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Prevention of drug-resistant tuberculosis is a global health priority. However, trials evaluating the effectiveness of treating infection among contacts of persons with drug-resistant tuberculosis are lacking. We conducted a double-blind, randomized, controlled trial comparing 6 months of daily levofloxacin (weight-based doses) with placebo to treat infection. The trial population comprised household contacts of persons with bacteriologically confirmed rifampicin-resistant or multidrug-resistant (MDR) tuberculosis in Vietnam. Contacts of any age with a positive tuberculin skin test or immunologic impairment were eligible. The primary end point was bacteriologically confirmed tuberculosis within 30 months. Secondary end points included grade 3 or 4 adverse events, death from any cause, and acquired drug resistance. Of 3948 persons screened for eligibility, 61 (1.5%) had coprevalent tuberculosis (defined as active tuberculosis disease diagnosed before randomization) and 2041 underwent randomization. Of these 2041 participants, 1995 (97.7%) completed 30 months of follow-up, had a primary end-point event, or died. Confirmed tuberculosis occurred in 6 participants (0.6%) in the levofloxacin group and 11 (1.1%) in the placebo group (incidence rate ratio, 0.55; 95% confidence interval [CI], 0.19 to 1.62); this difference was not significant. There was little difference in grade 3 or 4 adverse events between the two groups (risk difference, 1.0 percentage point; 95% CI, -0.3 to 2.4). Adverse events of any grade were reported in 306 participants (31.9%) taking levofloxacin and 125 (13.0%) taking placebo (risk difference, 18.9 percentage points; 95% CI, 14.2 to 23.6). No acquired fluoroquinolone resistance was observed. Although the incidence of tuberculosis was lower in the levofloxacin group than in the placebo group at 30 months, the difference was not significant. (Funded by the National Health and Medical Research Council of Australia; VQUIN MDR Australia New Zealand Clinical Trials Registry number, ACTRN12616000215426.).

In the absence of active tuberculosis, a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA) result defines latent infection with Mycobacterium tuberculosis, although test results may vary depending on immunodeficiency. This study compared the performance of TST and IGRAs in five different groups of immunocompromised patients, and evaluated their ability to identify those at risk for development of tuberculosis. Immunocompromised patients with HIV infection, chronic renal failure, rheumatoid arthritis, solid-organ or stem-cell transplantation, and healthy control subjects were evaluated head-to-head by the TST, QuantiFERON-TB-Gold in-tube test (ELISA), and T-SPOT.TB test (enzyme-linked immunospot) at 17 centers in 11 European countries. Development of tuberculosis was assessed during follow-up. Frequencies of positive test results varied from 8.7 to 15.9% in HIV infection (n = 768), 25.3 to 30.6% in chronic renal failure (n = 270), 25.0% to 37.2% in rheumatoid arthritis (n = 199), 9.0 to 20.0% in solid-organ transplant recipients (n = 197), 0% to 5.8% in stem-cell transplant recipients (n = 103), and 11.2 to 15.2% in immunocompetent control subjects (n = 211). Eleven patients (10 with HIV infection and one solid-organ transplant recipient) developed tuberculosis during a median follow-up of 1.8 (interquartile range, 0.2-3.0) years. Six of the 11 patients had a negative or indeterminate test result in all three tests at the time of screening. Tuberculosis incidence was generally low, but higher in HIV-infected individuals with a positive TST (3.25 cases per 100 person-years) than with a positive ELISA (1.31 cases per 100 person-years) or enzyme-linked immunospot result (1.78 cases per 100 person-years). No cases of tuberculosis occurred in patients who received preventive chemotherapy. Among immunocompromised patients evaluated in this study, progression toward tuberculosis was highest in HIV-infected individuals and was poorly predicted by TST or IGRAs. Clinical trial registered with www.clinicaltrials.gov (NCT 00707317).

This article examines the experiment conducted by Johannes Theodor Wilhelm Petruschky (1863–1945) on the eradication of tuberculosis using tuberculin. His research was inspired by the work of Robert Koch, who discovered the etiological agent of tuberculosis and conducted experiments using tuberculin as a therapeutic agent. Despite initial hopes, tuberculin proved ineffective in treating tuberculosis. Following Koch's ideas, Petruschky conducted studies in Gdańsk and later in the isolated community of Hel, where he attempted to eliminate tuberculosis through systematic diagnosis and prevention. He declared the experiment a success, claiming that Hel had become tuberculosis-free. However, his research faced criticism, particularly from Ernst Effler, who questioned the reliability of the epidemiological data. Ultimately, Petruschky's method did not stand the test of time, and his claims of successful eradication were discredited. Nevertheless, his model of patient surveillance contributed to the development of tuberculosis control systems.

