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Maeda S.,Research Institute of Tuberculosis | Hang N.T.L.,Medical Collaboration Center | Thuong P.H.,Hanoi Lung Hospital | Hung N.V.,National Lung Hospital | And 7 more authors.
Tuberculosis | Year: 2014

Beijing genotype strains are divided into two major sublineages, ancient (atypical) and modern (typical) types, but their phenotypic variations remain largely unknown. Mycobacterium tuberculosis (MTB) isolates from Hanoi, Vietnam, were analyzed by single-nucleotide polymorphisms and spoligotyping. Patient information and drug susceptibility patterns were obtained. Genetic clustering was assessed by variable number of tandem repeat (VNTR) locus sets. Multivariate analysis was also performed to investigate factors possibly associated with these sublineages. Of the 465 strains tested, 175 (37.6%) belonged to the ancient Beijing sublineage and 97 (20.9%) were of the modern Beijing sublineage. Patients with the Beijing genotype were significantly younger and more undernourished than those with non-Beijing genotype. The proportion of clustered strains calculated from 15 locus-optimized mycobacterial interspersed repetitive units [optimized-(MIRU)15]-, optimized-MIRU24-, optimized-MIRU28-, Japan Anti-Tuberculosis Association (JATA)15-, and JATA18-VNTRs were 55.7%, 49.2%, 33.8%, 44.5%, and 32.0%, respectively. Ancient and modern Beijing genotype strains were more frequently clustered than non-Beijing genotype strains, even when using VNTR sets with high discriminatory power. Isoniazid and streptomycin resistance tended to be more frequently observed in ancient Beijing strains than in modern Beijing strains and others. Our findings may provide insight into area-dependent differences in Beijing family strain characteristics. © 2014 The Authors.


Manabe T.,U.S. Center for Disease Control and Prevention | Thuy P.T.P.,Medical Collaboration Center | Takasaki J.,U.S. Center for Disease Control and Prevention | Huyen D.T.T.,Medical Collaboration Center | And 6 more authors.
PLoS ONE | Year: 2011

Background: Early initiation of treatment is essential for treatment of avian influenza A/H5N1 viral infection in humans, as the disease can lead to rapid development of severe pneumonia which can result in death. Contact with infected poultry is known to be a significant risk factor for contraction of H5N1 infection. However, handling and encountering poultry are a part of most peoples' daily lives, especially in rural communities in Vietnam where epidemic outbreaks among poultry have been continuously reported. Enhancing proper knowledge relating to H5N1 and to the importance of early initiation of treatment are crucial. The aim of this study was to develop an effective educational program to enhance awareness of H5N1 and motivate people to access to health care earlier when H5N1 infection is suspected or likely. Methodology and Principal Findings: A study was conducted in two agricultural communities (intervention and control groups) in the Ninh Binh province in Vietnam, where epidemic outbreaks of avian influenza have recently occurred in birds. A unique educational intervention was developed and provided to the intervention group, and no intervention was provided to the control group. A knowledge, attitude and practice (KAP) survey was conducted in both groups with a face-to-face interview by trained local healthcare workers at time points before and after the educational intervention. KAP scores were compared between the different time points and between the groups. How educational intervention influenced awareness relating to H5N1 and accessibility of healthcare in the population was analyzed. The study indicated an increased awareness of H5N1 and increased reliance on local health care workers. Conclusions: The novel educational program which was developed for this study impacted awareness of H5N1, and resulted in more people seeking early access to healthcare, and also resulted in earlier medical intervention for patients with H5N1 avian influenza infection in Vietnam. © 2011 Manabe et al.


