Antigen avoidance and environmental inhalation challenge for successful diagnosis of fibrotic hypersensitivity pneumonitis mimicking idiopathic pulmonary fibrosis.

A 77-year-old man was initially diagnosed with idiopathic pulmonary fibrosis (IPF) and treated with anti-fibrotic nintedanib. Despite undergoing anti-fibrotic treatment for one year, his condition remained unstable. The patient was admitted to our hospital for exertional dyspnea. We performed an exposure assessment, including 2-week antigen avoidance and an environmental inhalation challenge, and successfully re-diagnosed him with fibrotic hypersensitivity pneumonitis (HP), known as chronic farmer's lung. Adding oral glucocorticoids to the nintedanib treatment improved his condition. Although antigen avoidance and environmental inhalation challenge tests are not standardized, they may be useful for diagnosing fibrotic HP when properly applied.

[A case of pulmonary-limited Wegener granulomatosis mimicking bacterial pneumonia caused by Staphylococcus aureus].

A 56-year-old woman who had suffered from systemic lupus erythematosus and Sjögren syndrome was admitted complaining of persistent cough. Chest X-ray films showed an infiltrative shadow in the right middle lung field. Her serum PR3-ANCA titer was high, and granulomatous inflammation with Langhans giant cell was noted in a transbronchial biopsy specimen. About 3 months later, purulent sputum and high grade fever developed, with a new infiltrative shadow in the left upper lung field noted on a chest X-ray film. We treated her based on a diagnosis of bacterial pneumonia caused by methicillin-resistant Staphylococcus aureus, but her condition did not improve. We finally gave her a diagnosis of pulmonary-limited Wegener's granulomatosis. Her condition improved with the administration of sulfamethoxazole-trimethoprim, prednisolone and cyclophosphamide. We report a case of pulmonary-limited Wegener granulomatosis which mimicked bacterial pneumonia caused by methicillin-resistant Staphylococcus aureus. This case suggests that Wegener's granulomatosis should be considered on encountering pneumonia caused by Staphylococcus aureus.

[A case of relapsing sarcoidosis with pleurisy 14 years after spontaneous remission].

An 83-year-old woman was referred to our hospital with dyspnea on exertion and right pleural effusion. At the age of 69, she had been given a clinical diagnosis of sarcoidosis due to uveitis, bilateral hilar lymphadenopathy, bilateral multiple nodular shadows on chest images, and serum angiotensin-converting enzyme (SACE) level elevation. Remission was spontaneous. The pleural effusion was exudative lymphocyte-rich. On thoracoscopy, the macroscopic appearance of the parietal pleura was telangiectasia without nodular lesions and the pleural biopsy specimens revealed non-caseating epitheloid cell granulomas whose cultures were negative for acid-fast bacilli and fungi. A tuberculin skin test and QFT-2G were negative, thus we diagnosed sarcoidsis pleurisy.

Macrolide resistant Mycobacterium avium complex pulmonary disease following clarithromycin and ethambutol combination therapy.

RATIONALE: Whether two-drug therapy (clarithromycin and ethambutol) for Mycobacterium avium complex (MAC) pulmonary disease contributes to the development of macrolide-resistant MAC is unclear. OBJECTIVE: To compare the incidence of macrolide-resistant MAC between patients treated with two-drug therapy (clarithromycin and ethambutol) and the standard three-drug therapy (clarithromycin, ethambutol, and rifampicin) for MAC pulmonary disease. METHODS: We retrospectively reviewed 147 patients with treatment-naive MAC pulmonary disease who had received two-drug therapy (n = 47) or three-drug therapy (n = 100) between 1997 and 2016 at National Hospital Organization, Tenryu Hospital, Hamamatsu, Japan. The risk of development of macrolide-resistant MAC was evaluated by calculating the cumulative incidence rate using Gray's test. RESULTS: The median follow-up period was 74.5 months. During the follow-up period, one of the 47 patients (2.1%) in the two-drug group developed macrolide-resistant MAC, compared to 12 of the 100 patients (12.0%) in the three-drug group. The cumulative incidence rate of macrolide-resistant MAC was lower in the two-drug group than in the three-drug group (0.0023; 95% confidence interval, 0.002 to 0.107 versus 0.200; 95% confidence interval, 0.100 to 0.324, p = 0.0593). CONCLUSIONS: These results suggest that two-drug treatment with clarithromycin and ethambutol for MAC pulmonary disease does not lead to a higher incidence of resistance acquisition to clarithromycin than the standard three-drug treatment.

