"It's about time they taught us": a qualitative study evaluating the barriers to finding and screening child contacts under five at risk for TB in Gauteng Province, South Africa from the provider and caregiver perspectives.

BACKGROUND: Inadequate numbers of children under five years of age who are exposed to tuberculosis (TB) in the home (child contact) are initiated on TB preventive treatment (TPT) in South Africa. We assessed barriers of initiating isoniazid preventive therapy (IPT) in this age group. METHODS: We conducted a qualitative study at two primary health clinics in the Ekurhuleni district in Gauteng Province. Between April and July 2019, we enrolled facility managers, TB staff and parents or legal guardians of child contacts (caregivers) attending for care, at the two facilities. Semi-structured questionnaires, facility observations and in-depth interviews using a semi-structured interview guide were used to collect data. Findings from the semi-structured questionnaires with facility staff and facility observations were summarized. Thematic analysis with a deductive approach was used to analyse the data from the in-depth interviews with caregivers. RESULTS: Two facility managers took part in the study and were assisted to complete the semi-structured questionnaires by TB staff. Fifteen caregivers aged between 18 and 43 years were interviewed of which 13 (87%) were female. Facility managers and TB staff (facility staff) felt that even though caregivers knew of family members who were on TB treatment, they delayed bringing their children for TB screening and TPT. Facility staff perceived caregivers as not understanding the purpose and benefits of TB prevention strategies such as TPT. Caregivers expressed the desire for their children to be screened for TB. However, caregivers lacked knowledge on TB transmission and the value of TB prevention in children at high risk of infection. CONCLUSION: While facility staff perceived caregivers to lack responsibility, caregivers expressed limited knowledge on the value of screening their children for TB as reasons for not accessing TB preventive services. Health education on TB transmission, screening, and TB prevention strategies at a community level, clinics, creches, schools and via media are important to achieve the global end TB goal of early detection and prevention of TB.

Overcoming limitations of tuberculosis information systems: researcher and clinician perspectives.

SETTING: Tuberculosis (TB) diagnosis and treatment requires patients to have multiple encounters with health care systems and the different stakeholders who play a role in curing them to coordinate their efforts. To optimize this process, high-quality, readily available data are required. Data systems to facilitate these linkages are a neglected priority which, if weak, fundamentally undermine TB control interventions. OBJECTIVE: To describe lessons learnt from the use of programmatic data for TB patient care and research. DESIGN: We did a survey of researcher and clinical provider experiences with information systems and developed a tiered approach to addressing frequently reported barriers to high-quality care. RESULTS: Unreliable linkages, incomplete data, lack of a reliable unique patient identifier, and lack of data management expertise were the most important data-related barriers to high-quality patient care and research. We propose the creation of health service delivery environments that facilitate, prioritize, and evaluate high-quality data entry during patient or specimen registration. CONCLUSION: An integrated approach, focused on high-quality data, and centered on unique patient identification will form the foundation for linkages across health systems that reduce patient management errors, bolster surveillance, and enhance the quality of research based on programmatic data.

Treatment outcomes, diagnostic and therapeutic impact: Xpert vs. smear. A systematic review and meta-analysis.

BACKGROUND: Compared with smear microscopy, Xpert® MTB/RIF has the potential to reduce delays in tuberculosis (TB) diagnosis and treatment initiation, and improve treatment outcomes. We reviewed publications comparing treatment outcomes of drug-susceptible TB patients diagnosed using Xpert vs. smear. METHODS: Citations (2000-2016) reporting treatment outcomes of patients diagnosed using Xpert compared with smear were selected from PubMed, Scopus and conference abstracts. We conducted a systematic review and meta-analysis. Favorable (cured, completed) and unfavorable (failure, death, loss to follow-up) outcomes were pooled for meta-analysis; we also reviewed the number of TB cases diagnosed, time to treatment and empiric treatment. The Mantel-Haenszel method with a fixed-effect model was used; I² was calculated to measure heterogeneity. RESULTS: From 13 citations, 43 594 TB patients were included and 4825 were with known TB treatment outcome. From the pooled analysis, an unfavorable outcomes among those diagnosed using Xpert compared with smear was 20.2%, 541/2675 vs. 21.9%, 470/2150 (risk ratio 0.92, 95%CI 0.82-1.02). Statistical heterogeneity was low (I² = 0.0%, P = 0.910). Compared with smear, Xpert was reported to be superior in increasing the number of TB patients diagnosed (2/9 citations), increasing bacteriologically confirmed TB (7/9 citations), reducing empiric treatment (3/5 citations), reducing time to diagnosis (2/3 citations), and reducing time to treatment initiation (1/5 citations). CONCLUSIONS: Xpert implementation showed no discernible impact on treatment outcomes compared with conventional smear despite reduced time to diagnosis, time to treatment or reduced level of empiric treatment. Further research is required to learn more about gaps in the existing health system.

