QuantiFERON-TB Gold plus testing for the detection of LTBI among health care workers in major TB hospitals of the Northern Kyrgyz Republic.

BACKGROUND: Health care workers (HCW) are at increased risk of TB infection due to their close contact with infected patients with active TB. The objectives of the study were (1) to assess the prevalence of LTBI among HCW in the Northern Kyrgyz Republic, and (2) to determine the association of LTBI with job positions or departments. METHODS: HCWs from four TB hospitals in the Northern Kyrgyz Republic were tested with the interferon-gamma release assay (IGRA) Quantiferon-TB Gold plus (QFT) for the detection of an immune response to TB as marker of TB infection. Age was controlled for as a confounder. Univariate and multivariable analysis were performed using logistic regression to assess the association of the risk factors (job position, and department) with having a QTF positive result. Firth's penalized-likelihood estimates were used to account for the small-sample size. Pairwise comparisons using the Bonferroni correction (conservative) and comparisons without adjusting for multiple comparisons (unadjusted) were used to identify the categories where differences occurred. RESULTS: QFT yielded valid results for 404 HCW, with 189 (46.7%) having a positive test. In the National Tuberculosis Center there was an increased odds to have a positive QFT test for the position of physician (OR = 8.7, 95%, CI = 1.2-60.5, p = 0.03) and laboratory staff (OR = 19.8, 95% CI = 2.9-135.4, p < 0.01) when administration staff was used as the baseline. When comparing departments for all hospitals combined, laboratories (OR 7.65; 95%CI 2.3-24.9; p < 0.001), smear negative TB (OR 5.90; 95%CI 1.6-21.8; p = 0.008), surgery (OR 3.79; 95%CI 1.3-11.4; p = 0.018), and outpatient clinics (OR 3.80; 95%CI 1.1-13.0; p = 0.03) had higher odds of a positive QFT result than the admin department. Fifteen of the 49 HCW with follow-up tests converted from negative to positive at follow-up testing. CONCLUSIONS: This is the first report on prevalence and risk factors of LTBI for HCW in the Kyrgyz republic, and results indicate there may be an increased risk for LTBI among physicians and laboratory personnel. Further research should investigate gaps of infection control measures particularly for physicians and laboratory staff and lead to further improvement of policies.

Implementation of whole genome sequencing for tuberculosis diagnostics in a low-middle income, high MDR-TB burden country.

Whole genome sequencing (WGS) is revolutionary for diagnostics of TB and its mutations associated with drug-resistances, but its uptake in low- and middle-income countries is hindered by concerns of implementation feasibility. Here, we provide a proof of concept for its successful implementation in such a setting. WGS was implemented in the Kyrgyz Republic. We estimated needs of up to 55 TB-WGS per week and chose the MiSeq platform (Illumina, USA) because of its capacity of up to 60 TB-WGS per week. The project's timeline was completed in 93-weeks. Costs of large equipment and accompanying costs were 222,065 USD and 8462 USD, respectively. The first 174 WGS costed 277 USD per sequence, but this was skewed by training inefficiencies. Based on real prices and presuming optimal utilization of WGS capacities, WGS costs could drop to 167 and 141 USD per WGS using MiSeq Reagent Kits v2 (500-cycles) and v3 (600-cycles), respectively. Five trainings were required to prepare the staff for autonomous WGS which cost 48,250 USD. External assessment confirmed excellent performance of WGS by the Kyrgyz laboratory in an interlaboratory comparison of 30 M. tuberculosis genomes showing complete agreeance of results.

Implementing contact tracing for tuberculosis in Kyrgyz Republic and risk factors for positivity using QuantiFERON-TB Gold plus.