Intravenous immunoglobulin therapy for refractory interstitial lung disease associated with polymyositis/dermatomyositis.

Interstitial lung disease (ILD) associated with polymyositis/dermatomyositis (ILD-PM/DM), including amyopathic dermatomyositis (ADM), is recognized as an important condition because it frequently causes death, despite intensive therapy with high-dose corticosteroid and immunosuppressive agents, such as cyclosporine A and cyclophosphamide. Intravenous immunoglobulin therapy (IVIG) has shown efficacy for myopathy associated with PM/DM, but its usefulness for ILD-PM/DM is unclear. This study was designed to investigate the efficacy of IVIG for refractory ILD-PM/DM. A review was made of medical charts of five patients (2 men and 3 women) who were treated with IVIG for refractory ILD-PM/DM resistant to high-dose corticosteroid and cyclosporine A and/or cyclophosphamide. One patient had acute ILD-PM and four patients had acute ILD-ADM. Of the five patients, one patient with ILD-PM and one patient with ILD-ADM survived. No adverse reactions were seen due to IVIG treatment. There were no critical differences in the clinical parameters and clinical courses between survivors and nonsurvivors. IVIG treatment is safe and could be an effective salvage therapy for refractory ILD-PM/DM in certain cases, suggesting that further controlled trials are worthwhile.

[A case of pulmonary infection caused by Pseudomonas aeruginosa with anorexia nervosa].

A 19-year-old woman with anorexia nervosa (body weight 25 kg) was admitted to our hospital, showing a cavitary shadow in the left upper lung field on a chest radiograph film. We diagnosed a pulmonary abscess caused by Pseudomonas aeruginosa. A few days later, exacerbation, including enlargement of the cavitary shadow, ipsilateral pleural effusion and bilateral infiltrations, were observed. Finally, by using antibiotics such as Doripenem (DRPM) and Ciprofloxacin (CPFX), we were able to treat the disease by bronchoscopic and thoracic drainage. This case suggests we should take carefully treat anorexia nervosa patients with pulmonary infection.

Drug lymphocyte stimulation test in the diagnosis of adverse reactions to antituberculosis drugs.

BACKGROUND: Tuberculosis (TB) is a worldwide infectious disease. Recently, standard therapy has become very effective for treating patients with TB; however, as a result of this powerful regimen, serious side effects have become an important problem. The aim of this prospective study was to evaluate the usefulness of the drug lymphocyte stimulation test (DLST) to determine anti-TB drugs causing side effects. METHOD: Four hundred thirty-six patients with TB were admitted to our hospital for treatment between January 2002 and August 2007. DLST was performed in patients who had certain adverse drug reactions during TB treatment. The causative drug was identified by the drug provocation test (DPT). The tested drugs were mainly isoniazid (INH), rifampin (RIF), ethambutol (EMB) and pyrazinamide (PZA). RESULTS: Of 436 patients, 69 patients (15.8%) had certain adverse drug reactions to anti-TB drugs. Of the 261 agents that underwent the DLST and DPT, 28 agents (10.7%) in 20 patients (28.9%) were positive by DLST, and 67 agents (25.7%) in 46 patients (66.6%) were identified as causative drugs by DPT. The sensitivity of DLST was only 14.9% for all drugs (INH, 14.3%; RIF, 13.6%; EMB, 14.3%; PZA, 0%). CONCLUSIONS: DLST offers little contribution to the detection of causative agents in patients with adverse anti-TB drug reactions.

[A case of antiphospholipid syndrome associated with acute respiratory distress syndrome].

A 52-year old woman admitted to our hospital because of productive cough and dyspnea. Breathing room air arterial blood gases, revealed severe hypoxemia (P/F ratio 185 mmHg) and Chest CT showed diffuse ground glass opacities in both lung fields. Respiratory failure gradually improved after steroid pulse therapy, sivelestat sodium hydrate and antibiotics. However, a mosaic pattern attenuation in the lung parenchyma on Chest CT remained and ultrasonic cardiography showed dilation of right ventricle. Since the presence of V/Q mismatch in pulmonary perfusion and ventilation scintigrams and lupus anticoagulant were detected, we finally diagnosed acute respiratory distress syndrome (ARDS) and pulmonary thromboembolism (PTE) associated with antiphospholipid syndrome (APS). Therefore, this case reminded us that PTE and APS could cause ARDS.

