Takashi Yoshiyama

Comparison of the sensitivity and specificity of two whole blood interferon-gamma assays for M. tuberculosis infection

OBJECTIVES To compare the sensitivity and the specificity of the QuantiFERON-TB Gold (QFT-G) and QuantiFERON-TB Gold In Tube (QFT-GIT) diagnostic tests for Mycobacterium tuberculosis infection. METHODS One-hundred patients with culture and/or PCR confirmed M. tuberculosis infection and 168 volunteers with no risk factors for M. tuberculosis infection were tested to estimate sensitivity and specificity, respectively. RESULTS Analysis of data from the tuberculosis (TB) patients with valid results found the sensitivity of QFT-GIT (92.6%, 87/94) to be significantly higher than that for the QFT-G test (81.4%, 79/97; p=0.023). The specificity of both QFT-GIT and QFT-G was 98.8% (CI: 95.1%-99.8%) with 2 of the 160 low risk subjects with valid results for both tests being positive. Data analysis confirmed the manufacturers recommended test cut-off as being optimal, but identified higher sensitivity could be obtained by using a lower cut-off, with only a moderate decrease in specificity. CONCLUSIONS The QFT-GIT test had enhanced sensitivity for detection of M. tuberculosis infection over the QFT-G test, whilst maintaining equivalent high specificity. The logistic benefits of the QFT-GIT test format, as well as its higher sensitivity, should enable enhanced TB control.

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.

Cross-sectional studies of tuberculosis prevalence in Cambodia between 2002 and 2011.

OBJECTIVE To measure trends in the pulmonary tuberculosis burden between 2002 and 2011 and to assess the impact of the DOTS (directly observed treatment, short-course) strategy in Cambodia. METHODS Cambodias first population-based nationwide tuberculosis survey, based on multistage cluster sampling, was conducted in 2002. The second tuberculosis survey, encompassing 62 clusters, followed in 2011. Participants aged 15 years or older were screened for active pulmonary tuberculosis with chest radiography and/or for tuberculosis symptoms. For diagnostic confirmation, sputum smear and culture were conducted on those whose screening results were positive. FINDINGS Of the 40,423 eligible subjects, 37,417 (92.6%) participated in the survey; 103 smear-positive cases and 211 smear-negative, culture-positive cases were identified. The weighted prevalences of smear-positive tuberculosis and bacteriologically-positive tuberculosis were 271 (95% confidence interval, CI: 212-348) and 831 (95% CI: 707-977) per 100,000 population, respectively. Tuberculosis prevalence was higher in men than women and increased with age. A 38% decline in smear-positive tuberculosis (P = 0.0085) was observed with respect to the 2002 survey, after participants were matched by demographic and geographical characteristics. The prevalence of symptomatic, smear-positive tuberculosis decreased by 56% (P = 0.001), whereas the prevalence of asymptomatic, smear-positive tuberculosis decreased by only 7% (P = 0.7249). CONCLUSION The tuberculosis burden in Cambodia has declined significantly, most probably because of the decentralization of DOTS to health centres. To further reduce the tuberculosis burden in Cambodia, tuberculosis control should be strengthened and should focus on identifying cases without symptoms and in the middle-aged and elderly population.

Decreased activities of daily living is a strong risk factor for liver injury by anti-tuberculosis drugs

We evaluated the association between activities of daily living and drug‐induced liver injury by anti‐tuberculosis drugs.

Immunological Roles of Elevated Plasma Levels of Matricellular Proteins in Japanese Patients with Pulmonary Tuberculosis.

