Moderate Tuberculosis Incidence Research Articles

Spoligotype and Drug Susceptibility Profiles of Mycobacterium tuberculosis Complex Isolates in Golestan Province, North Iran.

IntroductionDespite the moderate incidence of tuberculosis (TB) in many parts of Iran, Golestan province had a permanently higher TB incidence rate than the national average. Moreover, Golestan province receives immigrants, mainly from TB-endemic areas of Iran and neighbor countries. Here, we aimed to characterize the circulating Mycobacterium tuberculosis complex (MTBC) isolates in terms of the spoligotype and drug resistance patterns, across Golestan province.Materials and MethodsA set of 166 MTBC isolates was collected during July 2014 to July 2015 and subjected to drug susceptibility testing for first- and second-line anti-TB drugs and spoligotyping.ResultsOf 166 MTBC isolates, 139 (83.7%) isolates were assigned to 28 spoligotype international types (SITs). The most frequent SITs were SIT127/Ural-2 (n=25, 15.1%), followed by SIT1/Beijing (n=21, 12.7%) and SIT3427/Ural-2 (n=18, 10.8%). The set of 18 isolates (10.8%) showed resistance to at least one drug, which mainly belonged to SIT1/Beijing (n=7, 38.9%), orphan patterns (n=4, 22.2%) and SIT357/CAS1-Delhi (n=3, 16.7%). In addition, four isolates (2.4%) were resistant to pyrazinamide. The analysis of mutation corresponded to resistance to rifampin and isoniazid showed that two isolates had Ser531Leu substitution in rpoB, four isolates had Ser315Thr substitution in katG and one isolate had [C(−15)T] in inhA locus.ConclusionHigh diversity in spoligotypes of the MTBC isolates and lack of dominant genotype might be due to residence of immigrants in this region and consequent reactivation of latent infection. In addition, due to the presence of extensively drug-resistant (XDR) isolates in Golestan province, it is important to conduct future studies to determine transmission pattern of drug-resistant isolates in this region.

The use of a borderline zone for the interpretation of interferon-gamma release assay results for serial screening of healthcare workers.

ObjectiveAn interferon-gamma release assay (IGRA) is used to screen for latent tuberculosis infection (LTBI). Among IGRAs, the QuantiFERON-TB Gold In-Tube (QFT-GIT) results are highly variable, so the borderline zone has been proposed to reduce unnecessary LTBI treatment. The aim of this study was to examine the proportion of the borderline zone of QFT-GIT in healthcare workers’ (HCWs) serial IGRA and to retrospectively identify the utility of predicting tuberculosis (TB) in a moderate TB incidence setting.MethodsThe participants were HCWs who had undergone serial LTBI screening between June 2013 and June 2018. IGRA-positive HCWs underwent examinations that included low-dose computed tomography (LDCT) and TB culture, if necessary. Applying the borderline zone (0.2-<0.7 IU/mL), the results were classified as definite negative, borderline negative, borderline positive and definite positive.ResultsThrough the follow-up of 477 HCWs, 441 (92.5%) invariant, 30 (6.3%) conversion, 2 (0.4%) reversion and 5 (1.0%) indeterminate results were observed with the manufacturer’s cutoff. Applying the borderline zone, 419 (87.8%) invariant, 22 (4.6%) conversion, 1 (0.2%) reversion and 36 (7.5%) decision pending, including 5 (1.0%) indeterminate results, were observed. At the time of screening, five TB cases were identified. Chest X-ray (CXR) identified one TB case, and LDCT identified four additional TB cases. After one year, two TB cases were diagnosed, and their screening QFT-GIT results were definite positive and borderline negative. In the Cochran-Armitage trend test, the greater the maximum difference in the QFT-GIT grade with the borderline zone was, the higher the probability of developing TB (P-value <0.001).ConclusionThe application of the borderline zone lowered the conversion rate but increased the decision pending rate. Introducing the borderline zone requires a careful approach, and a thorough examination needs to be performed to rule out TB in converters. HCWs with borderline QFT-GIT results also need close observation.

