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      Tuberculosis Immunoreactivity Surveillance in Malawi (Timasamala)—A protocol for a cross-sectional Mycobacterium tuberculosis immunoreactivity survey in Blantyre, Malawi

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          Abstract

          Tuberculosis (TB) transmission and prevalence are dynamic over time, and heterogeneous within populations. Public health programmes therefore require up-to-date, accurate epidemiological data to appropriately allocate resources, target interventions, and track progress towards End TB goals. Current methods of TB surveillance often rely on case notifications, which are biased by access to healthcare, and TB disease prevalence surveys, which are highly resource-intensive, requiring many tens of thousands of people to be tested to identify high-risk groups or capture trends . Surveys of “latent TB infection”, or immunoreactivity to Mycobacterium tuberculosis (Mtb), using tests such as interferon-gamma release assays (IGRAs) could provide a way to identify TB transmission hotspots , supplementing information from disease notifications, and with greater spatial and temporal resolution than is possible to achieve in disease prevalence surveys . This cross-sectional survey will investigate the prevalence of Mtb immunoreactivity amongst young children , adolescents and adults in Blantyre, Malawi, a high HIV-prevalence city in southern Africa. Through this study we will estimate the annual risk of TB infection (ARTI) in Blantyre and explore individual- and area-level risk factors for infection, as well as investigating geospatial heterogeneity of Mtb infection (and its determinants), and comparing these to the distribution of TB disease case-notifications. We will also evaluate novel diagnostics for Mtb infection (QIAreach QFT) and sampling methodologies (convenience sampling in healthcare settings and community sampling based on satellite imagery), which may increase the feasibility of measuring Mtb infection at large scale. The overall aim is to provide high-resolution epidemiological data and provide new insights into methodologies which may be used by TB programmes globally.

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          Most cited references56

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          The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis

          Tens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood. We conducted an individual participant data meta-analysis of cohort studies in which children (<19 years of age) with close tuberculosis exposure were investigated for tuberculosis and followed for incident disease. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models, and estimated adjusted hazard ratios (AHR) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. We pooled participant-level data from 46 cohort studies in 34 countries. We included 137,647 exposed children followed for 429,538 child-years, during which 1,299 prevalent and 999 incident cases were diagnosed. The two-year risk of developing tuberculosis among infected children not receiving preventive therapy was 19.0% from 0 to 5 years of age. The effectiveness of preventive therapy was 63% (AHR, 0.37, 95% confidence intervals [CI], 0.30–0.47) among all exposed children, and 85% (AHR, 0.15, 95% CI, 0.11–0.20) among those with a positive test of infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 90 days of the baseline visit. The risk of developing tuberculosis among exposed infants and young children is very high. The majority of cases occurred within weeks of contact investigation initiation and may not be preventable through prophylaxis. This suggests that alternative strategies for prevention, such as earlier initiation of preventive therapy through earlier diagnosis of adult cases or community-wide screening approaches, are needed.
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            Predictive value of interferon-γ release assays and tuberculin skin testing for progression from latent TB infection to disease state: a meta-analysis.

            Given the current lack of effective vaccines against TB, the accuracy of screening tests for determining or excluding latent TB infection (LTBI) is decisive in effective TB control. This meta-analysis critically appraises studies investigating the positive and the negative predictive value (PPV and NPV, respectively) from a test-determined LTBI state for progression to active TB of interferon-γ release assays (IGRAs) and the tuberculin skin test (TST). We searched MEDLINE, EMBASE, and Cochrane bibliographies for relevant articles. After qualitative evaluation, the PPV and NPV for progression of commercial and “in-house” IGRAs and the TST for persons not receiving preventive treatment in the context of the respective IGRA studies were pooled using both a fixed and a random-effect model. Weighted rates were calculated for all study populations and for groups solely at high risk of TB development. The pooled PPV for progression for all studies using commercial IGRAs was 2.7% (95% CI, 2.3%-3.2%) compared with 1.5% (95% CI, 1.2%-1.7%) for the TST (P < .0001). PPV increased to 6.8% (95% CI, 5.6%-8.3%) and 2.4% (95% CI, 1.9%-2.9%) for the IGRAs and the TST, respectively, when only high-risk groups were considered (P < .0001). Pooled values of NPV for progression for both IGRAs and the TST were very high, at 99.7% (95% CI, 99.5%-99.8%) and 99.4% (95% CI, 99.2%-99.5%), respectively, although they were significantly higher for IGRAs (P < .01). Commercial IGRAs have a higher PPV and NPV for progression to active TB compared with those of the TST, especially when performed in high-risk persons.
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              Heterogeneity in tuberculosis transmission and the role of geographic hotspots in propagating epidemics.