Elevated matricellular proteins (MCPs), including osteopontin (OPN) and galectin-9 (Gal-9), were observed in the plasma of patients with Manila-type tuberculosis (TB) previously. Here, we quantified plasma OPN, Gal-9, and soluble CD44 (sCD44) by enzyme-linked immunosorbent assay (ELISA), and another 29 cytokines by Luminex assay in 36 patients with pulmonary TB, six subjects with latent tuberculosis (LTBI), and 19 healthy controls (HCs) from Japan for a better understanding of the roles of MCPs in TB. All TB subjects showed positive results of enzyme-linked immunospot assays (ELISPOTs). Spoligotyping showed that 20 out of 36 Mycobacterium tuberculosis (MTB) strains belong to the Beijing type. The levels of OPN, Gal-9, and sCD44 were higher in TB (positivity of 61.1%, 66.7%, and 63.9%, respectively) than in the HCs. Positive correlations between OPN and Gal-9, between OPN and sCD44, and negative correlation between OPN and ESAT-6-ELISPOT response, between chest X-ray severity score of cavitary TB and ESAT-6-ELISPOT response were observed. Instead of OPN, Gal-9, and sCD44, cytokines G-CSF, GM-CSF, IFN-α, IFN-γ, IL-12p70, and IL-1RA levels were higher in Beijing MTB-infected patients. These findings suggest immunoregulatory, rather than inflammatory, effect of MCPs and can advance the understanding of the roles of MCPs in the context of TB pathology.

Clinical and microbiological features of definite Mycobacterium gordonae pulmonary disease: the establishment of diagnostic criteria for low-virulence mycobacteria

BACKGROUND Although Mycobacterium gordonae isolation from respiratory samples is usually regarded as contamination, M. gordonae can cause definite pulmonary disease. The establishment of a standard diagnostic criteria of pulmonary disease that is caused by this low virulence mycobacterium is obviously necessary. METHODS We performed clinical research on over 200 cases in which M. gordonae was isolated over an 8-year period, focusing on the M. gordonae subtype. Sequence analysis of rpoB was performed to identify the genotypes. RESULTS A total of 287 respiratory samples (209 cases) were positive for M. gordonae. Twenty-seven cases (12.9%) had a positive culture more than twice and 11 of these cases (5.3%) had more than three positive cultures. Ultimately, three cases (1.4%) were newly diagnosed as M. gordonae pulmonary disease using our own diagnostic criteria. In all of the identified M. gordonae cases, the cultures tested positive with a Mycobacteria Growth Indicator Tube test at 24 days; however, in patients with definitive pulmonary disease, the cultures were positive at 9 days. A subtype analysis revealed that all of the definitive disease cases had subtype C. CONCLUSION The time taken to detect a positive culture and subtype of the isolates could be used as the diagnostic criteria for definite M. gordonae pulmonary disease.

Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients.

Drug-induced liver injury (DILI) is a common adverse drug reaction in patients receiving antituberculosis (anti-TB) treatment. Among the anti-TB agents, isoniazid (INH) is the primary drug that causes hepatotoxicity in TB patients with DILI. Previous reports in several populations have consistently demonstrated an association between polymorphisms in the N-acetyltransferase 2 (NAT2) gene, which is responsible for INH hepatic metabolism, and a risk of DILI in TB patients. In this study, the genetic and baseline clinical data from 366 Japanese patients with TB (73 patients with DILI and 293 without DILI) were used to develop a system to predict DILI risk due to anti-TB agents. The distribution of the NAT2 acetylator status among the TB patients with DILI was 31 (42.5%), 29 (39.7%), and 13 (17.8%) for rapid, intermediate, and slow acetylators, respectively. A significant association was observed between NAT2 slow acetylators and DILI risk (odds ratio 4.32, 95% confidence interval 1.93–9.66, P value=5.56×10−4). A logistic regression model based on age and NAT2 genotype revealed that the area under the curve for the receiver-operating characteristic curve was 0.717. The findings demonstrated that slow NAT2 acetylator status is a significant predictor of the risk of DILI by anti-TB agents, and a personalized anti-TB treatment approach may aid in making treatment decisions and reducing the incidence of DILI.

