A case of MPO-ANCA positive vasculitis associated with diffuse alveolar hemorrhage and various cardiac conducting system abnormalities following propylthiouracil treatment]

A 50-year-old woman had been treated with propylthiouracil (PTU) for hyperthyroidism. She was admitted to our hospital because of hemosputum, and severe hypoxemia developed. The CT scan showed diffuse infiltration in both lung fields, bronchoalveolar lavage fluid revealed diffuse alveolar hemorrhage, and the level of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) was high; and therefore diffuse alveolar hemorrhage associated with MPO-ANCA positive vasculitis induced by PTU was diagnosed. Following corticosteroid therapy initiated after the termination of PTU, the pulmonary infiltration rapidly improved and the patient's MPO-ANCA level returned to normal. Recrudescence of diffuse alveolar hemorrhage occurred following a reduction in steroids, but no recurrence was found after cyclophosphamide therapy was combined with steroid therapy. During the course of therapy, various cardiac conducting system abnormalities which correlate with the course of steroid therapy were found, indicating that cardiac conducting system abnormalities may be associated with MPO-ANCA-positive vasculitis.     

Myeloperoxidase-antineutrophil cytoplasmic antibody positive alveolar hemorrhage during propylthiouracil therapy for hyperthyroidism]

A 62-year-old woman had been treated with propylthiouracil(PTU) for hyperthyroidism. Because bloody sputum, dyspnea, and severe hypoxemia developed, the patient was admitted to our hospital. Chest X-ray and chest computed tomographic (CT) films disclosed diffuse infiltrative shadows in both lung fields. Bronchoalveolar lavage revealed abundant hemosiderin-laden macrophages. Alveolar hemorrhage associated with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) positive vasculitis syndrome was diagnosed because of the high serum level of MPO-ANCA. After the initiation of steroid therapy and termination of PTU, the infiltrative shadows in both lung fields disappeared, PaO2 improved, and MPO-ANCA decreased. There have been some reports of MPO-ANCA positive vasculitis syndrome developing during PTU therapy, but most were concerned with renal disease. We concluded that PTU and similar agents should be given consideration as one of the possible causes of MPO-ANCA-induced alveolar hemorrhage.     

Serum amyloid protein A was a useful marker for steroid tapering in a case of MPO-ANCA-associated vasculitis]

A 55-year-old man was admitted complaining of hemosputa, fever and dyspnea. The chest radiographs and computed tomography showed a diffuse alveolar filling pattern; suggesting alveolar hemorrhage. Laboratory data demonstrated renal dysfunction with hematuria and proteinuria and serum MPO-ANCA was also elevated. Respiratory failure progressed rapidly within two days. Steroid pulse therapy and plasmapheresis was performed. Thereafter, symptoms and chest radiograph findings improved dramatically. However proteinuria persisted as steroid administration was tapered. Renal biopsy demonstrated gromeluronephritis and interstitial lymphocyte infiltration. After administering a second course of steroid semi-pulse therapy, her proteinuria improved. C-reactive protein and MPO-ANCA decreased to normal levels after the initial steroid therapy, but serum amyloid A protein (SAA) gradually elevated. The second course of steroid pulse therapy normalized SAA, and proteinuria improved. Based on these findings, SAA seems to be a more sensitive marker for steroid tapering than either CRP or MPO-ANCA.     

A case of MPO-ANCA-related vasculitis with chronic alveolar hemorrhage]

It has been reported that alveolar hemorrhage caused by ANCA-associated vasculitis occurs in the seriously acute stage. However, we report a rare case of chronic alveolar hemorrhage in a 26-year-old woman who had been on maintenance hemodialysis because of rapidly progressive glomerulonephritis (RPGN) since the age of 17. On a regular checkup at her clinic, chest radiographs revealed diffuse micronodular opacities in both lung fields when she was 22 years of age, and anemia was identified at 24. Before the patient was referred to our hospital, the shadows on the radiographs remained almost unchanged, whereas the anemia, for reasons unknown, slowly deteriorated. She was referred to our hospital because of micronodular opacities detected on a chest radiogram in an annual health check at the age of 26. She was asymptomatic, but her laboratory data showed a normochromic anemia (hemoglobin 6.3 g/dl), and the serum level of MPO-ANCA was 195 EU. Bronchoalveolar lavage at bronchoscopy macroscopically revealed bloody fluids containing hemosiderin-laden macrophages. Histological examination of the biopsy specimen by video-assisted thoracoscopic lung biopsy revealed pauci-immune pulmonary capillaritis and alveolar hemorrhage. She was diagnosed as having MPO-ANCA-related vasculitis, especially microscopic polyangiitis preceding RPGN, and the clinical course suggesting alveolar hemorrhage was progressing slowly. The diagnosis was therefore "chronic alveolar hemorrhage". We emphasize that it is necessary to consider alveolar hemorrhage when a patient who has been on maintenance hemodialysis for RPGN has a combination of anemia and diffuse micronodular opacities, even if the condition is not accompanied with any respiratory symptoms.     

