Background 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.Methods In this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) followup for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims:(1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixedeffects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022).Findings In total, study groups from 46 cohort studies in 34 countries-29 (63%) prospective studies and 17 (37%) retrospective-agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19•0% [95% CI 8•4-37•4]). The effectiveness of preventive therapy was 63% (adjusted HR 0•37 [95% CI 0•30-0•47]) among all exposed children, and 91% (adjusted HR 0•09 [0•05-0•15]) among those with a positive result for tuberculosis infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 9...

Five-year risk of TB among contacts with evidence of infection was higher compared with older estimates, and differed considerably by age. Incidence of TB among contacts with LTBI was low, suggesting limited impact may be expected of expanding preventive therapy.

The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically-identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% CI 8.0-29.2) among child contacts, 4.8% (3.0-7.7) among adult contacts, 5.0% (1.6-14.5) among migrants, and 4.8%(1.5-14.3) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk-stratification. We thus developed a personalised risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T-cell sensitization and clinical covariates. Internal-external cross-validation of the model demonstrated a random-effects meta-analysis C-statistic of 0.88 (0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the crude current approach to TB risk estimation among people with LTBI, in favour of our evidence-based and patient-centered method, in settings aiming towards pre-elimination worldwide. J.S.D.'s institution receives investigator-initiated research grants and consultancy income from GileadSciences, AbbVie, Bristol Myers Squibb and Merck. The Burnet Institute receives funding from the Victorian Government Operational Infrastructure Fund. C.L. reports honoraria from Chiesi, Gilead, Insmed, Janssen, Lucane, Novartis, Oxoid, Berlin Chemie (for participation at sponsored symposia) and from Oxford Immunotec (to attend a scientific advisory board meeting), all outside the submitted work. M.S. reports receipt of test kits free of charge from Qiagen and from Oxford Immunotec for investigator-initiated research projects. I.A. reports receiving free test kits from Qiagen for an

mIn order to switch from IS6110 and polymorphic GC-rich repetitive sequence (PGRS) restriction fragment length polymorphism (RFLP) to 24-locus variable-number tandem-repeat (VNTR) typing of Mycobacterium tuberculosis complex isolates in the national tuberculosis control program in The Netherlands, a detailed evaluation on discriminatory power and agreement with findings in a cluster investigation was performed on 3,975 tuberculosis cases during the period of 2004 to 2008. The level of discrimination of the two typing methods did not differ substantially: RFLP typing yielded 2,733 distinct patterns compared to 2,607 in VNTR typing. The global concordance, defined as isolates labeled unique or identically distributed in clusters by both methods, amounted to 78.5% (n ‫؍‬ 3,123). Of the remaining 855 cases, 12% (n ‫؍‬ 479) of the cases were clustered only by VNTR, 7.7% (n ‫؍‬ 305) only by RFLP typing, and 1.8% (n ‫؍‬ 71) revealed different cluster compositions in the two approaches. A cluster investigation was performed for 87% (n ‫؍‬ 1,462) of the cases clustered by RFLP. For the 740 cases with confirmed or presumed epidemiological links, 92% were concordant with VNTR typing. In contrast, only 64% of the 722 cases without an epidemiological link but clustered by RFLP typing were also clustered by VNTR typing. We conclude that VNTR typing has a discriminatory power equal to IS6110 RFLP typing but is in better agreement with findings in a cluster investigation performed on an RFLPclustering-based cluster investigation. Both aspects make VNTR typing a suitable method for tuberculosis surveillance systems. DNA fingerprinting of Mycobacterium tuberculosis isolates has been applied for the investigation of epidemiological links between tuberculosis (TB) cases in several countries since DNA typing techniques were developed in the early 1990s (1-4). In The Netherlands, IS6110 restriction fragment length polymorphism (RFLP) typing was used nationwide from 1993 until the end of 2008. Although RFLP typing revolutionized studies on the transmission of M. tuberculosis, the method remained technically demanding and time consuming. The analysis of the complex IS6110 RFLP banding pattern requires a sophisticated computer application and a high degree of expertise (5). Moreover, in the Netherlands, it took on average 44 days to the deliver the RFLP typing result to the Municipal Health Services, after the isolate had reached the laboratory (D. van Soolingen, personal communication). This major drawback significantly limited the usefulness of DNA fingerprinting in routine examination of transmission, as it in fact only offered retrospective confirmation of suspected epidemiological links. In 2006, 24-locus variable-number tandemrepeat (VNTR) typing was favorably evaluated and proposed as the new gold standard for typing of M. tuberculosis (6). In order to switch from RFLP to VNTR typing in 2008 in the Netherlands, it was considered necessary to establish a retrospective VNTR pattern database of possible sources of infection for a pr...

BackgroundDiagnosing HIV and/or TB is not sufficient; linkage to care and treatment is conditional to reduce the burden of disease. This study aimed to determine factors associated with linkage to HIV care and TB treatment at community-based services in Cape Town, South Africa.MethodsThis retrospective cohort study utilized routinely collected data from clients who utilized stand-alone (fixed site not attached to a health facility) and mobile HIV testing services in eight communities in the City of Cape Town Metropolitan district, between January 2008 and June 2012. Clients were included in the analysis if they were ≥12 years and had a known HIV status. Generalized estimating equations (GEE) logistic regression models were used to assess the association between determinants (sex, age, HIV testing service and co-infection status) and self-reported linkage to HIV care and/or TB treatment.ResultsLinkage to HIV care was 3 738/5 929 (63.1%). Linkage to HIV care was associated with the type of HIV testing service. Clients diagnosed with HIV at mobile services had a significantly reduced odds of linking to HIV care (aOR 0.7 (CI 95%: 0.6–0.8), p<0.001. Linkage to TB treatment was 210/275 (76.4%). Linkage to TB treatment was not associated with sex and service type, but was associated with age. Clients in older age groups were less likely to link to TB treatment compared to clients in the age group 12–24 years (all, p-value<0.05).ConclusionA large proportion of clients diagnosed with HIV at mobile services did not link to care. Almost a quarter of clients diagnosed with TB did not link to treatment. Integrated community-based HIV and TB testing services are efficient in diagnosing HIV and TB, but strategies to improve linkage to care are required to control these epidemics.

