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1.  Testing Pooled Sputum with Xpert MTB/RIF for Diagnosis of Pulmonary Tuberculosis To Increase Affordability in Low-Income Countries 
Journal of Clinical Microbiology  2015;53(8):2502-2508.
Tuberculosis (TB) is a global public health problem, with the highest burden occurring in low-income countries. In these countries, the use of more sensitive diagnostics, such as Xpert MTB/RIF (Xpert), is still limited by costs. A cost-saving strategy to diagnose other diseases is to pool samples from various individuals and test them with single tests. The samples in positive pool samples are then retested individually to identify the patients with the disease. We assessed a pooled testing strategy to optimize the affordability of Xpert for the diagnosis of TB. Adults with presumptive TB attending hospitals or identified by canvassing of households in Abuja, Nigeria, were asked to provide sputum for individual and pooled (4 per pool) testing. The agreement of the results of testing of individual and pooled samples and costs were assessed. A total of 738 individuals submitted samples, with 115 (16%) being Mycobacterium tuberculosis positive. Valid Xpert results for individual and pooled samples were available for 718 specimens. Of these, testing of pooled samples detected 109 (96%) of 114 individual M. tuberculosis-positive samples, with the overall agreement being 99%. Xpert semiquantitative M. tuberculosis levels had a positive correlation with the smear grades, and the individual sample-positive/pooled sample-negative results were likely due to the M. tuberculosis concentration being below the detection limit. The strategy reduced cartridge costs by 31%. Savings were higher with samples from individuals recruited in the community, where the proportion of positive specimens was low. The results of testing of pooled samples had a high level of agreement with the results of testing of individual samples, and use of the pooled testing strategy reduced costs and has the potential to increase the affordability of Xpert in countries with limited resources.
PMCID: PMC4508401  PMID: 26019204
2.  Comparative Meta-Analysis of Tuberculosis Contact Investigation Interventions in Eleven High Burden Countries 
PLoS ONE  2015;10(3):e0119822.
Screening of household contacts of tuberculosis (TB) patients is a recommended strategy to improve early case detection. While it has been widely implemented in low prevalence countries, the most optimal protocols for contact investigation in high prevalence, low resource settings is yet to be determined. This study evaluated contact investigation interventions in eleven lower and middle income countries and reviewed the association between context or program-related factors and the yield of cases among contacts.
We reviewed data from nineteen first wave TB REACH funded projects piloting innovations to improve case detection. These nineteen had fulfilled the eligibility criteria: contact investigation implementation and complete data reporting. We performed a cross-sectional analysis of the percentage yield and case notifications for each project. Implementation strategies were delineated and the association between independent variables and yield was analyzed by fitting a random effects logistic regression.
Overall, the nineteen interventions screened 139,052 household contacts, showing great heterogeneity in the percentage yield of microscopy confirmed cases (SS+), ranging from 0.1% to 6.2%). Compared to the most restrictive testing criteria (at least two weeks of cough) the aOR’s for lesser (any TB related symptom) and least (all contacts) restrictive testing criteria were 1.71 (95%CI 0.94−3.13) and 6.90 (95% CI 3.42−13.93) respectively. The aOR for inclusion of SS- and extra-pulmonary TB was 0.31 (95% CI 0.15−0.62) compared to restricting index cases to SS+ TB. Contact investigation contributed between <1% and 14% to all SS+ cases diagnosed in the intervention areas.
This study confirms that high numbers of active TB cases can be identified through contact investigation in a variety of contexts. However, design and program implementation factors appear to influence the yield of contact investigation and its concomitant contribution to TB case detection.
PMCID: PMC4374904  PMID: 25812013
3.  Implementing rapid testing for tuberculosis in Mozambique 
In Mozambique, pulmonary tuberculosis is primarily diagnosed with sputum smear microscopy. However this method has low sensitivity, especially in people infected with human immunodeficiency virus (HIV). Patients are seldom tested for drug-resistant tuberculosis.
The national tuberculosis programme and Health Alliance International introduced rapid testing of smear-negative sputum samples. Samples were tested using a polymerase-chain-reaction-based assay that detects Mycobacterium tuberculosis deoxyribonucleic acid and a mutation indicating rifampicin resistance; Xpert® MTB/RIF (Xpert®). Four machines were deployed in four public hospitals along with a sputum transportation system to transfer samples from selected health centres. Laboratory technicians were trained to operate the machines and clinicians taught to interpret the results.
Local setting
In 2012, Mozambique had an estimated 140 000 new tuberculosis cases, only 34% of which were diagnosed and treated. Of tuberculosis patients, 58% are HIV-infected.
Relevant changes
From 2012–2013, 1558 people were newly diagnosed with tuberculosis using sputum smears at intervention sites. Xpert® detected M. tuberculosis in an additional 1081 sputum smear-negative individuals, an increase of 69%. Rifampicin resistance was detected in 58/1081 (5%) of the samples. However, treatment was started in only 82% of patients diagnosed by microscopy and 67% of patients diagnosed with the rapid test. Twelve of 16 Xpert® modules failed calibration within 15 months of implementation.
