Latent Tuberculosis (TB) Infection Research Articles

Comparison of the Single Cell Immune Landscape between Subjects with High Mycobacterium tuberculosis Bacillary Loads during Active Pulmonary Tuberculosis and Household Members with Latent Tuberculosis Infection.

It is unclear how the immune system controls the transition from latent tuberculosis (TB) infection (LTBI) to active pulmonary infection (PTB). Here, we applied mass spectrometry cytometry time-of-flight (CyTOF) analysis of peripheral blood mononuclear cells to compare the immunological landscapes in patients with high tuberculous bacillary load PTB infections and LTBI. A total of 32 subjects (PTB [n = 12], LTBI [n = 17], healthy volunteers [n = 3]) were included. Participants with active PTBs were phlebotomized before administering antituberculosis treatment, whereas participants with LTBI progressed to PTB at the time of household screening. In the present study, CyTOF analysis identified significantly higher percentages of mucosal-associated invariant natural killer T (MAIT NKT) cells in subjects with LTBI than in those with active PTB and healthy controls. Moreover, 6 of 17 (35%) subjects with LTBI progressed to active PTB (LTBI progression) and had higher proportions of MAIT NKT cells and early NKT cells than those without progression (LTBI non-progression). Subjects with LTBI progression also showed a tendency toward low B cell levels relative to other subject groups. In conclusion, MAIT NKT cells were substantially more prevalent in subjects with LTBI, particularly those with progression to active PTB.

Development and Evaluation of a Promising Biomarker for Diagnosis of Latent and Active Tuberculosis Infection

Abstract Background Diagnosing latent tuberculosis (TB) infection (LTBI) and active TB (ATB) is crucial for preventing disease progression and transmission. However, current diagnostic tests have limitations in terms of accuracy and sensitivity, making it challenging to diagnose these different infection states. Therefore, this study intends to develop a promising biomarker for LTBI and ATB diagnosis to overcome the limitations of the current diagnostic tests. Methods We developed a novel multiepitope-based diagnostic biomarker (MEBDB) from LTBI region of differentiation antigens using bioinformatics and immunoinformatics. Immune responses induced by MEBDM were detected using enzyme-linked immunosorbent spot and cytometric bead assays. This study was conducted from April 2022 to December 2022 in the Senior Department of Tuberculosis at the 8th Medical Center of PLA General Hospital, China. Blood samples were collected from participants with ATB, individuals with LTBI, and healthy controls (HCs). The diagnostic efficacy of MEBDB was evaluated using receiver operating characteristic curves. Results A novel MEBDB, designated as CP19128P, was generated. CP19128P comprises 19 helper T lymphocyte epitopes, 12 cytotoxic T lymphocyte epitopes, and 8 B-cell epitopes. In silico simulations demonstrated that CP19128P possesses strong affinity for Toll-like receptors and elicits robust innate and adaptive immune responses. CP19128P generated significantly higher levels of tumor necrosis factor (TNF-α), interleukin 4 (IL-4), and IL-10 in ATB patients (n = 7) and LTBI (n = 8) individuals compared with HCs (n = 62) (P < 0.001). Moreover, CP19128P-induced specific cytokines could be used to discriminate LTBI and ATB from healthy subjects with high sensitivity and specificity. Combining IL-2 with IL-4 or TNF-α could differentiate LTBI from HCs (the area under the receiver operating characteristic curve [AUC], 0.976 [95% confidence interval [CI], 0.934–1.000] or 0.986 [0.956–1.000]), whereas combining IL-4 with IL-17A or TNF-α could differentiate ATB from HCs (AUC, 0.887 [0.782–0.993] or 0.984 [0.958–1.000]). Conclusions Our study revealed that CP19128P is a potential MEBDB for the diagnosis of LTBI and ATB. Our findings suggest a promising strategy for developing novel, accurate, and sensitive diagnostic biomarkers and identifying new targets for TB diagnosis and management.

