Whole-Genome Sequencing for Resistance Prediction and Transmission Analysis of Mycobacterium tuberculosis Complex Strains from Namibia.

Namibia is among 30 countries with a high burden of tuberculosis (TB), with an estimated incidence of 460 per 100,000 population and around 800 new multidrug-resistant (MDR) TB cases per year. Still, data on the transmission and evolution of drug-resistant Mycobacterium tuberculosis complex (Mtbc) strains are not available. Whole-genome sequencing data of 136 rifampicin-resistant (RIFr) Mtbc strains obtained from 2016 to 2018 were used for phylogenetic classification, resistance prediction, and cluster analysis and linked with phenotypic drug susceptibility testing (pDST) data. Roughly 50% of the strains investigated were resistant to all first-line drugs. Furthermore, 13% of the MDR Mtbc strains were already pre-extensively drug resistant (pre-XDR). The cluster rates were high, at 74.6% among MDR and 85% among pre-XDR strains. A significant proportion of strains had borderline resistance-conferring mutations, e.g., inhA promoter mutations or rpoB L430P. Accordingly, 25% of the RIFr strains tested susceptible by pDST. Finally, we determined a potentially new bedaquiline resistance mutation (Rv0678 D88G) occurring in two independent clusters. High rates of resistance to first-line drugs in line with emerging pre-XDR and likely bedaquiline resistance linked with the ongoing recent transmission of MDR Mtbc clones underline the urgent need for the implementation of interventions that allow rapid diagnostics to break MDR TB transmission chains in the country. A borderline RIFr mutation in the dominant outbreak strain causing discrepancies between phenotypic and genotypic resistance testing results may require breakpoint adjustments but also may allow individualized regimens with high-dose treatment. IMPORTANCE The transmission of drug-resistant tuberculosis (TB) is a major problem for global TB control. Using genome sequencing, we showed that 13% of the multidrug-resistant (MDR) M. tuberculosis complex strains from Namibia are already pre-extensively drug resistant (pre-XDR), which is substantial in an African setting. Our data also indicate that the ongoing transmission of MDR and pre-XDR strains contributes significantly to the problem. In contrast to other settings with higher rates of drug resistance, we found a high proportion of strains having so-called borderline low-level resistance mutations, e.g., inhA promoter mutations or rpoB L430P. This led to the misclassification of 25% of the rifampicin-resistant strains as susceptible by phenotypic drug susceptibility testing. This observation potentially allows individualized regimens with high-dose treatment as a potential option for patients with few treatment options. We also found a potentially new bedaquiline resistance mutation in rv0678.

Smoking and HIV associated with subclinical tuberculosis: analysis of a population-based prevalence survey.

BACKGROUND: Despite multiple tuberculosis (TB) prevalence surveys reporting a relatively high frequency of bacteriologically confirmed, active TB among individuals reporting no typical symptoms of disease, our understanding of this phenomenon is limited.OBJECTIVE: To quantify the epidemiological burden and estimate associations between individual-level variables and this "subclinical" presentation.METHODS: We performed a secondary analysis of TB prevalence survey data from the South African communities of the Zambia, South Africa Tuberculosis and AIDS Reduction trial. Generalized estimating equations were used to estimate the association between individual-level demographic, behavioral, socio-economic, and medical variables and the risk of bacteriologically positive TB among participants not reporting any symptoms consistent with active TB.RESULTS: The crude prevalence of TB was 2222.1 cases per 100 000 population (95% CI 2053.4-2388.5); 44.7% (295/660) of all documented prevalent cases of TB were subclinical. Current tobacco smoking (OR 2.37, 95% CI 1.41-3.99) and HIV-positive status (OR 3.26, 95% CI 2.31-4.61) were significantly associated with subclinical TB.CONCLUSION: Individuals who smoke or have HIV may be at increased risk of active TB and not report typical symptoms consistent with disease. This suggests possible shortcomings of symptom-based case finding which may need to be addressed in similar settings.

Estimating the magnitude of pulmonary tuberculosis patients missed by primary health care clinics in South Africa.

SETTING: The present study was conducted at 20 randomly selected primary health clinics across Buffalo City Metropolitan Health District, a high TB burden district in South Africa. OBJECTIVE: To estimate the proportion of TB patients missed by primary health clinics. DESIGN: We enrolled 1255 TB-symptomatic individuals exiting primary health clinics between March and December 2015. Participants were interviewed and asked to provide sputum for Xpert® MTB/RIF testing. RESULTS: Clinic staff screened 79.1% of participants seeking care for TB-related symptoms and 21.9% of those attending a clinic for other reasons (P < 0.001). Of those screened by clinic staff, 21.5% reported submitting sputum, although only 9.8% had available results. Study staff tested sputum from 779 participants not tested by clinic staff. Of these, 39 (5.0%) individuals tested positive for TB, three of whom were rifampicin-resistant; 15/39 (38.5%) were never screened and 24/39 (61.5%) were screened but not tested by clinic staff. We estimate that the health system missed 62.9-78.5% of TB patients attending primary health clinics for TB-related symptoms and 89.5-100% of those attending a clinic for other reasons. CONCLUSION: Low rates of TB screening and testing by the health system resulted in missed TB patients. Universal TB screening and testing of symptomatic individuals should be instituted in high TB burden communities in South Africa.