BACKGROUND: Effective active case finding (ACF) activities are essential for early identification of new cases of active tuberculosis (TB) and latent TB infection (LTBI). Accurate diagnostics as well as the ability to identify contacts at high risk of infection are essential for ACF, and have not been systematically reported from Central Asia. The objective was to implement a pilot ACF program to determine the prevalence and risk factors for LTBI and active TB among contacts of individuals with TB in Kyrgyz Republic using Quantiferon-TB Gold plus (QuantiFERON). METHODS: An enhanced ACF project in the Kyrgyz Republic was implemented in which close and household (home) contacts of TB patients from the Issyk-Kul Oblast TB Center were visited at home. QuantiFERON and the tuberculin skin test (TST) alongside clinical and bacteriological examination were used to identify LTBI and active TB cases among contacts. The association for QuantiFERON positivity and risk factors were analysed and compared to TST results. RESULTS: Implementation of ACF with QuantiFERON involved close collaboration with the national sanitary and epidemiological services (SES) and laboratories in the Kyrgyz Republic. From 67 index cases, 296 contacts were enrolled of whom 253 had QuantiFERON or TST results; of those 103 contacts had LTBI (positive TST or IGRA), and four (1.4%) active TB cases were detected. Index case smear microscopy (OR 1.76) and high household density (OR 1.97) were significant risk factors for QuantiFERON positivity for all contacts. When stratified by age, association with smear positivity disappeared for children below 15 years. TST was not associated with any risk factor. CONCLUSIONS: This is the first time that ACF activities have been reported for Central Asia, and provide insight for implementation of effective ACF in the region. These ACF activities using QuantiFERON led to increase in the detection of LTBI and active cases, prior to patients seeking treatment. Household density should be taken into consideration as an important risk factor for the stratification of future ACF activities.

Population structure of drug-resistant Mycobacterium tuberculosis in Central Asia.

BACKGROUND: Drug-resistant tuberculosis (TB) is a major public health concern threathing the success of TB control efforts, and this is particularily problematic in Central Asia. Here, we present the first analysis of the population structure of Mycobacterium tuberculosis complex isolates in the Central Asian republics Uzbekistan, Tajikistan, and Kyrgyzstan. METHODS: The study set consisted of 607 isolates with 235 from Uzbekistan, 206 from Tajikistan, and 166 from Kyrgyzstan. 24-loci MIRU-VNTR (Mycobacterial Interspersed Repetitive Units - Variable Number of Tandem Repeats) typing and spoligotyping were combined for genotyping. In addition, phenotypic drug suceptibility was performed. RESULTS: The population structure mainly comprises strains of the Beijing lineage (411/607). 349 of the 411 Beijing isolates formed clusters, compared to only 33 of the 196 isolates from other clades. Beijing 94-32 (n = 145) and 100-32 (n = 70) formed the largest clusters. Beijing isolates were more frequently multidrug-resistant, pre-extensively resistant (pre-XDR)- or XDR-TB than other genotypes. CONCLUSIONS: Beijing clusters 94-32 and 100-32 are the dominant MTB genotypes in Central Asia. The relative size of 100-32 compared to previous studies in Kazakhstan and its unequal geographic distribution support the hypothesis of its more recent emergence in Central Asia. The data also demonstrate that clonal spread of resistant TB strains, particularly of the Beijing lineage, is a root of the so far uncontroled MDR-TB epidemic in Central Asia.

Comparison of Xpert MTB/RIF with ProbeTec ET DTB and COBAS TaqMan MTB for direct detection of M. tuberculosis complex in respiratory specimens.

BACKGROUND: Nucleic acid amplification assays allow for the rapid and accurate detection of Mycobacterium tuberculosis (MTB) directly in clinical specimens thereby facilitating diagnosis of tuberculosis (TB). With the fully automated Xpert MTB/RIF system (Cepheid) an innovative solution of TB diagnostics has been launched. We performed a direct head-to-head comparison of Xpert MTB/RIF with two widely used commercial assays, ProbeTec ET DTB (DTB) (Becton-Dickinson) and COBAS TaqMan MTB (CTM-MTB) (Roche). METHODS: 121 pre-characterized respiratory specimens (68 culture-positive for MTB complex, 24 culture-positive for non-tuberculous mycobacteria and 29 culture-negative) taken from our frozen specimen bank were tested for the presence of MTB complex by the three assays. RESULTS: Among culture-positive samples (n = 68), overall sensitivity for detection of MTB complex was 74.6%, 73.8%, and 79.1% for Xpert MTB/RIF, CTM-MTB, and DTB, respectively. Within the subgroup of smear-negative TB samples (n = 51) sensitivity was 68% for Xpert MTB/RIF and CTM-MTB and 72% for DTB. Among smear-positive TB samples (n = 17), all (100%) were detected by DTB and 94.1% and 93.3% by Xpert MTB/RIF and CTM-MTB, respectively. Specificity was best for CTM-MTB (100%) and lowest for Xpert MTB/RIF (96.2%) due to misidentification of two NTM samples as MTB complex. CTM-MTB yielded the highest rate of invalid results (4.1%) (0.8% by Xpert MTB/RIF and DTB, respectively). CONCLUSIONS: The direct comparison of Xpert MTB/RIF with CTM-MTB and DTB yielded similar overall performance data. Whereas DTB was slightly superior to Xpert MTB/RIF in terms of sensitivity, at least in the sample collection tested here, CTM-MTB performed best in terms of specificity.