Interferon-gamma release assay for screening of tuberculosis infection in children

BackgroundInterferon-gamma release assay (IGRA) is the main tool for the diagnosis of latent tuberculosis (TB) infection (LTBI). However, the indeterminate results were more frequent in children, and the underlying reasons were largely speculative. We aimed to compare QuantiFERON-TB Gold In-Tube (QFT-GIT) with X.DOT-TB (XDOT) for diagnosing LTBI, and to identify the risk factors associated with indeterminate results in children.MethodsA retrospective study for children<18 years old, at risk for LTBI or progression to TB disease, received either QFT-GIT or X.DOT-TB tests was performed at Beijing Children’s Hospital from August 2019 to August 2022.ResultsA total of 33,662 children were recruited, including 15,129 (44.9%) tested with X.DOT-TB and 18,533 (55.1%) with QFT-GIT. Proportion of positive and indeterminate results in children with respiratory disease was significantly higher than did that with other diseases, respectively (P < 0.001). The indeterminate rate of X.DOT-TB and QFT-GIT results decreased with increasing age (P < 0.001). Proportion of QFT-GIT indeterminate results was higher than that of X.DOT-TB across age groups. Male, age and disease classification all presented a statistically significant association with indeterminate IGRA results.ConclusionsThe positive rates of X.DOT-TB and QFT-GIT in children were 3.1% and 1.8%, respectively. The X.DOT-TB assay performed better than QFT-GIT in children, and male, age and underlying diseases were associated with an increased risk of indeterminate IGRA results.

Predictors for False-Negative Interferon-Gamma Release Assay Results in Hemodialysis Patients with Latent Tuberculosis Infection.

The present study aimed to clinically evaluate the effect of T-cell dysfunction in hemodialysis (HD) patients with latent tuberculosis (TB) infection (LTBI) who were false-negatives in the QuantiFERON-TB Gold In-Tube (QFT-GIT) test. Whole blood samples from a total of 20 active TB patients, 83 HD patients, and 52 healthy individuals were collected, and the QFT-GIT test was used for measuring Mycobacterium tuberculosis (MTB)-specific interferon gamma (IFN-γ) level. The positive rate of the IFN-γ release assays (IGRAs) in HD patients was lower than the negative rate. The mean value of MTB-specific IFN-γ level, which determines the positive rate of the IGRA test, was highest in active TB, followed by HD patients and healthy individuals. Among HD patients, phytohemagglutinin A (PHA)-stimulated IFN-γ levels of approximately 40% were 10.00 IU/mL or less. However, there was no low level of PHA-stimulated IFN-γ in the healthy individuals. This reveals that T-cell function in HD patients was reduced compared to healthy individuals, which leads to the possibility that QFT-GIT results in HD patients are false-negative. The clinical manifestations of TB in patients on HD are quite non-specific, making timely diagnosis difficult and delaying the initiation of curative treatment, delay being a major determinant of outcome.

Mass spectrometry-based identification of new serum biomarkers in patients with latent infection pulmonary tuberculosis

Noninvasive and simple indicators for diagnosing latent tuberculosis (TB) infection (LTBI) and tracking progression from latent infection to active TB infection are still desperately needed. The aim of this study was to screen and identify possible biomarkers for diagnosing LTBI and monitoring the progression from latent infection to active TB infection, as well as to investigate the underlying processes and functions. To assess changes in metabolite composition associated with active tuberculosis infection in humans, whole blood supernatants were collected from patients with LTBI, drug-susceptible TB patients, drug-resistant TB patients, and healthy controls. The metabolites in all serum samples were extracted by oscillatory, deproteinization, and then detected by liquid chromatography-tandem mass spectrometry/MS analysis. Normalization by Pareto-scaling method, the difference analysis was carried out by Metaboanalyst 4.0 software, and 1-way analysis of variance analysis among groups showed that P-value < 0.05 was regarded as a different metabolite. To clarify the dynamic changes and functions of differential metabolites with disease progression, and explore its significance and mechanism as a marker by further cluster analysis, functional enrichment analysis, and relative content change analysis of differential metabolites. 65 metabolites were substantially different in four groups. Differential metabolites such as Inosine and Prostaglandin E1 may be important blood indicators for diagnosing mycobacterium tuberculosis latent infection, which were all tightly connected to amino acid metabolism, Biosynthesis of various secondary metabolites, Nucleotide metabolism, Endocrine system, Immune system, Lipid metabolism, and Nervous system. This study screened and identified Inosine, 16, 16-dimethyl-6-keto Prostaglandin E1, Theophylline, and Cotinine as potential serum biomarkers for diagnosing latent TB infection, and Cotinine as potential biomarkers for monitoring disease progression from healthy population to LTBI and then to active TB including drug-resistant TB infection and sensitive TB infection. Furthermore, this research provides a preliminary experimental basis to further investigate the development of metabolomics-based diagnosis of LTBI and monitoring the progress from latent infection to active TB infection.

