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.

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.

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.

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.

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.

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.

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.

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.

Tuberculosis among community-based health care researchers.

BACKGROUND: Occupational tuberculosis (TB) in hospital-based health care workers is reported regularly, but TB in community-based health care researchers has not often been addressed. OBJECTIVE: To investigate TB incidence in health care researchers in a high TB and human immunodeficiency virus prevalent setting in the Western Cape, South Africa. The health care researchers were employed at the Desmond Tutu TB Centre, Stellenbosch University. METHODS: A retrospective analysis was performed of routine information concerning employees at the Desmond Tutu TB Centre. The Centre has office-based and community-based employees. RESULTS: Of 180 researchers included in the analysis, 11 TB cases were identified over 250.4 person-years (py) of follow-up. All cases were identified among community-based researchers. TB incidence was 4.39 per 100 py (95%CI 2.45-7.93). The standardised TB morbidity ratio was 2.47 (95%CI 1.25-4.32), which exceeded the standard population rate by 147%. CONCLUSIONS: TB incidence in South Africa was 948 per 100,000 population per year in 2007; in the communities where the researchers worked, it was 1875/100,000. Community-based researchers in the study population have a 2.34 times higher TB incidence than the community. It is the responsibility of principal investigators to implement occupational health and infection control guidelines to protect researchers.

Antisense suppression of a potato alpha-SNAP homologue leads to alterations in cellular development and assimilate distribution.

Using the cDNA-AFLP method, we have isolated a transcript-derived fragment (TDF) which shows a differential expression pattern during tuber organogenesis of Solanum tuberosum L. The TDF was used to isolate a cDNA clone carrying a 1.5 kb insert and potentially coding for a 32.5 kDa peptide which, by homology, represents a potato homologue of an alpha-snap gene and has been designated Stsnap. Northern analysis showed that the Stsnap gene is expressed in actively dividing tissues throughout the potato plant. Analysis of genomic DNA from potato revealed that the Stsnap gene is likely to be a single-copy gene. The expression of antisense Stsnap cDNA under the control of the CaMV 35S promoter results in plants with an altered morphology such as curled leaves. Several of these transgenic lines also display cellular and developmental abnormalities with distinct changes in assimilate transport including accumulation of starch and soluble sugars in source leaves. We argue that these findings are consistent with the hypothetical function of the StSNAP gene product in vesicle targeting and fusion during plant development.

Differential substrate behaviour of phenol and aniline derivatives during conversion by horseradish peroxidase.

For the first time saturating overall k(cat) values for horseradish peroxidase (HRP) catalysed conversion of phenols and anilines are described. These k(cat) values correlate quantitatively with calculated ionisation potentials of the substrates. The correlations for the phenols are shifted to higher k(cat) values at similar ionisation potentials as compared to those for anilines. (1)H-NMR T(1) relaxation studies, using 3-methylphenol and 3-methylaniline as the model substrates, revealed smaller average distances of the phenol than of the aniline protons to the paramagnetic Fe(3+) centre in HRP. This observation, together with a possibly higher extent of deprotonation of the phenols than of the anilines upon binding to the active site of HRP, may contribute to the relatively higher HRP catalysed conversion rates of phenols than of anilines.