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1.  The tuberculin skin test in school going adolescents in South India: associations of socio-demographic and clinical characteristics with TST positivity and non-response 
BMC Infectious Diseases  2014;14(1):571.
Background
India has generally used 1 TU purified protein derivative (PPD) as opposed to 2 TU PPD globally, limiting comparisons. It is important to assess latent TB infection in adolescents given that they may be a target group for new post-exposure TB vaccines.
The aim of this study is to describe the pattern and associations of tuberculin skin test (TST) responses (0.1 ml 2 TU) in adolescents in South India.
Methods
6643 school-going adolescents (11 to <18 years) underwent TST. Trained tuberculin reader made the reading visit between 48 and 96 hours after the skin test
Results
Of 6608 available TST results, 9% had 0 mm, and 12% ≥10 mm responses. The proportion of TST positive (≥10 mm) was higher among older children, boys, those with a history of TB contact and reported BCG immunization Those with no TST response (0 mm) included younger participants (<14 years), those whose mothers were illiterate and those with a recent history of weight loss. Those of a higher socio-economic status (houses with brick walls, LPG gas as cooking fuel) and those with a visible BCG scar were less likely to be non-responders.
Conclusion
Proportion of non-responders was lower than elsewhere in the world. Proportion of TST positivity was higher in those already exposed to TB and in children who had been BCG immunized, with a zero response more likely in younger adolescents and those with recent weight loss.
doi:10.1186/s12879-014-0571-7
PMCID: PMC4243729
Tuberculosis; Latent tuberculosis infection; Tuberculin skin test; Children
2.  Two year mortality and associated factors in a cohort of children from rural Uganda 
BMC Public Health  2014;14:314.
Background
As part of site development for clinical trials in novel TB vaccines, a cohort of infants was enrolled in eastern Uganda to estimate the incidence of tuberculosis. The study introduced several mortality reduction strategies, and evaluated the mortality among study participants at two years. The specific of objective of this sub-study was to estimate 2 year mortality and associated factors in this community-based cohort.
Methods
A community based cohort of 2500 infants was enrolled from birth up to 8 weeks of age and followed for 1–2 years. During follow up, several mortality reduction activities were implemented to enhance cohort survival and retention. The verbal autopsy process was used to assign causes of death.
Results
A total of 152 children died over a median follow up period of 2.0 years. The overall crude mortality rate was 60.8/1000 or 32.9/1000 person years with 40 deaths per 1000 for children who died in their first year of life. Anaemia, malaria, diarrhoeal diseases and pneumonia were the top causes of death. There was no death directly attributed to tuberculosis. Significant factors associated with mortality were young age of a mother and child’s birth place not being a health facility.
Conclusion
The overall two year mortality in the study cohort was unacceptably high and tuberculosis disease was not identified as a cause of death. Interventions to reduce mortality of children enrolled in the cohort study did not have a significant impact. Clinical trials involving infants and young children in this setting will have to strengthen local maternal and child health services to reduce infant and child mortality.
doi:10.1186/1471-2458-14-314
PMCID: PMC4234345  PMID: 24708689
Mortality; Infants; Factors associated with mortality; Verbal autopsy
3.  Improved services to enrollees into an HIV rural care and treatment center in Tanzania 
Better quality of services is essential for the sustainability of HIV programs, in particular in rural Sub-Saharan Africa, to support the increasing number of individuals treated with combination antiretroviral therapy (cART). However, longitudinal data from rural care and treatment centers (CTC) are scarce. The objective was to assess trend in quality of care for HIV infected persons before start of combination antiretroviral therapy (pre-ART). A retrospective analysis of pre-ART registers and patient's files of 1950 patients enrolled in the Bagamoyo CTC in Tanzania between 2008 and 2010 analyzing was conducted; with parameters including year of enrollment, gender, age, CD4 cell count and WHO clinical stage at time enrollment. We noted a significant increase by 20% of total patients who had CD4 cell count performed from 69% (n=457) in 2008, 83% (n=493) 2009 to 89% (n=616) 2010 (X2= 87.014, P2= 14.945, P2= 85.028, P3. Efforts must be undertaken for more HIV testing and timely referral of HIV-infected patients to CTC.