57-Year-Old Man With Headache, Vomiting, and Gait Instability

57-Year-Old Man With Headache, Vomiting, and Gait Instability

Novel Automation of an Enzyme-Linked Immunosorbent Spot Assay Testing Method: Comparable Diagnostic Performance of the T-SPOT.TB Test Using Manual Density Gradient Cell Isolation versus Automated Positive Selection with the T-Cell Select Kit.

ABSTRACTThe diagnosis of latent tuberculosis (TB) infection (LTBI) is critical to improve TB treatment and control, and the T-SPOT.TB test is a commercial enzyme-linked immunosorbent spot assay used for this purpose. The objective of the study was to increase automation and extend the time between blood collection and processing for the T-SPOT.TB test from 0 to 8 h to 0 to 54 h. The previous maximum time between blood collection and processing for the T-SPOT.TB test is 32 h using T-Cell Xtend. For this, we compared the T-SPOT.TB test using manual peripheral blood mononuclear cell (PBMC) isolation by density gradient separation at 0 to 8 h (reference method, control arm) to an automated PBMC isolation method using magnetic beads (T-Cell Select kit) at 0 to 55 h postcollection. A total of 620 subjects were enrolled from 4 study sites, and blood samples were collected from each volunteer, comprising 1,850 paired samples in total. Overall agreement between both methods was 96.8% (confidence interval [CI], 95.9 to 97.6%), with 95.8% (CI, 93.5 to 97.5%) positive and 97.1% negative agreement (CI, 96.1 to 97.9%). In summary, there was a strong overall agreement between the automated and manual T-SPOT.TB test processing methods. The results suggest that the T-SPOT.TB test can be processed using automated positive selection with magnetic beads using T-Cell Select to decrease hands-on time. Also, this cell isolation method allowed for the time between blood collection and processing to range from 0 to 55 h. Additional studies in larger and diverse patient populations including immunocompromised and pediatric patients are needed.

Optimal Detection of Latent Mycobacterium tuberculosis Infection by Combined Heparin-Binding Hemagglutinin (HBHA) and Early Secreted Antigenic Target 6 (ESAT-6) Whole-Blood Interferon Gamma Release Assays.

ABSTRACTOptimal detection of latent tuberculosis (TB) infection (LTBI) remains a challenge, although it is essential to reach the goal of TB elimination. Our objective was to develop and clinically evaluate a user-friendly, 24-h, whole-blood (WB) interferon gamma (IFN-γ) release assay (IGRA) improving the detection of LTBI, compared to available tests. One milliliter of blood was divided into four aliquots and in vitro stimulated for 24 h with two different stage-specific mycobacterial antigens, i.e., heparin-binding hemagglutinin (HBHA) and early secreted antigenic target 6 (ESAT-6), a latency-associated antigen and a bacterial replication-related antigen, respectively, in addition to positive and negative controls. Clinical evaluation was performed on two independent cohorts of carefully selected subjects, i.e., a training cohort of 83 individuals and a validation cohort of 69 individuals. Both cohorts comprised LTBI subjects (asymptomatic people with a positive tuberculin skin test result and potential exposure to TB index cases), patients with active TB (aTB), and noninfected controls. The sensitivity and specificity of the WB-HBHA-IGRA to identify LTBI subjects among asymptomatic individuals were 93%. Combining the results in response to HBHA and ESAT-6 allowed us to identify LTBI subgroups. One group, with IFN-γ responses to HBHA only, was easily differentiated from patients with aTB. The other group, responding to both antigens like the aTB group, is likely at risk to reactivate the infection and should be prioritized for prophylactic anti-TB treatment. The combined WB-IGRA may be offered to clinicians for the selection of LTBI subjects to benefit from prophylactic treatment.

Type 2 Diabetes Mellitus and Latent Tuberculosis Infection Moderately Influence Innate Lymphoid Cell Immune Responses in Uganda.