Utility of Macrophage-activated Marker CD163 for Diagnosis and Prognosis in Pulmonary Tuberculosis.

RATIONALE: Among infectious diseases, tuberculosis (TB) is a leading cause of death worldwide. Accumulated knowledge has revealed that macrophages are deeply involved in the progression and pathogenesis of TB. We hypothesized that the evaluation of a macrophage activation marker may be useful in the diagnosis and assessment of pulmonary TB. OBJECTIVES: To examine the utility of the macrophage activation marker soluble CD163 (sCD163) as a diagnostic tool and measure of disease severity for pulmonary TB and tuberculous pleurisy. METHODS: We compared the concentration of sCD163 in serum samples of 180 patients with active pulmonary TB with concentrations in serum samples of 45 age- and sex-matched control subjects. We also measured sCD163 in pleural fluid samples of 100 patients with pleural disease, including 31 patients with tuberculous pleurisy. MEASUREMENTS AND MAIN RESULTS: We found increased serum concentrations of sCD163 in patients with active pulmonary TB compared with those of control subjects (1,643 ± 1,737 ng/ml vs. 533.9 ± 49.3 ng/ml; P < 0.0001). sCD163 levels were also higher in pleural fluid samples of patients with pulmonary TB than in those of patients with non-TB pleurisy (5,239 ± 2,436 ng/ml vs. 2,877 ± 1,191 ng/ml; P < 0.0001). The levels of sCD163 in pleural effusions were significantly higher than serum levels obtained simultaneously from the same patients, particularly for patients with tuberculous pleurisy. Patients with a serum level of sCD163 above 1,300 ng/ml, had a mortality rate that was five times higher than that of patients with a lower sCD163 level (44.6% vs. 6.6%; P < 0.0001 by log-rank test). Microscopic examination of lung and pleural tissue samples showed concordance of enhanced CD163 expression with the presence of caseating granulomas in tissue obtained from patients with TB. CONCLUSIONS: The macrophage activation marker CD163 was increased in patients with active pulmonary TB compared with age- and sex-matched control subjects. Increased levels of sCD163 were associated with increased mortality in patients with pulmonary TB. sCD163 also showed promise as a diagnostic tool for tuberculous pleurisy. These results warrant further study of sCD163 as a potentially useful biomarker for the diagnosis and assessment of pulmonary TB. Clinical trial registered with www.umin.ac.jp/ctr/index-j.htm (UMIN000003400).

Effects of MdmX on Mdm2-mediated downregulation of pRB.

Mdm2, a RING-finger type ubiquitin ligase, is overexpressed in a variety of human cancers. It promotes ubiquitination of the tumor suppressor p53 and can function as an oncogene by largely downregulating p53. Recently, we reported that Mdm2 degrades retinoblastoma tumor suppressor protein (pRB) via the ubiquitin-proteasome system. In the present study, we assessed the effects of MdmX, a structural homolog of Mdm2, on the Mdm2-mediated ubiquitination of pRB. MdmX is known to negatively regulate p53 function by enhancing the Mdm2-mediated ubiquitination and degradation of p53. Interestingly, MdmX inhibited the Mdm2-mediated pRB ubiquitination. Furthermore, an MdmX siRNA decreased the endogenous pRB level, while MdmX overexpression stimulated pRB functions in cultured cells. Therefore, MdmX may have different roles in the regulation of Mdm2 activity for ubiquitination of pRB and p53.

[Analysis of CD1 molecules in the process of granuloma formation with sarcoidosis].

There have been many reports studying the presentation for lipid antigen by CD1 molecules on dendritic cells (DC), mainly in the infection of acid-fast bacilli. But little is known about the expression of CD1 molecules in sarcoidosis. In this study, we analyzed the expression of CD1 molecules by immunohistochemical stain with monoclonal anti-CD1a, CD1b and CD1c antibody for the specimens of nine sarcoidosis patients (sarcoidosis group) and seven control cases (control group). Aggregation of CD1 positive cells was present adjacent to granulomas in five cases of the sarcoidosis group, but was absent in all cases of the control group. There were no differences in the results of laboratory findings or disease activity between CD1-positive and negative cases in the sarcoidosis group. These data suggest that the presentation of lipid antigens mediated by CD1 molecules on DC is involved in granuloma formation in sarcoidosis.

