Epidemiological characteristics of nontuberculous mycobacteriosis and bronchiectasis: comparative study using national mortality statistics from 1970 to 2015 in Japan.

Background: This study assessed longitudinal national data on mortality due to nontuberculous mycobacteriosis (NTMosis) and bronchiectasis and the association between the two diseases. Methods: We analysed the national death statistics of Japan from 1970 to 2015. The International Classification of Disease (ICD) codes were used to extract the relevant data. Crude mortality, age-adjusted mortality and standardised mortality rates were calculated using vital statistics and the population in 2000. We also identified domestic publications related to NTMosis and bronchiectasis with an internet-based search system. Results: The total number of bronchiectasis-related deaths remained at the same level, which was approximately 1000, for 45 years, although the number of deaths has consistently decreased in males but increased in females since the mid-1990s. A substantial increasing trend in females was also observed for NTMosis in the same period. The age-adjusted mortality data showed an increase in mortality in women due to NTMosis and confirmed the trend in bronchiectasis in women. The patterns in the number of domestic reports showed a recent slight increase in bronchiectasis and a marked increase in NTMosis. Conclusions: The trends in bronchiectasis-related mortality differed by sex. The epidemiological trends in the two diseases were associated, especially in elderly females since the mid-1990s. It is suggested that pulmonary NTMosis without pre-existing bronchiectasis might be a leading cause of postinfectious bronchiectasis in Japan.

Extended survival observed in adoptive activated T lymphocyte immunotherapy for advanced lung cancer: results of a multicenter historical cohort study.

PURPOSE: To clarify the long-term effect of immunotherapy, the effect of adoptive activated T lymphocyte immunotherapy on advanced lung cancer was evaluated in terms of survival time. In addition, the performance status of cancer patients under immunotherapy was examined. EXPERIMENTAL DESIGN: Over 5 × 10(9) alpha-beta T lymphocytes cultured ex vivo with an immobilized anti-CD3 antibody and interleukin-2 were injected intravenously into patients, once every 2 weeks for 3 months or longer. Follow-up of these patients was carried out using clinical records and by telephone interview questionnaire. Patients undergoing immunotherapy in immunotherapy clinics and those undergoing other anticancer therapies without immunotherapy in seven hospitals in Tokyo were enrolled in this study. Data were analyzed by a third-party statistician. Performance status was studied on another series of various cancer patients who underwent immunotherapy. RESULTS: The overall median survival time of the patients with the best supportive care, which was obtained using Kaplan-Meier's model, was 5.6 months, and those with immunotherapy alone, chemotherapy alone, and immuno-chemotherapy were 12.5, 15.7, and 20.8 months, respectively. Using Cox' proportional hazard model, we examined the possible factors on survival time by univariate analysis. Then, the patients were stratified by gender and histological type for multivariate analysis. Significantly low hazard ratios were observed for immunotherapy and radiotherapy in males with squamous cancer; for chemotherapy and radiotherapy in male with adenocarcinoma; and for immunotherapy in females with adenocarcinoma. Addition of immunotherapy to chemotherapy resulted in a statistically significant decrease in hazard ratio in females with adenocarcinoma. Studies on the performance status (PS), determined according to the European Cooperative Oncology Group criteria, revealed a continuous high level of PS under immunotherapy until around 2 months before death, in contrast to the gradual increase of tumor marker level. CONCLUSIONS: The effectiveness of immunotherapy on advanced lung cancer is limited but may extend life span under certain conditions. Immunotherapy itself provided no clinical benefit by itself as compared with chemotherapy, but a significant additive effect of immunotherapy on chemotherapy was observed in females with adenocarcinoma. Moreover, immunotherapy can maintain good quality of life of the patients until near the time of death.

[Nontuberculous mycobacteriosis mortality in Japan].