doi:10.11604/pamj.2013.16.34.1642
PMCID: PMC3932130  PMID: 24570795
HIV treatment program; Sub-Saharan Africa; HIV; WHO clinical stage; CD4 cell count
4.  Implementation of tuberculosis infection control in health facilities in Mukono and Wakiso districts, Uganda 
BMC Infectious Diseases  2013;13:360.
Background
Tuberculosis infection control (TBIC) is rarely implemented in the health facilities in resource limited settings. Understanding the reasons for low level of implementation is critical. The study aim was to assess TBIC practices and barriers to implementation in two districts in Uganda.
Methods
We conducted a cross-sectional study in 51 health facilities in districts of Mukono and Wakiso. The study included: a facility survey, observations of practices and eight focus group discussions with health workers.
Results
Quantitative: Only 16 facilities (31%) had a TBIC plan. Five facilities (10%) were screening patients for cough. Two facilities (4%) reported providing masks to patients with cough. Ventilation in the waiting areas was inadequate for TBIC in 43% (22/51) of the facilities. No facility possessed N95 particulate respirators.
Qualitative: Barriers that hamper implementation of TBIC elicited included: under-staffing, lack of space for patient separation, lack of funds to purchase masks, and health workers not appreciating the importance of TBIC.
Conclusion
TBIC measures were not implemented in health facilities in the two Ugandan districts where the survey was done. Health system factors like lack of staff, space and funds are barriers to implement TBIC. Effective implementation of TBIC measures occurs when the fundamental health system building blocks -governance and stewardship, financing, infrastructure, procurement and supply chain management are in place and functioning appropriately.
doi:10.1186/1471-2334-13-360
PMCID: PMC3735480  PMID: 23915376
TB infection control; Implementation; Health care workers; Health facilities; Barriers; Uganda
5.  Burden of tuberculosis disease among adolescents in a rural cohort in Eastern Uganda 
BMC Infectious Diseases  2013;13:349.
Background
The world health organization (WHO) declared tuberculosis (TB) a global emergency, mainly affecting people in sub-Saharan Africa. However there is little data about the burden of TB among adolescents. We estimated the prevalence and incidence of TB and assessed factors associated with TB among adolescents aged 12–18 years in a rural population in Uganda in order to prepare the site for phase III clinical trials with novel TB vaccines among adolescents.
Methods
In a prospective cohort study, we recruited 5000 adolescents and followed them actively, every 6 months, for 1–2 years. Participants suspected of having TB were those who had any of; TB signs and symptoms, history of TB contact or a positive tuberculin skin test (TST) of ≥10 mm. Laboratory investigations included sputum smear microscopy and culture.
Results
Of the 5000 participants, eight culture confirmed cases of TB were found at baseline: a prevalence of 160/100,000 (95% confidence interval (CI), 69–315). There were 13 incident TB cases detected in an average of 1.1 person years: an incidence of 235/100,000 person years (95% CI, 125–402). None of the confirmed TB cases were HIV infected. Predictors for prevalent TB disease were: a history of TB contact and a cough ≥ 2 weeks at baseline and being out of school, while the only predictor for incident TB was a positive TST during follow-up.
Conclusion
The TB incidence among adolescents in this rural part of Uganda seemed too low for a phase III TB vaccine trial. However, the study site demonstrated capability to handle a large number of participants with minimal loss to follow-up and its suitability for future clinical trials. Improved contact tracing in TB program activities is likely to increase TB case detection among adolescents. Future studies should explore possible pockets of higher TB incidence in urban areas and among out of school youth.
doi:10.1186/1471-2334-13-349
PMCID: PMC3735406  PMID: 23890464
6.  TB Incidence in an Adolescent Cohort in South Africa 
PLoS ONE  2013;8(3):e59652.