BackgroundType 2 diabetes mellitus (T2DM) is a major risk factor for the acquisition of latent tuberculosis (TB) infection (LTBI) and development of active tuberculosis (ATB), although the immunological basis for this susceptibility remains poorly characterised. Innate lymphoid cells (ILCs) immune responses to TB infection in T2DM comorbidity is anticipated to be reduced. We compared ILC responses (frequency and cytokine production) among adult patients with LTBI and T2DM to patients (13) with LTBI only (14), T2DM only (10) and healthy controls (11).MethodsUsing flow cytometry, ILC phenotypes were categorised based on (Lin−CD127+CD161+) markers into three types: ILC1 (Lin−CD127+CD161+CRTH2-CD117−); ILC2 (Lin−CD127+CD161+CRTH2+) and ILC3 (Lin−CD127+CD161+CRTH2−NKp44+/−CD117+). ILC responses were determined using cytokine production by measuring percentage expression of interferon-gamma (IFN-γ) for ILC1, interleukin (IL)-13 for ILC2, and IL-22 for ILC3. Glycaemic control among T2DM patients was measured using glycated haemoglobin (HbA1c) levels. Data were analysed using FlowJo version 10.7.1, and GraphPad Prism version 8.3.ResultsCompared to healthy controls, patients with LTBI and T2DM had reduced frequencies of ILC2 and ILC3 respectively (median (IQR): 0.01 (0.005-0.04) and 0.002 (IQR; 0.002-0.007) and not ILC1 (0.04 (0.02-0.09) as expected. They also had increased production of IFN-γ [median (IQR): 17.1 (5.6-24.9)], but decreased production of IL-13 [19.6 (12.3-35.1)]. We however found that patients with T2DM had lower ILC cytokine responses in general but more marked for IL-22 production (median (IQR): IFN-γ 9.3 (4.8-22.6); IL-13 22.2 (14.7-39.7); IL-22 0.7 (IQR; 0.1-2.1) p-value 0.02), which highlights the immune suppression status of T2DM. We also found that poor glycaemic control altered ILC immune responses.ConclusionThis study demonstrates that LTBI and T2DM, and T2DM were associated with slight alterations of ILC immune responses. Poor T2DM control also slightly altered these ILC immune responses. Further studies are required to assess if these responses recover after treatment of either TB or T2DM.

Evaluation of CD8+ response in QuantiFERON-TB Gold Plus as a marker of recent infection

BackgroundDiagnosis and treatment of latent tuberculosis (TB) infection (LTBI) is essential for the elimination of TB. Preventive therapy could be limited to those with recent TB contact. QuantiFERON-TB Gold Plus (QFT-Plus), a new Interferon-γ release assay, includes a new antigen tube (TB2), which elicits CD4+ and CD8+ T-cell responses. ObjectiveThe aim of the study was to evaluate CD8+ T-cell response as a marker of recent TB infection. DesignWe retrospectively studied 1165 patients who were screened for LTBI. Patients were divided according to history of recent exposure to TB (contact with a confirmed index case in the previous year). CD8+ T-cell activity was measured as the difference between QFT-Plus tubes (TB2-TB1) using two cut-offs (>0.35 IU/mL and >0.60 IU/mL). ResultsCD8+ T-cell activity was significantly higher in the exposed group for both cut-offs (96 - 13% vs 36 - 5% patients - OR 1.68, 95% CI 1.13–2.52 for >0.35 IU/mL and 77 vs 28 patients - OR 1.72 95% CI 1.10–2.70 for >0.60 IU/mL).CD8+ T-cell activity also showed an association with positive sputum smear of the index case and higher exposure time. ConclusionCD8+ T-cell activity as measured with TB2-TB1 shows a significant association with recent exposure to TB, especially in patients with higher exposure and may prove to be a useful tool in identifying patients with recent LTBI.

Cost-effectiveness analysis of 3 months of weekly rifapentine and isoniazid compared to isoniazid monotherapy in a Canadian arctic setting

ObjectiveTo assess the cost effectiveness of once weekly rifapentine and isoniazid for 12 weeks (3HP) to the current standard care for latent tuberculosis (TB) infection (LTBI) in Iqaluit, Nunavut.DesignA cost-effectiveness...