[An adult case of asymptomatic congenital tracheal stenosis].

A 42-year-old woman was admitted with abnormal chest radiographs. Though interstitial pneumonia associated with dermatomyositis was diagnosed, her chest radiograph also revealed a narrowed trachea about 6 mm in diameter. Bronchoscopy showed that her trachea lacked a membranous posterior segment and O-shaped complete tracheal rings were present throughout the trachea, indicating congenital tracheal stenosis. Congenital tracheal stenosis is a rare disorder and is usually recognized in the first few weeks of life, but the patient had no history of dyspnea or recurrent pneumonia. This case suggests that among healthy people there are a very few who have asymptomatic congenital tracheal stenosis.

The incidence and clinical characteristics of bronchiolitis obliterans organizing pneumonia syndrome after radiation therapy for breast cancer.

STUDY OBJECTIVE: Bronchiolitis obliterans organizing pneumonia (BOOP) syndrome after adjuvant radiation therapy for breast cancer has been recently recognized. However, the precise incidence of this syndrome remains to be determined. The aim of this study was to clarify the incidence and clinical characteristics of radiation-induced BOOP syndrome. METHODS: We conducted a retrospective analysis of 206 consecutive patients wit breast cancer undergoing tangential-field radiation therapy at our institution from 1992 to 2002. RESULTS: Among the patients, five (2.4%) developed BOOP syndrome. These five patients began with flu-like symptoms 2-7 months after the completion of radiation therapy. Four of them had received tamoxifen, an estrogen receptor antagonist, and the other one underwent cytotoxic chemotherapy. Their chest radiographs revealed peripheral alveolar opacities with migration outside the irradiated fields. Increased lymphocyte counts and elevated CD4/CD8 ratios were observed in the bronchoalveolar lavage fluid. Transbronchial biopsy revealed organizing pneumonia. The serum levels of KL-6, a marker of interstitial pneumonia, did not increase in any patients. Treatment with corticosteroids resulted in a rapid improvement, but two patients relapsed after the cessation of corticosteroids. CONCLUSIONS: These results suggest that BOOP syndrome after tangential-field radiation therapy for breast cancer is not rare and more attention should be directed to this condition as a radiation-induced pulmonary toxicity.

[Cyclosporin treatment of interstitial pneumonia and monitoring of serum concentration].

Recently, cyclosporin has been reported to be a promising drug for the treatment of interstitial pneumonia. Monitoring of the serum cyclosporin concentration is important for the safety and efficacy of treatment. We measured the concentrations of this drug just before (C0) and 2 hours after (C2) administration, and the area under the concentration-time curve from the start of administration for 5 hours (AUC 0-5) in 58 patients. We found that C2 has the strongest correlation with AUC 0-5, which indicates the efficacy of cyclosporin. In 11 cases of interstitial pneumonia, 5 showed deterioration despite cyclosporin treatment. Three of those 5 cases had low C2 and AUC 0-5 levels, indicating that they were low absorbers and slow absorbers, which may be associated with a poor response. Therefore, the monitoring of the cyclosporin concentration is important especially in progressive cases of interstitial pneumonia that deteriorate despite cyclosporin treatment.

[Clinical analysis of chronic hypersensitivity pneumonitis].

Chronic hypersensitivity pneumonitis (CHP) has a poor prognosis because of the difficulties in its diagnosis and treatment. Recently, we have encountered six cases of CHP (4 patients with the home-related type, a patient with bird fancier's lung, and one with flour-induced CHP), and we examined the clinical characteristics of these cases. Environmental provocation testing has been considered useful for diagnosing HP, but all patients gave negative results in short-term environmental exposure tests performed routinely for the diagnosis of HP. However, 5 patients had a positive response in long-term environmental exposure tests. Two patients died of respiratory failure after ten years' observation despite improvement of the causative environment, and were given steroid therapy. Radiographically and pathologically, the process of progressive and irreversible lesions were recognized in our series of CHP patients. The diagnosis of CHP should be carried out on the basis of the comprehensive findings including the detailed history, clinical course, radiography, and histology.