Le Hang N.T.,Medical Collaboration Center | Lien L.T.,Hanoi Lung Hospital | Kobayashi N.,National Center for Global Health and Medicine | Shimbo T.,International Clinical Research Center | And 10 more authors.
PLoS ONE | Year: 2011

Background: Imperfect sensitivity of interferon-γ release assay (IGRA) is a potential problem to detect tuberculosis. We made a thorough investigation of the factors that can lead to false negativity of IGRA. Methods: We recruited 543 patients with new smear-positive pulmonary tuberculosis in Hanoi, Viet Nam. At diagnosis, peripheral blood was collected and IGRA (QuantiFERON-TB Gold In-Tube) was performed. Clinical and epidemiological information of the host and pathogen was collected. The test sensitivity was calculated and factors negatively influencing IGRA results were evaluated using a logistic regression model in 504 patients with culture-confirmed pulmonary tuberculosis. Results: The overall sensitivity of IGRA was 92.3% (95% CI, 89.6%-94.4%). The proportions of IGRA-negative and -indeterminate results were 4.8% (95% CI, 3.1%-7.0%) and 3.0% (95% CI, 1.7%-4.9%). Age increased by year, body mass index <16.0, HIV co-infection and the increased number of HLA-DRB1*0701 allele that patients bear showed significant associations with IGRA negativity (OR = 1.04 [95% CI, 1.01-1.07], 5.42 [1.48-19.79], 6.38 [1.78-22.92] and 5.09 [2.31-11.22], respectively). HIV co-infection and the same HLA allele were also associated with indeterminate results (OR = 99.59 [95% CI, 15.58-625.61] and 4.25 [1.27-14.16]). Conclusions: Aging, emaciation, HIV co-infection and HLA genotype affected IGRA results. Assessment of these factors might contribute to a better understanding of the assay. © 2011 Hang et al.


PubMed | National Center for Global Health and Medicine, NHO Tokyo National Hospital, Tokyo Electron, The Research Institute of Tuberculosis Japan Anti Tuberculosis Association and 4 more.
Type: | Journal: International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases | Year: 2015

In the performance of interferon gamma release assays (IGRA) for the diagnosis of tuberculosis (TB) infection, false-negative results are a major obstacle. In active TB patients, treatment-dependent changes of the negative test results remain unknown.The treatment course of 19 smear-positive/culture-confirmed TB patients who had IGRA-negative results by QuantiFERON-TB in-tube (QFT-IT) method at the time of diagnosis (month 0) in a previous study, were monitored in the present study. Blood was further collected at months 2 and 7, and the concentrations of 27 immune molecules were measured in the plasma supernatants remaining after performing the IGRA, using a suspension array system.After initiating treatment, eight of the 19 QFT-IT-negative patients showed positive conversion, whereas the remaining 11 (58%) did not; the interferon gamma (IFN-) response was restored to levels higher than 1 IU/ml in only three of the eight patients with positive conversion. Plasma concentrations of interleukin 1 receptor antagonist, interleukin 2, and interferon gamma-induced protein 10 remained low after Mycobacterium tuberculosis-specific antigen stimulation at months 2 and 7 in the continuously QFT-IT-negative group, whereas the parameters were elevated only in the transiently QFT-IT-negative group.It was demonstrated that a majority of active TB patients showing negative IGRA results did not regain sufficient levels of immune responsiveness despite successful treatment.


PubMed | National Center for Global Health and Medicine, Tokyo Electron, Center for Clinical science, National Health Research Institute and 3 more.
Type: Journal Article | Journal: Human immunology | Year: 2014