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.
doi:10.1371/journal.pone.0059652
PMCID: PMC3606161  PMID: 23533639
7.  An Early Morning Sputum Sample Is Necessary for the Diagnosis of Pulmonary Tuberculosis, Even with More Sensitive Techniques: A Prospective Cohort Study among Adolescent TB-Suspects in Uganda 
The World Health Organization (WHO) recommends collection of two sputum samples for tuberculosis (TB) diagnosis, with at least one being an early morning (EM) using smear microscopy. It remains unclear whether this is necessary even when sputum culture is employed. Here, we determined the diagnostic yield from spot and the incremental yield from the EM sputum sample cultures among TB-suspected adolescents from rural Uganda. Sputum samples (both spot and early-morning) from 1862 adolescents were cultured by the Lowenstein-Jensen (LJ) and Mycobacterium Growth Indicator Tube (MGIT) methods. For spot samples, the diagnostic yields for TB were 19.0% and 57.1% with LJ and MGIT, respectively, whereas the incremental yields (not totals) of the early-morning sample were 9.5% and 42.9% (P < 0.001) with LJ and MGIT, respectively. Among TB-suspected adolescents in rural Uganda, the EM sputum culture has a high incremental diagnostic yield. Therefore, EM sputum in addition to spot sample culture is necessary for improved TB case detection.
doi:10.1155/2012/970203
PMCID: PMC3529437  PMID: 23304491
8.  Utilization of HIV and Tuberculosis Services by Health Care Workers in Uganda: Implications for Occupational Health Policies and Implementation 
PLoS ONE  2012;7(10):e46069.
Background
Access to HIV testing and subsequent care among health care workers (HCWs) form a critical component of TB infection control measures for HCWs. Challenges to and gaps in access to HIV services among HCWs may thus compromise TB infection control. This study assessed HCWs HIV and TB screening uptake and explored their preferences for provision of HIV and TB care.
Methods
A cross-sectional mixed-methods study involving 499 HCWs and 8 focus group discussions was conducted in Mukono and Wakiso districts in Uganda between October 2010 and February 2011.
Results
Overall, 5% of the HCWs reported a history of TB in the past five years. None reported routine screening for TB disease or infection, although 89% were willing to participate in a TB screening program, 77% at the workplace. By contrast, 95% had previously tested for HIV; 34% outside their workplace, and 27% self-tested. Nearly half (45%) would prefer to receive HIV care outside their workplace. Hypothetical willingness to disclose HIV positive status to supervisors was moderate (63%) compared to willingness to disclose to sexual partners (94%). Older workers were more willing to disclose to a supervisor (adjusted prevalence ratio [APR] = 1.51, CI = 1.16–1.95). Being female (APR = 0.78, CI = 0.68–0.91), and working in the private sector (APR = 0.81, CI = 0.65–1.00) were independent predictors of unwillingness to disclose a positive HIV status to a supervisor. HCWs preferred having integrated occupational services, versus stand-alone HIV care.
Conclusions
Discomfort with disclosure of HIV status to supervisors suggests that universal TB infection control measures that benefit all HCWs are more feasible than distinctions by HIVstatus, particularly for women, private sector, and younger HCWs. However, interventions to reduce stigma and ensuring confidentiality are also essential to ensure uptake of comprehensive HIV care including Isoniazid Preventive Therapy among HCWs.
doi:10.1371/journal.pone.0046069
PMCID: PMC3469628  PMID: 23071538
9.  High yield of culture-based diagnosis in a TB-endemic setting 
BMC Infectious Diseases  2012;12:218.
Background
In most of the world, microbiologic diagnosis of tuberculosis (TB) is limited to microscopy. Recent guidelines recommend culture-based diagnosis where feasible.
