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Potential population level impact on tuberculosis incidence of using an mRNA expression signature correlate-of-risk test to target tuberculosis preventive therapy.

ABSTRACT: Achieving the WHO End-Tuberculosis (TB) targets requires approaches to prevent progression to TB among individuals with Mycobacterium tuberculosis (M.tb) infection. Effective preventive therapy (PT) exists, but current tests have low specificity for identifying who, among those infected, is at risk of developing TB. Using mathematical models, we assessed the potential population-level impact on TB incidence of using a new more specific mRNA expression signature (COR) to target PT among HIV-uninfected adults in South Africa. We compared the results to the use of the existing interferon-? release assay (IGRA). With annual screening coverage of 30% COR-targeted PT could reduce TB incidence in 2035 by 20% (95% CI 15-27). With the same coverage, IGRA-targeted PT could reduce TB incidence by 39% (31-48) but would require greater use of PT resulting in a higher number needed to treat per TB case averted (COR: 49 (29-77); IGRA: 84 (59-123)). The relative differences between COR and IGRA were not sensitive to screening coverage. COR-targeted PT could contribute to reducing total TB burden in high incidence countries like South Africa by allowing more efficient targeting of treatment. To maximise impact, COR-like tests may be best utilised in the highest burden regions, or sub-populations, within these countries.

SUBMITTER: Sumner T

PROVIDER: S-EPMC6668474 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Potential population level impact on tuberculosis incidence of using an mRNA expression signature correlate-of-risk test to target tuberculosis preventive therapy.

Sumner Tom T Scriba Thomas J TJ Penn-Nicholson Adam A Hatherill Mark M White Richard G RG

Scientific reports 20190731 1

Achieving the WHO End-Tuberculosis (TB) targets requires approaches to prevent progression to TB among individuals with Mycobacterium tuberculosis (M.tb) infection. Effective preventive therapy (PT) exists, but current tests have low specificity for identifying who, among those infected, is at risk of developing TB. Using mathematical models, we assessed the potential population-level impact on TB incidence of using a new more specific mRNA expression signature (COR) to target PT among HIV-uninf ...[more]

PMID: 31366947

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Project description:BackgroundMozambican healthcare workers have high rates of latent and active tuberculosis, but occupational screening for tuberculosis is not routine in this setting. Furthermore, the specificity of tuberculin skin testing in this population compared with interferon gamma release assay testing has not been established.MethodsThis study was conducted among healthcare workers at Maputo Central Hospital, a public teaching quaternary care hospital in Mozambique. With a cross sectional study design, risk factors for tuberculosis were assessed using multivariable logistic regression. The care cascade is reported for participants who were prescribed six months of isoniazid preventive therapy for HIV or highly reactive testing for latent tuberculosis infection. The agreement of interferon-gamma release assay results with positive tuberculin skin testing was calculated.ResultsOf 690 screened healthcare workers, three (0.4%) had active tuberculosis and 426 (61.7%) had latent tuberculosis infection. Less education, age 35-49, longer hospital service, and work in the surgery department were associated with increased likelihood of being tuberculosis infected at baseline (p <?0.05). Sex, Bacillus Calmette-Guerin vaccination, HIV, outside tuberculosis contacts, and professional category were not. Three new cases of active tuberculosis developed during the follow-up period, two while on preventive therapy. Among 333 participants offered isoniazid preventive therapy, five stopped due to gastrointestinal side effects and 181 completed treatment. For HIV seropositive individuals, the agreement of interferon gamma release assay positivity with positive tuberculin skin testing was 50% among those with a quantitative skin test result of 5-10?mm, and among those with a skin test result ?10?mm it was 87.5%. For HIV seronegative individuals, the agreement of interferon gamma release assay positivity with a tuberculin skin test result of 10-14?mm was 63.6%, and for those with a quantitative skin test result ?15?mm it was 82.2%.ConclusionsThere is a high prevalence of tuberculosis infected healthcare workers at Maputo Central Hospital. The surgery department was most heavily affected, suggesting occupational risk. Isoniazid preventive therapy initiation was high and just over half completed therapy. An interferon gamma release assay was useful to discern LTBI from false positives among those with lower quantitative tuberculin skin test results.