[Eosinophilic pleural effusion associated with dantrolene administration].

A 42-year old man was admitted to our hospital for evaluation of pleural effusion in the right hemithorax. He had been treated for spastic paraplegia with dantrolene sodium for 28 months. The pleural fluid consisted of sterile exudates with a very high eosinophil count, and peripheral blood eosinophilia was noted. Thoracoscopy revealed no apparent abnormalities and a pleural biopsy specimen showed only non-specific inflammation. Two weeks after discontinuing dantrolene therapy, the pleural effusion disappeared. The toxicity of dantrolene in patients with pleural effusion must be taken into consideration when long-term dantrolene therapy is given.

[Secondary pulmonary alveolar proteinosis associated with myelodysplastic syndrome].

A 51-year-old man with myelodysplastic syndrome (MDS) was admitted to our hospital because of dyspnea on exertion in December 1999. Chest radiography showed ground-glass shadows in the middle and lower fields of both lungs, and chest computed tomography revealed a typical "crazy paving appearance". The bronchoalveolar lavage fluid was milky in appearance, and so secondary pulmonary alveolar proteinosis associated with MDS was diagnosed. Because there was no need to treat his MDS, we twice performed whole-lung lavage under general anesthesia in January and February 2000. The treatments were effective, and his abnormal chest radiography findings, laboratory data and pulmonary function were normalized. This was a rare case of secondary pulmonary alveolar proteinosis associated with MDS successfully treated with whole-lung lavage.

[A case of adenocarcinoma of the lung presenting symptoms of choroidal metastasis as the initial clinical manifestation].

A 51-year-old woman was referred to our hospital with a complaint of disturbance in vision. Ophthalmologic examination revealed multiple choroidal tumors. High-resolution CT showed a nodular shadow in the left lower lobe. Transbronchial biopsy and right supraclavicular lymph node biopsy specimens showed a poorly-differentiated adenocarcinoma. We concluded that the choroidal tumors had metastasized from the lung. Combined chemotherapy (CDDP + CPT-11) followed by irradiation of both eyes and brain were performed. Nevertheless, she died 6 months after the initial presentation. It is important to notice ophthalmologic symptoms because lung cancer may metastasize to the choroids.

Efficacy of clarithromycin and ethambutol for Mycobacterium avium complex pulmonary disease. A preliminary study.

RATIONALE: Patients with Mycobacterium avium complex pulmonary disease are frequently administered a combination of clarithromycin, ethambutol, and rifampicin. However, rifampicin is known to reduce the serum levels of clarithromycin. It remains unclear whether a reduction in clarithromycin serum levels influences the clinical outcome of the Mycobacterium avium complex pulmonary disease treatment regimen. OBJECTIVES: To compare a three-drug regimen (clarithromycin, ethambutol, and rifampicin) to a two-drug regimen (clarithromycin and ethambutol) for the treatment of Mycobacterium avium lung disease. METHODS: In a preliminary open-label study, we randomly assigned newly diagnosed, but as-yet untreated, patients with disease caused by Mycobacterium avium complex without HIV infection to either the three-drug or the two-drug regimen for 12 months. The primary endpoint was the conversion of sputum cultures to negative after 12 months of treatment. Patient data were analyzed using the intention-to-treat method. MEASUREMENTS AND MAIN RESULTS: Of 119 eligible patients, 59 were assigned to the three-drug regimen and 60 to the two-drug regimen. The rate of sputum culture conversion was 40.6% with the three-drug regimen and 55.0% with the two-drug regimen (difference, -14.4% [95% confidence interval, -32.1 to 3.4]). The incidence of adverse events leading to the discontinuation of treatment was 37.2 and 26.6% for the three-drug and the two-drug regimens, respectively. CONCLUSIONS: This preliminary study suggests that treatment with clarithromycin and ethambutol is not inferior to treatment with clarithromycin, ethambutol, and rifampicin for Mycobacterium avium complex lung disease. Our findings justify a larger clinical trial to compare long-term clinical outcomes for the two treatment regimens. Clinical trial registered with http://www.umin.ac.jp/english/ (UMIN000002819).