UNLABELLED: The aim of this research was to clarify epidemiological characteristics of nontuberculous mycobacteriosis deaths in Japan. We analyzed the frequency of deaths due to nontuberculous mycobacteriosis (NTM) and regional differences using the Vital Statistics of Japan, published by the Ministry of Health, Labour and Welfare. The crude death rate was calculated using the Population Census of Japan published every 5 years (Ministry of Internal Affairs and Communications). In addition, changes in the proportions of death cases due to NTM disease among total autopsies were calculated using the Annual of the Pathological Autopsy in Japan (The Japanese Society of Pathology). RESULTS: NTM disease deaths appeared for the first time in 1970, with a marked increase by 2007, when there were 912 certified deaths. The increase was more marked after the mid-1990s. The number of women's deaths exceeded 300 in 1999 and reached 570 in 2007, while that of men exceeded 300 in 2001 and remained at nearly the same level until 2007. The death rate increased in all eight regions of Japan. The highest single-year regional death rate was 212 in Kanto in 2005. However, correcting by population size, the crude death rate was higher in the western regions of Japan than in the eastern ones. The proportion of NTM among total autopsies also showed an increase from 0.066% in 1993 to 0.304% in 2007. Included in the report is a comparison of trends of NTM deaths with those of major respiratory diseases including tuberculosis, emphysema, bronchial asthma and airway cancers.

[Archaeology of tubercle bacilli and tuberculosis].

Accumulated information obtained in the 10 years since the clarification of the whole genome arrangement of tubercle bacilli has enabled us to presume a long history of tubercle bacilli from its first appearance on earth to the present epidemics in the world. It is presumed that tubercle bacilli appeared around 35,000 years ago through horizontal transfer mutation from a kind of environmental mycobacteria that could be tracked back 2,500,000 years, and expanded thereafter by 'bottleneck effects'. These mutated mycobacterial species adapted to humans, appearing in central Africa and then being carried to India-Oceanian and Middle East countries. The oldest human bone tuberculosis in a mummy of 9,000 years ago was found on the east coast of the Mediterranean Sea. Explosive transmission of tuberculosis was presumed to have progressed along with urbanized human life in the world-oldest Mesopotamian culture, followed by spreading to other areas, including East Asia, the Mediterranean region, Russia, and North Europe. The second epidemics, caused by a mutated Beijing family of the modern type, prevailed in central China and Southeast Asian countries, following the marked population growth in this area during the next 1,000 years. The majority of Beijing family strains isolated in Japan and Korea are, however, found to be of the ancient type, differing from the isolates from continental China, which are mainly of the modern type. The results of these studies may cast a new light on the understanding of tuberculosis epidemiology and also clinical medicine.

[Bacteriological and pathological analysis on the pathogenetic factors for cavitary and nodular bronchiectatic type of pulmonary Mycobacterium avium-intracellulare complex disease].

A total of 101 strains of Mycobacterium avium complex (MAC), consisting of 86 M. avium and 15 M. intracellulare strains, were examined by DNA sequencing. The frequency of radiological types [cavitary (Cav) type and nodular bronchiectatic (NB) type] was similar in each species, thus, both species are equal causes of the two radiological types of MAC disease. We also examined serovars of the isolated strains using extracted glycopeptidelipid antigens and thin layer chromatography. Cav type patients discharged a single serovar MAC, while NB type patients discharged two serovar MACs simultaneously. RFLP pattern obtained by the use of IS1245, revealed no clustering of the strains specific for Cav type and NB type. Histopathological examinations of the bronchial lesions in 40 MAC cases and 49 multi-drug resistant tuberculosis (MDR-TB) cases were performed on the surgically removed lung specimens. Lymphocytic infiltration, epithelioid cell granuloma formation, epithelial desquamation and ulceration, as well as smooth muscle atrophy as a cause of bronchiolectasis, were observed more often and were more severe in the peripheral bronchial walls of the NB type than the Cav type of MAC, and as compared with those of MDR-TB cases.

[Clinical studies on the pathogenetic factors of cavitary and nodular bronchiectatic types in pulmonary Mycobacterium avium complex disease].