Diagnostic benefits of adding EspC, EspF and Rv2348-B to the QuantiFERON Gold In-tube antigen combination

Interferon (IFN)-γ release assays (IGRAs) are used to diagnose latent tuberculosis (TB) infection (LTBI). To improve the accuracy of these tests, different approaches, such as alternative cytokine detection and using different antigens, are considered. Following this purpose, this study aims to evaluate the addition of EspC, EspF and Rv2348-B to those present in the QuantiFERON-TB Gold In-Tube (QFN-G-IT). We included 115 subjects: 74 active TB patients, 17 LTBI individuals and 24 healthy controls. Whole blood samples were collected in QFN-G-IT and in-house tubes containing different combinations of EspC, EspF and Rv2348-B, together with ESAT-6, CFP-10, and TB7.7. After overnight incubation at 37 ºC, plasma was harvested and IFN-γ quantified. IFN-γ levels in the QFN-G-IT and in-house tubes correlated very good (Spearman Rho(r) > 0.86). In-house antigen combinations distinguished healthy individuals from those with active TB and LTBI (specificities and sensitivities higher than 87.5% and 96.3%, respectively [AUC > 0.938]). Adding EspC, EspF and Rv2348-B, increased the sensitivity of the test, being the addition of EspC and Rv2348-B the combination that yielded a higher sensitivity with no specificity loss. Addition of these antigens could improve diagnosis in patients with impaired or immature immune response who are at high risk of developing TB.

Model-based Cost-effectiveness of State-level Latent Tuberculosis Interventions in California, Florida, New York, and Texas.

Targeted testing and treatment (TTT) for latent tuberculosis (TB) infection (LTBI) is a recommended strategy to accelerate TB reductions and further TB elimination in the United States. Evidence on cost-effectiveness of TTT for key populations can help advance this goal. We used a model of TB transmission to estimate the numbers of individuals who could be tested by interferon-γ release assay and treated for LTBI with 3 months of self-administered rifapentine and isoniazid (3HP) under various TTT scenarios. Specifically, we considered rapidly scaling up TTT among people who are non-US-born, diabetic, living with human immunodeficiency virus (HIV), homeless or incarcerated in California, Florida, New York, and Texas-states where more than half of US TB cases occur. We projected costs (from the healthcare system perspective, in 2018 dollars), 30-year reductions in TB incidence, and incremental cost-effectiveness (cost per quality-adjusted life-year [QALY] gained) for TTT in each modeled population. The projected cost-effectiveness of TTT differed substantially by state and population, while the health impact (number of TB cases averted) was consistently greatest among non-US-born individuals. TTT was most cost-effective among persons with HIV (from $2828/QALY gained in Florida to $11 265/QALY gained in New York) and least cost-effective among people with diabetes (from $223 041/QALY gained in California to $817 753/QALY in New York). The modeled cost-effectiveness of TTT for LTBI varies across states but was consistently greatest among people with HIV; moderate among people who are non-US-born, incarcerated, or homeless; and least cost-effective among people with diabetes.

Chronic Immune Activation in TB/HIV Co-infection.

HIV co-infection is the most critical risk factor for the reactivation of latent tuberculosis (TB) infection (LTBI). While CD4+ T cell depletion has been considered the major cause of HIV-induced reactivation of LTBI, recent work in macaques co-infected with Mycobacterium tuberculosis (Mtb)/simian immunodeficiency virus (SIV) suggests that cytopathic effects of SIV resulting in chronic immune activation and dysregulation of T cell homeostasis correlate with reactivation of LTBI. This review builds on compelling data that the reactivation of LTBI during HIV co-infection is likely to be driven by the events of HIV replication and therefore highlights the need to have optimum translational interventions directed at reactivation due to co-infection.

