Xpert MTB/RIF assay for diagnosis of pulmonary tuberculosis in children: a prospective, multi-centre evaluation.

BACKGROUND: Following endorsement by the World Health Organisation, the Xpert MTB/RIF assay has been widely incorporated into algorithms for the diagnosis of adult tuberculosis (TB). However, data on its performance in children remain scarce. This prospective, multi-centre study evaluated the performance of Xpert MTB/RIF to diagnose pulmonary tuberculosis in children. METHODS: Children older than eight weeks and younger than 16 years with suspected pulmonary tuberculosis were enrolled at three TB endemic settings in Tanzania and Uganda, and assigned to five well-defined case definition categories: culture-confirmed TB, highly probable TB, probable TB, not TB, or indeterminate. The diagnostic accuracy of Xpert MTB/RIF was assessed using culture-confirmed TB cases as reference standard. RESULTS: In total, 451 children were enrolled. 37 (8%) had culture-confirmed TB, 48 (11%) highly probably TB and 62 probable TB (13%). The Xpert MTB/RIF assay had a sensitivity of 68% (95% CI, 50%-82%) and specificity of 100% (95% CI, 97%-100%); detecting 1.7 times more culture-confirmed cases than smear microscopy with a similar time to detection. Xpert MTB/RIF was positive in 2% (1/48) of highly probable and in 3% (2/62) of probable TB cases. CONCLUSIONS: Xpert MTB/RIF provided timely results with moderate sensitivity and excellent specificity compared to culture. Low yields in children with highly probable and probable TB remain problematic.

Assessment of the novel T-cell activation marker-tuberculosis assay for diagnosis of active tuberculosis in children: a prospective proof-of-concept study.

BACKGROUND: The diagnosis of paediatric tuberculosis is complicated by non-specific symptoms, difficult specimen collection, and the paucibacillary nature of the disease. We assessed the accuracy of a novel immunodiagnostic T-cell activation marker-tuberculosis (TAM-TB) assay in a proof-of-concept study to identify children with active tuberculosis. METHODS: Children with symptoms that suggested tuberculosis were prospectively recruited at the NIMR-Mbeya Medical Research Center in Mbeya, and the Ifakara Health Institute in Bagamoyo, Tanzania, between May 10, 2011, and Sept 4, 2012. Sputum and peripheral blood mononuclear cells were obtained for Mycobacterium tuberculosis culture and performance assessment of the TAM-TB assay. The children were assigned to standardised clinical case classifications based on microbiological and clinical findings. FINDINGS: Among 290 children screened, we selected a subgroup of 130 to ensure testing of at least 20 with culture-confirmed tuberculosis. 17 of 130 children were excluded because of inconclusive TAM-TB assay results. The TAM-TB assay enabled detection of 15 of 18 culture-confirmed cases (sensitivity 83·3%, 95% CI 58·6-96·4). Specificity was 96·8% (95% CI 89·0-99·6) in the cases that were classified as not tuberculosis (n=63), with little effect from latent tuberculosis infection. The TAM-TB assay identified five additional patients with highly probable or probable tuberculosis, in whom M tuberculosis was not isolated. The median time to diagnosis was 19·5 days (IQR 14-45) for culture. INTERPRETATION: The sputum-independent TAM-TB assay is a rapid and accurate blood test that has the potential to improve the diagnosis of active tuberculosis in children. FUNDING: European and Developing Countries Clinical Trials Partnership, German Federal Ministry of Education and Research, and Swiss National Science Foundation.

Diagnostic accuracy of computer-aided detection of pulmonary tuberculosis in chest radiographs: a validation study from sub-Saharan Africa.