We investigated the clinical, laboratory and radiological findings of 273 newly diagnosed cases of pulmonary Mycobacterium avium complex (MAC) disease, who were diagnosed in our hospital during 7 years from January 1996 to December 2002. Radiological findings of all cases were classified at the time of diagnosis into 2 patterns, the cavitary (Cav) type and the nodular bronchiectasis (NB) type. Clinical and laboratory findings at the time of diagnosis of 44 death cases were compared with those of 273 newly diagnoses cases, to analyze the prognostic factors of this disease. MAC disease cases showed a marked increase in number in recent years, but only in women. Mean age at the first visit was 65.7 years in men and 63.2 years in women, and when limited to fatal cases, it was 72.3 years in men and 69.4 years in women. Low body weight in terms of body mass index (BMI) and moderately low serum albumin level were found at the time of the first hospital visit in all the newly diagnosed and death cases. In the fatal cases, the peripheral blood lymphocyte counts revealed a relatively smaller number than the normal range, and the PPD skin test showed a negative reaction in 57.7% of all cases, suggesting the presence of lowered cell-mediated immunity at the time of diagnosis. Whether malnutrition occurs as a result of MAC disease or the individuals with lower nutrition level are easy to develop to MAC disease remains to be clarified. In regard to radiological findings, many cavitary (Cav) type cases were found in men and nodular bronchiectasis (NB) type in women among newly diagnosed cases, while the cavitary type was observed in many in both men and women fatal cases. The mean duration period from diagnosis to death was 28.3 months in men and 60.2 months in women, showing a longer survival after diagnosis, perhaps due to earlier hospital visits by women. The average age at death was 74.4 years old in men and 73.8 years old in women, and the two radiological patterns did not change throughout the entire disease course.

Propionibacterium acnes is the most common bacterium commensal in peripheral lung tissue and mediastinal lymph nodes from subjects without sarcoidosis.

BACKGROUND: In studies of the unknown etiology of sarcoidosis, Propionibacterium acnes (a possible agent) was found in the lungs and lymph nodes of many sarcoidosis patients and some control subjects. P. acnes might be commensal not only to the skin, conjunctivae, and intestine, but also to the lungs and lymph nodes of individuals without sarcoidosis. METHODS: We cultured peripheral lung tissue and various lymph nodes obtained from patients with diseases other than sarcoidosis. DNA of 45 isolates of P. acnes from these patients, 67 isolates from normal skin, conjunctiva, and intestine, and 39 isolates from sarcoid lymph nodes were compared by random amplified polymorphic DNA analysis. RESULTS: P. acnes was isolated from half of 43 lungs and 8 of 11 mediastinal lymph nodes, mostly in pure culture. P. acnes was isolated from half of 20 gastric and 3 of 12 intestinal lymph nodes; intestinal bacteria were also numerous. In general, fewer than 500 colony-forming units of P. acnes per gram tissue were isolated, but 4 lung tissue specimens, 2 of which had a few granulomas, had many more. P. acnes strains from a particular site (lung, lymph node, skin or conjunctivae, and intestine) were genetically similar, more than isolates obtained from different sites. Lymph-node isolates from subjects with and without sarcoidosis differed little. CONCLUSION: These results suggest that P. acnes normally resides in peripheral lung tissue and mediastinal lymph nodes and that the strains of P. acnes isolated from sarcoid lymph nodes were not specific to sarcoidosis.

Proposed criteria for mixed-dust pneumoconiosis: definition, descriptions, and guidelines for pathologic diagnosis and clinical correlation.

We defined mixed-dust pneumoconiosis (MDP) pathologically as a pneumoconiosis showing dust macules or mixed-dust fibrotic nodules (MDF), with or without silicotic nodules (SN), in an individual with a history of exposure to mixed dust. We defined the latter arbitrarily as a mixture of crystalline silica and nonfibrous silicates. According to our definition of MDP, therefore, MDF should outnumber SN in the lung to make a pathologic diagnosis of MDP. In the absence of confirmation of exposure, mineralogic analyses can be used to support the pathologic diagnosis. The clinical diagnosis of MDP requires the exclusion of other well-defined pneumoconioses, including asbestosis, coal workers' pneumoconiosis, silicosis, hematite miners' pneumoconiosis, welders' pneumoconiosis, berylliosis, hard metal disease, silicate pneumoconiosis, diatomaceous earth pneumoconiosis, carborundum pneumoconiosis, and corundum pneumoconiosis. Typical occupations associated with the diagnosis of MDP include metal miners, quarry workers, foundry workers, pottery and ceramics workers, and stonemasons. Irregular opacities are the major radiographic findings in MDP (ILO 1980), in contrast to silicosis, in which small rounded opacities predominate. Clinical symptoms of MDP are nonspecific. MDP must be distinguished from a variety of nonoccupational interstitial pulmonary disorders.

[Pulmonary Mycobacterium avium complex (MAC) disease showing middle lobe syndrome--pathological findings of 2 cases suggesting different mode of development].

