmonary aspergillosis and Gram-negative septicemia of urinary origin. At necropsy, the lungs displayed peri-arterial granulomatous formations made of mononuclear and histiocytic cells with disruption of the internal elastic lamina (Fig 3). In addition, endocarditis vegetations and focal renal sclerosis were observed.

DISCUSSION

In 1985, Van der Woude et al[4] reported the presence of IgG autoantibodies against cytoplasmic components of neutrophils (ANCA) in the serum of patients with Wegener's granulomatosis. Subsequently, ANCA were found in patients with classic polyarteritis nodosa, microscopic polyarteritis as well as in patients with necrotizing and crescentic glomerulonephritis.[6,7] Recently Falk and Jennette[7] have reported positive reactions but with lower titers in a few patients with systemic lupus erythematosus while no antibodies were detected among normal individuals. Two types of antibodies were identified by indirect immunofluorescence microscopy and ELISA. Autoantibodies that artifactually distribute in a perinuclear pattern on alcohol-fixed neutrophils on immunofluorescence microscopy had specificity for myeloperoxidase by ELISA, whereas antibodies that produce diffuse cytoplasmic immunostaining did not display such reactivity.[7] Both types of antibodies were detected in the necrotizing vasculitides. The presence of ANCA in these diseases could reflect a common pathogenetic mechanism, but the relationship between ANCA and vascular injury has not been elucidated so far. Interestingly, if it is urgently required, ANCA detection can be performed in less than 3 h.

The diagnosis of Wegener's disease requires evidence of both necrotizing vasculitis and granulomas in one or more of the affected sites.[3] In this respect, airway biopsy is a noninvasive procedure which is sometimes useful, but very often it will only show nonspecific inflammatory changes.[3] As in our cases, renal biopsy often demonstrates focal necrotizing glomerulonephritis without evidence of granulomas.[3] This procedure is mainly indicated to evaluate the intensity and the potential reversibility of the renal lesions. Granulomas and vasculitis most often are present in open-lung biopsy specimens.[3] However, in the particular setting of alveolar hemorrhage, lung biopsy frequently fails to identify the underlying disease.[8] In addition, thoracotomy carries a considerable risk in severely ill patients. In only a few cases, the diagnosis could be established by transbronchial biopsy, which still remains an agressive technique.[9-11]

In conclusion, the demonstration of ANCA in the setting of acute respiratory failure provides an early diagnostic indication for necrotizing vasculitis and particularly for Wegener's granulomatosis. We suggest that appropriate immunosuppressive therapy could be started as soon as the presence of ANCA in the serum has been demonstrated.

ACKNOWLEDGEMENT: The ELISA was performed using a kit kindly provided by Dr. Wieslander (Biocarb, and University of Lund, Sweden).

(*1) Chest,

([unkeyable]) Immunology,

([unkeyable]) Pathology, and

(Section) Nephrology Departments, Erasme Hospital, Free University of Brussels, Beligum.

REFERENCES

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4 Van der Woude FJ, Rasmussen N, Lobatto S, Wiik A, Permin H, Van Es LA, et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet 1985; 1:425-29

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11 Ackerman Z, Orbach H, Burstein M, Breuer R. Transbronchial biopsies in Wegener's granulomatosis. Ann Intern Med 1986; 105:801-02

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