Akihiro Ohkado

Clonal Expansion of Multidrug- Resistant and Extensively Drug- Resistant Tuberculosis, Japan

Strain clustering suggests community transmission plays a critical role in incidence.

Detection of Tuberculosis Infection Hotspots Using Activity Spaces Based Spatial Approach in an Urban Tokyo, from 2003 to 2011

Background Identifying ongoing tuberculosis infection sites is crucial for breaking chains of transmission in tuberculosis-prevalent urban areas. Previous studies have pointed out that detection of local accumulation of tuberculosis patients based on their residential addresses may be limited by a lack of matching between residences and tuberculosis infection sites. This study aimed to identify possible tuberculosis hotspots using TB genotype clustering statuses and a concept of “activity space”, a place where patients spend most of their waking hours. We further compared the spatial distribution by different residential statuses and describe urban environmental features of the detected hotspots. Methods Culture-positive tuberculosis patients notified to Shinjuku city from 2003 to 2011 were enrolled in this case-based cross-sectional study, and their demographic and clinical information, TB genotype clustering statuses, and activity space were collected. Spatial statistics (Global Moran’s I and Getis-Ord Gi* statistics) identified significant hotspots in 152 census tracts, and urban environmental features and tuberculosis patients’ characteristics in these hotspots were assessed. Results Of the enrolled 643 culture-positive tuberculosis patients, 416 (64.2%) were general inhabitants, 42 (6.5%) were foreign-born people, and 184 were homeless people (28.6%). The percentage of overall genotype clustering was 43.7%. Genotype-clustered general inhabitants and homeless people formed significant hotspots around a major railway station, whereas the non-clustered general inhabitants formed no hotspots. This suggested the detected hotspots of activity spaces may reflect ongoing tuberculosis transmission sites and were characterized by smaller residential floor size and a higher proportion of non-working households. Conclusions Activity space-based spatial analysis suggested possible TB transmission sites around the major railway station and it can assist in further comprehension of TB transmission dynamics in an urban setting in Japan.

Transmission of specific genotype streptomycin resistant strains of Mycobacterium tuberculosis in the Tokyo Metropolitan Area in Japan.

BackgroundFrom 2003 through to 2004, an outbreak of tuberculosis was identified at a university campus in Yokohama City, located in the southern part of the Tokyo Metropolitan Area (TMA). All Mycobacterium tuberculosis (M. tuberculosis) strains detected with regards to this outbreak turned out to be Streptomycin resistant with matched patterns of 14 IS6110 bands of Restriction Fragment Length Polymorphism (RFLP). The M. tuberculosis bacilli, which had the matched IS6110 band patterns with resistance to Streptomycin to those of bacilli isolated in the outbreak, were also concurrently detected through either the population-based or the hospital-based DNA fingerprinting surveillance of M. tuberculosis either in Shinjuku City or in Kawasaki City respectively.The aim of the present study is to describe the spread of the specific genotype strains of M. tuberculosis in the TMA as observed in the above incident, and to identify the possible transmission routes of the strains among people living in urban settings in Japan.MethodsWe applied Variable Numbers of Tandem Repeats (VNTR) analysis to all M. tuberculosis isolates which were resistant to Streptomycin with a matched IS6110-RFLP band pattern (M-strains). They were isolated either from cases related to the tuberculosis outbreak that happened at a university, or through DNA fingerprinting surveillance of M. tuberculosis both in Shinjuku City and in Kawasaki City. For VNTR analysis, 12MIRU loci, 4ETR loci, seven loci by Supply, four loci by Murase (QUB15, Mtub24, VNTR2372, VNTR3336) were selected.ResultsOut of a total of 664 isolates collected during the study period, 46 isolates (6.9%) were identified as M-strains. There was a tendency that there was a higher proportion of those patients whose isolates belonged to M4-substrains, with four copies of tandem repeat at the ETR-C locus, to have visited some of the internet-cafés in the TMA than those whose isolates belonged to M5-substrains, with five copies at the ETR-C locus, although statistically not significant (38.1% vs. 10.0%, Exact p = 0.150).ConclusionAlthough firm conclusions could not be reached through the present study, it suggested that we have to take into consideration that tuberculosis can be transmitted in congregated facilities like internet cafés where tuberculosis high-risk people and general people share common spaces.