A case of diffuse alveolar hemorrhage associated with interstitial pneumonia and systemic sclerosis]

A 73-year-old female with interstitial pneumonia and systemic sclerosis was admitted with bloody sputum and fever. A chest radiograph showed bilateral infiltrative shadows superimposed on interstitial pneumonia. A chest computed tomograph also showed bilateral airspace consolidations and honeycomb formation. Mechanical ventilation was required because of respiratory failure. At intubation, fiberoptic bronchoscopy revealed bilateral bronchi to be filled with bloody secretions. Her serum myeloperoxidase-anti-neutrophil cytoplasmic antibody titer was slightly elevated. Steroid pulse therapy (1000 mg/day methylprednisolone for 3 days) and cyclophosphamide pulse therapy (500 mg cyclophosphamide) followed by 60 mg/day prednisolone was introduced on the basis of a diagnosis of diffuse alveolar hemorrhage. Her respiratory condition improved and chest infiltrative shadows disappeared and weaning from mechanical ventilation was successful. However, she died of ventilation insufficiency due to progression of her chronic respiratory failure. A necropsy specimen obtained from the left lung showed fibrosis, predominantly in peripheral areas of lobules, and accumulation of hemosiderin-laden macrophages, which findings were consistent with usual interstitial pneumonia and diffuse alveolar hemorrhage. A review of the world literature revealed 4 case reports of diffuse alveolar hemorrhage associated with interstitial pneumonia and systemic sclerosis. We should be aware of this rare but serious complication in the management of interstitial pneumonia associated with systemic sclerosis.     

Propylthiouracil (PTU)-induced vasculitis associated with antineutrophil antibody against myeloperoxidase (MPO-ANCA)

A 54-year-old woman had been administered propylthiouracil (PTU) for Graves' disease for 4 years. Recently, she complained of hemoptysis due to pulmonary alveolar hemorrhage causing anemia, and also had microhematuria. Antineutrophil cytoplasmic antibody against myeloperoxidase (MPO-ANCA) was positive, and she was diagnosed with PTU-induced vasculitis. Cessation of PTU and the administration of corticosteroids ameliorated these manifestations.     

A case of ANCA-associated vasculitis with diffuse alveolar hemorrhage successfully treated by plasmapheresis]

A 65-year-old man was admitted due to rapidly progressing dyspnea experienced over a 3-day period. Chest radiography and computed tomography conducted upon admission showed diffuse bilateral interstitial infiltrate. Bronchoalveolar lavage fluid contained blood and siderophores, which suggested pulmonary alveolar hemorrhage. Laboratory data showed that the serum MPO-ANCA level was elevated, and so ANCA-associated pulmonary hemorrhage was diagnosed. Although aggressive immunosuppressive agents were administered, including steroids and cyclophosphamides, the patient's condition worsened. Plasmapheresis using fresh frozen plasma was performed on day 5, after which his symptoms improved dramatically. Plasmapheresis was done 6 times, and the pulmonary lesions resolved. The patient was discharged 6 months later. This case report suggests that plasmapheresis may be an effective treatment for ANCA-associated vasculitis with diffuse alveolar hemorrhage that is resistant to aggressive immunosuppressive therapy.     

Mixed connective tissue disease associated with MPO-ANCA-positive polyangiitis

The patient was a 42-year-old woman diagnosed as having MCTD and Sj?gren's syndrome in 1989, and who was taking oral prednisolone. Proteinuria and microscopic hematuria were pointed out for the first time in December 2004. She was referred to our hospital because of massive hemoptysis. Advanced renal failure, anemia and pulmonary alveolar hemorrhage were diagnosed on admission. She was positive for serum MPO-ANCA. The patient was started on a therapy that included steroids, cyclophosphamide and plasmapheresis. However, her respiratory condition was untreatable and she died on the 16th day of hospitalization. The autopsy revealed alveolar hemorrhage in the lungs and crescentic glomerulonephritis. This patient was considered as a rare case of MCTD associated with MPO-ANCA-positive microscopic polyangiitis.     