What causes symptoms suggestive of tuberculosis in HIV-positive people with negative initial investigations?

OBJECTIVE: To identify the causes of symptoms suggestive of tuberculosis (TB) among people living with the human immunodeficiency virus (PLHIV) in South Africa. METHODS: A consecutive sample of HIV clinic attendees with symptoms suggestive of TB (1 of cough, weight loss, fever or night sweats) at enrolment and at 3 months, and negative initial TB investigations, were systematically evaluated with standard protocols and diagnoses assigned using standard criteria. TB was 'confirmed' if Mycobacterium tuberculosis was identified within 6 months of enrolment, and 'clinical' if treatment started without microbiological confirmation. RESULTS: Among 103 participants, 50/103 were pre-antiretroviral therapy (ART) and 53/103 were on ART; respectively 68% vs. 79% were female; the median age was 35 vs. 45 years; the median CD4 count was 311 vs. 508 cells/mm³. Seventy-two (70%) had 5% measured weight loss and 50 (49%) had cough. The most common final diagnoses were weight loss due to severe food insecurity (n = 20, 19%), TB (n = 14, 14%: confirmed n = 7; clinical n = 7), other respiratory tract infection (n = 14, 14%) and post-TB lung disease (n = 9, 9%). The basis for TB diagnosis was imaging (n = 7), bacteriological confirmation from sputum (n = 4), histology, lumbar puncture and other (n = 1 each). CONCLUSION: PLHIV with persistent TB symptoms require further evaluation for TB using all available modalities, and for food insecurity in those with weight loss.

Lessons learnt conducting minimally invasive autopsies in private mortuaries as part of HIV and tuberculosis research in South Africa.

Current estimates of the burden of tuberculosis (TB) disease and cause-specific mortality in human immunodeficiency virus (HIV) positive people rely heavily on indirect methods that are less reliable for ascertaining individual-level causes of death and on mathematical models. Minimally invasive autopsy (MIA) is useful for diagnosing infectious diseases, provides a reasonable proxy for the gold standard in cause of death ascertainment (complete diagnostic autopsy) and, used routinely, could improve cause-specific mortality estimates. From our experience in performing MIAs in HIV-positive adults in private mortuaries in South Africa (during the Lesedi Kamoso Study), we describe the challenges we faced and make recommendations for the conduct of MIA in future studies or surveillance programmes, including strategies for effective communication, approaches to obtaining informed consent, risk management for staff and efficient preparation for the procedure.

Les estimations actuelles du poids de la tuberculose (TB) maladie et de la mortalité qui lui est due parmi les patients positifs à l'infection par le virus de l'immunodéficience humaine (VIH) dépendent beaucoup de méthodes indirectes, qui sont moins fiables pour vérifier les causes de décès au niveau individuel et de modèles mathématiques. Une autopsie peu invasive (MIA) est utile au diagnostic de maladies infectieuses, fournit une approximation raisonnable de l'étalon or de la vérification de la cause du décès c'est-à-dire une autopsie diagnostique complète. Si elle est utilisée en routine, elle pourrait améliorer les estimations de mortalité spécifique d'une cause. A partir de nos expériences de MIA sur des adultes positifs au VIH dans des morgues privées d'Afrique du Sud (au cours de l'étude Lesedi Kamoso), nous décrivons les défis rencontrés et faisons des recommandations pour la réalisation de MIA dans des études futures ou des programmes de surveillance, incluant des stratégies de communication efficaces, des approches visant à obtenir un consentement éclairé, une prise en charge du risque pour le personnel et une préparation efficace de la procédure.