Secondary analysis of tuberculosis stigma data from a cluster randomised trial in Zambia and South Africa (ZAMSTAR).

SETTING: Zambian and South African TB and HIV Reduction (ZAMSTAR) cluster-randomised trial (CRT) communities, 2006-2009. OBJECTIVES: To develop TB stigma items, and evaluate changes in them in response to a household intervention aimed at reducing TB transmission and prevalence but not tailored to reduce stigma. DESIGN: TB stigma was measured at baseline and 18 months later among 1826 recently diagnosed TB patients and 1235 adult members of their households across 24 communities; 12 of 24 communities were randomised to receive the household intervention. We estimated the impact of the household intervention on TB stigma using standard CRT analytical methods. RESULTS: Among household members, prevalence of blame and belief in transmission myths fell in both study arms over time: adjusted prevalence ratios (aPRs) comparing the household intervention with the non-household intervention arm were respectively 0.61 (95%CI 0.26-1.44) and 0.77 (95%CI 0.48-1.25) at 18-month follow-up. Among TB patients, at baseline a low percentage experienced social exclusion and poor treatment by health staff and a relatively high percentage reported 'being made fun of', with little change over time. Disclosure of TB status increased over time in both study arms. Internalised stigma was less prevalent in the household arm at both baseline and follow-up, with an aPR of 0.85 (95%CI 0.41-1.76). Variability in stigma levels between countries and across communities was large. CONCLUSION: Robust TB stigma items were developed. TB stigma was not significantly reduced by the household intervention, although confidence intervals for estimated intervention effects were wide. We suggest that stigma-specific interventions are required to effectively address TB stigma.

Symptom screening rules to identify active pulmonary tuberculosis: Findings from the Zambian South African Tuberculosis and HIV/AIDS Reduction (ZAMSTAR) trial prevalence surveys.

BACKGROUND: High tuberculosis (TB) burden countries should consider systematic screening among adults in the general population. We identified symptom screening rules to be used in addition to cough ≥2 weeks, in a context where X-ray screening is not feasible, aiming to increase the sensitivity of screening while achieving a specificity of ≥85%. METHODS: We used 2010 Zambia South Africa Tuberculosis and HIV/AIDS Reduction (ZAMSTAR) survey data: a South African (SA) training dataset, a SA testing dataset for internal validation and a Zambian dataset for external validation. Regression analyses investigated relationships between symptoms or combinations of symptoms and active disease. Sensitivity and specificity were calculated for candidate rules. RESULTS: Among all participants, the sensitivity of using only cough ≥2 weeks as a screening rule was less than 25% in both SA and Zambia. The addition of any three of six TB symptoms (cough <2 weeks, night sweats, weight loss, fever, chest pain, shortness of breath), or 2 or more of cough <2 weeks, night sweats, and weight loss, increased the sensitivity to ~38%, while reducing specificity from ~95% to ~85% in SA and ~97% to ~92% in Zambia. Among HIV-negative adults, findings were similar in SA, whereas in Zambia the increase in sensitivity was relatively small (15% to 22%). CONCLUSION: High TB burden countries should investigate cost-effective strategies for systematic screening: one such strategy could be to use our rule in addition to cough ≥2 weeks.

A systematic review of prediction models for prevalent pulmonary tuberculosis in adults.

A systematic review was conducted to describe the quality and characteristics of prediction models for prevalent pulmonary tuberculosis (PTB) in adults at routine TB care settings. A prediction model was defined as the combination of two or more clinical predictors designed to estimate the probability of having TB. Studies using culture-confirmed PTB as reference standard were included. Models for in-patients, children or specific patient populations were excluded. PubMed, Scopus and the Cochrane Library and abstracts from the International Union Against Tuberculosis and Lung Disease, American Thoracic Society and European Respiratory Society conferences were searched. The CHARMS (Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies) checklist was used for data extraction and quality assessment. From 13 671 identified records, six were included for data extraction; three assessed smear-negative, culture-positive PTB as outcome and three focused on human immunodeficiency virus infected individuals only. Reporting of model development, performance and evaluation was poor. In four studies, predictive performance was evaluated using the development data set (apparent performance), one study did an internal validation and one study did an external validation. Results were not pooled due to heterogeneity. Existing prediction models for estimating prevalent PTB in adults at primary care level are poorly reported and validated and are not useful for TB screening. The World Health Organization symptom screen is recommended.

Tuberculosis cure rates and the ETR.Net: investigating the quality of reporting treatment outcomes from primary healthcare facilities in Mpumalanga province, South Africa.