              The importance of high-incidence "hotspots" to population-level tuberculosis (TB) incidence remains poorly understood. TB incidence varies widely across countries, but within smaller geographic areas (e.g., cities), TB transmission may be more homogeneous than other infectious diseases. We constructed a steady-state compartmental model of TB in Rio de Janeiro, replicating nine epidemiological variables (e.g., TB incidence) within 1% of their observed values. We estimated the proportion of TB transmission originating from a high-incidence hotspot (6.0% of the city's population, 16.5% of TB incidence) and the relative impact of TB control measures targeting the hotspot vs. the general community. If each case of active TB in the hotspot caused 0.5 secondary transmissions in the general community for each within-hotspot transmission, the 6.0% of people living in the hotspot accounted for 35.3% of city-wide TB transmission. Reducing the TB transmission rate (i.e., number of secondary infections per infectious case) in the hotspot to that in the general community reduced city-wide TB incidence by 9.8% in year 5, and 29.7% in year 50-an effect similar to halving time to diagnosis for the remaining 94% of the community. The importance of the hotspot to city-wide TB control depended strongly on the extent of TB transmission from the hotspot to the general community. High-incidence hotspots may play an important role in propagating TB epidemics. Achieving TB control targets in a hotspot containing 6% of a city's population can have similar impact on city-wide TB incidence as achieving the same targets throughout the remaining community.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Project administrationRole: Writing – review & editing
                Role: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Project administrationRole: ResourcesRole: Writing – review & editing
                Role: Project administrationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLOS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                24 May 2024
                2024
                : 19
                : 5
                : e0291215
                Affiliations
                [1 ] Clinical Research Department, London School of Hygiene & Tropical Medicine, London, United Kingdom
                [2 ] Malawi Liverpool Wellcome Programme, Blantyre, Malawi
                [3 ] Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
                [4 ] Helse Nord TB Initiative, Kamuzu University of Health Sciences, Blantyre, Malawi
                [5 ] School of Health & Wellbeing, University of Glasgow, Glasgow, United Kingdom
                [6 ] Department of Paediatrics, Queen Elizabeth Central Hospital, Blantyre, Malawi
                [7 ] Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom
                [8 ] Malawi National Tuberculosis and Leprosy Control Programme, Lilongwe, Malawi
                8th Medical Center of Chinese PLA General Hospital, CHINA
                Author notes

                Competing Interests: The manufacturers of QFT-Plus and QIAreach QFT (QIAGEN) have agreed to provide tests at reduced or no cost for the purposes of research. The investigators will retain all control over research questions and design, data analysis and dissemination, and the manufacturer will play no role in study design, collection, analysis, and interpretation of data, or writing up the study findings.

                ‡ These authors also contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-3502-0744
                https://orcid.org/0000-0002-4072-9715
                https://orcid.org/0000-0002-3100-5512
                https://orcid.org/0000-0002-6524-3754
                https://orcid.org/0000-0003-4470-3608
                https://orcid.org/0000-0002-7542-4065
                https://orcid.org/0000-0003-1242-839X
                https://orcid.org/0000-0002-0329-9613
                Article
                PONE-D-23-26780
                10.1371/journal.pone.0291215
                11125513
                38787869
                25f9e4f0-68ce-45d3-bab4-c32074ac9603
                © 2024 Rickman et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 September 2023
                : 28 February 2024
                Page count
                Figures: 2, Tables: 1, Pages: 20
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100010269, Wellcome Trust;
                Award ID: 225482/Z/22/Z
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100010269, Wellcome Trust;
                Award ID: 200901/Z/16/Z
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100010269, Wellcome Trust;
                Award ID: 206575/Z/17/Z
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100020171, Foreign, Commonwealth and Development Office;
                Award ID: 2018/S 196-443482
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100020171, Foreign, Commonwealth and Development Office;
                Award ID: 2018/S 196-443482
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100020171, Foreign, Commonwealth and Development Office;
                Award ID: 2018/S 196-443482
                Award Recipient :
                This work was supported by the Wellcome Trust [225482/Z/22/Z, 200901/Z/16/Z, 206575/Z/17/Z], and by the UK Foreign, Commonwealth and Development Office [“Leaving no-one behind: transforming gendered pathways to health for TB”; (2018/S 196-443482]; however, the views expressed do not necessarily reflect the UK government’s official policies. The manufacturers of QFT-Plus and QIAreach QFT (QIAGEN) have agreed to provide tests at reduced or no cost for the purposes of research. The investigators will retain all control over research questions and design, data analysis and dissemination, and the manufacturer will play no role in study design, collection, analysis, and interpretation of data, or writing up the study findings.
                Categories
                Study Protocol
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Bacterial Diseases
                Tuberculosis
                Medicine and Health Sciences
                Medical Conditions
                Tropical Diseases
                Tuberculosis
                Biology and Life Sciences
                Organisms
                Bacteria
                Actinobacteria
                Mycobacterium Tuberculosis
                Medicine and Health Sciences
                Epidemiology
                Medical Risk Factors
                Medicine and Health Sciences
                Diagnostic Medicine
                Virus Testing
                People and Places
                Geographical Locations
                Africa
                Malawi
                People and Places
                Population Groupings
                Age Groups
                Children
                Adolescents
                People and Places
                Population Groupings
                Families
                Children
                Adolescents
                Medicine and health sciences
                Epidemiology
                HIV epidemiology
                Medicine and Health Sciences
                Epidemiology
                Disease Surveillance
                Infectious Disease Surveillance
                Medicine and Health Sciences
                Medical Conditions
                Infectious Diseases
                Infectious Disease Control
                Infectious Disease Surveillance
                Custom metadata
                No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.

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