Methods
In order to evaluate the relative and absolute incremental diagnostic yield of culture-based diagnosis in a high-incidence community in Cape Town, South Africa, subjects evaluated for suspected TB had their samples processed for microscopy and culture over a 21 month period.
Results
For 2537 suspect episodes with 2 smears and 2 cultures done, 20.0% (508) had at least one positive smear and 29.9% (760) had at least one positive culture. One culture yielded 1.8 times more cases as 1 smear (relative yield), or an increase of 12.0% (absolute yield). Based on the latter value, the number of cultures needed to diagnose (NND) one extra case of TB was 8, compared to 19 if second specimens were submitted for microscopy.
Conclusion
In a high-burden setting, the introduction of culture can markedly increase TB diagnosis over microscopy. The concept of number needed to diagnose can help in comparing incremental yield of diagnosis methods. Although new promising diagnostic molecular methods are being implemented, TB culture is still the gold standard.
doi:10.1186/1471-2334-12-218
PMCID: PMC3482573  PMID: 22978323
Tuberculosis; Diagnosis; Culture; Microscopy
11.  The Tuberculin Skin Test versus QuantiFERON TB Gold® in Predicting Tuberculosis Disease in an Adolescent Cohort Study in South Africa 
PLoS ONE  2011;6(3):e17984.
Setting
This study was conducted in a high tuberculosis (TB) burden area in Worcester, South Africa, with a notified all TB incidence rate of 1,400/100,000.
Main Objective
To compare the predictive value of a baseline tuberculin skin test (TST) with that of the QuantiFERON TB Gold (In-tube) assay (QFT) for subsequent microbiologically confirmed TB disease among adolescents.
Methods
Adolescents aged 12–18 years were recruited from high schools in the study area. At baseline, blood was drawn for QFT and a TST administered. Participants were followed up for up to 3.8 years for incident TB disease (median 2.4 years).
Results
After exclusions, 5244 (82.4%) of 6,363 adolescents enrolled, were analysed. The TB incidence rate was 0.60 cases per 100 person years (pyrs) (95% CI 0.43–0.82) for baseline TST positive (≥5 mm) participants and 0.64 cases per 100 pyrs (95% CI 0.45–0.87) for baseline QFT positive participants. TB incidence rates were 0.22 per 100 pyrs (0.11–0.39) and 0.22 per 100 pyrs (0.12–0.38) among those with a negative baseline TST and QFT respectively. Sensitivity for incident TB disease was 76.9% for TST and 75.0% for QFT (p = 0.81). Positive predictive value was 1.4% for TST and 1.5% for QFT.
Conclusion
Positive TST and QFT tests were moderately sensitive predictors of progression to microbiologically confirmed TB disease. There was no significant difference in the predictive ability of these tests for TB disease amongst adolescents in this high burden setting. Therefore, these findings do not support use of QFT in preference to TST to predict the risk of TB disease in this study population.
doi:10.1371/journal.pone.0017984
PMCID: PMC3066222  PMID: 21479236
12.  Direct and indirect costs of tuberculosis among immigrant patients in the Netherlands 
BMC Public Health  2009;9:283.
Background
In low tuberculosis (TB) incidence countries TB affects mostly immigrants in the productive age group. Little empirical information is available about direct and indirect TB-related costs that patients face in these high-income countries. We assessed the direct and indirect costs of immigrants with TB in the Netherlands.
Methods
A cross-sectional survey at 14 municipal health services and 2 specialized TB hospitals was conducted. Interviews were administered to first or second generation immigrants, 18 years or older, with pulmonary or extrapulmonary TB, who were on treatment for 1–6 months. Out of pocket expenditures and time loss, related to TB, was assessed for different phases of the current TB illness.