BACKGROUND: Tuberculosis control programs rely on accurate collection of routine surveillance data to inform program decisions including resource allocation and specific interventions. The electronic TB register (ETR.Net) is dependent on accurate data transcription from both paperbased clinical records and registers at the facilities to report treatment outcome data. The study describes the quality of reporting of TB treatment outcomes from facilities in the Ehlanzeni District, Mpumalanga Province. METHODS: A descriptive crossectional study of primary healthcare facilities in the district for the period 1 January - 31 December 2010 was performed. New smear positive TB cure rate data was obtained from the ETR.Net followed by verification of paperbased clinical records, both TB folders and the TB register, of 20% of all new smear positive cases across the district for correct reporting to the ETR.Net. Facilities were grouped according to high (>70%) and low cure rates (≤ 70%) as well as high (> 20%) and low (≤ 20%) error proportions in reporting. Kappa statistic was used to determine agreement between paperbased record, TB register and ETR.Net. RESULTS: Of the100 facilities (951 patient clinical records), 51(51%) had high cure rates and high error proportions, 14(14%) had a high cure rate and low error proportion whereas 30(30%) had low cure rates and high error proportions and five (5%) had a low cure rate with low error proportion. Fair agreement was observed (Kappa = 0.33) overall and between registers. Of the 473 patient clinical records which indicated cured, 383(81%) was correctly captured onto the ETR.Net, whereas 51(10.8%) was incorrectly captured and 39(8.2%) was not captured at all. Over reporting of treatment success of 12% occurred on the ETR.Net. CONCLUSIONS: The high error proportion in reporting onto the ETR.Net could result in a false sense of improvement in the TB control programme in the Ehlanzeni district.

Scanty smears associated with initial loss to follow-up in South African tuberculosis patients.

BACKGROUND: Smear-positive patients should be started on anti-tuberculosis treatment promptly. However, studies show that up to 38% of diagnosed patients are initial loss to follow-up (LTFU), meaning they do not start treatment after diagnosis. We investigated determinants of initial LTFU at primary health care facilities. DESIGN: In a facility-matched case-control study, health care facilities were visited from October 2010 to September 2012. After identification from registers, patients were traced and invited to complete a questionnaire. RESULTS: Of 973 participants, 233 (24%) were cases and 740 (74%) controls. Initial LTFU was associated with smear grade (pooled adjusted odds ratio [aOR] 0.73, 95% confidence interval [CI] 0.64-0.90, scanty at baseline) for participants identified at facilities, but not with age (overall P = 0.80) or sex (aOR 0.83, 95%CI 0.58-1.20). Of the 233 cases, 197 (85%) were traced in the community, of whom 58 (29%) were found. Among the group found, initial LTFU was associated with age (aOR 3.38, 95%CI 1.15-9.95) and smear grade (aOR 0.08, 95%CI 0.02-0.34, scanty at baseline). CONCLUSION: Scanty smear positivity was associated with initial LTFU. Tuberculosis programmes should start scanty smear-positive patients on treatment early and develop alternative community tracing strategies. Health care worker training could address the first aspect, and the use of technology to improve treatment initiation, such as mobile phone applications, the second.

Health care workers' gender bias in testing could contribute to missed tuberculosis among women in South Africa.

SETTING: Eight communities with high tuberculosis (TB) prevalence, Western Cape, South Africa. OBJECTIVE: To identify sex differences in TB health-seeking behaviour and diagnosis in primary health care facilities and how this influences TB diagnosis. DESIGN: We used data from a prevalence survey among 30,017 adults conducted in 2010 as part of the Zambia, South Africa Tuberculosis and AIDS Reduction (ZAMSTAR) trial. RESULTS: A total of 1670 (5.4%) adults indicated they had a cough of ⩾2 weeks, 950 (56.9%) of whom were women. Women were less likely to report a cough of ⩾2 weeks (5.1% vs. 6.4%, P < 0.001), but were more likely to seek care for their cough (32.6% vs. 26.9%, P = 0.012). Of all adults who sought care, 403 (80.0%) sought care for their cough at a primary health care (PHC) facility (79.0% women vs. 81.4% men, P = 0.511). Women were less likely to be asked for a sputum sample at the PHC facility (63.3% vs. 77.2%, P = 0.003) and less likely to have a positive sputum result (12.6% vs. 20.7%, P = 0.023). CONCLUSION: The attainment of sex equity in the provision of TB health services requires adherence to testing protocols. Everyone, irrespective of sex, who seeks care for a cough of ⩾2 weeks should be tested.

Why test for tuberculosis? A qualitative study from South Africa.

Setting: Early testing and treatment initiation are crucial for controlling the tuberculosis (TB) epidemic, especially in high-burden countries such as South Africa. Objective: To explore reasons why patients opted to test for TB and the context in which they were tested. Design: This qualitative study was nested in a larger study evaluating patients who did not initiate anti-tuberculosis treatment after diagnosis. In-depth interviews were conducted with 41 patients across five provinces of South Africa. Results: While most patients presented for testing because of their symptoms, unfortunately many waited until their symptoms were severe and thus remained infectious for longer. Outreach campaigns and TB screening at primary health care facilities were perceived favourably, although some respondents were unclear as to the nature of the tests being performed and had concerns about the implications. Positive health care worker attitudes towards presumptive TB patients contributed towards prompt testing and treatment initiation. Conclusion: As patients often delayed presenting for testing, strategies to engage early with presumptive TB patients so that testing and treatment can commence without delay should be a priority for TB programmes.