Low antimicrobial resistance rates of Mycobacterium tuberculosis complex between 2000 and 2015 in Gipuzkoa, northern Spain

ObjectiveAlthough the incidence of tuberculosis (TB) has declined, TB drug resistance remains a major problem. The TB rate in Gipuzkoa (northern Spain) is higher than the European average. The objective of this study was to determine the antimicrobial susceptibility of 1855 Mycobacterium tuberculosis complex isolates (94.5% of confirmed cases between 2000 and 2015). MethodsSusceptibility testing was performed using the agar proportion method and a commercial broth system (MGIT 960). In isoniazid- or rifampicin-resistant strains, we studied genetic determinants of drug resistance and genotype (MIRU-VNTR). ResultsThe annual mean incidence of TB was 24.5 cases per 100,000 population on average, and tended to decrease. The multidrug-resistant TB rate was 0.5% (9/1855), and no extensively drug-resistant TB strains were detected. Rates of resistance to isoniazid and rifampicin were 3.9% (range, 3.4–4.3%) and 0.6% (range, 0.4–1.4%), respectively. TB resistance was more common among foreign-born individuals and those who had received previous TB treatment. Genotyping of 102 resistant strains showed predominance of the Euro-American lineage, although 4/9 multidrug-resistant strains had Eastern lineages (2 East African-Indian, and 2 East Asian [Beijing]). ConclusionsIn Gipuzkoa, with a moderate incidence of TB, resistance was very low, mostly being detected among individuals who were born abroad or who had a history of TB treatment.

Reproducibility of the T-SPOT.TB test for screening Mycobacterium tuberculosis infection in Japan

ObjectivesThe interferon-gamma release assay (IGRA) is useful for diagnosing Mycobacterium tuberculosis infections, especially in countries where Bacille Calmette–Guérin vaccinations are performed. However, reproducibility of the IGRA is unclear, as recent data suggest high IGRA conversion and reversion rates in serial tests among healthcare workers. This longitudinal study aimed to evaluate reproducibility of T-SPOT.TB for screening M. tuberculosis infections in Japan. MethodsResults of T-SPOT.TB tests performed between April 2014 and March 2016 at two hospitals in Yokohama, Japan, where the incidence of tuberculosis was 18.0 per 100,000 population in 2014, were analyzed. ResultsIn total, 3890 T-SPOT.TB tests were included. Overall, positive and negative test rates were 8.4% and 87.6%, respectively. Among 373 serial tests within two years, conversion and reversion rates were only 1.1% and 12.5%, respectively. Almost all patients who were initially negative (98.9%) remained so. There was no statistically significant difference between the outcomes observed at the two hospitals. ConclusionsThe conversion rate of T-SPOT.TB in Japan is as low as that recently reported in other countries where the incidence of tuberculosis is low. These data indicate that T-SPOT.TB is a reproducible tuberculosis screening tool at local hospitals in areas with a moderate incidence of tuberculosis.

Low antimicrobial resistance rates of Mycobacterium tuberculosis complex between 2000 and 2015 in Gipuzkoa, northern Spain

ObjectiveAlthough the incidence of tuberculosis (TB) has declined, TB drug resistance remains a major problem. The TB rate in Gipuzkoa (northern Spain) is higher than the European average. The objective of this study was to determine the antimicrobial susceptibility of 1855 Mycobacterium tuberculosis complex isolates (94.5% of confirmed cases between 2000 and 2015). MethodsSusceptibility testing was performed using the agar proportion method and a commercial broth system (MGIT 960). In isoniazid- or rifampicin-resistant strains, we studied genetic determinants of drug resistance and genotype (MIRU-VNTR). ResultsThe annual mean incidence of TB was 24.5 cases per 100,000 population on average, and tended to decrease. The multidrug-resistant TB rate was 0.5% (9/1855), and no extensively drug-resistant TB strains were detected. Rates of resistance to isoniazid and rifampicin were 3.9% (range, 3.4–4.3%) and 0.6% (range, 0.4–1.4%), respectively. TB resistance was more common among foreign-born individuals and those who had received previous TB treatment. Genotyping of 102 resistant strains showed predominance of the Euro-American lineage, although 4/9 multidrug-resistant strains had Eastern lineages (2 East African-Indian, and 2 East Asian [Beijing]). ConclusionsIn Gipuzkoa, with a moderate incidence of TB, resistance was very low, mostly being detected among individuals who were born abroad or who had a history of TB treatment.