BACKGROUND: Chest radiography to diagnose and screen for pulmonary tuberculosis has limitations, especially due to inter-reader variability. Automating the interpretation has the potential to overcome this drawback and to deliver objective and reproducible results. The CAD4TB software is a computer-aided detection system that has shown promising preliminary findings. Evaluation studies in different settings are needed to assess diagnostic accuracy and practicability of use. METHODS: CAD4TB was evaluated on chest radiographs of patients with symptoms suggestive of pulmonary tuberculosis enrolled in two cohort studies in Tanzania. All patients were characterized by sputum smear microscopy and culture including subsequent antigen or molecular confirmation of Mycobacterium tuberculosis (M.tb) to determine the reference standard. Chest radiographs were read by the software and two human readers, one expert reader and one clinical officer. The sensitivity and specificity of CAD4TB was depicted using receiver operating characteristic (ROC) curves, the area under the curve calculated and the performance of the software compared to the results of human readers. RESULTS: Of 861 study participants, 194 (23%) were culture-positive for M.tb. The area under the ROC curve of CAD4TB for the detection of culture-positive pulmonary tuberculosis was 0.84 (95% CI 0.80-0.88). CAD4TB was significantly more accurate for the discrimination of smear-positive cases against non TB patients than for smear-negative cases (p-value<0.01). It differentiated better between TB cases and non TB patients among HIV-negative compared to HIV-positive individuals (p<0.01). CAD4TB significantly outperformed the clinical officer, but did not reach the accuracy of the expert reader (p = 0.02), for a tuberculosis specific reading threshold. CONCLUSION: CAD4TB accurately distinguished between the chest radiographs of culture-positive TB cases and controls. Further studies on cost-effectiveness, operational and ethical aspects should determine its place in diagnostic and screening algorithms.

Health workers' performance in the implementation of Patient Centred Tuberculosis Treatment (PCT) strategy under programmatic conditions in Tanzania: a cross sectional study.

BACKGROUND: Patient Centred Tuberculosis Treatment (PCT) is a promising treatment delivery strategy for Mycobacterium tuberculosis (TB). It aims to improve adherence to treatment by giving patients the choice of having drug intake supervised at the health facility by a medical professional or at home by a supporter of their choice. METHODS: A cross-sectional survey was undertaken in three districts of Tanzania during October 2007, one year after PCT was rolled out nationally. Semi-structured questionnaires were used to assess whether key elements of the PCT approach were being implemented, to evaluate supporters' knowledge, to capture opinions on factors contributing to treatment completion, and to assess how treatment completion was measured. Transcripts from open-ended responses were analysed using framework analysis. RESULTS: Interviews were conducted with 127 TB patients, 107 treatment supporters and 70 health workers. In total, 25.2% of TB patients were not given a choice about the place of treatment by health workers, and only 13.7% of those given a choice reported that they were given adequate time to make their decision. Only 24.3% of treatment supporters confirmed that they were instructed how to complete patients' treatment cards. Proper health education was the factor most frequently reported by health workers as favouring successful completion of TB treatment (45.7%). The majority of health workers (68.6%) said they checked returned blister packs to verify whether patients had taken their treatment, but only 20.0% checked patients' treatment cards. CONCLUSIONS: The provision of choice of treatment location, information on treatment, and guidance for treatment supporters need to be improved. There is a requirement for regular re-training of health workers with effective supportive supervision if successful implementation of the PCT approach is to be sustained.

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 (X(2)= 87.014, P(2)= 14.945, P(2)= 85.028, P(3). Efforts must be undertaken for more HIV testing and timely referral of HIV-infected patients to CTC.

Adherence to tuberculosis therapy among patients receiving home-based directly observed treatment: evidence from the United Republic of Tanzania.

BACKGROUND: Non-adherence to tuberculosis (TB) treatment is the leading contributor to the selection of drug-resistant strains of Mycobacterium tuberculosis and subsequent treatment failure. Tanzania introduced a TB Patient Centred Treatment (PCT) approach which gives new TB patients the choice between home-based treatment supervised by a treatment supporter of their own choice, and health facility-based treatment observed by a medical professional. The aim of this study was to assess the extent and determinants of adherence to anti-TB therapy in patients opting for home-based treatment under the novel PCT approach. METHODS: In this cross-sectional study, the primary outcome was the percentage of patients adherent to TB therapy as detected by the presence of isoniazid in urine (IsoScreen assay). The primary analysis followed a non-inferiority approach in which adherence could not be lower than 75%. Logistic regression was used to examine the influence of potentially predictive factors. RESULTS: A total of 651 new TB patients were included. Of these, 645 (99.1%) provided urine for testing and 617 patients (95.7%; 90%CI 94.3-96.9) showed a positive result. This result was statistically non-inferior to the postulated adherence level of 75% (p<0.001). CONCLUSIONS: Adherence to TB therapy under home-based Directly Observed Treatment can be ensured in programmatic settings. A reliable supply of medication and the careful selection of treatment supporters, who preferably live very close to the patient, are crucial success factors. Finally, we recommend a cohort study to assess the rate of adherence throughout the full course of TB treatment.

APOPO's tuberculosis research agenda: achievements, challenges and prospects.