Contexte : La précocité des tests à la recherche de tuberculose (TB) et de l'initiation du traitement est cruciale dans la lutte contre l'épidémie, surtout dans les pays durement touchés comme l'Afrique du Sud.Objectif : Explorer les raisons pour lesquelles les patients ont décidé de faire un test de TB et le contexte dans lequel ce test a été réalisé.Schéma : Cette étude qualitative a été réalisée au sein d'une étude plus vaste évaluant les patients qui n'ont pas débuté leur traitement de TB après le diagnostic. Des entretiens approfondis ont été réalisés avec 41 patients dans cinq provinces d'Afrique du Sud.Résultats : Les patients se sont présentés pour un test en raison de leurs symptômes, mais malheureusement beaucoup ont attendu que leurs symptômes soient graves et ils sont donc restés contagieux plus longtemps. Les campagnes de stratégies avancées et le dépistage de TB dans des structures de soins de santé primaires ont été perçus favorablement, même si certains répondants n'étaient pas sûrs de la nature des tests à faire et étaient préoccupés par leurs implications. Une attitude positive des prestataires de soins vis-à-vis de patients présumés tuberculeux a contribué à la rapidité du dépistage et de la mise en route du traitement.Conclusion : Les patients ont souvent retardé le moment de réaliser un test ; c'est pourquoi des stratégies visant à intervenir auprès de patients présumés atteints de TB précocement de façon que le test et le traitement soient réalisés sans délai devraient être une priorité pour les programmes TB.

Marco de referencia: La práctica de las pruebas diagnósticas de la tuberculosis (TB) y el comienzo del tratamiento en forma oportuna son fundamentales en el control de la epidemia, sobre todo en los países con una alta carga de morbilidad como Suráfrica.Objetivo: Examinar las razones por las cuales los pacientes acuden en busca de pruebas diagnósticas de la TB y el contexto en el cual se practican estas pruebas.Método: Un estudio cualitativo anidado en un estudio más amplio, en el cual se evaluaron los pacientes que no iniciaron el tratamiento tras recibir el diagnóstico de TB. Se practicaron entrevistas exhaustivas a 41 pacientes en cinco provincias de Suráfrica.Resultados: Los pacientes acudieron en busca de pruebas diagnósticas debido a los síntomas que presentaban, pero desafortunadamente muchos esperaron hasta que las manifestaciones eran más graves y permanecieron contagiosos durante un período más prolongado. Las campañas de sensibilización y detección de la TB en los centros de atención primaria de salud se percibían de manera favorable, aunque algunos de los participantes no comprendían claramente el tipo de exámenes que se practicaban y se preocupaban por sus consecuencias. Las actitudes positivas de los profesionales de salud frente a los pacientes con presunción clínica de TB favorecieron una práctica temprana de las pruebas y una pronta iniciación del tratamiento.Conclusión: Con frecuencia los pacientes retrasan el momento de acudir en busca de pruebas diagnósticas; por esta razón en los programas contra la TB debe ser prioritaria la introducción de estrategias que fomenten un contacto temprano con los pacientes que pueden padecer TB, a fin de practicar sin demora las pruebas diagnósticas e iniciar oportunamente el tratamiento.

Antiretroviral treatment among co-infected tuberculosis patients in integrated and non-integrated facilities.

BACKGROUND: South Africa has the second worst tuberculosis-human immunodeficiency virus (TB-HIV) syndemic in the world: in 2011, the TB-HIV co-infection rate was estimated at 65%. Integration of TB and HIV health-care services was implemented to increase antiretroviral treatment (ART) uptake among eligible patients. AIM: To evaluate whether integrated TB and HIV facilities had better ART uptake among eligible patients compared to non-integrated facilities. METHODS: A cross-sectional study using routine TB programme data from January to December 2010. ART eligibility was defined as a CD4+ cell count <350 cells/µl. RESULTS: Respectively 2761 (86.8%) and 3611 (84.7%) patients were eligible for ART at integrated and non-integrated facilities (P < 0.001). The proportion of patients started on ART at integrated facilities did not differ significantly from that of non-integrated facilities (35.9% vs. 37.1%, P = 0.340), but the proportion with unknown HIV status (31.8% vs. 24.5%, P < 0.001) and unknown CD4+ cell count (40.9% vs. 30.4%, P < 0.001) did. CONCLUSION: Integration of TB and HIV services in the Free State (2009-2010) was not associated with improved ART uptake. The reasons why are not clear. Of concern are the high proportions of unknown HIV status and CD4+ cell count results, especially at integrated facilities, and the small proportion of patients on ART, which may indicate poor implementation of integration.

Contexte : L'Afrique du Sud est au deuxième rang dans le monde de la « syndémie ¼ tuberculose/virus d'immunodéficience humaine (TB-VIH) : en 2011, le taux de coïnfection TB-VIH a été estimé à 65%. L'intégration des services de soins de la TB et du VIH a été mise en œuvre pour augmenter la mise sous traitement antirétroviral (ART) chez les patients éligibles.Objectif : Evaluer si les structures intégrant TB et VIH comparées aux structures non-intégrées ont un meilleur taux de prise d'ART parmi les patients éligibles.Méthodes : Etude transversale utilisant les données de routine des programmes TB de janvier à décembre 2010. L'éligibilité à l'ART a été définie comme un comptage de CD4+ <350 cellules/µl.Résultats : Respectivement 2761 (86,8%) et 3611 (84,7%) patients ont été éligibles pour l'ART dans les structures intégrées et non-intégrées (P < 0,001). La proportion de patients mis sous ART dans des structures intégrées comparées aux structures non-intégrées n'a pas été significativement différente (35,9% contre 37,1%; P = 0,340); par contre, la différence a été significative pour les patients de statut VIH inconnu (31,8% contre 24,5%; P < 0,001) et de comptage de CD4+ inconnu (40,9% contre 30,4%; P < 0,001).Conclusion : L'intégration des services de TB et VIH dans le Free State (2009­2010) n'a pas été associée à une amélioration de la prise de l'ART. Les raisons n'en sont pas très claires. Par contre, il est préoccupant de constater la proportion élevée de statut VIH inconnu et d'absence de résultats de comptage des CD4+, surtout dans les structures intégrées, et la faible proportion de patients sous ART, qui témoigne d'une mise en œuvre médiocre de l'intégration.