Sensitivity and specificity of Cobas TaqMan MTB real-time polymerase chain reaction for culture-proven Mycobacterium tuberculosis: meta-analysis of 26999 specimens from 17 Studies

Since 2010, studies on the diagnostic accuracy of COBAS TaqMan MTB (CTM) have been frequently reported with an unignorable discrepancy. The key inclusion criterion for this systematic review was original studies that could provide sufficient data for calculating the sensitivity and the specificity of CTM for M tuberculosis (TB) or M tuberculosis complex. The reference test was Mycobacterium culture. We used bivariate model for meta-analyses. Of the 201 candidate articles, we finally identified 17 eligible articles.Concerning the respiratory specimens, 1900 culture positive specimens and 20983 culture negative specimens from 15 studies were assessed. This provided the summary estimate sensitivity of 0.808 (95% CI 0.758–0.850) and the summary estimate specificity of 0.990 (95% CI 0.981–0.994). The area under curve was 0.956. The diagnostic odds ratio was 459 (95% CI 261–805, I2 26%). For the smear positive respiratory specimens, the sensitivity was 0.952 (95% CI 0.926–0.969) and the specificity was 0.916 (95% CI 0.797–0.968). For the smear negative respiratory specimens, the sensitivity and the specificity were 0.600 (95% CI 0.459–0.726) and 0.989 (95% CI 0.981–0.993), respectively. The diagnostic accuracy was poorer for the non-respiratory specimens, than for the respiratory specimens, but was acceptable. We believe that the information obtained from this study will aid physicians’ decision making.

Poor performance status is a strong predictor for death in patients with smear-positive pulmonary TB admitted to two Japanese hospitals

BACKGROUND Estimation of performance status (PS) has been assessed as a tool to determine which patients with newly diagnosed pulmonary TB (PTB) are most at risk of dying. This simple prediction rule has not been validated in patients with PTB with different background characteristics and from different geographic areas. METHODS A retrospective cohort study was conducted in two Japanese hospitals in different regions and included 432 inpatients with newly diagnosed smear-positive non-multidrug-resistant lung TB without HIV infection. The patients had a mean ± SD age of 64.9 ± 19.7 years and 135 were female (31.3%). Detailed nursing charts were reviewed to estimate PS, which was graded 0 (best condition), 1, 2, 3 or 4 (worst condition), for each patient. RESULTS Single variable and multivariable Cox regression analyses models revealed that a one-point increase in PS was associated with a 2.8-fold (95% CI 2.2-3.6) and 2.3-fold (95% CI 1.8-3.0), adjusted for age, gender, comorbidities and treatment regimen, increase in the HR for death (p < 0.001 for both models). Kaplan-Meier curves also showed a significant difference in mortality among different PS groups (p < 0.001). CONCLUSION PS was strongly associated with mortality from PTB in the study cohort. Estimation of PS at the start of treatment for newly diagnosed PTB patients could be a useful tool in case management in resource-limited countries.

Epidemiological, clinical and mechanistic perspectives of tuberculosis in older people: Tuberculosis in older people

With the ageing population globally, tuberculosis (TB) in older people becomes a major clinical and public health challenge. In many Asian countries, especially those located in the eastern and southeastern parts of the continent, geriatric TB is a significant problem. TB in the older patients is more difficult to diagnose in the early course of disease, and has poorer treatment outcomes, largely as increased failure and death. More drug‐induced adverse reactions are also experienced by this population during TB therapy. Oxidative stress and mitochondrial dysfunction are now well recognized to be associated with the ageing process, and it is likely that the cellular and molecular perturbations interact inextricably with the immunological dysfunction biophysiologically inherent to ageing. These underlying mechanistic bases putatively contribute to the development of TB in the geriatric population and worsen the disease outcomes, especially when the TB is compounded by co‐morbid conditions such as smoking and diabetes mellitus. Unravelling these mechanisms further would yield knowledge that might potentially help to prevent reactivated TB in older people, and also to better manage the established disease with drug regimens and other new therapeutic strategies. In addition, addressing the social elements associated with geriatric TB is also imperative in the relief of individual patient suffering and improvement of overall disease control.