Multidrug-resistant tuberculosis in Belarus: the size of the problem and associated risk factors.

OBJECTIVE: To assess the problem of multidrug-resistant tuberculosis (MDR-TB) throughout Belarus and investigate the associated risk factors. METHODS: In a nationwide survey in 2010-2011, 1420 tuberculosis (TB) patients were screened and 934 new and 410 previously treated cases of TB were found to meet the inclusion criteria. Isolates of Mycobacterium tuberculosis from each eligible patient were tested for susceptibility to anti-TB drugs. Sociobehavioural information was gathered in interviews based on a structured questionnaire. FINDINGS: MDR-TB was found in 32.3% and 75.6% of the new and previously treated patients, respectively, and, 11.9% of the 612 patients found to have MDR-TB had extensively drug-resistant TB (XDR-TB). A history of previous treatment for TB was the strongest independent risk factor for MDR-TB (odds ratio, OR: 6.1; 95% confidence interval, CI: 4.8-7.7). The other independent risk factors were human immunodeficiency virus (HIV) infection (OR: 2.2; 95% CI: 1.4-3.5), age < 35 years (OR: 1.4; 95% CI: 1.0-1.8), history of imprisonment (OR: 1.5; 95% CI: 1.1-2.0), disability sufficient to prevent work (OR: 1.9; 95% CI: 1.2-3.0), alcohol abuse (OR: 1.3; 95% CI: 1.0-1.8) and smoking (OR: 1.5; 95% CI: 1.1-2.0). CONCLUSION: MDR-TB is very common among TB patients throughout Belarus. The numerous risk factors identified for MDR-TB and the convergence of the epidemics of MDR-TB and HIV infection call not only for stronger collaboration between TB and HIV control programmes, but also for the implementation of innovative measures to accelerate the detection of TB resistance and improve treatment adherence.

Résumé OBJECTIF: Évaluer le problème de la tuberculose multirésistante (TB-MR) sur le territoire biélorusse et explorer les facteurs de risque associés. MÉTHODES: Au cours d'une enquête nationale menée en 2010-2011, 1420 cas de tuberculose (TB) ont été dépistés et 934 cas nouveaux ainsi que 410 cas précédemment traités ont été jugés conformes aux critères d'inclusion. Des isolats de Mycobacterium tuberculosis provenant de chaque patient admissible ont été testés pour leur sensibilité envers les médicaments antituberculeux. Des informations sociocomportementales ont été recueillies lors d'entretiens basés sur un questionnaire structuré. RÉSULTATS: La TB-MR a été détectée dans respectivement 32,3% et 75,6% des cas nouveaux et des cas traités antérieurement, et 11,9% des 612 patients porteurs de la TB-MR présentaient une forme de tuberculose ultrarésistante (TB-UR). Un historique de traitement antérieur pour la TB représentait le principal facteur de risque indépendant pour la TB-MR (rapport des cotes, RC: 6,1; intervalle de confiance à 95%, IC: 4,8 à 7,7). Les autres facteurs de risque indépendants comprenaient l'infection par le virus d'immunodéficience humaine (VIH) (RC: 2,2; IC à 95%: 1,4 à 3,5), l'âge <35 ans (RC: 1,4 ; IC à 95%: 1,0 à 1,8), un historique d'emprisonnement (RC: 1,5; IC à 95%: 1,1 à 2,0), une invalidité suffisante pour empêcher le travail (RC: 1,9 ; IC à 95%: 1,2 à 3,0), l'alcoolisme (RC: 1,3; IC à 95%: 1,0 à 1,8) et le tabagisme (RC: 1,5; IC à 95%: 1,1 à 2,0). CONCLUSION: La TB-MR est très fréquente chez les patients atteints de tuberculose en Bélarus. Les nombreux facteurs de risque identifiés pour la TB-MR et la convergence entre l'épidémie de TB-MR et l'infection par le VIH exigent non seulement de renforcer la collaboration entre les programmes antituberculeux et de lutte contre le VIH, mais aussi la mise en œuvre de mesures innovantes pour accélérer la détection de la résistance à la tuberculose et améliorer l'observance du traitement.