Tuberculosis and diabetes in low and moderate tuberculosis incidence countries.

In countries with low and moderate incidence of tuberculosis (TB), the disease tends to concentrate in specific high-risk populations such as people with diabetes mellitus (DM). We review the updated evidence on the association between 1) DM and active TB, and 2) DM and latent tuberculous infection (LTBI), and 3) we summarize the findings on the population-level impact of DM on TB epidemiology, with particular focus on low- and moderate-incidence settings. We conducted an updated review of studies on DM and active TB, and found 11 more cohort studies published after the previous systematic review from 2008. The updated pooled relative risk (RR) (2.03, 95%CI 1.62-2.55) of all the studies was substantially lower than the three-fold risk increase in the previous review. Substantial heterogeneity of RR across studies was found. Possible reasons for such heterogeneity include different levels of residual confounding, the effect of modification by age, and different levels of glycemic control in the population. In a recently published systematic review on DM and LTBI, one cohort study and 12 cross-sectional studies were identified. The results from cross-sectional studies suggest a significant but modestly increased risk of LTBI among patients with DM (pooled odds ratio 1.18, 95%CI 1.06-1.30). We reviewed evidence on the population-level impact of DM on TB epidemiology in studies using population-attributable fraction analysis and infectious disease modelling. Those studies revealed that DM accounted for a substantial TB burden in low- and moderate-incidence countries. Finally, we discussed the complex association of obesity, DM and TB risk and the impact of the global obesity pandemic on TB epidemiology.

Impact of smoking on sputum culture conversion and pulmonary tuberculosis treatment outcomes in Brazil: a retrospective cohort study.

ABSTRACTObjective:To evaluate the impact of smoking on pulmonary tuberculosis (PTB) treatment outcomes and the two-month conversion rates for Mycobacterium tuberculosis sputum cultures among patients with culture-confirmed PTB in an area with a moderate incidence of tuberculosis in Brazil. Methods:This was a retrospective cohort study of PTB patients diagnosed and treated at the Thoracic Diseases Institute of the Federal University of Rio de Janeiro between 2004 and 2012. Results:Of the 298 patients diagnosed with PTB during the study period, 174 were included in the outcome analysis: 97 (55.7%) were never-smokers, 31 (17.8%) were former smokers, and 46 (26.5%) were current smokers. Smoking was associated with a delay in sputum culture conversion at the end of the second month of TB treatment (relative risk = 3.58 &091;95% CI: 1.3-9.86&093;; p = 0.01), as well as with poor treatment outcomes (relative risk = 6.29 &091;95% CI: 1.57-25.21&093;; p = 0.009). The association between smoking and a positive culture in the second month of treatment was statistically significant among the current smokers (p = 0.027). Conclusions:In our sample, the probability of a delay in sputum culture conversion was higher in current smokers than in never-smokers, as was the probability of a poor treatment outcome.

Implementation of isoniazid preventive therapy in children aged under 5 years exposed to tuberculosis in Benin.