Marco de referencia: Suráfrica ocupa el segundo puesto de los países con la más alta sindemia de tuberculosis (TB) e infección por el virus de la inmunodeficiencia humana (VIH) en todo el mundo. Se estimó que en el 2011 la tasa de coinfección por el VIH y la TB fue 65%. Se integraron los servicios de atención de la TB y el VIH con el propósito de fomentar la aceptación del tratamiento antirretrovírico (ART) por parte de los pacientes que reúnen las condiciones para recibirlo.Objetivo: Comparar la utilización del ART en los centros integrados de atención de la TB y VIH y en centros no integrados.Método: Se llevó a cabo un estudio transversal de los datos sistemáticos del programa contra la TB de enero a diciembre del 2010. El criterio de inclusión al ART fue un recuento de linfocitos CD4+ <350 células/µl.Resultados: En los centros de atención integrada se encontraron 2761 pacientes aptos al ART (86,8%) y 3611 en los centros no integrados (84,7%) (P < 0,001). La diferencia en la proporción de pacientes que comenzó el tratamiento no fue estadísticamente significativa (35,9% contra 37,1%; P = 0,340); se observó una diferencia significativa en el porcentaje de pacientes que desconocía su situación frente al VIH (31,8% en los centros integrados contra 24,5% en los demás centros; P < 0,001) y en la proporción de pacientes VIH cuyos resultados del recuento de linfocitos CD4+ se desconocía (40,9% contra 30,4%; P < 0,001).Conclusión: La integración de los servicios de atención de la TB y la VIH en la Provincia del Estado Libre de Suráfrica (del 2009 al 2010) no se asoció con una mayor utilización del ART y las razones de este resultado no son claras. Son fuente de inquietud la alta proporción de pacientes que desconocen su situación frente al VIH y la falta de resultados del recuento de linfocitos CD4+, sobre todo en los centros de atención integrada y la baja proporción de pacientes que recibe ART; esta situación puede obedecer a una deficiencia en la integración de los servicios.

Are we justified in treating for multidrug-resistant tuberculosis based on positive follow-up smear results?

SETTING: National Institute for Research in Tuberculosis, India. OBJECTIVE: To assess, among new culture-confirmed smear-positive pulmonary tuberculosis (TB) patients, the proportion of follow-up smear-positives that were culture-negative (S+C-) by month of follow-up examination, human immunodeficiency virus (HIV) status, pre-treatment drug susceptibility status and smear grading. DESIGN: We extracted follow-up smear (fluorescence microscopy) and culture (Löwenstein-Jensen) results of patients enrolled in clinical trials from January 2000 to August 2012 and treated with the WHO Category I regimen (2EHRZ3/4HR3). RESULTS: Of 520 patients, including 176 who were HIV-infected, respectively 199, 81, 47 and 43 were smear-positive at months 2, 4, 5 and 6; of these, respectively 138 (69%), 62 (75%), 32 (68%) and 27 (63%) were culture-negative. The S+C- phenomenon was more pronounced among '1+ positive' patients than in 2+ or 3+ positive patients and in 'pan-susceptible' patients than in those with any resistance, and did not vary by HIV status. CONCLUSION: Nearly two thirds of patients with follow-up smears positive at months 5 and 6 were culture-negative. Starting multidrug-resistant TB (MDR-TB) treatment empirically based on smear results, even in resource-limited settings, is incorrect and can have hazardous consequences. There is an urgent need to revisit the WHO recommendation concerning empirical MDR-TB treatment.

Symptom reporting among prevalent tuberculosis cases who smoke, are HIV-positive or have hyperglycaemia.

Data from a tuberculosis (TB) prevalence survey conducted in 24 communities in Zambia and the Western Cape, South Africa, January-December 2010, were analysed to determine the influence of smoking, hyperglycaemia and human immunodeficiency virus (HIV) infection on TB symptom reporting in culture-confirmed TB cases. Of 123 790 adults eligible for enrolment, 90 601 (73%) consented and 64 463 had evaluable sputum samples. ORs and 95%CIs were calculated using a robust standard errors logistic regression model adjusting for clustering at community level. HIV-positive TB cases were more likely to report cough, weight loss, night sweats and chest pain than non-HIV-positive TB cases. TB cases who smoked or had hyperglycaemia did not report symptoms differently from cases without these comorbidities.