Las estimaciones actuales de morbilidad por tuberculosis (TB) y de mortalidad por causas específicas en las personas positivas frente al virus de la inmunodeficiencia humana (VIH) se fundamentan en su mayor parte en métodos indirectos que son menos fiables para determinar las causas de muerte individuales y en modelizaciones matemáticas. La autopsia mínimamente invasiva (MIA) es útil en el diagnóstico de las enfermedades infecciosas, ofrece un sustituto aceptable al método de referencia para determinar la causa de muerte (que es la autopsia diagnóstica completa), y cuando se usa de manera sistemática, mejora las estimaciones de la mortalidad por causas específicas. A partir de su experiencia con la MIA en adultos con infección por el VIH en empresas fúnebres privadas en Suráfrica (durante el estudio Lesedi Kamoso), los autores describen las dificultades que encontraron y formulan recomendaciones que se pueden aplicar en el futuro al realizar la autopsia mínimamente invasiva en estudios de investigación o en programas de vigilancia; se preconizan estrategias de comunicación efectivas, métodos de obtención del consentimiento informado, la gestión de riesgos para el personal y la preparación eficiente del procedimiento.

Implementation and Operational Research: What Happens After a Negative Test for Tuberculosis? Evaluating Adherence to TB Diagnostic Algorithms in South African Primary Health Clinics.

INTRODUCTION AND BACKGROUND: Diagnostic tests for tuberculosis (TB) using sputum have suboptimal sensitivity among HIV-positive persons. We assessed health care worker adherence to TB diagnostic algorithms after negative sputum test results. METHODS: The XTEND (Xpert for TB-Evaluating a New Diagnostic) trial compared outcomes among people tested for TB in primary care clinics using Xpert MTB/RIF vs. smear microscopy as the initial test. We analyzed data from XTEND participants who were HIV positive or HIV status unknown, whose initial sputum Xpert MTB/RIF or microscopy result was negative. If chest radiography, sputum culture, or hospital referral took place, the algorithm for TB diagnosis was considered followed. Analysis of intervention (Xpert MTB/RIF) effect on algorithm adherence used methods for cluster-randomized trials with small number of clusters. RESULTS: Among 4037 XTEND participants with initial negative test results, 2155 (53%) reported being or testing HIV positive and 540 (14%) had unknown HIV status. Among 2155 HIV-positive participants [684 (32%) male, mean age 37 years (range, 18-79 years)], there was evidence of algorithm adherence among 515 (24%). Adherence was less likely among persons tested initially with Xpert MTB/RIF vs. smear [14% (142/1031) vs. 32% (364/1122), adjusted risk ratio 0.34 (95% CI: 0.17 to 0.65)] and for participants with unknown vs. positive HIV status [59/540 (11%) vs. 507/2155 (24%)]. CONCLUSIONS: We observed poorer adherence to TB diagnostic algorithms among HIV-positive persons tested initially with Xpert MTB/RIF vs. microscopy. Poor adherence to TB diagnostic algorithms and incomplete coverage of HIV testing represents a missed opportunity to diagnose TB and HIV, and may contribute to TB mortality.

Pooling sputum from multiple individuals for Xpert® MTB/RIF testing: a strategy for screening high-risk populations.

SETTING: Symptom-based screening for tuberculosis (TB) disease is limited by poor performance of symptom screening in several key populations. We tested the hypothesis that pooling sputum from multiple individuals for Xpert(®) MTB/RIF testing would reduce the number of tests required while retaining an acceptable sensitivity, thus allowing the use of Xpert for TB screening. METHODS: We compared pooling ratios that would require the least number of assays using Xpert and determined that for a population with a TB prevalence of approximately 3%, a 1:5 pooling ratio is optimal. To evaluate sensitivity, we generated pools of one specimen with known Mycobacterium tuberculosis culture positivity (smear microscopy-positive or -negative) with four culture-negative specimens. RESULTS: All 20 of the pools generated from a smear- and culture-positive sputum sample were positive using Xpert. Of the 22 pools with a smear-negative, culture-positive sample, we included 17 in the analysis, of which 13 (76%) were Xpert-positive. CONCLUSIONS: Pooling of sputum samples using Xpert achieved reasonable sensitivity and warrants further evaluation of the systematic screening of high TB prevalence populations.