Two different processes have been proposed for pathogenesis of Mycobacterium avium complex (MAC) disease which show the middle lobe syndrome: 1) middle lobe bronchiectasis followed by MAC infection and 2) MAC disease resulted in secondary bronchiectasis. Two surgical specimen from MAC cases showing middle lobe syndrome were studied histo-pathologically. The first case was a 60 year-old female with frequent bloody sputum, who had been diagnosed as bronchiectasis in her childhood. Pathological examination of the resected middle lobe showed prominent cylindric bronchiectasis in the indurated middle lobe, and epithelioid cell granulomas were scattered limited to the fibrous bronchial walls, without any granulomas in the lung parenchyma. These findings suggested a secondary infection of MAC to the non-specific pre-existed bronchiectasis. The second case of a 55 year-old female having repeated bloody sputum, who was diagnosed to be tuberculosis but no improvement with anti-tuberculosis drugs. Pathological examination of the middle lobe showed scattered epithelioid cell granulomas with lymphocytic infiltration in the lung parenchyma. A few epithelioid cell granulomas were also found in the mucosa of middle lobe bronchi. In this case, pulmonary MAC lesions seemed to precede the central bronchial lesion with later development of bronchiectasis. Summarizing above findings two different mode of pathogenesis ways may be considered; one is non-specific bronchiectasis followed by middle lobe MAC disease and the other is pulmonary MAC lesion in the middle lobe as a primary change.

[Pulmonary Mycobacterium avium complex disease showing nodular bronchiectasis--: pathological findings in two cases].

Histopathological examinations were carried out on 2 cases of Mycobacterium avium complex (MAC) disease of nodular bronchiectasis (NB) type on radiograms. The removed lung specimens revealed histological findings of granulomatous bronchiolopneumonia, consisting of epithelioid cell granulomas with lymphocytic infiltrations without exudation in the alveolar areas surrounding the respiratory bronchiole. The central bronchiolar walls were also affected by epithelioid cell granulomas with lymphocytic infiltration, occasionally showing polypoid protrusion into the bronchiolar lumen accompanying emphysema in the peripheral alveolar area. Bronchial lesions seemed to progress from peripheral to central airway with consequent atrophy and disappearance of intramural smooth muscles, resulted in bronchioloectasis. These histological findings well correspond to radiographical 'nodular bronchiectasis'. Large histiocytic granulomas without caseous necrosis developed in some area, which are not usually found in tuberculosis lesions. Epithelioid cell granulomas were occasionally found in the hilar lymph nodes as well as in the walls of lymphatic vessel in the pulmonary interlobular tissues, indicating intrapulmonary lymphatic spread of the mycobacteria.

Impaired and imbalanced cellular immunological status assessed in advanced cancer patients and restoration of the T cell immune status by adoptive T-cell immunotherapy.

Recent progress has been made in understanding the mechanisms of antitumor immune responses, which may further clarify the immune status of cancer patients. In this study, we performed a detailed evaluation of the immunological status of 47 patients with advanced solid cancer, who had received no immunosuppressive treatment, and compared the results with 32 healthy subjects. Flow-cytometry data for peripheral blood were obtained using 19 monoclonal antibodies against various cell surface and intracellular molecules. Absolute numbers of T cells, several T cell subsets, B cells, and NK cells were significantly decreased in patients compared with healthy subjects. The percentage of CD27(+)CD45RA(+) T cells was lower and that of CD27(-)CD45RA(-) T cells was higher in patients compared with controls. Regulatory and type 2 helper T cells were elevated in patients relative to healthy subjects. The percentage of perforin(+) NK cells was significantly lower in patients than in controls. These results suggest a dysfunctional anti-tumor immune response in cancer patients. Furthermore, peripheral blood from 26 of 47 cancer patients was analyzed after adoptive T cell immunotherapy (ATI). ATI increased the number of T cell subsets, but not B and NK cells. The number and percentage of regulatory T cells decreased significantly. These results suggest that ATI can restore impaired and imbalanced T cell immune status.

A steady increase in nontuberculous mycobacteriosis mortality and estimated prevalence in Japan.

