Granulomatosis and polyangitis followed by alveolar proteinosis in a 32-year-old woman.

A 32-year-old white woman reported worsening dyspnea for 1 month without cough or fever. She had received a diagnosis of granulomatosis and polyangitis (GPA) 13 months previously, confi rmed by kidney biopsy and an elevated serum antinuclear cytoplasmic antibody level. Her initial presentation of GPA included renal failure and alveolar hemorrhage with rash and arthralgias. At the time of our evaluation, she was dyspneic and hypoxemic with an oxygen saturation level of 86% on room air. She had bilateral diffuse rales without jugular venous distention, a cardiac gallop, rash, or synovitis. Her medications included 40 mg/d of prednisone and 75 mg/d of cyclophosphamide with double-strength trimethoprim-sulfamethoxazole 3 times weekly. She had not experienced a GPA recurrence previously. Her WBC count was 5,100 per m L with a hemoglobin count of 8.5 g/dL and a platelet count of 221,000 per m L. A CT scan of the chest ( Fig 1 ) revealed bilateral, diffuse ground-glass opacities. A subsequent bronchoscopy revealed a cloudy lavage that was negative for pathogenic infectious agents, includ ing Pneumocystis jiroveci . There was no evidence of diffuse alveolar hemorrhage. Her antinuclear cytoplasmic antibody pro fi le, erythrocyte sedimentation rate, and urinalysis results were normal. Lung function studies revealed an FVC of 2.70 L (74% predicted), a diffusing capacity of lung for carbon monoxide (D lco ) of 34% predicted, and a 6-min walk of 182 m with desaturation to 80% while receiving supplemental oxygen at 3 L/min by nasal cannula. Despite increasing the prednisone to 60 mg/d and cyclophosphamide to 100 mg/d for a presumptive recurrence of her vas culitis as well as using empirical antimicrobial therapy for infection, her condition failed to improve. An open-lung biopsy revealed prominent alveolar accumulation of proteinaceous material that was positive using periodic acid-Schiff stain and focal accu mulations of hemosiderin-laden macrophages without active vasculitis ( Fig 2 ). A whole-lung lavage was attempted, but signifi cant postoperative hypoxia and poor functional status allowed only a unilateral lavage. The lavage revealed opalescent, pink material that cleared by the completion of the procedure. Clinically, the patient continued to experience significant exertional dyspnea and hypoxemia. One week after the procedure, lung function studies revealed an FVC of 2.09 L (58% predicted) and a D lco of 32% predicted. A repeat chest CT scan 2 weeks after the attempted whole-lung lavage revealed persistent and diffuse ground-glass opacities. A serum antibody test for granulocytemacrophage colony-stimulating factor (GM-CSF) was negative on two separate determinations. Because of the reported risk of subcutaneous GM-CSF in patients who are immunosuppressed 1 and the suggestion of safety with the aerosolized form of GM-CSF in such patients, 2 we initiated the use of aerosolized GM-CSF with 250 m g bid Leukine (Immunex Corporation): 1 week on and 1 week off for 3 months. A chest CT scan 4 weeks after starting this therapy showed complete resolution of the ground-glass opacities. Lung function studies revealed an FVC of 3.42 L (95% predicted), a D lco of 70% predicted, and a 6-min walk of 337 m with a saturation of 97% on room air with walking. At a 6-month follow-up visit, the patient continued to be without dyspnea, cough, or exercise intolerance. Her lung function studies 9 months after presentation demonstrated an FVC of 3.66 L (102% predicted), a D lco of 71% predicted, and a 6-min walk of 346 m. She remained on standard immunosuppressive therapy without a GPA relapse. To our knowledge, this is the fi rst reported case of GPA and pulmonary alveolar proteinosis (PAP) occurring in the same patient. PAP was fi rst identifi ed in 27 patients and described by Rosen et al 3 in 1958 as “a remarkable disease of the lung that consists of the fi lling of alveoli by a periodic acid Schiff positive material rich in lipid.” This lipid rich-material was subsequently recognized to be surfactant. There are three forms of PAP: congenital, secondary, and acquired or idiopathic . 4 The treatment depends on the type and cause. We believe that the active pulmonary disease in the patient was PAP rather than GPA, in that she failed to respond to immunosuppressive therapy directed toward GPA and antimicrobial therapy directed at suspected infection. In addition, her open-lung biopsy was diagnostic of PAP without concomitant evidence of GPA. The time course of her improvement correlated with the treatment of PAP using aerosolized GM-CSF. 5 The acquired form of PAP is usually associated with autoantibodies to GM-CSF. 6 The patient did not demonstrate autoantibodies on two separate occasions,