Cerebral pachyleptomeningitis associated with MPO-ANCA induced by PTU therapy

A 34-year-old woman with hyperthyroidism, who had been previously treated with propylthiouracil (PTU) is reported. She was admitted because of clumsiness in her left hand and abnormal behavior. A neurological examination demonstrated impairment of higher cortical function, and weakness and hyperreflexia of the left leg. An MRI scan with gadolinium enhancement showed pachyleptomeningeal thickening in the right frontoparietal lobe. Blood tests revealed a high MPO-ANCA titer of 122 EU (normal:<10 EU). After steroid administration, the neurological symptoms and the MRI findings improved markedly. This is the first report of PTU-induced cerebral pachyleptomeningitis associated with a high serum MPO-ANCA titer.     

A case report of pulmonary-renal syndrome treated with continuous hemodiafiltration and hemodialysis

This case describes a 40-year-old man complaining of general malaise, dyspnea with hemoptysis and anuria. Laboratory data indicated renal failure and the presence of systemic inflammation. His chest radiograph and computed tomography showed bilateral diffuse interstitial alveolar infiltration. These findings indicated acute deterioration of chronic renal dysfunction complicated by interstitial pneumonitis. He initially received daily conventional hemodialysis (HD), an antibiotic and oxygen therapy. However, his renal and pulmonary function continued to deteriorate. Antineutrophil cytoplasm antibodies against myeloperoxidase (MPO-ANCA) and antibodies against proteinase 3 (PR3-ANCA) were negative. We suspected that his pulmonary-renal syndrome was caused by ANCA-negative vasculitis. We applied mechanical ventilation, pulsed methylprednisolone therapy and continuous hemodiafiltration (CHDF) combined with HD. PaO(2)/FiO(2) ratio and mean pulmonary arterial pressure gradually improved after initiation of CHDF. He was finally separated from mechanical ventilation after 44 days in the hospital. He is currently alive with the support of conventional HD.     

A case of Wegener's granulomatosis presenting as severe acute respiratory failure]

A 19-year-old man was admitted to another hospital. Pulmonary suppuration was diagnosed and was treated with antibiotics. However, he developed acute respiratory failure, which required intubation and ventilation with 100% oxygen. After treatment with nitric oxide inhalation and corticosteroid pulse therapy, the patient's condition stabilized and he gradually regained a satisfactory pulmonary function. He was discharged about 3 months after admission with a pulmonary function close to normal. Approximately 1 month later, the patient was admitted to our hospital because of a 2-week history of fever and chest and ocular pain. A chest radiograph obtained upon admission showed a nodule with a cavity in the upper lobe of the right lung. Pulmonary suppuration was again suspected, and antibiotics were given. The fever persisted and chest radiograph on hospital day 19 showed marked extension of the nodules. At that time, the patient complained of nasal obstruction and hoarseness and his sclera showed intense congestion, indicating episcleritis. Wegener's granulomatosis was diagnosed on the basis of the clinical picture, PR3-ANCA titer (63 EU) and nasal biopsy findings. After treatment with prednisolone and cyclophosphamide, his condition stabilized, and he recovered gradually. However, his condition remains poor despite continued therapy. This is an extremely rare case of Wegener's granulomatosis presenting as severe acute respiratory failure.     

Idiopathic pulmonary hemosiderosis in adult

Idiopathic pulmonary hemosiderosis (IPH) is a rare unknown origin disease characterized by diffuse alveolar hemorrhage (DPH). It rarely occurs in adults. We report a case of 50-year-old man, hospitalized with acute respiratory insuffiency. The chest radiograph and computed tomography scan showed bilateral interstitial and ground-glass opacities. The diagnosis of IPH was confirmed by broncho-alveolar lavage (BAL) and surgical pulmonary biopsy. There was no sign of capillaritis or granuloma in the anatomopathologic study. No remission was obtained after two months of high-dose corticosteroid therapy     

An autopsy case of MPO-ANCA-positive microscopic polyangiitis with manifestations of pulmonary hemorrhage and diffuse alveolar damage]

