Th2-biased immune responses are important in a murine model of chronic hypersensitivity pneumonitis.

BACKGROUND: Chronic hypersensitivity pneumonitis (HP) can lead to irreversible pulmonary fibrosis. A good animal model is essential to elucidate the mechanisms of this disease. We previously reported that a Th2 predominance may play an important role in the fibrogenesis in chronic HP patients. A study was undertaken to evaluate whether Th2-biased immune responses were crucial during the processes of lung fibrosis in a murine model of chronic HP. METHODS: Instillation of pigeon dropping extracts (PDE) was conducted 3 days a week for 6 or 12 weeks in C57BL/6, BALB/c and A/J mice to establish models of chronic HP. We evaluated the histopathological features, immunohistochemistry, collagen content, bronchoalveolar lavage fluid (BALF) profiles and Th1/Th2 cytokines in BALF or lung tissue with RT-PCR and ELISA. RESULTS: Thickening of the alveolar walls and structural alterations were observed only in the A/J mice after 12 weeks of exposure to PDE. The fibrosis scores were significantly increased in 12-week A/J mice compared to those in the other strains. Immunohistochemistry evaluation showed that PDE was engulfed by alveolar macrophages that were incorporated into the alveolar septa of 12-week A/J mice. Interleukin (IL)-4 mRNA increased significantly in 6- and 12-week A/J mice. IL-13 mRNA showed a significant increase in 12-week A/J mice compared with 6-week A/J mice. TGF-ß1 mRNA at 12 weeks was significantly increased in A/J mice compared with the other groups. CONCLUSION: Th2-biased genetic backgrounds may play an important role in fibrosing processes in the present chronic HP model.

Clinical features of the 2009 swine-origin influenza A (H1N1) outbreak in Japan.

To clarify the clinical symptoms of the influenza A virus during the 2009 pandemic influenza outbreak, we describe the clinical features of outpatients diagnosed with type A influenza by use of the rapid influenza diagnostic test (RIDT) from September to December 2009. Questionnaires were used to collect prospective data on 1,122 cases with influenza-like illness at our medical institutions. The independent predictors of influenza A virus were identified on the basis of demographic features and the clinical symptoms of the patients who tested positive for influenza A virus in the RIDT test. Of the 1,122 cases tested, 389 (34.7%) were positive for the influenza A virus. The median age of the influenza-positive patients was 14, and 58.9% of the patients were male. The symptoms fever, cough, rhinorrhea, and headache were statistically dominant. A history of recent contact with persons suffering from influenza or influenza-like illness at home, school, or in the workplace was significantly more common in the positive group than in the negative group. Pneumonia was observed in 2 (0.5%) of the positive patients, but the symptoms were only severe enough to require hospitalization in 1 of the 2. No deaths were observed among the 389 RIDT-positive patients. Although the spread of influenza A virus was both rapid and extensive, mainly among children under the age of 18, it seemed to be mild. Appropriate interpretation of the RIDT on the basis of recent clinical information, and early treatment with antiviral drugs might help to prevent severe illness from influenza pandemics in the future.

[Measurement of bird specific antibody in bird-related hypersensitivity pneumonitis].

Since the avian antigen is one of the important causative antigens in hypersensitivity pneumonitis, measurement of bird-specific antibody should be readily available. We measured IgG and IgA antibodies against pigeons and budgerigars by the ImmunoCap system in bird-related hypersensitivity pneumonitis (BRHP) to evaluate their diagnostic utility. In acute BRHP, antibodies markedly increased and showed high sensitivity and specificity ranging from 75-100% based on the cut-off values determined by ROC analysis. In chronic BRHP, antibody reactivity slightly increased, showing a sensitivity of 27-73% and specificity of 45-100%. Pigeon antibodies evaluated by the ImmunoCap system showed a good correlation with anti-pigeon dropping extract antibodies measured by ELISA. In conclusion, measurement of antibodies against pigeons and budgerigars are helpful for the diagnosis of BRHP.

[A case of pyothorax caused by Mycobacterium avium].

A 74-year-old woman was admitted to our hospital in December, 2003 because of anorexia and weight loss lasting from August, 2003. Chest CT scan showed empyema with a niveau in the right lung and infiltrative and nodular shadows in the left lung. Acid-fast bacilli were detected in pleural effusion. Polymerase chain reaction (PCR) test was negative for Mycobacterium tuberculosis (M. tuberculosis) but positive for Mycobacterium avium (M. avium). PCR test for M. avium was also positive in bronchial lavage fluid, and many colonies of M. avium complex ( MAC) were cultured from pleural effusion. After we administered 4 drugs including RFP, EB, SM, and CAM, cultured colonies of M. avium decreased, the inflammatory reaction improved, and infiltrates in the left upper lobe has disappeared. These improvements confirmed the diagnosis of empyema caused by M. avium. Since nontuberculous mycobacteria induced empyema has rarely been reported, the clinical features of this disease should further be examined.