Isoniazid preventive therapy use among patients on antiretroviral therapy: a missed opportunity.

Isoniazid preventive therapy (IPT) with antiretroviral therapy (ART) reduces incident tuberculosis among patients infected with the human immunodeficiency virus. We describe IPT use among patients on ART at two primary care clinics in South Africa. Of 597 participants interviewed, 100 (16.8%) reported IPT use; 73.4% (365/497) with no reported IPT use were eligible for IPT. IPT use was associated with age <35 years (aOR 1.90, 95%CI 1.18-3.06), and receiving care at one clinic as opposed to the other (aOR 4.72, 95%CI 2.69-7.93). The high proportion of patients on ART eligible for IPT represents a missed opportunity for IPT scale-up.

Willingness to participate in trials and to be vaccinated with new tuberculosis vaccines in HIV-infected adults.

BACKGROUND: New tuberculosis (TB) vaccines are required to meet global targets for TB control. OBJECTIVES: To determine willingness to participate (WTP) in new TB vaccine trials, willingness to be vaccinated with a newly licensed TB vaccine and associated factors among human immunodeficiency virus (HIV) infected persons. SETTING: Two primary care clinics in South Africa. DESIGN: Cross-sectional study design. Participants were asked about WTP and willingness to be vaccinated. Demographic, clinical, knowledge of TB and perception of risk information were collected. Log binomial regression was used to determine associated factors. RESULTS: A total of 827 participants were included in the analysis: 80.4% female, 72.2% on antiretroviral therapy, median age 35 years (interquartile range [IQR] 29-42 years), CD4 count 523 cells/µl (IQR 427-659 cells/µl). WTP and willingness to be vaccinated were high, at 84.5% and 92.6%, respectively. WTP was associated with knowledge about TB (prevalence ratio [PR] 1.10, 95% confidence interval [CI] 1.03-1.17) and perception of risk (PR 1.07, 95%CI 1.01-1.13). Willingness to be vaccinated was associated with employment (PR 1.04, 95%CI 1.01-1.08) and perception of risk (PR 1.05, 95%CI 1.01-1.09). CONCLUSIONS: There was high WTP in TB vaccine trials and willingness to be vaccinated among HIV-infected patients with good TB knowledge and high perceived risk of contracting TB.

Spectrum of non-tuberculous mycobacteria identified using standard biochemical testing vs. 16S sequencing.

Non-tuberculous mycobacterial isolates from gold miners were speciated using standard biochemical testing (SBT) and 16S rDNA sequencing. Of 237 isolates tested, SBT identified 126, compared with all 237 identified using sequencing. Of 111 isolates unspeciated by SBT but identified by sequencing, 38 (34.2%) were identified as Mycobacterium gordonae and 8 (7.2%) were new species. Of 126 isolates speciated by both methods, 37 were discordant, with 14/17 M. gordonae isolates incorrectly identified as M. scrofulaceum using SBT. The majority of these were the potentially pathogenic strain D, M. gordonae. Sequencing is preferable where available to guide treatment.

Trends in drug-resistant tuberculosis in a gold-mining workforce in South Africa, 2002-2008.

SETTING AND OBJECTIVE: To describe trends in drug-resistant tuberculosis (TB) in two gold-mining workforces, South Africa, 2002-2008. DESIGN: TB programme data analysis. RESULTS: TB case notification rates decreased between 2002 and 2008 from 4006 to 3018 per 100,000 and from 3192 to 2468/100,000 for Companies A and B, respectively. Human immunodeficiency virus (HIV) prevalence exceeded 80% in TB episodes with known status. The proportion of TB episodes with multidrug-resistant TB (MDR-TB) increased from 6/129 (4.7%) to 17/85 (20.0%) among previously treated cases, and from 4/38 (10.4%) to 7/28 (25.0%) in Companies A and B, respectively (tests for trend, Company A, P < 0.001; Company B, P = 0.304). Case notifications of MDR-TB increased during 2002-2008 from 39.8 to 122.9/100,000/year in Company A and from 7.8 to 96.8/100,000/year in Company B. Coverage of second-line drug susceptibility testing (DST) among MDR-TB episodes was low. Previous treatment exposure was a strong risk factor for MDR-TB (prevalence ratio 8.78, 95%CI 5.94-12.97 in previously treated vs. untreated individuals). CONCLUSION: Despite decreasing TB notifications overall, MDR-TB notifications and proportions of episodes with MDR-TB increased in the larger company. Cure must be ensured in first episodes to prevent acquired resistance. Improved coverage of culture, DST and HIV testing is required to allow treatment to be optimised.