A 68-year-old woman was admitted to our hospital because of fever of unknown origin and pain in the lower extremities. Six weeks after onset, diffuse infiltrative shadows were observed on chest X-ray films, and marked hypoxemia and progressive renal dysfunction suddenly developed. Corticosteroid therapy (2 courses of pulse therapy, each consisting of methylprednisolone at 500 mg/day for 3 days) was not effective, and the patient died 9 weeks after onset because of respiratory failure. Serologic tests were positive for MPO-ANCA. Histopathologic findings at autopsy disclosed arteriolar fibrinoid necrosis in tissues of the liver, spleen, lungs, and kidneys, thus yielding a diagnosis of microscopic polyangiitis. Lung specimens also demonstrated massive alveolar hemorrhaging in the mid-lung fields and diffuse alveolar damage (DAD) in all lobes. Pulmonary hemorrhage coexistent with DAD worsens the prognosis for microscopic polyangiitis in patients positive for MPO-ANCA.     

A case of rapidly progressive interstitial pneumonia with anti-pL-12-antibodies successfully treated by pulse methylprednisolone and cyclophosphamide

A 51-year old man with severe acute respiratory failure was referred to our hospital. He presented with cyanotic digits, high fever and dyspnea. The chest radiograph and chest CT scan showed diffuse ground-glass-opacities and reticular shadows in both lung fields. We diagnosed acute interstitial pneumonia. The pulmonary infiltration seen on chest radiograph diminished gradually after pulse methylprednisolone and cyclophosphamide therapy. Later, we screened his sera for antibodies to anti-aminoacyl tRNA synthetase to diagnose anti-aminoacyl tRNA synthetase syndrome because anti-PL-12 antibodies were positive. This case has been followed but no myositis or recurrence of interstitial pneumonia has been recognized.     

Anti-glomerular basement membrane antibody disease with granulomatous lesions on renal biopsy

We present the case of a 56-year-old woman with anti-glomerular basement membrane (anti-GBM) antibody disease accompanied by granulomatous reaction in the kidney. Three months prior to admission to our kidney center, she had suffered from interstitial pneumonia and had a slightly elevated level of MPO-ANCA (13 EU). Her serum level of creatinine was normal (0.72 mg/dl) but proteinuria (1+) and hematuria (2+, 1-4/HF) were present. She was admitted to our hospital because of general fatigue, loss of appetite, high fever (over 38.5 degrees C) and a rapid decline in renal function (creatinine 8.50 mg/dl). Hemodialysis therapy was started immediately after admission. The serological study was negative for MPO-ANCA and PR3-ANCA but positive for anti-GBM antibody (139 EU). Renal biopsy demonstrated necrotizing glomeruli, cellular crescents and grauloma formation with multinucleated giant cells. Immunofluorescence microscopy revealed linear staining of IgG and C3. We diagnosed graulomatous, crescentic and necrotizing glomerulonephritis, patho-logically. She was diagnosed as having anti-GBM antibody disease because alveolar hemorrhage was absent. Steroid therapy including methylprednisolone pulse therapy (500 mg/day, 3 days) and 2 courses of plasma exchange were effective in reducing the fever, anti-GBM antibody titer and C-reactive protein level. Her renal function recovered and she was able to quit hemodialysis therapy 68 days after the start of hemodialysis and she has shown no signs of pulmonary alveolar hemorrhage to date. The present case suggests that intensive therapy may restore renal function in anti-GBM disease even though renal function was sufficiently damaged and required hemodialysis therapy and active pathological changes were observed in renal biopsy specimens.     

Extracorporeal membrane oxygenation to rescue profound pulmonary hemorrhage due to idiopathic pulmonary hemosiderosis in a child

Idiopathic pulmonary hemosiderosis (IPH) is a rare cause of diffuse alveolar hemorrhage (DAH) in pediatric patients. During the acute phase, death due to massive alveolar hemorrhage and subsequent severe respiratory failure with associated multiple organ failure often occurs. We report the case of an 11-year-old girl who developed severe hypoxemic respiratory failure and pulmonary hemorrhage. Extracorporeal membrane oxygenation (ECMO) was instituted on the next day because medical treatment and mechanical ventilation failed to maintain oxygenation. She was successfully decannulated 5 days later without ECMO-related complications. Four months later, she was intubated again and the diagnosis of IPH was made by open lung biopsy. She was treated with systemic steroid therapy and discharged smoothly. We suggest that ECMO provides a chance of recovery and survival for patients with IPH, even if accompanied by severe pulmonary hemorrhage.     