Project description:BACKGROUND:Tuberculosis (TB) is one of the major infectious diseases that seriously endanger people's health. In Shandong province, the relationship between the level of economic development and TB incidence has not been studied. This study aims to provide more research basis for the government to prevent and control TB by exploring the impact of different economic factors on TB incidence. METHODS:By constructing threshold regression model (TRM), we described the extent to which different economic factors contribute to TB registered incidence and differences in TB registered incidence among seventeen cities with different levels of economic development in Shandong province, China, during 2006-2017. Data were retrieved from the China Information System for Disease Control and Prevention. RESULTS:Per capita medical expenditure (regression coefficient, -0.0314462; SD, 0.0079305; P?>?|t|, 0.000) and per capita savings (regression coefficient, 0.0001924; SD, 0.0000566; P?>?|t|, 0.001) passed the significance test at the level of 1%.They are the two economic indicators that have the greatest impact on TB registered incidence. Through the threshold test, we selected the per capita savings as the threshold variable. In the three stages of per capita savings (<9772.8086 China Yuan(CNY); 9772.8086-33,835.5391 CNY; >33,835.5391 CNY), rural per capita income always has a significant negative impact on the TB registered incidence (The regression coefficients are -?0.0015682, -?0.0028132 and?-?0.0022253 respectively. P is 0.007,0.000 and 0.000 respectively.).In cities with good economies, TB registered incidence was 38.30% in 2006 and dropped to 25.10% by 2017. In cities with moderate economies, TB registered incidence peaked in 2008 at 43.10% and dropped to 27.1% by 2017.In poorer cities, TB registered incidence peaked in 2008 at 56.30% and dropped to 28.9% in 2017. CONCLUSION:We found that per capita savings and per capita medical expenditure are most closely related to the TB incidence. Therefore, relevant departments should formulate a more complete medical system and medical insurance policy to effectively solve the problem of "difficult and expensive medical treatment". In order to further reduce the TB incidence, in addition to timely and accurate diagnosis and treatment, it is more important for governments to increase investment in medicine and health care.

Project description:RationaleHealthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent Mycobacterium tuberculosis (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial.ObjectivesTo measure frequency of TST reversion following IPT, and variation in interferon-gamma (IFN-?) responses to Mtb, in healthy Ugandan TB HHC with primary Mtb infection evidenced by TST conversion.MethodsProspective cohort study of healthy, HIV-uninfected, TST-negative TB HHC with TST conversions. Repeat TST was performed 12 months following conversion (3 months following completion of 9 month IPT course) to assess for stable conversion vs. reversion. Whole blood IFN-? responses to Mtb antigen 85B (MtbA85B) and whole Mtb bacilli (wMtb) were measured in a subset (n?=?27 and n?=?42, respectively) at enrollment and TST conversion, prior to initiation of IPT.ResultsOf 122 subjects, TST reversion was noted in 25 (20.5%). There were no significant differences in demographic, clinical, or exposure variables between reverters and stable converters. At conversion, reverters had significantly smaller TST compared to stable converters (13.7 mm vs 16.4 mm, respectively; p?=?0.003). At enrollment, there were no significant differences in IFN-? responses to MtbA85B or wMTB between groups. At conversion, stable converters demonstrated significant increases in IFN-? responses to Ag85B and wMtb compared to enrollment (p?=?0.001, p<0.001, respectively), while there were no significant changes among reverters.ConclusionsTST reversion following IPT is common following primary Mtb infection and associated with unique patterns of Mtb-induced IFN-? production. We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies of cell mediated immune responses to Mtb infection be prioritized to identify immune phenotypes protective against development of TB disease.

Project description:BackgroundTuberculosis (TB) is the ninth leading cause of death worldwide and the leading cause from a single infectious agent. Bacillus Calmette-Guerin (BCG) is the only licensed vaccine for TB, yet its efficacy remains debated with variations in vaccine sub-strains, policies, and practices observed across the world. Three BCG vaccination policies were implemented across adjoining regions in the South West of Ireland from 1972; neonatal vaccination (vaccinated Region-A), vaccination of children aged 10-12 years (vaccinated Region-B) and no vaccination (unvaccinated Region-C). The aim of this study is to examine the impact of different BCG vaccination policies on incidence of TB disease in the South of Ireland over a 13-year period.MethodsCases of active TB disease from 2003 to 2016 were identified through surveillance data. Residential addresses for each case were geocoded using the Google Maps API. Addresses were linked to 2011 census population data and to Local Health Offices BCG coverage data for study regions A-C. A steady-state population was assumed to calculate the 13-year incidence of TB disease. Using SatScan (v9.4.4), spatial clusters were identified at a small area level with the spatial scan statistic based on the discrete Poisson probability distribution.ResultsOf 621 TB disease cases identified, 510 could be linked to the study area based on the reported addresses. The median age was 42 years (range 4 months - 94 years), 65% male and 66% Irish born. The incidence of TB disease was higher in the unvaccinated population, region-C 132/100,000 (95% CI 116-150) versus vaccinated region-A 56/100,000 (95%CI 45-69) and region-B 44/100,000 (95%CI 29-63). A spatial cluster analysis identified a single high-risk cluster in region -C where the relative risk (vs. the areas outside of the cluster) was 4.94 (95% CI 4.03 to 5.96).ConclusionOur study demonstrates significant regional variation in the incidence of TB in demographically similar populations based on BCG vaccination policy. This observation is particularly noteworthy in a country with low TB disease incidence such as Ireland. These findings strengthen existing data demonstrating efficacy of BCG vaccination for primary prevention of TB disease.

Dataset Information

Potential population level impact on tuberculosis incidence of using an mRNA expression signature correlate-of-risk test to target tuberculosis preventive therapy.

Publications

Potential population level impact on tuberculosis incidence of using an mRNA expression signature correlate-of-risk test to target tuberculosis preventive therapy.

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