Trend and treatment status of latent tuberculosis infection patients in Japan – Analysis of Japan TB Surveillance data

Objective and method Management of latent tuberculosis infection (LTBI) is one of the core elements of End TB Strategy. Japan is one of the few countries in which notification of LTBI is mandatory, yet so far, the data has not been analyzed in detail. We thus conducted a cross-sectional study to examine the trend of LTBI, its treatment outcome and factors predicting treatment non-completion in Japan for the period of 2007 and 2014, using the data from the electronic Japan Tuberculosis Surveillance system. Treatment completion was defined as those whose reason for terminating the treatment was recorded as “treatment completed” and whose treatment duration was 180 days or more. Results During the study period, a total of 50,268 LTBI patients were notified, of which 49,525, who had started treatment, were analyzed for characteristics. 57.5% were females, and 38.5% were aged 25–44 years. As for the job category, healthcare professionals, that is medical doctors, nurses and other healthcare workers, consisted the largest group (30.4%). Overall, the number of LTBI notification has been on an increase, with a large increase observed among those aged 65 years and above. Of the 49,525 patients, the information regarding reason for termination of treatment was available for 46,128 (93.1%). Of them, 33,156 (71.9%) had completed treatment as according to the study definition. The risk factors for not completing LTBI treatment included being aged 65 years and above (adjusted odds ratio [aOR] 1.27, 95% confidence interval [95%CI] 1.10–1.47), foreign-born (aOR 1.14, 95%CI 1.02–1.28), healthcare professional (aOR 1.44, 95%CI 1.24–1.69), full-time and part-time worker (aOR 1.40, 95%CI, 1.20–1.63) and detected via contact investigation (aOR 1.26, 95%CI 1.12–1.41). Conclusions Our study results revealed that the treatment completion rate was 71.9%, falling short of the national target of 85%, and also that the treatment duration was recorded as less than 180 days for approximately 20% of those who were reported as having completed treatment. Further studies may be built on ours to explore the reasons for not completing the treatment across different population groups, and identify those who benefit the most, and who has the greatest impact on ending TB, by receiving LTBI treatment.

Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis

BACKGROUND Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ. METHODS Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1-3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology. FINDINGS Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8-9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1-7·3), but no significant effect on mortality (aOR 0·7, 0·4-1·1) or acquired rifampicin resistance (aOR 0·1, 0·0-1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2-0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates. INTERPRETATION In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis. FUNDING World Health Organization and Canadian Institutes of Health Research.

Profile of tuberculosis among the foreign-born population in Japan, 2007-2014.

The proportion of foreign-born people among the newly notified tuberculosis (TB) patients has been increasing in recent years and potentially poses a new challenge to TB control in Japan. In this report, we analysed the data from the Japan TB surveillance system between 2007 and 2014 to gain an overview of the trends and characteristics of foreign-born TB patients in Japan. We found that the proportion of foreign-born TB patients was especially high among the younger age groups – 44.1% among the 20–29 years age group in 2014. The largest groups of foreign-born patients were from China and the Philippines; however, the number of those from Nepal and Viet Nam was on the rise. Students comprised the second largest professional category group for TB after regular workers, and its proportion increased over the study period. Compared to Japan-born TB patients, foreign-born patients were more likely to be diagnosed through routine medical check-ups. Treatment successes and patients still on treatment were significantly lower among foreign-born patients than their Japan-born counterparts; and transferred-out and unknown outcomes were higher. Our results indicated that distinctive subgroups within the foreign-born population in Japan, especially students and regular workers, might have a higher risk of developing TB. Measures to ensure early diagnosis and treatment adherence should be adapted to such populations.

Strengthened tuberculosis control programme and trend of multi-drug resistant tuberculosis rate in Osaka City, Japan.

Osaka City has the highest tuberculosis (TB) notification rates in Japan. In the period 1999-2003, the TB control programme was strengthened, and the Stop TB Strategy was implemented to reduce the number of notified cases. The objective of this study was to assess the effect of these control activities in Osaka City, including the implementation of directly observed treatment (DOT), by analysing TB surveillance and routinely collected data. We reviewed the surveillance data of all sputum smear-positive pulmonary tuberculosis (PTB) cases registered in the Osaka City Public Health Office from 2001 to 2008 and data collected from the routine TB programme. The DOT implementation rate increased from 0% in 2001 to 68% in 2008 for smear-positive PTB cases of the general public and to 61% for all PTB cases of the homeless. The proportion of smear-positive PTB cases that had treatment failure and default combined, declined from 8.0% (52 of 650) in 2001 to 3.6% (20 of 548) in 2006. The proportion of cases among the homeless with previous treatment declined from 28% in 2001 to 15% in 2008. The proportion of cases with multidrug resistant-TB (MDR-TB) among those without previous treatment declined from 1.7% in 2001 to 0.9% in 2008. It is logical that reduction in the failure and default rate would lead to the reduction of cases with previous treatment and TB transmission, including resistant TB, therefore to the reduction of MDR-TB rates.

A combination of quantitative and qualitative methods in investigating risk factors for lost to follow-up for tuberculosis treatment in Japan – Are physicians and nurses at a particular risk?