RATIONALE: Pulmonary disease caused by nontuberculous mycobacteria is generally reported to have a good prognosis. However, the actual mortality rate over time has not been reported in a large-scale survey. OBJECTIVES: To determine the annual trend in mortality from nontuberculous mycobacteriosis, based on nearly four decades of patient data, and to estimate the prevalence of these cases in 2005. METHODS: The annual mortality rate and regional distribution of nontuberculous mycobacteriosis-related deaths in Japan were obtained from Vital Statistics of Japan, which is published annually. The crude and age-adjusted mortality rates and associated regional differences were calculated from the Japanese census data. A 5-year follow-up study including 309 patients with pulmonary nontuberculous mycobacteriosis who visited and registered at our institute from 2004 to 2006 was conducted to determine the 5-year prognosis and the annual mortality rate. MEASUREMENTS AND MAIN RESULTS: The crude mortality rates for both sexes have increased since 1970, and the mortality rate from pulmonary disease was greater in women after 2005. The age-adjusted rates of disease also showed a gradual increase until 2010 in women. Geographically, higher standardized mortality ratios were observed in middle and western Japan, particularly in the southern coastal regions along the Pacific Ocean. In a clinical follow-up study, the mortality rate was approximately 1-2% annually. The prevalence of pulmonary nontuberculous mycobacteriosis was estimated to be 6- to 10-fold higher than the annual incidence. CONCLUSIONS: There was a constant and steady increase of nontuberculous mycobacteriosis-related mortality in Japan, and this mortality rate showed significant geographical variation. The prevalence of environmental mycobacterial disease in Japan is higher than reported in most other countries.

Clinical factors on cavitary and nodular bronchiectatic types in pulmonary Mycobacterium avium complex disease.

BACKGROUND AND OBJECTIVE: Pulmonary Mycobacterium avium complex (MAC) disease is the most common pulmonary non-tuberculous mycobacteriosis (NTM). The clinical and radiological findings were similar to those of pulmonary tuberculosis, both of which are characterized by upper lobe cavities. On the other hand, the presence of middle and lower field lesions with centrilobular nodules and bronchiectasis has been noted. We analyzed the clinical feature of these two radiologically different types and identified their prognostic factors. METHODS: The clinical, laboratory and radiological findings of 273 cases of MAC disease, newly diagnosed during the recent 7 years periods, were investigated. They were radiologically classified into cavitary (Cav) and nodular bronchiectasis (NB) types at the time of diagnosis. The findings of 44 fatal cases were compared with those of the newly diagnosed cases. RESULTS: A prominent increase in the number of cases was recently found only in females. Low body mass index (BMI) and moderately reduced serum albumin were found at the time of first hospital visit in both newly diagnosed and fatal cases. In the latter, peripheral blood lymphocyte count was slightly decreased, and tuberculin skin test was negative in 57.7% of the cases. Radiologically, Cav type was prevalent in males and NB type in females in the newly diagnosed cases, while in the fatal cases Cav type was frequently found in both males and females. The two radiological patterns did not change during the entire disease course. CONCLUSION: Cav type in females was one of the pathogenetic factors. Deterioration of cell-mediated immunity may underlie MAC disease.

Correlation between suspended particles in the environmental air and causes of disease among inhabitants: cross-sectional studies using the vital statistics and air pollution data in Japan.

To identify the diseases that correlate with suspended particle concentration in the ambient air, a cross-sectional epidemiological study was conducted using the annual vital statistics and air pollution estimates of 1881 points throughout Japan. The concentration of suspended particulate matters (SPMs) 10 microm or less in diameter were hypothetically converted to PM(2.5) values (converted PM(2.5) or cPM(2.5)) by using a conversion factor obtained from 25 estimates in Japan. Among various causes of death, a significant correlation was observed between both the SPM and cPM(2.5) (SPM/cPM(2.5)) levels and the age-adjusted death rates of ischemic heart disease or hypertensive heart disease in both genders. Correlation was noted with pneumonia, asthma, chronic bronchitis/emphysema, or lung cancer only in females. Unexpectedly, breast, endometrial, and ovarian cancer also showed significant increases in mortality rates related to the SPM/cPM(2.5) level, suggesting a role for suspended particles in the ambient air with or without gaseous component as a possible endocrine-disrupting, estrogenic agent. Multivariate regression analysis of confounding factors, smoking rate, population density, and hormone-related factors revealed consistent significance of SPM/cPM(2.5) in these diseases.