Lessons learnt
Using rapid tests to diagnose tuberculosis is promising but logistically challenging. More affordable and durable platforms are needed. All patients diagnosed with tuberculosis need to start and complete treatment, including those who have drug resistant strains.
PMCID: PMC4339961  PMID: 25883406
4.  A pragmatic approach to measuring, monitoring and evaluating interventions for improved tuberculosis case detection 
International Health  2014;6(3):181-188.
The inability to detect all individuals with active tuberculosis has led to a growing interest in new approaches to improve case detection. Policy makers and program staff face important challenges measuring effectiveness of newly introduced interventions and reviewing feasibility of scaling-up successful approaches. While robust research will continue to be needed to document impact and influence policy, it may not always be feasible for all interventions and programmatic evidence is also critical to understand what can be expected in routine settings. The effects of interventions on early and improved tuberculosis detection can be documented through well-designed program evaluations. We present a pragmatic framework for evaluating and measuring the effect of improved case detection strategies using systematically collected intervention data in combination with routine tuberculosis notification data applying historical and contemporary controls. Standardized process evaluation and systematic documentation of program implementation design, cost and context will contribute to explaining observed levels of success and may help to identify conditions needed for success. Findings can then guide decisions on scale-up and replication in different target populations and settings.
PMCID: PMC4153747  PMID: 25100402
Active case finding; Case detection; Screening; Tuberculosis
5.  A Multi-Site Evaluation of Innovative Approaches to Increase Tuberculosis Case Notification: Summary Results 
PLoS ONE  2014;9(4):e94465.
Globally, TB notifications have stagnated since 2007, and sputum smear positive notifications have been declining despite policies to improve case detection. We evaluate results of 28 interventions focused on improving TB case detection.
We measured additional sputum smear positive cases treated, defined as the intervention area's increase in case notification during the project compared to the previous year. Projects were encouraged to select control areas and collect historical notification data. We used time series negative binomial regression for over-dispersed cross-sectional data accounting for fixed and random effects to test the individual projects' effects on TB notification while controlling for trend and control populations.
Twenty-eight projects, 19 with control populations, completed at least four quarters of case finding activities, covering a population of 89.2 million. Among all projects sputum smear positive (SS+) TB notifications increased 24.9% and annualized notification rates increased from 69.1 to 86.2/100,000 (p = 0.0209) during interventions. Among the 19 projects with control populations, SS+TB case notifications increased 36.9% increase while in the control populations a 3.6% decrease was observed. Fourteen (74%) of the 19 projects' SS+TB notification rates in intervention areas increased from the baseline to intervention period when controlling for historical trends and notifications in control areas.
Interventions were associated with large increases in TB notifications across many settings, using an array of interventions. Many people with TB are not reached using current approaches. Different methods and interventions tailored to local realities are urgently needed.
PMCID: PMC3983196  PMID: 24722399
6.  An Evaluation of Systematic Tuberculosis Screening at Private Facilities in Karachi, Pakistan 
PLoS ONE  2014;9(4):e93858.
In Pakistan, like many Asian countries, a large proportion of healthcare is provided through the private sector. We evaluated a systematic screening strategy to identify people with tuberculosis in private facilities in Karachi and assessed the approaches' ability to diagnose patients earlier in their disease progression.
Methods and Findings
Lay workers at 89 private clinics and a large hospital outpatient department screened all attendees for tuberculosis using a mobile phone-based questionnaire during one year. The number needed to screen to detect a case of tuberculosis was calculated. To evaluate early diagnosis, we tested for differences in cough duration and smear grading by screening facility. 529,447 people were screened, 1,010 smear-positive tuberculosis cases were detected and 942 (93.3%) started treatment, representing 58.7% of all smear-positive cases notified in the intervention area. The number needed to screen to detect a smear-positive case was 124 (prevalence 806/100,000) at the hospital and 763 (prevalence 131/100,000) at the clinics; however, ten times the number of individuals were screened in clinics. People with smear-positive TB detected at the hospital were less likely to report cough lasting 2–3 weeks (RR 0.66 95%CI [0.49–0.90]) and more likely to report cough duration >3 weeks (RR 1.10 95%CI [1.03–1.18]). Smear-positive cases at the clinics were less likely to have a +3 grade (RR 0.76 95%CI [0.63–0.92]) and more likely to have +1 smear grade (RR 1.24 95%CI [1.02–1.51]).
Tuberculosis screening at private facilities is acceptable and can yield large numbers of previously undiagnosed cases. Screening at general practitioner clinics may find cases earlier than at hospitals although more people must be screened to identify a case of tuberculosis. Limitations include lack of culture testing, therefore underestimating true TB prevalence. Using more sensitive and specific screening and diagnostic tests such as chest x-ray and Xpert MTB/RIF may improve results.
PMCID: PMC3976346  PMID: 24705600
7.  Results from early programmatic implementation of Xpert MTB/RIF testing in nine countries 
The Xpert MTB/RIF assay has garnered significant interest as a sensitive and rapid diagnostic tool to improve detection of sensitive and drug resistant tuberculosis. However, most existing literature has described the performance of MTB/RIF testing only in study conditions; little information is available on its use in routine case finding. TB REACH is a multi-country initiative focusing on innovative ways to improve case notification.