Development of Microscopic Polyangiitis in Patients with Chronic Airway Disease

Microscopic polyangiitis (MPA) is a rare systemic vasculitis syndrome, which is often accompanied by positive myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA). While pulmonary involvement of MPA consists mainly of diffuse alveolar hemorrhage and interstitial pneumonia, bronchiectasis has been reported as a pulmonary lesion in association with MPA. To investigate the clinical features of patients with MPA, focusing on the presence or the absence of preceding chronic airway diseases (CAD), we conducted a retrospective observational study of 26 patients in the last 13 years at Saga University Hospital. The clinical records and radiologic chest examinations were reviewed retrospectively. Pulmonary manifestations were alveolar hemorrhage in 3 patients (12%) and interstitial pneumonia in 5 (19%). Bronchiectasis, defined by the findings of chest radiograph and computed tomography, was found in 9 patients (35%). Four patients (15%) with bronchiectasis and one patient (4%) with chronic bronchitis had experienced chronic bronchial suppuration prior to the onset of MPA. Ten patients were classified as having chronic airway disease (CAD) before the onset of MPA. MPO-ANCA tended to be lower in the CAD group than in the non-CAD group. None of the patients in the CAD group had pulmonary hemorrhage or interstitial pneumonia. Only one patient (10%) in the CAD group died within 90 days of the onset of MPA, while 7 (43.8%) of the non-CAD group died. Our study suggests that MPA may result in part from CAD and that the clinical course of MPA with CAD may be different from MPA without CAD.     

A case of microscopic polyangitis presented with acute pericarditis]

We report a case of microscopic polyangitis presenting with acute pericarditis. A 75-year-old man, who had recurrent acute pericarditis, was referred by a cardiologist because of bilateral infiltrates in the chest radiograph, microhematuria and progressive renal failure. The test for MPO-ANCA was positive. Transbronchial and renal biopsies were compatible with microscopic polyangitis, showing alveolar hemorrhage and crescentic glomerulonephritis. After 3 days, intravenous methylpredonisolone was given, followed by oral prednisolone 40 mg/day, and the patient's radiographic infiltrates cleared and renal dysfunction improved. However, he died from opportunistic infection 109 days after the onset of treatment.     

Case of systemic sclerosis presenting with alveolar hemorrhage and positive anti-neutrophil cytoplasmic myeloperoxidase antibody(MPO-ANCA) without pathological renal involvement]

We report a 54-year-old woman with systemic sclerosis who presented alveolar hemorrhage. She noticed shortness of breath in May 1997. She was diagnosed having interstitial pneumonitis and systemic sclerosis with sclerodactylia of bilateral fingers in December. She developed bloody sputum and dyspnea suddenly on March 12, 1999. Bloody lavage fluid with hemosiderin-laden macropharge was observed by bronchial fiber scopic examination. The elevated level of MPO-ANCA was detected without anti-DNA antibody. Administration of intravenous methylprednisolone(1g per day, 3 days) followed by 40 mg per day of prednisolone achieved complete response, and MPO-ANCA level was decreased. Mild proteinuria and microhematuria was detected on admission, but renal biopsy revealed no findings of crescent formation or angiitis. With coadministration of oral cyclophosphamide she doesn't have any renal involvement or recurrence of alveolar hemorrhage during these four years. MPO-ANCA level remains negative. Alveolar hemorrhage, which is uncommon pulmonary event in systemic sclerosis, is often coexist with renal angiitis in the context of "pulmo-renal syndrome". MPO-ANCA is said to be related to pulmo-renal syndrome and is sometimes induced by D-penicillamine. This patient is really important in considering the pathogenesis of alveolar hemorrhage because she had no renal vasculitic lesions or D-penicillamine intake.     

Successful treatment of steroid-resistant methotrexate-induced interstitial pneumonia with peripherally administered ulinastatin

A 76-year-old woman with rheumatoid arthritis who had been taking methotrexate (MTX) for 9 months was admitted because of acute respiratory failure. A chest radiograph revealed diffuse ground-glass attenuation. MTX-induced interstitial pneumonia (IP) was strongly suspected. Her respiratory failure worsened in spite of steroid pulse therapy. Intravenous administration of ulinastatin, however, dramatically improved her clinical condition. The second ulinastatin treatment was also effective. This case suggests that peripherally administered ulinastatin may be effective for steroid-resistant MTX-induced IP.