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Setting: The impact of the genetic characteristics of Mycobacterium tuberculosis on the clustering of multidrug-resistant tuberculosis (MDR-TB) has not been analyzed together with clinical and demographic characteristics., Objective: To determine factors associated with genotypic clustering of MDR-TB in a community-based study., Design: We measured the proportion of clustered cases among MDR-TB patients and determined the impact of clinical and demographic characteristics and that of three M. tuberculosis genetic characteristics: lineage, drug resistance-associated mutations, and rpoA and rpoC compensatory mutations., Results: Of 174 patients from California and Texas included in the study, the number infected by East-Asian, Euro-American, Indo-Oceanic and East-African-Indian M. tuberculosis lineages were respectively 70 (40.2%), 69 (39.7%), 33 (19.0%) and 2 (1.1%). The most common mutations associated with isoniazid and rifampin resistance were respectively katG S315T and rpoB S531L. Potential compensatory mutations in rpoA and rpoC were found in 35 isolates (20.1%). Hispanic ethnicity (OR 26.50, 95%CI 3.73-386.80), infection with an East-Asian M. tuberculosis lineage (OR 30.00, 95%CI 4.20-462.40) and rpoB mutation S531L (OR 4.03, 95%CI 1.05-23.10) were independent factors associated with genotypic clustering., Conclusion: Among the bacterial factors studied, East-Asian lineage and rpoB S531L mutation were independently associated with genotypic clustering, suggesting that bacterial factors have an impact on the ability of M. tuberculosis to cause secondary cases.

Objective: A population-based study of 135 multidrug-resistant tuberculosis (MDR-TB) patients reported to the Centers for Disease Control and Prevention (CDC) during 2005-2007 found 73% were hospitalized. We analyzed factors associated with hospitalization., Methods: We assessed statistically significant multivariable associations with US in-patient TB diagnosis, frequency of hospitalization, length of hospital stay, and in-patient direct costs to the health care system., Results: Of 98 hospitalized patients, 83 (85%) were foreign-born. Blacks, diabetics, or smokers were more likely, and patients with disseminated disease less likely, to receive their TB diagnosis while hospitalized. Patients aged ⩾65 years, those with the acquired immune-deficiency syndrome (AIDS), or with private insurance, were hospitalized more frequently. Excluding deaths, length of stay was greater for patients aged ⩾65 years, those with extensively drug-resistant TB (XDR-TB), those residing in Texas, those with AIDS, those who were unemployed, or those who had TB resistant to all first-line medications vs. others. Average hospitalization cost per XDR-TB patient (US$285 000) was 3.5 times that per MDR-TB patient (US$81 000), in 2010 dollars. Hospitalization episode costs for MDR-TB rank third highest and those for XDR-TB highest among the principal diagnoses., Conclusions: Hospitalization was common and remains a critical care component for patients who were older, had comorbidities, or required complex management due to XDR-TB. MDR-TB in-patient costs are among the highest for any disease.

Setting: An Hoa Clinic, a district-level human immunodeficiency virus (HIV) clinic in Ho Chi Minh City, Viet Nam., Objective: To assess the performance of chest radiograph (CXR) in screening for pulmonary tuberculosis (PTB) among HIV-infected individuals and identify misdiagnosed opportunities., Design: This cross-sectional study was conducted in 397 HIV-infected patients consecutively enrolled at the An Hoa Clinic in Ho Chi Minh City, Viet Nam, from August 2009 to June 2010. The performance of CXR in TB screening was assessed based on its sensitivity, specificity, positive likelihood ratio and negative likelihood ratio., Results: Symptom screening alone missed 50% of PTB cases. The combination of CXR and symptom screening yielded an additional 28.6% (8/28) in PTB screening as compared with symptom screening alone, and should be applied routinely, especially in high TB prevalent settings., Conclusion: CXR is a good predictor for PTB even in HIV-infected individuals. The combination of CXR and screening for common TB symptoms considerably improved the sensitivity of detecting active PTB in people living with HIV. If available, routine sputum culture and the World Health Organization-endorsed Xpert(®) MTB/RIF assay should be implemented to achieve a more accurate diagnosis.