Background The treatment success rate of pulmonary tuberculosis (PTB) patients aged 64 years and below in Japan, a tuberculosis (TB) middle-burden country with a notification of 13.9 per 100,000 populations in 2016, has been fluctuating around 70% for some years. In order to improve treatment outcome, it is critical to address those lost to follow-up (LTFU). The objective of the study therefore was to describe the characteristics of, and analyze the risk factors for those LTFU among pulmonary TB patients aged between 15 and 64, and discuss policy implications. Methods The study used a mixed method of quantitative and qualitative approach, and was conducted in two phases. The first involved analysis of cohort data from the national TB surveillance of PTB patients newly notified between 1 January 2006 and 31 December 2015. The second phase involved focus group (FGD) discussions with public health nurses, who are responsible for supporting TB patients’ adherence to medication, on the possible reasons why some patients become lost to follow-up. Results Analysis of the surveillance data suggested that among all patients, positive sputum smear (adjusted odds ratio, [aOR] 0.52, 95% confidence interval [CI] 0.47–0.58) and cavitary lesion on chest x-ray (aOR 0.79, 95%CI 0.72–0.85) decreased the risk, while not requiring hospitalization increased the risk of LTFU (aOR 1.46, 95%CI 1.33–1.60). Among females, being a physician (aOR 2.07 95%CI 1.23–3.48) and nurse (aOR 1.18, 95%CI 1.91–1.37) were identified as additional risk factors for LTFU. The analysis of focus group discussions revealed three possible themes which may be useful in understanding why nurses and physicians were at a higher risk of becoming LTFU–firstly, the possibility that physicians and nurses were finding it difficult to make medication taking a routine, secondly, their low risk perception towards TB is affecting their adherence behavior, and thirdly, their unwillingness to accept DOTS was increasing their risk of becoming LTFU. Conclusions The analysis of surveillance data and FGD transcripts indicated that patient education for those starting their treatment as an outpatient, and establishing DOTS that is both acceptable and realistic to physicians and nurses, may be two issues which need to be addressed urgently.

A situational analysis of latent tuberculosis infection among incarcerated population in Japan

Background The World Health Organization recommends that systematic testing and screening of latent tuberculosis infection (LTBI) among the incarcerated population “should be considered”, though based on evidence of either low or very low quality. However, in Japan, a TB middle-burden country, systematic screening for LTBI in correctional facilities is currently not conducted. As part of a larger study to determine the cost-effectiveness of LTBI screening in correctional facilities in Japan, this study was conducted to determine the situation of LTBI, including treatment outcome, among the incarcerated population in Japan, and provide the essential data for cost-effectiveness analysis. Method A cross-sectional study was conducted between 2017 and 2018 with public health centers which have one or more correctional facilities under their jurisdiction. Questionnaire surveys were sent to collect information on their policy of managing LTBI patients notified from correctional facilities, including whether or not there was a standardized procedure for initiating LTBI treatment, and also to collect sociodemographic information and treatment outcome of LTBI patients who were notified from the respective correctional facilities in 2015 and 2016. Results The survey was sent to a total of 163 public health centers, out of which 133 (81.6%) responded. 8 of the 133 public health centers actively guided the correctional facilities regarding LTBI treatment initiation through a standardized procedure, while 115 either had not established such procedure or were unaware of how LTBI treatment was being initiated in the correctional facilities. A total of 91 LTBI patients were notified from the correctional facilities in 2015 and 2016, and the information of 89 were available for analysis. 82 were males, and 83 were Japan-born. Treatment outcome was known for 88 patients, of which 70 had completed treatment. Of the 18 who did not complete the treatment, 15 had been lost to follow-up upon release from the facilities. Among those who had been released whilst on treatment, the proportion of those who completed the treatment was higher in those patients who received pre-release visit by a public health nurse, than those who did not. Conclusions LTBI treatment was often being initiated without consideration for the patients’ prison term. The treatment completion rate within jail was high, indicating the possibility that incarcerated population can benefit for LTBI treatment. On the other hand, the completion rate decreased significantly among those who had been released while still on treatment. In order to optimize the benefit, initiation of LTBI must carefully be considered upon the patient’s prison term, as well as coordination among the relevant organizations to ensure continuity of care after release.

Pulmonary tuberculosis and non-recent immigrants in Japan – some issues for post-entry interventions

Foreign-born persons are considered one of the high-risk populations for tuberculosis (TB), and numerous studies have discussed the potential role of pre-entry TB screening for immigrants. However, rates of TB disease among immigrants can remain high several years after entry. In Japan, approximately 50% of TB among foreign-born persons occurs among those who have entered Japan more than five years before being diagnosed, i.e. non-recent immigrants. However, little attention has been paid so far to the issue of TB control among the non-recent immigrants. A detailed analysis of the Japan Tuberculosis Surveillance data was therefore conducted to describe the characteristics of TB among non-recent immigrants and discuss policy implications in terms of post-entry interventions in Japan. The main findings were as follows: 1) the proportion of pulmonary TB cases aged 65 years and older was higher among non-recent than recent immigrants (9.8% vs 1.2%); 2) the proportion of those with social risk factors including homelessness and and being on social welfare assistance was higher among non-recent than recent immigrants; and 3) the proportion of those detected via routine screening at school or workplace was significantly lower among non-recent immigrants aged between 25 and 64 than among recent immigrants in the same age group (15.4% vs 28.7%). Our results suggested the need to increase the opportunities for and simultaneously improve the take-up rate of community-based screening for non-recent immigrants.