[Penicillamine-induced bronchiolitis obliterans diagnosed by transbronchial lung biopsy].

A 57-year-old woman had been treated with penicillamine (200 mg/day) for degenerative arthritis initially misdiagnosed as rheumatoid arthritis since 2003. She presented with dyspnea and was admitted to our hospital in 2004. Pulmonary function tests revealed mixed pattern of dysfunction with severe airway obstruction. Chest computed tomography showed mosaic ground-glass opacities. Bronchoalveolar lavage fluid (BALF) demonstrated increase in total cells and lymphocytes. Since specimens of transbronchial lung biopsy (TBLB) showed lymphocytic infiltration in membranous bronchiole and occlusion of the membranous bronchiole lumen, bronchiolitis obliterans was diagnosed by TBLB. After penicillamine, which had been administered for 7 months, was stopped, she was successfully treated with steroid and macrolides.

[Adenosine deaminase 2 in the diagnosis of tuberculous pleuritis].

PURPOSE: We examined the usefulness of adenosine deaminase 2 (ADA2) in the diagnosis of tuberculous pleuritis. SUBJECTS: A hundred cases, 78 male and 22 female, with pleural effusion were examined. With regard to pleural effusion, 18 cases were transudate and 82 cases (9 tuberculous pleuritis, 27 lung cancer, 8 mesothelioma, 5 malignant diseases except lung cancer and mesothelioma, 5 benign asbestos pleurisy, 10 empyema, 10 parapneumonic effusion, one SLE, one parasitic infection, and 6 undetermined etiology) were exudates. The last 6 cases with unknown origin were excluded in this study. RESULTS: Pleural adenosine deaminase (ADA) was 90.4 +/- 22.4 U/l (mean +/- SD) and pleural ADA2 was 80.4 +/- 21.9 U/l in tuberculous pleuritis, both were significantly higher than those in non-tuberculous exudates (p < 0.001). In the diagnosis of tuberculous pleuritis, pleural ADA showed 100% sensitivity and 88% specificity, whereas pleural ADA2 showed 100% sensitivity and 91% specificity. CONCLUSION: Pleural ADA2 is useful in the diagnosis of tuberculous pleuritis, which has similar sensitivity and a little better specificity compared with pleural ADA.

Interleukin-17A and Neutrophils in a Murine Model of Bird-Related Hypersensitivity Pneumonitis.

Hypersensitivity pneumonitis (HP) is an immune mediated lung disease induced by the repeated inhalation of a wide variety of antigens. Bird-related hypersensitivity pneumonitis (BRHP) is one of the most common forms of HP in human and results from the inhalation of avian antigens. The findings of a recent clinical analysis suggest that in addition to Th1 factors, the levels of interleukin(IL)-17 and IL-17-associated transcripts are increased in the setting of HP, and that both IL-17A and neutrophils are crucial for the development of pulmonary inflammation in murine models of HP. Our objectives were to investigate the roles of IL-17A and neutrophils in granuloma-forming inflammation in an acute HP model. We developed a mouse model of acute BRHP using pigeon dropping extract. We evaluated the process of granuloma formation and the roles of both IL-17A and neutrophils in a model. We found that the neutralization of IL-17A by the antibody attenuated granuloma formation and the recruitment of neutrophils, and also decreased the expression level of chemokine(C-X-C motif) ligand 5 (CXCL5) in the acute HP model. We confirmed that most of the neutrophils in the acute HP model exhibited immunoreactivity to the anti-IL-17 antibody. We have identified the central roles of both IL-17A and neutrophils in the pathogenesis of granuloma formation in acute HP. We have also assumed that neutrophils are an important source of IL-17A in an acute HP model, and that the IL-17A-CXCL5 pathway may be responsible for the recruitment of neutrophils.

Utility of immunological tests for bird-related hypersensitivity pneumonitis.