Liquid vs. solid culture for tuberculosis: performance and cost in a resource-constrained setting.

SETTING: National Health Laboratory Services tuberculosis (TB) laboratory, South Africa. OBJECTIVES: To compare Mycobacterium Growth Indicator Tube (MGIT) with Löwenstein-Jensen (LJ) medium with regard to Mycobacterium tuberculosis yield, time to positive culture and contamination, and to assess MGIT cost-effectiveness. DESIGN: Sputum from gold miners was cultured on MGIT and LJ. We estimated cost per culture, and, for smear-negative samples, incremental cost per additional M. tuberculosis gained with MGIT using a decision-tree model. RESULTS: Among 1267 specimens, MGIT vs. LJ gave a higher yield of mycobacteria (29.7% vs. 22.8%), higher contamination (16.7% vs. 9.3%) and shorter time to positive culture (median 14 vs. 25 days for smear-negative specimens). Among smear-negative samples that were culture-positive on MGIT but negative/contaminated on LJ, 77.3% were non-tuberculous mycobacteria (NTM). Cost per culture on LJ, MGIT and MGIT+LJ was respectively US$12.35, US$16.62 and US$19.29. The incremental cost per additional M. tuberculosis identified by standard biochemical tests and microscopic cording was respectively US$504.08 and US$328.10 using MGIT vs. LJ, or US$160.80 and US$$109.07 using MGIT+LJ vs. LJ alone. CONCLUSION: MGIT gives higher yield and faster results at relatively high cost. The high proportion of NTM underscores the need for rapid speciation tests. Minimising contaminated cultures is key to cost-effectiveness.

Predominance of a single genotype of Mycobacterium tuberculosis in regions of Southern Africa.

SETTING: Zimbabwe and Zambia. OBJECTIVE: To determine the genetic diversity of Mycobacterium tuberculosis strains isolated from tuberculosis (TB) patients in Zimbabwe and Zambia. DESIGN: M. tuberculosis isolates cultured from TB patients presenting at referral hospitals in Zimbabwe and health care clinics in Zambia were characterised by IS6110 genotyping and/or spoligotyping using internationally standardised methods. Genotypic data were compared to those from Cape Town and the SpolDB3.0 database. RESULTS: A predominant group of strains could be identified among 116/246 (47.2%) Zimbabwean isolates by their characteristic IS6110-banding pattern and unique spoligotype signature, where spacers 21-24, 27-30 and 33-36 were deleted. Comparison with strains from Cape Town showed that they were closely related to a family of strains present in 2.3% of Cape Town patients. Comparison of the spoligotypes with those obtained from 114 isolates from Zambia showed that 74 (65%) of these isolates had the same spoligotype signature. Spoligotypes in the SpolDB3.0 database showed that this group of strains was rarely isolated in other parts of the world, but was commonly isolated in Southern Africa. CONCLUSION: A predominant group of strains infecting approximately half of the patients in the study are major contributors to the TB epidemic in this region. We have designated this group of strains the Southern Africa 1 (SAF1) family.

Clonal expansion of a globally disseminated lineage of Mycobacterium tuberculosis with low IS6110 copy numbers.

Knowledge of the clonal expansion of Mycobacterium tuberculosis and accurate identification of predominant evolutionary lineages in this species remain limited, especially with regard to low-IS6110-copy-number strains. In this study, 170 M. tuberculosis isolates with

Dysentery in patients infected with human immunodeficiency virus in Zimbabwe: an emerging role for Schistosoma mansoni and Escherichia coli O157?