Bovine tuberculosis (bTB) is a threat to cattle health and public safety. The current control programs are hampered by wildlife reservoirs and socioeconomic barriers. Vaccinating cattle with Bacillus Calmette-Guérin (BCG) effectively reduces transmission, offering a potential solution for controlling bTB. A key requirement for vaccination strategies using BCG is the validation of defined antigens to differentiate infections among vaccinated animals (DIVA). We compared tuberculin with DIVA peptide cocktails (ESAT-6, CFP-10, and Rv3615c) in 67 unvaccinated and 67 BCG-vaccinated cattle exposed to M. bovis in a natural setting. The cattle were tested every 4 months with a skin test and every 2 months with interferon-gamma (IFN-γ) release assays (IGRA) over a year of exposure. Before exposure, the DIVA skin, DIVA IGRA, and tuberculin tests showed 100% specificity in unvaccinated control calves. After exposure, the DIVA skin, DIVA IGRA, and comparative cervical tuberculin (CCT) tests had comparable sensitivities of 46% (95% CI 36, 56), 45% (95% CI 35, 55), and 47 (95% CI 37, 57), respectively, when assessed against animals positive by M. bovis culture PCR. The results suggest that test-and-slaughter control strategies using tests with low sensitivity are not expected to be effective in controlling bTB in high-prevalence herds, and highlight an urgent need to improve the sensitivity of diagnostic tests for bTB in these settings.

The World Health Organization recommends evaluation of all household contacts (HHC) of index tuberculosis (TB) patients for TB disease (TBD) and TB infection (TBI). Tests to identify TBI and TBD are preferred but can be skipped in persons living with HIV and children <5 years. There is equipoise on the need for these tests in other HHC. We conducted a superiority, open label cluster-randomized trial in Benin and Brazil to compare three strategies to evaluate HHC aged 5-50 of persons newly diagnosed with drug susceptible pulmonary TBD: Standard: tuberculin skin testing (TST) for TBI and if positive, chest X-ray (CXR) to rule out TBD; rapid molecular test (RMT): same as Standard, except CXR replaced by an RMT; and No-TST: CXR for all but no TST. Randomization was computer-generated and stratified by country, in blocks of variable length. The primary outcome was TB preventive therapy (TPT) initiation among HHC considered eligible (positive TST, if done, and no evidence of TBD on CXR or RMT). Secondary outcomes were: completion of investigations to detect TBI and TBD, detection of TBD, TPT completion, severe adverse events, and societal costs. Among 1,589 participating HHC enrolled from 29 January 2020, to 30 November 2022, 474 were randomized to the standard, 583 to the RMT, and 532 to the no-TST strategies; all were included in the analyses. Of 848 HHC considered eligible for TPT, 802 (94.6%) initiated TPT, with no difference between strategies (95%, 94%, and 95% for the standard, RMT, and no-TST strategies, respectively). Of the secondary outcomes, protocol-mandated investigations to detect TBI and exclude possible TBD were completed for 93.4% overall, with slight differences between arms (93%, 95%, and 93% for the standard, RMT, and no-TST strategies, respectively). Adverse events resulting in discontinuation of TPT occurred in 3 (0.4%) participants in total (with 1, 0, and 2 events among participants in the Standard, RMT, and no-TST arms, respectively). The proportion completing TPT was similar with Standard and RMT strategies but was 13% lower (95% confidence interval: 3% to 23% lower) with the No-TST strategy. Societal costs per HHC completing investigations were $61 ($56-$65) with the standard strategy, compared to $52 ($49-$55) with the RMT strategy and $74 ($72-$77) with the no-TST strategy. This randomized trial provides high-quality evidence that TST followed by selected use of CXR or an RMT to exclude disease can achieve high rates of TPT initiation at reasonable costs. A limitation of the trial is the potential study effect, which may have affected adherence by providers and HHCs. RMT could replace CXR in the management of HHC in resource limited settings. clinicaltrials.gov NCT04528823.