Two large tuberculosis (TB) centres under a well-functioning National TB Programme (NTP) in Benin, West Africa. To assess the feasibility and results of integrating a programme of isoniazid preventive therapy (IPT) in children aged <5 years exposed to TB as part of the existing routine activities of the NTP. All children aged <5 years living in the household of a patient with smear-positive pulmonary TB were examined by a doctor and received IPT if no evidence of TB was detected. The children were followed clinically by a nurse for 6 months. From January 2013 to June 2014, 496 children were examined and prescribed IPT among 499 notified contacts; 86% adhered to IPT for at least 6 months. There were six deaths and three cases of active TB among the children, all during the first 3 months of follow-up. In an African country with moderate TB incidence and a well-functioning NTP, the integration of IPT into the NTP for children aged <5 years exposed to TB in the family was feasible based on simple tools associated with the follow-up of index cases. The rate of adherence to IPT was high.

Timing of Tuberculosis Transmission and the Impact of Household Contact Tracing. An Agent-based Simulation Model

Household contact tracing has recently been endorsed for global tuberculosis (TB) control, but its potential population-level impact remains uncertain. To project the maximum impact of household contact tracing for TB in a moderate-burden setting. We developed a stochastic, agent-based simulation model of a simplified TB epidemic, calibrated to a setting of moderate TB incidence. We used data from the literature to generate "community-driven" and "household-driven" scenarios in which 22 and 50% of TB transmission occurred within the household, respectively. In each scenario, we simulated an intervention in which the household members are screened and treated for TB at the time of an index patient's active TB diagnosis. By the time of TB diagnosis, 75 to 95% of initial household infections had already occurred, but only 1.5 to 3.0% of contacts had sufficient time to progress to active TB. With 100% sensitive tracing of all contacts for 5 consecutive years, TB incidence declined by 10 to 15%, with a mean year-over-year decline of 2% per year. Effects were sustained for many years after stopping the intervention. Providing preventive therapy with contact tracing nearly doubled this impact (17-27% decline in incidence). Impact was proportional to sensitivity and coverage; thus, if 50% of contacts were screened with a 50% sensitive test, TB incidence declined by only 0.5% per year. Household contact tracing is unlikely to transform TB epidemiology in isolation but has the potential, especially with provision of preventive therapy, to augment a comprehensive package of interventions that could substantially reduce the population-level burden of TB.

Molecular Epidemiology of Mycobacterium tuberculosis Complex in Singapore, 2006-2012

BackgroundTuberculosis remains common in Singapore, increasing in incidence since 2008. We attempted to determine the molecular epidemiology of Mycobacterium tuberculosis complex (MTC) isolates locally, identifying major circulating genotypes and obtaining a glimpse of transmission dynamics.MethodologyNon-duplicate MTC isolates archived between 2006 and 2012 at the larger clinical tuberculosis laboratory in Singapore were sampled for spoligotyping and MIRU-VNTR typing, with case data obtained from the Singapore Tuberculosis Elimination Program registry database. Isolates between 2008 and 2012 were selected because of either multidrug-resistance or potential epidemiological linkage, whereas earlier isolates were randomly selected. Separate analyses were performed for the early (2006-2007) and later (2008-2012) study phases in view of potential selection bias.Principal FindingsA total of 1,612 MTC isolates were typed, constituting 13.1% of all culture-positive tuberculosis cases during this period. Multidrug-resistance was present in 91 (5.6%) isolates – higher than the national prevalence in view of selection bias. The majority of isolates belonged to the Beijing (45.8%) and EAI (22.8%) lineages. There were 347 (30.7%) and 133 (27.5%) cases clustered by combined spoligotyping and MIRU-VNTR typing from the earlier and later phases respectively. Patients within these clusters tended to be of Chinese ethnicity, Singapore resident, and have isolates belonging to the Beijing lineage. A review of prior contact investigation results for all patients with clustered isolates failed to reveal epidemiological links for the majority, suggesting either unknown transmission networks or inadequate specificity of the molecular typing methods in a country with a moderate incidence of tuberculosis.ConclusionOur work demonstrates that Singapore has a large and heterogeneous distribution of MTC strains, and with possible cross-transmission over the past few years based on our molecular typing results. A universal MTC typing program coupled with enhanced contact investigations may be useful in further understanding the transmission dynamics of tuberculosis locally.