This article describes Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO) recent use of specially trained African giant pouched rats as detectors of pulmonary tuberculosis in people living in Tanzania. It summarizes the achievements and challenges encountered over the years and outlines future prospects. Since 2008, second-line screening by the rats has identified more than 2000 tuberculosis-positive patients who were missed by microscopy at Direct Observation of Treatment--Short Course centres in Tanzania. Moreover, data that are reviewed herein have been collected with respect to the rats' sensitivity and specificity in detecting tuberculosis. Findings strongly suggest that scent-detecting rats offer a quick and practical tool for detecting pulmonary tuberculosis and within the year APOPO's tuberculosis-detection project will be extended to Mozambique. As part of its local capacity building effort, APOPO hires and trains Tanzanians to play many important roles in its TB detection project and provides research and training opportunities for Tanzanian students.

APOPO's Tuberculosis Research Agenda: Achievements; Challenges and Prospects

Abstract:This article describes Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO) recent use of specially trained African giant pouched rats as detectors of pulmonary tuberculosis in people living in Tanzania. It summarizes the achievements and challenges encountered over the years and outlines future prospects. Since 2008; second-line screening by the rats has identified more than 2000 tuberculosis-positive patients who were missed by microscopy at Direct Observation of Treatment - Short Course centres in Tanzania. Moreover; data that are reviewed herein have been collected with respect to the rats' sensitivity and specificity in detecting tuberculosis. Findings strongly suggest that scent-detecting rats offer a quick and practical tool for detecting pulmonary tuberculosis and within the year APOPO's tuberculosis-detection project will be extended to Mozambique. As part of its local capacity building effort; APOPO hires and trains Tanzanians to play many important roles in its TB detection project and provides research and training opportunities for Tanzanian students

Patient-centred tuberculosis treatment delivery under programmatic conditions in Tanzania: a cohort study.

BACKGROUND: Directly observed therapy (DOT) remains the cornerstone of the global tuberculosis (TB) control strategy. Tanzania, one of the 22 high-burden countries regarding TB, changed the first-line treatment regimen to contain rifampicin-containing fixed-dose combination for the full 6 months of treatment. As daily health facility-based DOT for this long period is not feasible for the patient, nor for the health system, Tanzania introduced patient centred treatment (PCT). PCT allows patients to choose for daily DOT at a health facility or at their home by a supporter of choice. The introduction of fixed dose combinations in the intensive and continuation phase made PCT feasible by eliminating the risk of selective drug taking by patients and reducing the number of tablets to be taken. The approach was tested in three districts with the objective to assess the effect of this strategy on TB treatment outcomes METHODS: Cohort analysis comparing patients treated under the PCT strategy (registered April-September 2006) with patients treated under health-facility-based DOT (registered April-September 2005). The primary outcome was the cure rate. Differences were assessed by calculating the risk ratios. Associations between characteristics of the supporters and treatment outcomes in the group of patients opting for home-based DOT were assessed through logistic regression. RESULTS: In the PCT cohort there were 1208 patients and 1417 were included in the historic cohort. There was no significant difference in cure rates between the cohorts (risk ratio [RR]: 1.06; 95% confidence interval [CI]: 0.96-1.16). In the PCT cohort, significantly more patients had successful treatment (cure or treatment completed; RR: 1.10; 95%CI: 1.01-1.15). There were no characteristics of supporters that were associated with treatment outcome. CONCLUSION: The PCT approach showed similar cure rates and better treatment success rates compared to daily health-facility DOT. The results indicate that there are no specific prerequisites for the supporter chosen by the patient. The programmatic setting of the study lends strong support for scaling-up of TB treatment observation outside the health facility.

Implementation of a national anti-tuberculosis drug resistance survey in Tanzania.

BACKGROUND: A drug resistance survey is an essential public health management tool for evaluating and improving the performance of National Tuberculosis control programmes. The current manuscript describes the implementation of the first national drug resistance survey in Tanzania. METHODS: Description of the implementation process of a national anti-tuberculosis drug resistance survey in Tanzania, in relation to the study protocol and Standard Operating Procedures. RESULTS: Factors contributing positively to the implementation of the survey were a continuous commitment of the key stakeholders, the existence of a well organized National Tuberculosis Programme, and a detailed design of cluster-specific arrangements for rapid sputum transportation. Factors contributing negatively to the implementation were a long delay between training and actual survey activities, limited monitoring of activities, and an unclear design of the data capture forms leading to difficulties in form-filling. CONCLUSION: Careful preparation of the survey, timing of planned activities, a strong emphasis on data capture tools and data management, and timely supervision are essential for a proper implementation of a national drug resistance survey.