Background Interferon-gamma release assays (IGRAs) are widely used for detecting latent tuberculosis infection (LTBI). However, these tests can yield indeterminate results, posing challenges for clinical management. The management of these indeterminate outcomes varies, creating uncertainty in clinical practice. This study systematically evaluates the effectiveness of repeat IGRA testing versus additional tuberculin skin testing (TST) in resolving indeterminate IGRA results during LTBI screening. Methods We conducted a systematic review and meta-analysis, searching PubMed, Embase, Web of Science, and the Cochrane Library databases on May 18, 2024, without start date or language restrictions. Studies were included if they screened for LTBI in healthy or high-risk populations using IGRA, reported indeterminate results, and managed these results with repeat IGRA testing and/or additional TST. A random-effects model was used to calculate pooled results. Results A total of 59 studies were included in this analysis. Among these, 40 studies assessed the use of additional TST in individuals with indeterminate IGRA results, yielding a pooled confirmation rate of 98.6% (95% CI: 96.2–99.8%). Additionally, 27 studies examined repeat IGRA testing, which resulted in a pooled confirmation rate of 68.9% (95% CI: 57.0–79.6%). Furthermore, eight studies evaluated both TST and repeat IGRA testing, with the pooled confirmation rate for the TST being 93.7% (95% CI: 78.7–99.9%), higher than the pooled confirmation rate for repeat testing at 76.5% (95% CI: 44.6–97.1%). However, there was no statistically significant difference in the confirmation rates between the two testing methods (OR = 2.13, 95% CI: 0.47–9.76). Conclusions In managing indeterminate IGRA results during LTBI screening, head-to-head studies show no significant difference in confirmation rates between additional TST and repeat IGRA. Across nearly 60 studies, additional TST tends to have a slightly higher confirmation rate, though the difference is not statistically significant. Clinically, for patients with an initial indeterminate IGRA who are immunocompetent, with convenient sample collection or a need for rapid results, additional TST may help achieve more reliable outcomes. Selection of follow-up testing should consider the cause of indeterminate results, feasibility, and risk of patient loss to follow-up.

There are currently two tests for diagnosing latent tuberculosis infection (LTBI); TST and IGRA. However, it is still unclear that which one of these tests performs better in high TB-burden settings. 1511 household contacts of pulmonary TB patients were enrolled to compare the performance of TST and IGRA for LTBI. At baseline all participant underwent testing for IGRA [QuantiFERON-TB® Gold In-tube (QFT-GIT) assay] and TST [2 tuberculin unit (TU), purified protein derivative (PPD), RT23, Staten Serum Institute (SSI), Copenhagen, Denmark]. All the household contacts were followed-up for two years for incident TB cases. Active TB was diagnosed in 76 household contacts at an incidence rate of 2.14 per 1000 person-years. Both, TST [Hazard Ratio (HR): 1.14, 95% confidence interval (CI): 0.72-1.79, p = 0.57], as well as QFT-GIT assay (HR: 1.66, 95% CI: 0.97-2.84, p = 0.06) results at baseline were not significantly associated with subsequent development of active TB among household contacts of pulmonary TB patients. Neither TST nor IGRA predicted subsequent development of active TB among household contacts of pulmonary TB patients during follow-up. However, keeping in view the cost, and other logistics, TST remains the most preferred method for LTBI diagnosis in resource-limited, high TB-burden settings.

Bovine tuberculosis (bTB), caused by Mycobacterium bovis ( M. bovis ), represents a significant problem for the agriculture industry as well as posing a risk for human health. Current diagnostic tests for bTB target the cell-mediated immune (CMI) response to infection with M. bovis , primarily through screening of animals with the tuberculin skin test. Epigenetic modifications have been shown to alter the course of the immune response and differentially methylated regions (DMRs) might also influence the outcome of the skin test in cattle. Whole Genome Bisulphite Sequencing (WGBS) was used to profile DNA methylation levels from peripheral blood of a group of cattle identified as test positive for M. bovis (positive for the single intradermal comparative tuberculin test (SICTT) and/or the interferon-γ release assay compared to a test negative control group [ n  = 8/group, total of 16 WGBS libraries]. Although global methylation profiles were similar for both groups across the genome, 223 DMRs and 159 Differentially Promoter Methylated Genes (DPMGs) were identified between groups with an excess of hypermethylated sites in SICTT positive cattle (threshold > 15% differential methylation). Genes located within these DMRs included the Interleukin 1 receptor ( IL1R1 ) and MHC related genes ( BOLA and BOLA-DQB ). KEGG pathway analysis identified enrichment of genes involved in Calcium and MAPK signalling, as well as metabolism pathways. Analysis of DMRs in a subset of SICTT negative cattle that were IFN-γ positive showed differential methylation of genes including Interleukin 10 Receptor, alpha ( IL10RA ), Interleukin 17 F ( IL17F ) and host defence peptides ( DEFB and BDEF109 ). This study has identified a number of immune gene loci at which differential methylation is associated with SICTT test results and the degree of methylation could influence effective host immune responses.