Resumen OBJETIVO: Evaluar el problema de la tuberculosis multirresistente (TB-MR) en Bielorrusia e investigar los factores de riesgo asociados. MÉTODOS: En una encuesta a nivel nacional llevada a cabo entre 2010 y 2011, se evaluó a 1420 pacientes con tuberculosis (TB) y se consideró que 934 nuevos casos de TB y 410 casos de TB previamente tratados reunían los criterios de inclusión. Se analizaron cepas de Mycobacterium tuberculosis de cada paciente elegible con el fin de determinar la susceptibilidad a los fármacos antituberculosos. Se recopiló información socioconductual mediante entrevistas basadas en un cuestionario estructurado. RESULTADOS: Se detectó TB-MR en el 32,3% y el 75,6% de los pacientes de nuevo diagnóstico y tratados previamente, respectivamente, y se observó que el 11,9% de los 612 pacientes con TB-MR presentaba tuberculosis ultrarresistente (TB-XR). Los antecedentes de tratamiento previo de la TB resultaron ser el factor de riesgo independiente que más predispone a sufrir TB-MR (razón de posibilidades, OR: 6,1; intervalo de confianza del 95%, IC: 4,8­7,7). Los demás factores de riesgo independientes fueron el virus de la inmunodeficiencia humana (VIH) (OR: 2,2; IC del 95%: 1,4­3,5), edad < 35 años (OR: 1,4; IC del 95%: 1,0­1,8), antecedentes de encarcelamiento (OR: 1,5; IC del 95%: 1,1­2,0), incapacidad suficiente para impedir el trabajo (OR: 1,9; IC del 95%: 1,2­3,0), alcoholismo (OR: 1,3; IC del 95%: 1,0­1,8) y tabaquismo (OR: 1,5; IC del 95%: 1,1­2,0). CONCLUSIÓN: La TB.MR es muy frecuente entre los pacientes con tuberculosis en Bielorrusia. Los numerosos factores de riesgo identificados para la TB-MR, unidos a la convergencia de las epidemias de TB-MR y la infección por el VIH, exigen no solo una mayor colaboración entre los programas de control de la TB y del VIH, sino también la aplicación de medidas innovadoras destinadas a acelerar la detección de la resistencia a la TB y mejorar el cumplimiento terapéutico.

Alarming levels of drug-resistant tuberculosis in Belarus: results of a survey in Minsk.

Resistance to anti-tuberculosis (TB) medicines is a major public health threat in most countries of the former Soviet Union. As no representative and quality-assured information on the magnitude of this problem existed in Belarus, a survey was conducted in the capital city of Minsk. Between November 2009 and December 2010, 156 consecutively diagnosed new and 68 previously treated culture-positive TB patients residing in Minsk were enrolled in the survey. Mycobacterium tuberculosis isolates were obtained from each patient and tested for susceptibility to first- and second-line anti-TB drugs. Multidrug-resistant (MDR)-TB was found in 35.3% (95% CI 27.7-42.8) of new patients and 76.5% (95% CI 66.1-86.8) of those previously treated. Overall, nearly one in two patients enrolled had MDR-TB. Extensively drug-resistant TB was reported in 15 of the 107 MDR-TB patients (14.0%, 95% CI 7.3-20.7). Patients <35 yrs of age have shown a two times higher odds ratio of multidrug-resistant TB than those aged >35 yrs. The findings of this survey in Minsk city are alarming and represent the highest proportions of MDR-TB ever recorded in the world. This study greatly contributes to the understanding of the burden of drug-resistant TB in urban areas of Belarus.