We selected a convenience sample of nine TB REACH projects for inclusion to cover a range of implementers, regions and approaches. Standard quarterly reports and machine data from the first 12 months of MTB/RIF implementation in each project were utilized to analyze patient yields, rifampicin resistance, and failed tests. Data was collected from September 2011 to March 2013. A questionnaire was implemented and semi-structured interviews with project staff were conducted to gather information on user experiences and challenges.
All projects used MTB/RIF testing for people with suspected TB, as opposed to testing for drug resistance among already diagnosed patients. The projects placed 65 machines (196 modules) in a variety of facilities and employed numerous case-finding strategies and testing algorithms. The projects consumed 47,973 MTB/RIF tests. Of valid tests, 7,195 (16.8%) were positive for MTB. A total of 982 rifampicin resistant results were found (13.6% of positive tests). Of all tests conducted, 10.6% failed. The need for continuous power supply was noted by all projects and most used locally procured solutions. There was considerable heterogeneity in how results were reported and recorded, reflecting the lack of standardized guidance in some countries.
The findings of this study begin to fill the gaps among guidelines, research findings, and real-world implementation of MTB/RIF testing. Testing with Xpert MTB/RIF detected a large number of people with TB that routine services failed to detect. The study demonstrates the versatility and impact of the technology, but also outlines various surmountable barriers to implementation. The study is not representative of all early implementer experiences with MTB/RIF testing but rather provides an overview of the shared issues as well as the many different approaches to programmatic MTB/RIF implementation.
PMCID: PMC3898850  PMID: 24383553
New diagnostics; Xpert MTB/RIF; Tuberculosis; Case detection; Innovation
8.  Population-Level Impact of Active Tuberculosis Case Finding in an Asian Megacity 
PLoS ONE  2013;8(10):e77517.
The potential population-level impact of private-sector initiatives for tuberculosis (TB) case finding in Southeast Asia remains uncertain. In 2011, the Indus Hospital TB Control Program in Karachi, Pakistan, undertook an aggressive case-finding campaign that doubled notification rates, providing an opportunity to investigate potential population-level effects.
We constructed an age-structured compartmental model of TB in the intervention area. We fit the model using field and literature data, assuming that TB incidence equaled the estimated nationwide incidence in Pakistan (primary analysis), or 1.5 times greater (high-incidence scenario). We modeled the intervention as an increase in the rate of formal-sector TB diagnosis and evaluated the potential impact of sustaining this rate for five years.
In the primary analysis, the five-year intervention averted 24% (95% uncertainty range, UR: 18-30%) of five-year cumulative TB cases and 52% (95% UR: 45-57%) of cumulative TB deaths. Corresponding reductions in the high-incidence scenario were 12% (95% UR: 8-17%) and 27% (95% UR: 21-34%), although the absolute number of lives saved was higher. At the end of five years, TB notification rates in the primary analysis were below their 2010 baseline, incidence had dropped by 45%, and annual mortality had fallen by 72%. About half of the cumulative impact on incidence and mortality could be achieved with a one-year intervention.
Sustained, multifaceted, and innovative approaches to TB case-finding in Asian megacities can have substantial community-wide epidemiological impact.
PMCID: PMC3797738  PMID: 24147015
9.  Screening for HIV among tuberculosis patients: a cross-sectional study in Sindh, Pakistan 
BMJ Open  2012;2(5):e001677.
To describe feasibility and results of systematic screening of tuberculosis (TB) patients for HIV.
Cross-sectional study.
Six selected sentinel sites (public DOTS clinics) in the province of Sindh, Pakistan.
All TB patients aged 16–60 years registered for treatment from April 2008 to March 2012.
Demographic information of registered TB patients, screening for HIV through rapid testing and confirmation by referral lab of Sindh AIDS Control Program, according to national guidelines.
Of a total of 18 461 registered TB patients, 12 882 fulfilled the inclusion criteria and were given education and counselling. Of those counselled 12 552 (97.4%) were screened for HIV using a rapid test. Men made up 48% of the sample and 76.5% of patients had pulmonary TB. Of the total patients tested, 42 (0.34%) were HIV-positive after confirmatory testing at the Sindh AIDS Control Program Laboratory. Prevalence of HIV among male patients was 0.67% whereas prevalence among female patients was 0.03% (p value <0.001). Prevalence of HIV among pulmonary TB patients was 0.29% and among extrapulmonary TB patients was 0.48% (p value=0.09).
In public DOTS clinics in Pakistan it is feasible to test TB patients for HIV. Prevalence of HIV is three times higher among TB patients as compared with the general population in Pakistan. Although the results are not representative of Pakistan or Sindh province they cover a large catchment area and closely match WHO estimate for the country. Routinely screening all TB patients for HIV infection, especially targeting men and ensuring antiretroviral therapy, can significantly improve TB/HIV collaborative activities in Pakistan and identify many cases of HIV, improve health outcomes and save lives.
PMCID: PMC3488723  PMID: 23087016
HIV screening; Concentrated epidemic

Results 1-9 (9)