Assessment of patient preference in allocation and observation of anti-tuberculosis medication in three districts in Tanzania.

BACKGROUND: The new tuberculosis (TB) treatment in Tanzania contains rifampicin for six months. Direct observation of drug intake at the health facility for this period is not feasible. METHODS: Patients and health staff in three districts were interviewed to assess the burden of the current treatment strategy, and opinions on a proposed new strategy where patients are able to choose the place of treatment and the treatment supervisor, and receive treatment as a daily combination tablet. RESULTS: The study included 343 patients in 42 facilities. Daily collection of drugs was perceived as burdensome irrespective of distance needed to travel. Eighty percent of patients viewed medication taken at home or at a closer health facility as an improvement in TB-services. The proposed new treatment strategy was rated favorably by 85% of patients and 75% of health staff. Fifty-three percent of patients would opt for home-based treatment, and 75% would choose a family member or the spouse as treatment supporter. CONCLUSION: Home-based supervision of TB treatment with fewer drugs is an expressed preference of TB patients in Tanzania. Such a strategy is now being assessed in a pilot study. If effective and feasible, the strategy will contribute to an improved TB control strategy.

Low specificity of HIV-testing on sputum specimens kept at ambient temperatures for 4 to 7 days: a blinded comparison.

BACKGROUND: HIV testing on sputum using the QraQuick HIV1/2(R) assay has high sensitivity and specificity, and holds promise for application in tuberculosis surveys. Its performance under conditions that may occur during surveys in resource-poor countries is however, unknown. We assessed, in a blinded comparison with HIV serum testing, the sensitivity and specificity of the OraQuick(R) assay for detecting HIV antibody in sputum specimens kept at ambient temperature for up to 7 days, with and without decontaminant. METHODS: Paired sputum and blood specimens from consecutively diagnosed smear-positive tuberculosis patients were tested with OraQuick(R) and 2 HIV-1/2 ELISA's. Sputum was tested within 24 hours of collection, split into 2 aliquots with and without addition of cetylpyridium chloride, and tested again after 4 and 7 days. RESULTS: Complete data was available for 377/435 (87%) enrolled patients; 132 (35%) tested HIV positive on serum. The sensitivity of the sputum test was 94.7% (95% CI 89.4-97.8) on day 1, 93.2% on day 4 and 92.9% on day 7. The specificity was 92.9% (95% CI 88.9-95.8) on day 1, and declined to 76.7% on day 4 (p < 0.001) and to 62.7% on day 7 (p < 0.001). Adding cetylpyridium chloride further decreased the specificity to 67.8% on day 4 (p = 0.04) and to 49.6% on day 7 (p = 0.004). CONCLUSION: Transportation of sputum specimens at ambient temperatures for 4 days or more, and addition of decontaminant, strongly affect the specificity of the OraQuick(R) assay. Unless applied within one day, this assay is not suitable for estimation of HIV-prevalence among tuberculosis patients in survey settings.

Evaluation of efficacy of community-based vs. institutional-based direct observed short-course treatment for the control of tuberculosis in Kilombero district, Tanzania.

Tuberculosis (TB) has reappeared as a serious public health problem. Non-compliance to antituber-culous drug treatment is cited as one of the major obstacles to the containment of the epidemic. Compliance may be optimized by Directly Observed Treatment (DOT) and short-course treatment regimens. Since 1986, Tanzanian TB patients have received daily DOT at health facilities for the first 2 months of the treatment course. However, adherence and cure rates have been falling as the number of TB cases continues to increase and the burden on already stretched health facilities threatens to become unmanageable. We used an open cluster randomized controlled trial to compare community-based DOT (CBDOT) using a short-course drug regimen with institutional-based DOT (IBDOT). A total of 522 (301 IBDOT and 221 CBDOT) patients with sputum-positive TB were recruited. Overall, there was no significant difference in conversion and cure rates between the two strategies [M-H pooled odds ratio (OR) 0.62; 95% confidence interval (CI) 0.23, 1.71 and OR = 1.58; 95% CI 0.32, 7.88, respectively] suggesting that CBDOT may be a viable alternative to IBDOT. CBDOT may be particularly useful in parts of the country where people live far from health facilities.