Background: Isoniazid-resistant (INHr) Mycobacterium tuberculosis isolates often have katG mutations, and katG is a virulence factor in animal models. It is unclear if katG mutations or other mutations influence the characteristics of human disease., Objective: To determine if the presence of INHr-conferring mutations were associated with distinct clinical features of tuberculosis (TB)., Methods: In a retrospective case-control study, INHr-conferring mutations were determined by DNA sequencing. We examined associations between clinical characteristics in patients with INHr M. tuberculosis (stratified by groups of relevant INHr-conferring mutations, including katG-S315T and inhA-C(-)15T mutations) and pan-susceptible (PS) isolates., Results: Twenty-nine INHr TB cases and 50 PS controls were evaluated. Disease characteristics were not statistically different between INHr and PS cases. However, patients infected with non-katG mutants were associated with a higher rate of sputum culture conversion at 1 month after adjustment for relevant covariates (adjusted OR [aOR] 4.4, 95%CI 1.1-23.6, P = 0.04). Patients infected with katG mutants were associated with a higher rate of unilateral disease (aOR 4.7, 95%CI 1.0-34.3, P = 0.05)., Conclusions: Most INHr TB cases with non-katG mutations have disease associated with faster response to treatment, and most cases with katG mutants have localized lung involvement.

To investigate the prevalence of extensively drug-resistant tuberculosis (XDR-TB) in Chinese populations, we analyzed the drug resistance profiles of 1787 Mycobacterium tuberculosis isolates through a population-based surveillance project in Shandong Province, China. We found 330 (18.5%; 95%CI 16.1-20.3) isolates resistant to ≥1 first-line drug and 65 (3.6%; 95%CI 2.9-4.6) multidrug-resistant (MDR) isolates, of which 13 (20.0%; 95%CI 11.9-31.4) were XDR; 47/65 MDR-TB isolates (70.8%; 95%CI 58.2-81.4) were resistant to fluoroquinolones. Our results indicate that inadequate application of second-line anti-tuberculosis drugs has caused increased prevalence of XDR-TB in certain Chinese populations.

Setting: District 6, An Hoa Clinic in Ho Chi Minh City (HCMC), Viet Nam., Objective: To evaluate the performance of various algorithms in tuberculosis (TB) screening and diagnosis in a human immunodeficiency virus (HIV) infected population in HCMC, Viet Nam., Design: A cross-sectional study of 397 consecutive HIV-infected patients seeking care at the An Hoa Clinic from August 2009 to June 2010. Data on participant demographics, clinical status, chest radiography (CXR) and laboratory results were collected. A multiple logistic regression model was developed to assess the association of covariates and pulmonary TB (PTB)., Results: The prevalence of sputum culture-confirmed PTB, acid-fast bacilli (AFB) positive TB, and multidrugresistant TB among the 397 HIV-infected patients was respectively 7%, 2%, and 0.3%. Adjusted odds ratios for low CD4+ cell count, positive sputum smear, and CXR to positive sputum culture were respectively 3.17, 32.04 and 4.28. Clinical findings alone had poor sensitivity, but combining CD4+ cell count, AFB sputum smear and CXR had a more accurate diagnostic performance., Conclusion: Results suggest that symptom screening had poor clinical performance, and support the routine use of sputum culture to improve the detection of TB disease in HIV-infected individuals in Viet Nam. However, when routine sputum culture is not available, an algorithm combining CD4+ cell count, AFB sputum smear and CXR is recommended for diagnosing PTB.

T-SPOT®.TB and the tuberculin skin test (TST) were used to screen for latent tuberculosis infection among 899 Chinese college students. The positivity rates for T-SPOT®.TB and TST were respectively 13.0% (95% confidence interval [CI] 10.4-15.9) and 24.9% (95%CI 21.5-28.6) among students with a bacille Calmette-Guérin (BCG) scar (agreement of both tests 72.3%; 95%CI 68.6-75.8; κ = 0.118), and respectively 17.3% (95%CI 11.7-24.2) and 23.7% (95%CI 17.3-31.2) among those without a BCG scar (agreement 73.1%; 95%CI 65.4-79.9; κ = 0.179). These results demonstrate low agreement between the TST and T-SPOT.TB in the Chinese population studied.