BACKGROUND: The reaction of specific antibodies and sensitized lymphocytes to antigens is important in hypersensitivity pneumonitis (HP). However, there are no known studies evaluating the utility of the lymphocyte proliferation test (LPT) or specific antibodies to avian antigens in diagnosing bird-related HP. In this study, we examined the sensitivity and specificity of these two tests. METHODS: Patients with acute bird-related HP (n=10), chronic bird-related HP (n=35), acute summer-type HP (n=14), and other interstitial pneumonia (IP) (n=76) were evaluated. The optimal cutoff values were determined by receiver operating curve (ROC) analyses of specific antibodies in serum and bronchoalveolar lavage fluid (BALF), and by conducting the LPT on mononuclear cells in peripheral blood and BALF. RESULTS: The sensitivity and specificity of the antibodies were 80-100% and 92-100% in acute bird-related HP, and 26-79% and 73-93% in chronic bird-related HP, respectively. The sensitivity and specificity of the LPT were 50-100% and 100% in acute bird-related HP, and 46% and 91% in chronic bird-related HP, respectively. CONCLUSIONS: Specific antibodies and the LPT are quite useful for diagnosing acute bird-related HP. The presence of specific antibodies in BALF and the results of LPT with peripheral blood mononuclear cells are particularly useful for diagnosing chronic bird-related HP.

[Case of pubic tuberculous osteomyelitis and pericarditis during anti-tuberculosis chemotherapy].

56 year-old man was referred to the department of orthopedics in our hospital for further investigation on right inguinal pain. The patient was initially diagnosed as bacterial myelitis in right pubic bone and was treated with antibiotics. Since his symptom did not improve, the curettage was performed. Histological examination of the pubic bone obtained during the operation showed epithelioid cell granulomas with caseous necrosis, supporting the diagnosis of tuberculous osteomyelitis. Chest X-ray film revealed small nodular lesions in both upper lung fields. Sputum was positive for acid-fast bacilli and Amplified Mycobacterium Tuberculosis Direct Test (TB-MTD) was positive. The diagnosis of pubic tuberculous osteitis and pulmonary tuberculosis was confirmed. Specimens from the pubic bone and sputum were both culture positive for Mycobacterium tuberculosis, and bacilli were sensitive to anti-tuberculosis drugs. The antituberculosis chemotherapy was started with INH, RFP, SM and PZA. Symptoms had gradually improved, however 3 months after starting treatment, high fever developed and chest X-ray revealed heart enlargement and bilateral pleural effusion. Pericardial effusion showed exudative nature with lymphocyte predominancy and high level of ADA, 98.4 U/l. Pleural effusion was transudate. TB-MTD and culture were negative both in pericardial and pleural effusion. Paradoxical reaction was thought to be the cause of pericarditis. TB chemotherapy was continued and pericardial drainage was performed. One month later, fever improved, and pleural effusion and pericardial effusion disappeared. Transient elevated transaminase was observed, and was thought to be the side effect of anti TB drugs. All symptoms gradually improved, and he was discharged after 6 months TB chemotherapy.

Pneumocystis pneumonia during Postoperative Adjuvant Chemotherapy for Breast Cancer.

A 72-year-old woman underwent a mastectomy with one-stage breast reconstruction using silicone implant for right breast cancer. Postoperatively, she had received adjuvant chemotherapy with fluorouracil, epirubicin, and cyclophosphamide (FEC regimen). She was admitted for febrile neutropenia after the third course of chemotherapy. She remained febrile for a week, and she complained of dyspnea on hospital day 8. Computed tomography scan demonstrated widespread patchy ground glass changes in both lungs and serum (1→3)-ß-D-glucan was elevated to 20 pg/mL. Oral trimethoprim-sulfamethoxazole was started on the strong clinical suspicion of PCP, and the patient subsequently made a rapid recovery from fever and dyspnea.

Epithelial-mesenchymal transition in chronic hypersensitivity pneumonitis.

Chronic hypersensitivity pneumonitis (HP) causes progressive and irreversible pulmonary fibrosis, a disease also observed in conjunction with idiopathic pulmonary fibrosis (IPF). Previous studies have demonstrated that the myofibroblast, a cell type whose origins involve the epithelial-mesenchymal transition (EMT), may play a role in the pathogenesis of IPF. The goal of this study was to determine whether EMT has a role in the pathogenesis of chronic HP. Lung specimens from a chronic HP model and from patients with chronic HP were analyzed. Cellular co-localization of epithelial and mesenchymal markers on the same alveolar epithelial cells (AECs) were examined using immunohistochemistry and cadherin switching by western blotting as indicators of EMT. EMT cells in the AECs were significantly more prevalent in lung specimens from Th2-prone A/J mice than in specimens from Th1-prone C57BL/6 mice. The percentage of EMT cells was correlated with the mRNA expressions of IL-13 and TGF-ß1, the fibrosis score, and the collagen content in the A/J mice. In human, EMT cells in the AECs were significantly more prevalent in lungs specimens from patients with usual interstitial pneumonia pattern than in specimens from patients with nonspecific interstitial pneumonia pattern at the moderate stage of fibrosis. In conclusion, EMT may play an important role in the fibrotic process of chronic HP under the Th2-biased environment.