Systematic Survey of Clonal Complexity in Tuberculosis at a Populational Level and Detailed Characterization of the Isolates Involved

Clonally complex infections by Mycobacterium tuberculosis are progressively more accepted. Studies of their dimension in epidemiological scenarios where the infective pressure is not high are scarce. Our study systematically searched for clonally complex infections (mixed infections by more than one strain and simultaneous presence of clonal variants) by applying mycobacterial interspersed repetitive-unit (MIRU)-variable-number tandem-repeat (VNTR) analysis to M. tuberculosis isolates from two population-based samples of respiratory (703 cases) and respiratory-extrapulmonary (R+E) tuberculosis (TB) cases (71 cases) in a context of moderate TB incidence. Clonally complex infections were found in 11 (1.6%) of the respiratory TB cases and in 10 (14.1%) of those with R+E TB. Among the 21 cases with clonally complex TB, 9 were infected by 2 independent strains and the remaining 12 showed the simultaneous presence of 2 to 3 clonal variants. For the 10 R+E TB cases with clonally complex infections, compartmentalization (different compositions of strains/clonal variants in independent infected sites) was found in 9 of them. All the strains/clonal variants were also genotyped by IS6110-based restriction fragment length polymorphism analysis, which split two MIRU-defined clonal variants, although in general, it showed a lower discriminatory power to identify the clonal heterogeneity revealed by MIRU-VNTR analysis. The comparative analysis of IS6110 insertion sites between coinfecting clonal variants showed differences in the genes coding for a cutinase, a PPE family protein, and two conserved hypothetical proteins. Diagnostic delay, existence of previous TB, risk for overexposure, and clustered/orphan status of the involved strains were analyzed to propose possible explanations for the cases with clonally complex infections. Our study characterizes in detail all the clonally complex infections by M. tuberculosis found in a systematic survey and contributes to the characterization that these phenomena can be found to an extent higher than expected, even in an unselected population-based sample lacking high infective pressure.

Discontinuation of Respiratory Isolation for Possible Tuberculosis: Do Two Negative Sputum Smear Results Suffice?

Analysis of acid-fast bacillus smear results at a hospital with a moderate incidence of tuberculosis confirms recent recommendations that 2 negative smear results suffice for discontinuation of respiratory isolation. Use of polymerase chain reaction analysis further increases the confidence with which the diagnosis of active tuberculosis likely to be transmitted to others can be excluded.

Tuberculosis recurrences: reinfection plays a role in a population whose clinical/epidemiological characteristics do not favor reinfection.

Tuberculosis (TB) recurrences can be due to either reactivation by the same strain (standard assumption) or reinfection by a new strain. Reinfection has mainly been studied in selected populations with a high risk of reexposure to TB. Our aim was to analyze the role of reinfection in TB recurrences in unselected populations, without the clinical/epidemiological circumstances that favor the involvement of a new different strain of Mycobacterium tuberculosis in the recurrence. A molecular typing analysis was performed with 92 sequential isolates of M tuberculosis from 43 patients with recurrent TB, during a 12-year period. The subjects were both positive and negative for the human immunodeficiency virus, most did not adhere to anti-TB therapy, and they lived in an area with a moderate incidence of TB. Recurrence was considered as being caused by reinfection when the molecular fingerprints for the strains involved in the sequential episodes of TB were different. In 14 (33%) of the 43 patients, different M tuberculosis strains were involved in the first and in subsequent episodes of TB. Reinfection was found for patients who were both positive and negative for the human immunodeficiency virus, and most patients did not adhere to anti-TB therapy. Differences between the reinfection and reactivation groups were not significant (P =.77) according to the time interval between episodes. Reinfection plays an important role in recurrent TB in a population without the clinical/epidemiological circumstances that are usually assumed to favor it. Reinfection should, thus, be considered as a cause of TB recurrences in a wider context than before.