Setting: An inner city neighborhood in Houston, Texas, known for a high rate of drug use., Objective: To determine the prevalence of latent tuberculosis infection (LTBI) using the QuantiFERON-TB Gold (QFT-G) test, the TSPOT.TB test and the tuberculin skin test (TST) in drug users and to evaluate the performance of the QFT-G and TSPOT.TB tests vs. the TST., Design: Cross-sectional study. Bivariate and multivariate logistic regression analyses were used to determine risks associated with each test outcome., Results: The prevalence of LTBI in 119 drug users studied was 28% by TST and 34% by QFT-G and T-SPOT.TB. Kappa statistics indicated fair to moderate concordance between QFT-G and TSPOT.TB vs. TST. About one-fifth of the population that tested negative with TST was positive with either QFT-G or T-SPOT.TB. On multivariate analysis, the likelihood of testing QFT-positive or T-SPOT.TB-positive increased by 8% and 6%, respectively, for every year of age; TST positivity was associated with smoking crack at home; being Caucasian or having a history of alcohol use was positively associated with a positive T-SPOT.TB test., Conclusion: Interferon-gamma release assays (IGRAs) are superior to the TST in drug users with a higher prevalence of LTBI. Future studies need to assess the predictive value of IGRAs on the progression from LTBI to active TB in high-risk populations.

A single nucleotide polymorphism (SNP), +874T/A, in the first intron of the interferon-gamma (IFN-gamma) gene, has presented associations with human susceptibility to tuberculosis (TB) in some ethnic populations, but not in others. In this population-based case-control study with adult TB patients from Houston, Texas, we found no significant differences of + 874T/A genotypic frequencies between cases and ethnically-matched controls or between advanced forms of TB disease (extra-pulmonary involvement or presence of cavitary disease) and pulmonary TB. Given possible sample size limitations, our results suggest that the IFN-gamma +874T/A mutation has no association with TB susceptibility or TB disease severity.

Objective: To determine the predictors of recurrence of tuberculosis (TB), the drug resistance pattern of Mycobacterium tuberculosis strains recovered from recurrent TB patients, and the frequency of re-infection with a new M. tuberculosis strain among patients with recurrent disease., Design: A population-based, retrospective case-control study using the Houston Tuberculosis Initiative database., Results: We found that, among 100 patients with recurrent TB who completed adequate therapy for a first episode of TB, not receiving directly observed therapy, pulmonary disease, HIV/AIDS diagnosis, not having a family physician, being unemployed and using public transportation were predictors of recurrent disease. There was a significant increase in drug-resistant M. tuberculosis strains in the second episode of disease compared to the first episode (21.3% vs. 8.2%, P = 0.04). Exogenous re-infection with a new strain of M. tuberculosis was found to cause 24-31% of recurrent TB., Conclusion: Recurrent TB in Houston is associated with a significant increase in drug-resistant M. tuberculosis strains. Re-infection with a new M. tuberculosis strain causes a significant proportion of recurrent TB in an area of low TB incidence. Patients with HIV/AIDS constitute a population at increased risk of disease recurrence.

Background: The increases in extra-pulmonary tuberculosis (EPTB) have been largely due to human immunodeficiency virus co-infection. The rates of EPTB have remained constant despite the decline in pulmonary tuberculosis (PTB) cases., Objective: To evaluate covariates associated with EPTB., Methods: A 4-year cohort of EPTB patients was compared with PTB cases. Enrollees were assessed for TB risk, medical records were reviewed, and Mycobacterium tuberculosis isolates were fingerprinted., Results: We identified 538 EPTB cases (28.6%) in a total of 1878 enrollees. The most common sites of infection were lymph nodes (43%) and pleura (23%). EPTB cases included 320 (59%) males, 382 (71%) patients were culture-positive, and 332 (86.9%) patient isolates were fingerprinted. Fewer EPTB than PTB patients belonged to clustered M. tuberculosis strains (58% vs. 65%; P = 0.02). A multivariate model identified an increased risk for EPTB among African Americans (OR = 1.9, P = 0.01), HIV-seropositive (OR = 3.1, P < 0.01), liver cirrhosis (OR = 2.3, P = 0.02), and age <18 years (OR = 2.0, P = 0.04). Patients with concomitant pulmonary and extra-pulmonary infections were more likely to die within 6 months of TB diagnosis (OR = 2.3, P < 0.01)., Conclusions: African American ethnicity is an independent risk factor for EPTB. Mortality at 6 months is partly due to the dissemination of M. tuberculosis and the severity of the underlying co-morbidity.