Ankylosing spondylitis and psoriatic arthritis: revisiting screening of latent tuberculosis infection and its follow-up during anti-tumor necrosis factor therapy in an endemic area

OBJECTIVES:To retrospectively evaluate the performance and distinctive pattern of latent tuberculosis (TB) infection (LTBI) screening and treatment in patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) under anti-tumor necrosis factor (TNF) therapy and determine the relevance of re-exposure and other risk factors for TB development.METHODS:A total of 135 and 83 patients with AS and PsA, respectively, were evaluated for LTBI treatment before receiving anti-TNF drugs via the tuberculin skin test (TST), chest radiography, and TB exposure history assessment. All subjects were evaluated for TB infection at 3-month intervals.RESULTS:The patients with AS were more often treated for LTBI than were those with PsA (42% versus 30%, p=0.043). The former also presented a higher frequency of TST positivity (93% versus 64%, p=0.002), although they had a lower frequency of exposure history (18% versus 52%, p=0.027) and previous TB (0.7% versus 6%, p=0.03). During follow-up [median, 5.8 years; interquartile range (1QR), 2.2-9.0 years], 11/218 (5%) patients developed active TB (AS, n=7; PsA, n=4). TB re-exposure was the main cause in seven patients (64%) after 12 months of therapy (median, 21.9 months; IQR, 14.2-42.8 months) and five LTBI-negative patients. TB was identified within the first year in four patients (36.3%) (median, 5.3 months; IQR, 1.2-8.8 months), two of whom were LTBI-positive. There was no difference in the TB-free survival according to the anti-TNF drug type/class; neither synthetic drug nor prednisone use was related to TB occurrence (p>0.05).CONCLUSION:Known re-exposure is the most critical factor for incident TB cases in spondyloarthritis. There are also some distinct features in AS and PsA LTBI screening, considering the higher frequency of LTBI and TST positivities in patients with AS. Annual risk reassessment taking into consideration these peculiar features and including the TST should be recommended for patients in endemic countries.

Tuberculosis Disease in Children and Adolescents on Therapy With Antitumor Necrosis Factor-ɑ Agents: A Collaborative, Multicenter Paediatric Tuberculosis Network European Trials Group (ptbnet) Study.

In adults, anti-tumor necrosis factor-α (TNF-α) therapy is associated with progression of latent tuberculosis (TB) infection (LTBI) to TB disease, but pediatric data are limited. Retrospective multicenter study within the Paediatric Tuberculosis Network European Trials Group, capturing patients <18 years who developed TB disease during anti-TNF-α therapy. Sixty-six tertiary healthcare institutions providing care for children with TB participated. Nineteen cases were identified: Crohn's disease (n = 8; 42%) and juvenile idiopathic arthritis (n = 6; 32%) were the commonest underlying conditions. Immune-based TB screening (tuberculin skin test and/or interferon-γ release assay) was performed in 15 patients before commencing anti-TNF-α therapy but only identified 1 LTBI case; 13 patients were already receiving immunosuppressants at the time of screening. The median interval between starting anti-TNF-α therapy and TB diagnosis was 13.1 (IQR, 7.1-20.3) months. All cases presented with severe disease, predominantly miliary TB (n = 14; 78%). One case was diagnosed postmortem. TB was microbiologically confirmed in 15 cases (79%). The median duration of anti-TB treatment was 50 (IQR, 46-66) weeks. Five of 15 (33%) cases who had completed TB treatment had long-term sequelae. LTBI screening is frequently false-negative in this patient population, likely due to immunosuppressants impairing test performance. Therefore, patients with immune-mediated diseases should be screened for LTBI at the point of diagnosis, before commencing immunosuppressive medication. Children on anti-TNF-α therapy are prone to severe TB disease and significant long-term morbidity. Those observations underscore the need for robust LTBI screening programs in this high-risk patient population, even in low-TB-prevalence settings.

Enhancing the public health impact of latent tuberculosis infection diagnosis and treatment (ACT4): protocol for a cluster randomised trial

IntroductionTreatment of latent tuberculosis (TB) infection (LTBI) is an important component of the End-TB strategy. However, the number of individuals who successfully complete LTBI treatment remains low as there are...

Latent tuberculosis infection in healthcare workers in low- and middle-income countries: an updated systematic review.