Information on bloody diarrhoea in HIV-positives is scarce. A prospective study was therefore performed, in Zimbabwe, to determine and compare the pathogens associated with bloody diarrhoea in 25 antiretroviral-naïve HIV-infected patients and 15 non-HIV-infected patients. Stool cultures and colonic biopsies were performed. Shigella was isolated from 18 (45%) of the subjects, Schistosoma mansoni from eight (16%), Escherichia coli H7:O157 from three (8%) and Campylobacter jejunii from two (5%). There was no evidence of Salmonella, Entamoeba histolytica or cytomegalovirus infection. Shigella dysenteriae type-1 occurred more often in the HIV-negatives than the HIV-positives (P = 0.02). Although HIV-associated bloody diarrhoea in Zimbabwe appears to be most frequently caused by Shigella, it may also be commonly the result of infection with Sc. mansoni or shiga-toxin-producing E. coli. A larger study specifically to examine the role of Sc. mansoni and E. coli O157 is warranted.

Storage of breast milk: effect of temperature and storage duration on microbial growth.

OBJECTIVE: To study the effect of storage duration at varying temperature ranges, the pattern of microbial isolates and the quantity of colony-forming units (CFU) on expressed breast milk. DESIGN: Cross sectional study. SETTING: Bacteriology laboratory, University of Zimbabwe in Parirenyatwa Hospital, Harare. MAIN OUTCOME MEASURES: The temperature, storage duration and types of micro-organisms in freshly expressed breast milk. RESULTS: Freshly expressed human breast milk contained microbial non-pathogens of skin flora. There was no growth of organisms in stored breast milk after four hours, eight hours, 24 hours and 72 hours storage duration at temperature ranges 0 to 4 degrees C (freezing temperature), 4 to 10 degrees C (refrigerator temperature), 15 to 27 degrees C (room temperature) and 30 to 38 degrees C (high temperature) respectively. Growth was detected after the storage durations and organisms isolated were both pathogens and non-pathogens with low counts. Average colony counts was (CFU < 200). CONCLUSION: The study revealed that storage duration for expressed breast milk should not exceed 24 hours in refrigerator temperature (4 to 10 degrees C), eight hours at room temperature (15 to 27 degrees C) and four hours at high temperature (30 to 38 degrees C). Although freezing temperature (0 to 4 degrees C) seemed safest for breast milk storage, short-term storage in a freezer is not recommended due to likely the hazards of the thawing process.

TB infection: an exploratory study of BCG protective properties and the possible role of environmental mycobacteria.

OBJECTIVE: To evaluate the presence of environmental mycobacterial strains and explore the implications for BCG vaccination against TB. DESIGN: Multimethod approach which included structured interviews and medical records examination. Soil and water samples were analysed using standard microbiology methods. SETTING: Beatrice Infectious Diseases Hospital, Public Health laboratories, University of Zimbabwe Medical School and several residential areas in Harare. SUBJECTS: 129 tuberculosis inpatients at Beatrice Infectious Diseases Hospital, 26 Public Health Laboratory technicians handling TB specimens and 51 fourth year medical students. MAIN OUTCOME MEASURES: Vaccination status of TB inpatients, medical students and laboratory technicians, protective efficacy of BCG in all subjects, presence of environmental mycobacterium in the environment. RESULTS: The type of tuberculosis did not differ significantly between vaccinated and non-vaccinated TB patients x2(df = 1) = 0.171 p > 0.05. There was no apparent difference between the revaccinated and non-vaccinated laboratory technicians. One respondent out of each of the revaccinated and non-vaccinated laboratory technicians had developed pulmonary tuberculosis. Among the fourth year medical students, four had positive tuberculin test results, even though they had not been vaccinated at the University clinic. Environmental mycobacteria presumptively identified as Mycobacterium scrofulaceum and Mycobacterium intracellulare were isolated from both the water and soil samples taken from a few selected areas in Harare. Of the 129 TB in-patients, 88 (68.2%) had previously been vaccinated against TB. Similarly among the 51 medical students 44(86.3%) had been vaccinated. Laboratory technicians re-vaccinated on the job were nine out of 26. CONCLUSION: The results obtained seemed to indicate that BCG protective efficacy did wane with time and revaccination appeared not to be useful. Environmental mycobacterium that could influence the BCG efficacy do exist in our environment.