Mannose-binding lectin (MBL) binds to pathogens and induces complement-mediated opsonophagocytosis. Although the association between MBL2 polymorphisms and tuberculosis (TB) has been studied in various populations, the results are controversial. We explored the stages of TB associated with MBL2 polymorphisms. X/Y (rs7096206) and A/B (rs1800450) were genotyped in 765 new patients with active pulmonary TB without HIV infection and 556 controls in Hanoi, Viet Nam. The MBL2 nucleotide sequences were further analyzed, and plasma MBL levels were measured in 109 apparently healthy healthcare workers and 65 patients with TB. Latent TB infection (LTBI) was detected by interferon-gamma release assay (IGRA). The YA/YA diplotype, which exhibited high plasma MBL levels, was associated with protection against active TB in younger patients (mean age = 32) 45 years old (odds ratio, 0.61; 95% confidence interval, 0.46-0.80). The resistant diplotype was less frequently found in the younger patients at diagnosis (P = 0.0021). MBL2 diplotype frequencies and plasma MBL levels were not significantly different between the IGRA-positive and -negative groups. MBL2 YA/YA exhibited a protective role against the development of TB in younger patients, whereas the MBL2 genotype and MBL levels were not associated with LTBI. High MBL levels may protect against the early development of pulmonary TB after infection.


PubMed | National Center for Global Health and Medicine, NHO Tokyo National Hospital, Tokyo Electron, Tokyo Women's Medical University and 6 more.
Type: Journal Article | Journal: The Journal of infection | Year: 2014

We investigated the relationship between tuberculosis recurrence and Mycobacterium tuberculosis antigen-stimulated interferon-gamma (IFN-) responses during treatment.Plasma IFN- levels in active pulmonary tuberculosis patients (n = 407) were analyzed using QuantiFERON-TB Gold In-Tube (QFT-IT) at 0, 2, and 7 months of the 8-month treatment received from 2007 to 2009 and the patients were followed up for another 16 months after treatment. Risk factors for recurrence were assessed using the log-rank test and Cox proportional hazard models. Random coefficient models were used to compare longitudinal patterns of IFN- levels between groups.QFT-IT showed positive results in 95.6%, 86.2%, and 83.5% at 0, 2, and 7 months, respectively. The antigen-stimulated IFN- responses varied significantly during the treatment course (P < 0.0001). Unexpectedly, positive-to-negative conversion of QFT-IT results between 0 and 2 months was significantly associated with earlier recurrence (adjusted hazard ratio, 5.57; 95% confidence interval, 2.28-13.57). Time-dependent changes in IFN- levels were significantly different between the recurrence and nonrecurrence groups (P < 0.0001).Although the IGRA response varies individually, early response during the treatment course may provide an insight into host immune responses underlying tuberculosis recurrence.


Hijikata M.,National Health Research Institute | Shojima J.,National Health Research Institute | Matsushita I.,National Health Research Institute | Tokunaga K.,University of Tokyo | And 8 more authors.
Human Genetics | Year: 2012

Interferon-γ (IFN-γ) is a key molecule of T helper 1 (Th1)-immune response against tuberculosis (TB), and rare genetic defects of IFN-c receptors cause disseminated mycobacterial infection. The aim of the present study was to investigate whether genetic polymorphisms found in the Th1-immune response genes play a role in TB. In our study, DNA samples were collected from two series of cases including 832 patients with new smear-positive TB and 506 unrelated individuals with no history of TB in the general population of Hanoi, Vietnam. Alleles of eight microsatellite markers located around Th1-immune response-related genes and single nucleotide polymorphisms near the promising microsatellites were genotyped. A set of polymorphisms within the interferon gamma receptor 2 gene (IFNGR2) showed a significant association with protection against TB (P = 0.00054). Resistant alleles tend to be less frequently found in younger age at diagnosis (P = 0.011). Luciferase assays revealed high transcriptional activity of the promoter segment in linkage disequilibrium with resistant alleles. We conclude that the polymorphisms of IFNGR2 may confer resistance to the TB development of newly infected individuals. Contribution of the genetic factors to TB appeared to be different depending on age at diagnosis. © The Author(s) 2011.