Des données émanant d';une enquête de prévalence de la tuberculose (TB), réalisées dans 24 communautés de Zambie et de la province du Cap Ouest en Afrique du Sud de janvier à décembre 2010, ont été analysées afin de déterminer l'influence du tabagisme, de l'hyperglycémie et de l'infection par le virus de l'immunodéficience humaine (VIH) sur l'expression des symptômes de TB dans des cas de TB confirmés par la culture. Sur 123 790 adultes éligibles, 90 601 (73%) ont consenti et 64 463 ont produit des échantillons de crachats utilisables. Les OR et les IC à 95% ont été calculés grâce à un modèle de régression logistique des erreurs standard robustes en ajustant le regroupement au niveau des communautés. Les patients atteints de TB et VIH positifs rapportaient plus volontiers de la toux, une perte de poids, des sueurs nocturnes et des douleurs thoraciques que les patients non VIH positifs. Par contre, les cas de TB qui fumaient ou présentaient une hyperglycémie ne signalaient pas de symptômes différents des patients qui n'avaient pas ces co-morbidités.

En el presente estudio se analizaron los datos de una encuesta reciente sobre la prevalencia de tuberculosis (TB), que se había llevado a cabo en 24 comunidades en Zambia y en el Cabo Occidental de Suráfrica de enero a diciembre del 2010, con el fin de determinar la influencia del tabaquismo, la hiperglucemia y la infección por el virus de la inmunodeficiencia humana (VIH) sobre los síntomas de TB que refieren los pacientes con diagnóstico de TB confirmada por cultivo. De los 123 790 adultos aptos para el estudio, 90 601 dieron su consentimiento (73%) y 64 463 aportaron muestras de esputo adecuadas. Se calculó el cociente de posibilidades y el intervalo de confianza del 95% mediante un modelo consistente de regresión logística y errores estándar, tras corregir la agregación de los datos por comunidad. Fue más frecuente que los pacientes con TB que eran positivos frente al VIH refirieran tos, pérdida de peso, sudoración nocturna y dolor torácico que los pacientes sin esta coinfección. No hubo diferencia en los síntomas comunicados por los pacientes tuberculosos que fumaban o que presentaban hiperglucemia, en comparación con los pacientes sin estas enfermedades concurrentes.

Factors influencing increased expertise for a sustainable workforce at a research centre in South Africa.

SETTING: The Desmond Tutu Tuberculosis (TB) Centre (DTTC), Stellenbosch University, South Africa. OBJECTIVES: 1) To determine whether access to designated funding is associated with the development of expertise in employees, and 2) which other factors are associated with the development of expertise in employees. DESIGN: This was a retrospective study. The target population consisted of all employees at the DTTC during the period 1 January 2004 to 31 December 2011. Improvement in expertise during employment was the primary outcome; the secondary outcome was an increase in educational level linked to the National Qualifications Framework. RESULTS: There was no association between access to funding and expertise development, but an association between the number of months employed and improvement of expertise during employment was observed (OR 1.03, 95%CI 1.02-1.04, P < 0.001), controlling for age at appointment, sex, access to designated funding and education level. CONCLUSION: The study shows that almost a third of employees increased their expertise, more than 90% had access to designated funding and personnel employed for a longer duration were more likely to experience improvements in expertise. We encourage research organisations in low- and middle-income countries to implement strategies to retain employees in order to build their expertise.

Contexte : Le Centre Antituberculeux Desmond Tutu (DTTC), à l'Université de Stellenbosch, en Afrique du Sud.Objectifs : 1) Déterminer si l'accès au financement est associé au développement d'une expertise chez les employés, et 2) déterminer quels autres facteurs sont associés au développement de l'expertise des employés.Schéma : Cette étude était rétrospective. La population cible était constituée par les employés du DTTC entre le 1e janvier 2004 et le 31 décembre 2011. L'amélioration de l'expertise pendant la période de fonction était le premier résultat attendu ; le deuxième était une augmentation du niveau de connaissances en relation avec le Cadre National de Certification.Résultats : Il n'a pas été démontré d'association entre l'accès au financement et le développement de l'expertise, mais on a mis en évidence une association entre le nombre de mois de travail et cette amélioration (OR 1.03 ; IC95% 1,02­1.04 ; P< 0,001), en contrôlant l'âge lors de l'entrée en fonction, le sexe, l'accès au financement et le niveau d'instruction.Conclusion : L'étude montre que près d'un tiers du personnel a accru son expertise, plus de 90% ont eu accès au financement et que les personnes employées pendant une durée plus longue avaient davantage de chances d'améliorer leur expertise. Nous encourageons les organismes de recherche des pays à revenu faible et moyen à mettre en œuvre des stratégies visant à retenir leur personnel afin de renforcer leur expertise.