Tuberculin skin testing is simple and relatively inexpensive, but the specificity of PPD is affected by BCG vaccination. Determine optimal dose and specificity of recombinant ESAT-6 and CFP-10 (C-Tb) produced in Lactococcus lactis for diagnosis of M. tuberculosis infection. In a dose finding phase I trial 0.01 or 0.1 µg preserved and unpreserved C-Tb was injected by Mantoux technique in 38 patients with active tuberculosis and induration responses measured. In a phase II specificity trial in 151 uninfected, BCG vaccinated participants 0.1 µg C-Tb was compared to 2 TU PPD. 0.1 µg C-Tb gave a median induration of 15 mm after 2 days. Phenol preservation did not affect the response. The specificity of C-Tb was 99.3% (95% CI 96-100%) regarding indurations ≥5 mm as a positive outcome. This was higher than the specificity of PPD (63% using a cut-off of 5 mm or 92% using a cut-off of 15 mm to adjust for non-specific BCG responses). Local adverse reactions following C-Tb injection included transient itching and discomfort as expected components of the immune response. C-Tb offers a simple and convenient skin test to diagnose M. tuberculosis infection using a single, universal cut-off unaffected by BCG vaccination. ClinicalTrials.gov NCT01033929 and NCT01241188.

Background This study aimed to evaluate the diagnostic performance of ESAT6-CFP10 (EC) skin test in healthy population and determine the factors influencing the booster effect. Methods We conducted a randomized, double-blind, parallel controlled trial in healthy population. The experiment was divided into two stages. In the first stage, all participants underwent T-SPOT, TB-PPD, and EC tests. In the second stage, to evaluate whether BCG vaccination affected the efficacy of skin tests, the participants with three negative results in the first stage were randomly assigned to the BCG and placebo groups at a ratio of 2:1 and underwent three tests. The positivity rates and concordance of the three tests were calculated in both stages, and a logistic regression model was constructed to determine the factors influencing the booster effect of EC in the second stage. Safety observations were continued until the skin test results were available. Results In the first stage, 1,564 participants were enrolled in the study. The positivity rates of the T-SPOT, EC, and TB-PPD tests in all the participants were 18.89%, 10.37%, and 53.96%, respectively. The concordance between the EC and T-SPOT tests was 88.97% (kappa = 0.56), and that between the TB-PPD and T-SPOT tests was 58.19% (kappa = 0.20). In the second stage, 585 participants were assigned to the BCG or placebo group. In the BCG group, the positivity rates for the T-SPOT, EC, and TB-PPD tests were 4.76%, 7.30%, and 73.65%, respectively. The concordance between the EC and T-SPOT tests was 94.92% (kappa = 0.55), and that between the TB-PPD and T-SPOT tests was 29.84% (kappa = 0.02). In the placebo group, the positivity rates for the T-SPOT, EC, and TB-PPD tests were 6.88%, 11.88%, and 39.38%, respectively. The concordance between the EC and T-SPOT tests was 91.25% (kappa = 0.49), and that between the TB-PPD and T-SPOT tests was 66.25% (kappa = 0.17). The logistic regression model showed that age ≥ 60 years (odds ratio [OR] = 5.42, 95% confidence interval [CI]: 2.05–14.26) and retest positivity of T-SPOT test (OR = 44.87, 95% CI: 16.58–135.21) were stimulative factors of EC booster effect. Adverse reactions occurred in 168 (10.74%) and 33 participants (5.64%) in the first and second stage, respectively. Most of these were local adverse reactions, including injection site pain, pruritus, and rash. Conclusions The diagnostic performance of the EC skin test was similar to that of the T-SPOT test in the healthy population and was unaffected by BCG vaccination. The booster effects were more inclined to occur in population with retest positivity of T-SPOT or age ≥ 60 years. Clinical trials Registration NCT02795260, Clinical Study of Recombinant Mycobacterium Tuberculosis Allergen ESAT6-CFP10 on Healthy People Aged 18–65(III-healthy), Registration Date: June 10, 2016.