Kobayashi K.,University of Tokyo | Yuliwulandari R.,University of Tokyo | Yuliwulandari R.,YARSI University | Yanai H.,University of Tokyo | And 7 more authors.
Tissue Antigens | Year: 2012

Tuberculosis (TB) is caused by Mycobacterium tuberculosis and is a major cause of morbidity and mortality worldwide. Many candidate genes have been investigated for a possible association with TB. Toll-like receptors (TLRs) are known to play important roles in human innate immune systems. Polymorphisms in and functions of TLRs have been investigated to identify associations with specific infectious diseases, including TB. Here, we examined whether single-nucleotide polymorphisms (SNPs) in TLRs and genes in TLR signaling were associated with TB susceptibility in Indonesian and Vietnamese populations. A statistically significant association was observed between TB susceptibility in a classified Indonesian female group and rs352139, an SNP located in the intron of TLR9, using the genotype (P = 2.76E-04) and recessive (AA vs AG+GG, P = 2.48E-04, odds ratio = 1.827, 95% confidence interval = 1.321-2.526) models. Meta-analysis of the Indonesian and Vietnamese populations showed that rs352139 was significantly associated with TB in the recessive model. This finding indicated that a TLR9 polymorphism might have an important role in the susceptibility to M. tuberculosis in Asian populations. © 2011 John Wiley & Sons A/S.


Kobayashi K.,University of Tokyo | Yuliwulandari R.,University of Tokyo | Yuliwulandari R.,YARSI University | Yanai H.,University of Tokyo | And 6 more authors.
Human Immunology | Year: 2011

Tuberculosis (TB) caused by Mycobacterium tuberculosis is a major cause of morbidity and mortality worldwide. Thus far, many candidate genes have been investigated for their possible association with TB. Dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN) encoded by CD209 is the major receptor of M tuberculosis on human dendritic cells. Previous studies reported inconsistent results on the association between CD209 polymorphisms and TB. We examined whether 9 single nucleotide polymorphisms (SNPs) of CD209 are associated with TB in 2 southeast Asian populations (Indonesian and Vietnamese) by Fisher's exact test. The SNP at -939 in the promoter region exhibited a significant association with TB in Indonesian (GG vs GA + AA, p = 0.0051, odds ratio [OR] = 0.68, 95% confidence interval [CI] = 0.52-0.89) but not in Vietnamese populations. Further extensive studies are required to confirm the contribution of CD209 polymorphisms to TB susceptibility. © 2011 American Society for Histocompatibility and Immunogenetics.


Sakurada S.,National Center for Global Health and Medicine | Hang N.T.L.,Medical Collaboration Center | Ishizuka N.,National Center for Global Health and Medicine | Toyota E.,NHO Tokyo Hospital | And 7 more authors.
BMC Infectious Diseases | Year: 2012

Background: Inter-rater agreement in the interpretation of chest X-ray (CXR) films is crucial for clinical and epidemiological studies of tuberculosis. We compared the readings of CXR films used for a survey of tuberculosis between raters from two Asian countries.Methods: Of the 11,624 people enrolled in a prevalence survey in Hanoi, Viet Nam, in 2003, we studied 258 individuals whose CXR films did not exclude the possibility of active tuberculosis. Follow-up films obtained from accessible individuals in 2006 were also analyzed. Two Japanese and two Vietnamese raters read the CXR films based on a coding system proposed by Den Boon et al. and another system newly developed in this study. Inter-rater agreement was evaluated by kappa statistics. Marginal homogeneity was evaluated by the generalized estimating equation (GEE).Results: CXR findings suspected of tuberculosis differed between the four raters. The frequencies of infiltrates and fibrosis/scarring detected on the films significantly differed between the raters from the two countries (P < 0.0001 and P = 0.0082, respectively, by GEE). The definition of findings such as primary cavity, used in the coding systems also affected the degree of agreement.Conclusions: CXR findings were inconsistent between the raters with different backgrounds. High inter-rater agreement is a component necessary for an optimal CXR coding system, particularly in international studies. An analysis of reading results and a thorough discussion to achieve a consensus would be necessary to achieve further consistency and high quality of reading. © 2012 Sakurada et al; BioMed Central Ltd.

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