Marco de referencia: El Centro Desmond Tutu de atención de la tuberculosis (DTTC) de la Universidad Stellenbosch en Suráfrica.Objetivos: 1) Determinar si la obtención de atribución de financiamientos contribuye a perfeccionar la competencia profesional de los empleados; y 2) definir los demás factores que fomentan el mejoramiento de la pericia de los profesionales.Método: Fue este un estudio retrospectivo de los empleados del DTTC del 1° de enero del 2004 al 31 de diciembre del 2011. El principal criterio de evaluación fue el perfeccionamiento de la competencia profesional de los empleados durante el tiempo de ocupación del cargo. El criterio secundario fue el progreso académico de los profesionales, según los criterios del Marco Nacional de Cualificaciones.Resultados: No se observó ninguna asociación entre el acceso al financiamiento y el mejoramiento de las competencias, pero la duración en meses en el empleo se asoció con un progreso en los conocimientos y la experiencia de los empleados (OR 1,03; IC95% de 1,02 a 1,04; P < 0,001), una vez corregidos los datos en función de la edad del nombramiento, el sexo, el acceso a la atribución de financiamiento y el grado de instrucción.Conclusión: Los resultados del estudio ponen de manifiesto que cerca de un tercio de los empleados perfeccionó sus competencias, más del 90% contaba con acceso a la atribución de financiamiento y que era más probable que las personas empleadas por períodos más prolongados mejorasen sus conocimientos teóricos y prácticos. Se recomienda a las organizaciones de investigación de los países con recursos medianos y bajos que introduzcan estrategias encaminadas a fidelizar a sus empleados, con el fin de mejorar y consolidar las competencias.

Factors affecting treatment outcomes in drug-resistant tuberculosis cases in the Northern Cape, South Africa.

The Northern Cape Province has low cure rates (21%) for multidrug-resistant tuberculosis (TB). We audited the programme to identify factors affecting treatment outcomes. Cases admitted to two drug-resistant TB units from 2007 to 2009 had data extracted from clinical folders. Unfavourable treatment outcomes were found in 58% of the 272 cases. A multivariable regression analysis found that male sex was associated with unfavourable outcome (P = 0.009). Weight at diagnosis (P < 0.001) and oral drug adherence (P < 0.001) were also associated with an unfavourable outcome; however, injectable drug adherence was not (P = 0.395). Positive baseline smear and human immunodeficiency virus positive status were not associated with unfavourable outcome. Shorter, more patient-friendly regimens may go a long way to improving adherence and outcomes.

La province du Nord du Cap a des taux de réussite thérapeutique faibles (21%) pour les tuberculoses (TB) multirésistantes. Nous avons effectué un audit du programme afin d'identifier les facteurs affectant les résultats du traitement. Les dossiers cliniques des cas admis dans deux unités de traitement de la TB pharmacorésistante de 2007 à 2009 ont permis d'extraire les données requises. Sur 272 patients, 58% ont eu un échec thérapeutique. Une analyse de régression multivariée a constaté que le sexe masculin était associé à un résultat défavorable (P = 0,009). Le poids au moment du diagnostic (P < 0,001) et l'adhérence au traitement oral (P < 0,001) étaient également associés à un mauvais résultat, mais l'adhérence aux médicaments injectables ne l'était pas (P = 0,395). Un frottis positif au départ et un statut du virus de l'immunodéficience humaine positif n'étaient pas associés à un mauvais résultat. En bref, des protocoles mieux adaptés aux patients ont du chemin à faire pour améliorer l'adhérence et les résultats.

La Provincia Septentrional del Cabo presenta bajas tasas de curación (21%) de la tuberculosis (TB) multidrogorresistente. Se practicó una auditoría del programa con el fin de detectar los factores que influyen sobre los desenlaces terapéuticos. Se analizaron los casos hospitalizados entre el 2007 y el 2009 en dos unidades de atención de la TB resistente a partir de los datos de las historias clínicas. Se observaron desenlaces desfavorables en 58% de los 272 casos. Un análisis de regresión multifactorial puso en evidencia que el sexo masculino se asociaba con desenlaces desfavorables (P = 0,009). El peso en el momento del diagnóstico (P < 0,001) y el cumplimiento con el tratamiento por vía oral (P < 0,001) se asociaron con un desenlace desfavorable, pero no así el cumplimiento con el tratamiento intravenoso (P = 0,395). Los resultados iniciales de la baciloscopia del esputo y de la serología frente al virus de la inmunodeficiencia humana no se asociaron con desenlaces desfavorables. La utilización de regímenes de tratamiento más cortos y más centrados en el paciente podría contribuir a mejorar considerablemente el cumplimiento y los desenlaces terapéuticos.

Tuberculosis patients in primary care do not start treatment. What role do health system delays play?

SETTING: Primary health care facilities in five provinces of South Africa. OBJECTIVE: To investigate the association between the proportion of sputum results with a prolonged smear turnaround time and the proportion of smear-positive tuberculosis (TB) cases initially lost to follow-up. DESIGN: The unit of investigation was a primary health care facility and the outcome was the initial loss to follow-up rate per facility, which was calculated by comparing the sputum register with the TB treatment register. A prolonged turnaround time was defined as more than 48 h from when the sputum sample was documented in the sputum register to receipt of the result at the facility. RESULTS: The mean initial loss to follow-up rate was 25% (95%CI 22-28). Smear turnaround time overall was inversely associated with initial loss to follow-up (P = 0.008), when comparing Category 2 (33-66% turnaround time within 48 h) with Category 1 (0-32%) (OR 0.73, 95%CI 0.48-1.13, P = 0.163) and when comparing Category 3 (67-100%) with Category 1 (OR 0.62, 95%CI 0.39-0.99, P = 0.045). The population preventable fraction of initial loss to follow-up (when turnaround time was <48 h in ≥67% of smear results) was 21%. CONCLUSION: Initial loss to follow-up should be reported as part of the TB programme to ensure that patients are initiated on treatment to prevent transmission within communities.