BackgroundCurrent diagnostic tests cannot identify which infected individuals are at risk for progression to tuberculosis (TB). Our aim was to identify biomarkers which can predict the development of TB prior to clinical diagnosis.MethodIn a retrospective case–control study, RNA of 14 HIV-infected drug users obtained before TB diagnosis (cases) and of 15 who did not develop TB (controls) was analyzed for the expression of 141 genes by dcRT-MLPA followed by Lasso regression analysis.FindingsA combined analysis of IL13 and AIRE had the highest discriminatory power to identify cases up to 8 months prior to clinical diagnosis. Cases expressing IL13 had a gene expression pattern strongly enriched for type I IFN related signaling genes, suggesting that these genes represent processes that contribute to TB pathogenesis.InterpretationWe here demonstrated that biomarkers, such as IL13-AIRE, can identify individuals that progress to TB within a high risk population, months prior to clinical diagnosis.

We aimed to determine the coverage and yield of tuberculosis contact investigation, and compliance with guidelines, and to identify opportunities for improvement.Data were extracted from records on contacts of pulmonary tuberculosis patients at the Public Health Service (Amsterdam, the Netherlands) from 2008 to 2011. Additional data were obtained from the national tuberculosis register.Among 3743 contacts of 235 pulmonary tuberculosis index patients, 2337 (62%) were screened for latent tuberculosis infection (LTBI). Those less likely to be screened for LTBI included contacts of sputum smearnegative index patients (adjusted odds ratio (aOR) 0.6, 95% CI 0.4-0.9) and bacille Calmette Guérin (BCG)-vaccinated contacts (aOR 0.06, 95% CI 0.04-0.09). Among BCG-vaccinated contacts, the proportion screened increased from 9% in 2008 to 43% in 2011 (p-value for trend ,0.001). LTBI diagnosis among contacts screened was associated with non-Dutch nationality (aOR 2.8, 95% CI 1.9-4.1) and being a close contact (aOR 4.0, 95% CI 1.9-8.3). Of the 254 contacts with LTBI diagnosis, 142 (56%) started preventive treatment. Starting treatment was associated with Dutch nationality (aOR 2.6, 95% CI 1.2-5.4) and being a close contact (aOR 10.5, 95% CI 1.5-70.7). Treatment completion was achieved by 129 (91%) of the 142 contacts who started treatment.Two areas for improvement were identified: further expanding LTBI screening, particularly among BCGvaccinated contacts and contacts of sputum smear-negative index patients, and expanding preventive treatment among contacts with LTBI. @ERSpublications We need to expand LTBI screening among vaccinated contacts and improve preventive treatment among contacts with LTBI

jThe population structure of 3,776 Mycobacterium tuberculosis isolates was determined using variable-number tandem-repeat (VNTR) typing. The degree of clonality was so high that a more relaxed definition of clustering cannot be applied. Among recent immigrants with non-Euro-American isolates, transmission is overestimated if based on identical VNTR patterns. DNA typing is a powerful tool to trace tuberculosis (TB) transmission and outbreaks. Clustering of Mycobacterium tuberculosis isolates based on identical DNA fingerprints is commonly used as a proxy for recent transmission (1). However, this assumption is not always correct and depends on many factors, such as circulation of genetically similar strains, evolution of M. tuberculosis over time, transmission rate, DNA typing methods applied, duration of the study period, sampling, and effectiveness of TB control (2, 3). Various studies have shown that not all cases in DNA fingerprint clusters have epidemiological links with other cases in the cluster (4, 5). Moreover, epidemiological links have been found between cases caused by bacteria with slightly different DNA fingerprints (6). Clustering results among cases in the immigrant population especially should be interpreted with caution (7, 8), as isolates from these patients often belong to genetically compact strain lineages predominating in the countries of origin (9,10,11,12).In the Netherlands, more than 70% of all TB cases are found among foreign-born persons, and extensive information on each patient is stored in a national registry. We aimed to investigate the population structure of M. tuberculosis isolates among native and immigrant cases and to determine the consequences for the interpretation of recent transmission based on variable-number tandem-repeat (VNTR) typing results.Culture-confirmed TB cases from October 2003 to December 2008 were included in this study. Patient information was obtained from the Netherlands Tuberculosis Register (NTR), held by the KNCV Tuberculosis Foundation. In total, 3,975 M. tuberculosis isolates were typed by IS6110/PGRS restriction fragment length polymorphism (RFLP) and standard 24-locus VNTR typing (13,14) at the RIVM or by Genoscreen (Lille). Molecular data were matched with demographic data using the date of birth, sex, postal area code, and year of diagnosis, resulting in 3,793 (95%) matching cases. After exclusion of 17 foreign-born individuals because of incomplete data for several variables, 3,776 (95%) cases remained eligible.Genotype information was uploaded to the MIRU-VNTRplus web-application (http://www.miru-vntrplus.org) (15) for phylogenetic lineage prediction, which was performed stepwise as described by . Isolates that were part of the CAS, Beijing, EAI, Mycobacterium bovis, and Mycobacterium africanum lineages were categorized as non-Euro-American and the remaining as a Euro-American superlineage (16).Clonal complexes, defined as groups of at least two isolates differing in not more than 3/24 loci, were identified on a minimum-spanning tree with BioN...