Objective: To evaluate the covariates associated with extrathoracic tuberculosis lymphadenitis (ETBL) among adult HIV-seronegative patients., Methods: Enrollees were interviewed for TB risk assessment, their medical records were reviewed, and their Mycobacterium tuberculosis isolates underwent molecular characterization. Between 1 October 1995 and 30 September 1999, HIV-negative patients with ETBL were compared with other HIV-negative TB patients., Results: We identified 73 ETBL cases (5%) out of a total of 1371 adult HIV-negative enrollees. Significant variables predicting ETBL in the univariate analysis included age < 45 years, female sex, Asian ethnicity, foreign birth, BCG vaccination, and infection with a M. tuberculosis isolate identified in major genetic group 1. Further analysis by birth country revealed increased ETBL risk for persons from countries other than the Americas and with a TB incidence > 25 per 100 000 per year. The multivariate model demonstrated increased risk for ETBL for patients of female sex (OR = 2.6, P < 0.01) and birth in Africa or South-east Asia (OR = 4.8; P = 0.03 and OR = 33.6; P = 0.01, respectively)., Conclusions: In adult HIV-negative patients, ETBL occurs more frequently in females and in immigrants from countries other than the Americas; persons from India, South-east Asia and the Eastern Mediterranean exhibited the highest risk among these regions.

Setting: Houston Tuberculosis Initiative (HTI) and Baylor College of Medicine, Houston, Texas., Objective: To further explore the association between the polymorphisms of NRAMP1 and human susceptibility/resistance to tuberculosis (TB), specifically to determine whether the reported association shown for blacks and Asians holds true for Caucasian populations., Design: In a case-control study, 135 adult Caucasian TB patients and 108 adult Caucasian HIV-seronegative non-TB controls were analyzed for the association between the polymorphisms in NRAMP1 gene and clinical TB., Results: Heterozygote at 5'(GT)n, a dinucleotide repeat polymorphism in the promoter of NRAMP1, was observed at significantly higher frequencies among HIV-negative patients with pulmonary TB (41.6%; OR 2.02; 95%CI 1.11-3.64), extra-pulmonary TB (66.7%; OR 4.80; 95%CI 1.34-17.15), and HIV-seropositive TB patients (50%; OR 3.77; 95%CI 1.33-10.66) in comparison with the controls (27.8%). Homozygotes (GT)(10,10) were over-represented among HIV-positive TB patients (18.2%; OR 6.86; 95%CI 1.55-30.21) compared to the controls (5.5%)., Conclusion: These findings suggest that the 5'(GT)n polymorphism of NRAMP1 modifies TB susceptibility in this Caucasian population, and could possibly be related to the site of infection among HIV-negative individuals and HIV-coinfected TB.

Objective: Descriptive study of molecular epidemiologic patterns of tuberculosis cases among ethnic minorities in Houston, Texas., Design: Population-based, prospective, active surveillance, and molecular epidemiology study., Patients: Tuberculosis cases reported to the City of Houston Tuberculosis Control Office between October 1995 and September 1998., Results: During the study period, 1,139 culture-positive patients were enrolled for whom isolates of their culture specimen were available. Of these, 910 were part of an ethnic minority. Molecular characterization identified 689 of 1,139 isolates to be clonally related. Factors significantly associated with tuberculosis strain clustering in a multivariable logistic regression analysis were: birth in the United States, a history of homelessness, infection with the human immunodeficiency virus (HIV), pulmonary disease, infection with a tuberculosis strain from principal genetic group 1 or 3, living in a residence with five or more persons present, and use of public transportation more than once weekly. Asian ethnicity and increasing age were associated with decreased odds of clustering., Conclusions: Ethnicity was not a significant covariate for strain clustering after adjustments for factors related to socio-economic status.