Tuberculosis cases missed in primary health care facilities: should we redefine case finding?

SETTING: This study was conducted in Cape Town in two primary health care facilities in a sub-district with a high prevalence of bacteriologically confirmed pulmonary tuberculosis (TB). OBJECTIVE: To determine the proportion of adults with respiratory symptoms who attend health care facilities but are not examined for nor diagnosed with TB in facilities where routine TB diagnosis depends on passive case finding. DESIGN: A total of 423 adults with respiratory symptoms exiting primary health care services were consecutively enrolled during April-July 2011. RESULTS: Twenty-one (5%) participants were diagnosed with culture-positive TB. None had sought care at the facility for their respiratory symptoms, none were asked about respiratory symptoms during their visit and none were asked to produce a sputum sample. Nine cases had attended the facility for reasons regarding their own health, while 12 cases were accompanying someone else attending the facility, or for another reason. CONCLUSION: Patients with infectious TB attend primary health care facilities, but are not recognised and diagnosed as cases. Health care staff should search actively within facilities for cases who attend the health care services to ensure that cases are not missed. Intensified case finding should start within the facility, and should not be limited to patients who report respiratory symptoms or who are human immunodeficiency virus positive.

Uptake of HIV testing and HIV positivity among presumptive tuberculosis patients at Puducherry, South India.

SETTING: Puducherry, a district in South India with a low prevalence of human immunodeficiency virus (HIV) infection (<1% among antenatal women). OBJECTIVES: 1) To estimate the proportion of patients with known HIV status who were HIV-positive, 2) to describe the demographic and clinical characteristics of patients with unknown HIV status among presumptive TB patients, and 3) to assess the additional workload at HIV testing centres. DESIGN: In this cross-sectional study, consecutive presumptive TB patients attending microscopy centres for diagnosis during March-May 2013 were asked if they knew their HIV status. Patients with unknown HIV status were offered voluntary counselling and HIV testing. RESULTS: Of 1886 presumptive TB patients, HIV status was ascertained for 842 (44.6%); 28 (3.3%) were HIV-positive. The uptake of HIV testing was significantly higher in younger age groups, males, residents of Puducherry and smear-positive TB patients. The median increase in the number of clients tested for HIV per day per testing centre was 1 (range 0-6). CONCLUSION: The uptake of HIV testing was low. HIV prevalence was higher among presumptive TB patients than in antenatal women, and as high as in TB patients. With minimal increase in workload at HIV testing centres, HIV testing could be implemented using existing resources.

Number of sputum specimens during treatment follow-up of tuberculosis patients: two or one?

SETTING: National Institute for Research in Tuberculosis clinics in Chennai and Madurai, India. OBJECTIVE: To examine the pattern of serial smears (negative-negative [NN], negative-positive [NP], positive-negative [PN], positive-positive [PP]) during treatment follow-up of culture-confirmed new smear-positive tuberculosis (TB) patients, and the proportion of culture-negatives in each category. DESIGN: We reviewed the records and extracted follow-up smear (fluorescent microscopy) and culture (Löwenstein-Jensen) results of patients enrolled in clinical trials from January 2000 to August 2012 and treated with the Category I regimen (2EHRZ3/4HR3). Data entry and analysis were performed using EpiData. RESULTS: Among 520 patients (176 infected with the human immunodeficiency virus), the proportions of culture-negative patients with NN, discordant (PN or NP) and PP patterns were approximately 98%, 80% and 40%, respectively. The smear-positive culture-negative phenomenon was more frequent in follow-up smear results graded 1+, followed by 2+ and 3+. CONCLUSION: There is justification for discontinuing the examination of second specimens during treatment follow-up among TB patients. However, a positive result on the first smear needs to be confirmed by a second positive result before making clinical management decisions. The World Health Organization may need to reconsider its recommendation on this issue.

Breath analysis as a potential diagnostic tool for tuberculosis.

SETTING: Cape Town, South Africa. OBJECTIVES: We investigated the potential of breath analysis by gas chromatography-mass spectrometry (GC-MS) to discriminate between samples collected prospectively from patients with suspected tuberculosis (TB). DESIGN: Samples were obtained in a TB-endemic setting in South Africa, where 28% of culture-proven TB patients had Ziehl-Neelsen (ZN) negative sputum smear. A training set of breath samples from 50 sputum culture-proven TB patients and 50 culture-negative non-TB patients was analysed using GC-MS. We used support vector machine analysis for classification of the patient samples into TB and non-TB. RESULTS: A classification model with seven compounds had a sensitivity of 72%, a specificity of 86% and an accuracy of 79% compared with culture. The classification model was validated with breath samples from a different set of 21 TB and 50 non-TB patients from the same area, giving a sensitivity of 62%, a specificity of 84% and an accuracy of 77%. CONCLUSION: This study shows that GC-MS breath analysis is able to differentiate between TB and non-TB breath samples even among patients with a negative ZN sputum smear but a positive culture for Mycobacterium tuberculosis. We conclude that breath analysis by GC-MS merits further research.