Results
In total 60 patients were interviewed. Average direct costs spent by households with a TB patient amounted €353. Most costs were spent when being hospitalized. Time loss (mean 81 days) was mainly due to hospitalization (19 days) and additional work days lost (60 days), and corresponded with a cost estimation of €2603.
Conclusion
Even in a country with a good health insurance system that covers medication and consultation costs, patients do have substantial extra expenditures. Furthermore, our patients lost on average 2.7 months of productive days. TB patients are economically vulnerable.
doi:10.1186/1471-2458-9-283
PMCID: PMC2734849  PMID: 19656370
13.  High Prevalence of Tuberculosis in Previously Treated Patients, Cape Town, South Africa 
Emerging Infectious Diseases  2007;13(8):1189-1194.
More than half of smear-positive case-patients had previously undergone treatment.
The tuberculosis (TB) notification rate is high and increasing in 2 communities in Cape Town, South Africa. In 2002, we conducted a prevalence survey among adults >15 years of age to determine the TB prevalence rate; 15% of households in these communities were randomly sampled. All persons living in sampled households were eligible for chest radiography and sputum examination. Of the 3,483 adults who completed a questionnaire, 2,608 underwent chest radiography and sputum examination. We detected 26 bacteriologically confirmed TB cases and a prevalence of 10.0/1,000 (95% confidence interval [CI] 6.2–13.8 per 1,000). We found 18 patients with smear-positive TB, of whom 8 were new patients (3.1/1,000, 95% CI 0.9–5.1/1,000). More than half of patients with smear-positive TB (10, 56%) had previously been treated. Such patients may contribute to transmission of Mycobacterium tuberculosis and the high TB prevalence rate. Successful treatment of TB patients must be a priority.
doi:10.3201/eid1308.051327
PMCID: PMC2828063  PMID: 17953090
Survey; recurrence; tuberculosis; prevalence; South Africa; research
14.  High Incidence of Pulmonary Tuberculosis a Decade after Immigration, Netherlands 
Emerging Infectious Diseases  2004;10(4):736-739.
Incidence rates of pulmonary tuberculosis among immigrants from high incidence countries remain high for at least a decade after immigration into the Netherlands. Possible explanations are reactivation of old infections and infection transmitted after immigration. Control policies should be determined on the basis of the as-yet unknown main causes of the persistent high incidence.
doi:10.3201/eid1004.030530
PMCID: PMC3323101  PMID: 15200873
Tuberculosis, pulmonary, incidence; migrants, screening, Netherlands
15.  Tuberculosis treatment outcome monitoring in European Union countries: systematic review 
The European Respiratory Journal  2012;41(3):635-643.
Treatment success measured by treatment outcome monitoring (TOM) is a key programmatic output of tuberculosis (TB) control programmes. We performed a systematic literature review on national-level TOM in the 30 European Union (EU)/European Economic Areas (EEA) countries to summarise methods used to collect and report data on TOM.
Online reference bibliographic databases PubMed/MEDLINE and EMBASE were searched to identify relevant indexed and non-indexed literature published between January 2000 and August 2010.
The search strategy resulted in 615 potentially relevant indexed citations, of which 27 full-text national studies (79 data sets) were included for final analysis. The selected studies were performed in 10 EU/EEA countries and gave a fragmented impression of TOM in the EU/EEA. Publication year, study period, sample size, databases, definitions, variables, patient and outcome categories, and population subgroups varied widely, portraying a very heterogeneous picture.
This review confirmed previous reports of considerable heterogeneity in publications of TOM results across EU/EEA countries. PubMed/MEDLINE and EMBASE indexed studies are not a suitable instrument to measure representative TOM results for the 30 EU/EEA countries. Uniform and complete reporting to the centralised European Surveillance System will produce the most timely and reliable results of TB treatment outcomes in the EU/EEA.
doi:10.1183/09031936.00030612
PMCID: PMC3585717  PMID: 22790913
Cohort analysis; death; failure; surveillance; treatment success; tuberculosis control

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