Healthcare workers (HCWs) are at increased risk of latent tuberculosis (TB) infection (LTBI) and TB disease.We conducted an updated systematic review of the prevalence and incidence of LTBI in HCWs in low- and middle-income countries (LMICs), associated factors, and infection control practices. We searched MEDLINE, Embase and Web of Science (January 1, 2005-June 20, 2017) for studies published in any language. We obtained pooled estimates using random effects methods and investigated heterogeneity using meta-regression.85 studies (32 630 subjects) were included from 26 LMICs. Prevalence of a positive tuberculin skin test (TST) was 14-98% (mean 49%); prevalence of a positive interferon-γ release assay (IGRA) was 9-86% (mean 39%). Countries with TB incidence ≥300 per 100 000 had the highest prevalence (TST: pooled estimate 55%, 95% CI 41-69%; IGRA: pooled estimate 56%, 95% CI 39-73%). Annual incidence estimated from the TST was 1-38% (mean 17%); annual incidence estimated from the IGRA was 10-30% (mean 18%). The prevalence and incidence of a positive test was associated with years of work, work location, TB contact and job category. Only 15 studies reported on infection control measures in healthcare facilities, with limited implementation.HCWs in LMICs in high TB incidence settings remain at increased risk of acquiring LTBI. There is an urgent need for robust implementation of infection control measures.

Prevalence of tuberculosis infection among South African adolescents

Background: We aimed to measure changes in adolescent prevalence of latent tuberculosis (TB) infection (LTBI) over a 10-year period (2005-2015), in which TB disease incidence fell 34% from 1,038 – 682 per 100,000 per annum, in order to evaluate impact of effective TB control efforts on transmission to children. Methods & Materials: We compared baseline data from a TB cohort study (2005-2007) and a TB vaccine trial (2014-2015), which enrolled adolescents from the same 8 high schools near Cape Town, South Africa. LTBI was defined by positive QuantiFERON®-TB Gold In-Tube (QFT) test. Data were analysed by two-sample test of equality of proportions for survey data and logistic regression for survey data. Results: We analysed data from 6,848 adolescents with median age of 15.5 years (range 12.3 - 19.1). 4,880 (71%) adolescents were tested between 2005-2007 and 1,968 (29%) between 2014-2015. Prevalence of LTBI was 43.8% (95% Confidence Interval (CI) 28.4-59.1) vs 48.5% (CI: 41.1-55.8); and annual risk of Mycobacterium tuberculosis infection (ARTI) was 3.6% (CI: 2.1-5.5) vs 4.2% (CI: 3.4-5.2), in the period 2005-2007 vs 2014-2015, respectively. Marked heterogeneity in LTBI prevalence was observed at school level, ranging from 12-65%. LTBI prevalence increased on average by 13% between age 12-18 years in lower socio-economic quintile schools, in which average LTBI was 54% in 2005-2007 and 53% in 2014-2015, consistent with ongoing, but stable risk of TB transmission. By contrast, LTBI prevalence did not increase with age in highest socio-economic quintile schools, in which average LTBI prevalence increased from 20-38% over the same period, consistent with increased risk of transmission prior to school entry. Conclusion: Adolescent LTBI prevalence remained high over a decade, suggesting TB transmission to children was not yet impacted by effective TB control efforts that had reduced regional TB disease notification rate by more than one-third. Trends in school LTBI prevalence should be interpreted in the context of socio-economic and other TB risk factors that affect risk of transmission prior to school entry.

Latent tuberculosis infection: Opportunities and challenges.

Diagnosing and treating latent tuberculosis (TB) infection (LTBI) is recognized by the World Health Organization as an important strategy to accelerate the decline in global TB and achieve TB elimination. Even among low-TB burden countries that have achieved high rates of detection and successful treatment for active TB, a number of barriers have prevented implementing or expanding LTBI treatment programmes. Of those infected with TB, relatively few will develop active disease and the current diagnostic tests have a low predictive value. LTBI treatment using isoniazid (INH) has low completion rates due to the long duration of therapy and poor tolerability. Both patients and physicians often perceive the risk of toxicity to be greater than the risk of reactivation TB. As a result, LTBI treatment has had a limited or negligible role outside of countries with high resources and low burden of disease. New tools have emerged including the interferon-gamma release assays that more accurately diagnose LTBI, particularly in people vaccinated with Bacillus Calmette-Guerin (BCG). Shorter, better tolerated treatment using rifamycins are proving safe and effective alternatives to INH. While still imperfect, TB prevention using these new diagnostic and treatment tools appear cost effective in modelling studies in the United States and have the potential to improve TB prevention efforts globally. Continued research to understand the host-organism interactions within the spectrum of LTBI is needed to develop better tools. Until then, overcoming the barriers and optimizing our current tools is essential for progressing toward TB elimination.