Background: Tuberculosis (TB) is a major public health problem globally. Little is known about TB incidence in adolescents who are a proposed target group for new TB vaccines. We conducted a study to determine the TB incidence rates and risk factors for TB disease in a cohort of school-going adolescents in a high TB burden area in South Africa. Methods: We recruited adolescents aged 12 to 18 years from high schools in Worcester, South Africa. Demographic and clinical information was collected, a tuberculin skin test (TST) performed and blood drawn for a QuantiFERON TB Gold assay at baseline. Screening for TB cases occurred at follow up visits and by surveillance of registers at public sector TB clinics over a period of up to 3.8 years after enrolment. Results: A total of 6,363 adolescents were enrolled (58% of the school population targeted). During follow up, 67 cases of bacteriologically confirmed TB were detected giving an overall incidence rate of 0.45 per 100 person years (95% confidence interval 0.29-0.72). Black or mixed race, maternal education of primary school or less or unknown, a positive baseline QuantiFERON assay and a positive baseline TST were significant predictors of TB disease on adjusted analysis. Conclusion: The adolescent TB incidence found in a high burden setting will help TB vaccine developers plan clinical trials in this population. Latent TB infection and low socio-economic status were predictors of TB disease. © 2013 Mahomed et al.
The study took place in the town of Worcester and surrounding villages, approximately 100 kilometres from Cape Town, South Africa. The total population of the municipal area from which the adolescents were drawn was estimated as 146,101 by the Department of Health in 2005, the year when recruitment started. According to the national Census of 2001, there were 21,056 adolescents aged 12–18 (14% of the total population) in the municipal area targeted and 83% of these adolescents were attending schools. The study area was a subset of the municipal area and consisted of a major town and two villages within this area. Based on the Census 2001 population data for the municipal area and high school attendance data of 10,492 in the study area, we estimated that there were 12,641 adolescents aged 12–18 years in the study area in total. All adolescents aged 12–18 years attending all 11 publicly funded high schools in the study area were approached to participate. The very few small private schools in the study area were not approached. At enrolment, demographic, socio-economic and clinical information were collected through interview of parents and the participating adolescent [11]. Blood was taken for QuantiFERON® TB Gold In-tube (Cellestis, Victoria, Australia) (QFT) and a tuberculin skin test (TST) was administered at baseline. Those with previous or current TB or with a previous severe reaction to TST did not have a TST performed, in order to prevent severe allergic reactions. The reading of the tuberculin skin test took place between 48 and 96 hours after administration, slightly longer than the more commonly used limit of 72 hours but there are data and recommendations which suggest that this is acceptable [16], [17]. A trained nurse examined each adolescent for a BCG scar. Participants were screened for TB at baseline (the overall number of cases diagnosed will be reported here but details of these cases are the subject of another publication (4 above)). All participants enrolled were scheduled for follow up visits after two years which included a blood draw for QFT and the administration of a TST. About half underwent three monthly visits prior to this which included six monthly QFTs and annual TSTs to compare follow up strategies while the other half were seen only at baseline and two year visit (details of the comparison of the two follow up strategies will be reported separately). At follow up visits, those with new symptoms or a new household contact compared to baseline, a converted TST (≥10 mm increase from baseline) or converted QFT (change from negative to positive) were investigated for active TB. In addition, passive surveillance was conducted of TB clinic and hospital admission registers in the area for any TB cases diagnosed between visits. Investigation for TB involved the collection of two sputum samples for smear examination on two separate occasions. For persons with at least one positive smear, a culture was performed, a chest x-ray done and an HIV test offered. The radiologist’s report on the chest –x ray was used to classify chest-x-ray findings. Enrolment started in July 2005 and was completed in April 2007. Follow up was completed at the end of February 2009. Owing to financial constraints, about 10% of the two year visits were performed one to two months short of two years towards the end of the study. Follow up was thus continued for a minimum of 22 months. Those completing their two year visits were followed up passively until all other subjects had completed their two year visits. This gave a maximum follow up time of 3.8 years. The protocol definition of a TB case was a diagnosis of intrathoracic tuberculosis with either two positive sputum smears and/or one single positive sputum culture (“bacteriologically confirmed TB”). However, data on all individuals placed on TB treatment by a physician were recorded (“all TB”). A chest x-ray consistent with active tuberculosis was defined as “compatible with TB” – this included pleural effusions. An “abnormal chest x-ray” was defined as any abnormality judged to be evidence of active disease including TB and evidence of old/previous disease. Those agreeing to participate determined the sample size. Based on routine TB programme data, we expected to find an incidence rate of bacteriologically confirmed TB of 0.5 per 100 person years. With an anticipated sample size of 6,500 and an expected incidence rate of bacteriologically confirmed TB of 0.5 per 100 person years over two years of follow up, we expected to yield a 95% confidence interval (precision) of approximately 0.4 to 0.6/100 person years. Data were captured in a Microsoft Access database, and analysed with STATA version 11.0 (Statacorp, Texas, USA). Data were verified and validated prior, during and after data entry according to a data entry standard operating procedure. Total person-time for TB incidence analysis was calculated from date of enrolment to date of the last visit of the last participant, TB diagnosis or death, whichever occurred first. Those lost to follow-up were assigned the duration of time to when last seen plus half the duration between that visit and the next missed visit. Univariate analysis was performed on demographic, socio-economic and clinical characteristics examining their association with “bacteriologically confirmed TB”. Hazard rates with 95% confidence intervals were calculated using poisson regression. The design effect was accounted for during statistical analysis, the clusters being the 11 schools from which the participants were enrolled. Kappa statistics were used to evaluate collinearity amongst the potential risk factor variables to avoid over-matching in building models for multivariate analysis. The risk factors for TB disease were analysed in a multivariate Cox regression model using the statistically significant variables (p<0.05) on univariate analysis to determine adjusted hazard ratios. This study was approved by the Faculty of Health Sciences Human Research Ethics Committee of the University of Cape Town. Written informed consent was obtained from the parents of adolescents and assent obtained from adolescents.
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