Browsing by Subject "tuberculosis"

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    A scoping review on the use of telerehabilitation in physiotherapy in low and middle income countries
    (2025) Ndzamba, Bonginkosi; Denti, Paolo; Resendiz Galvan, Juan Eduardo
    Introduction: Ethambutol is a bacteriostatic drug, administered as part of a fixed-dose combination regimen for the treatment of tuberculosis (TB). Individuals with comorbid HIV have reported reduced serum concentrations of ethambutol. We aimed to evaluate the pharmacokinetics of ethambutol in individuals with both drug-susceptible TB and HIV, identify covariates that influence ethambutol pharmacokinetics, and evaluate the current World Health Organization's (WHO) ethambutol dosing recommendations. Method: We used pharmacokinetic data from the TB-HAART open-label trial that investigated the outcomes of individuals with dual TB and HIV infections treated with first-line anti-TB drugs and antiretroviral therapy (ART). Modelling and simulation was performed using nonlinear mixed-effects modelling in the software NONMEM®. Results: A two-compartment disposition model with transit absorption best fitted the pharmacokinetic data. Allometry using fat-free mass and weight best scaled disposition parameters for body size for the final model. The typical clearance of ethambutol was 34.8 L/h. The Antib-4® formulation of ethambutol showed a 27.8% reduction in bioavailability and a 37.1% increase in mean transit time compared to the e-275 Rifafour® formulation. Creatinine clearance, presence of ART from day 13, and CD4+ T-cell count were also tested but did not improve the model fit. Our simulations showed that, with the current WHO fixed-dose combination regimen, individuals with weight 55 kg weight bands. Therefore, to balance exposures we proposed an additional 275 mg ethambutol dose. Similarly, our simulations suggest that the multidrug-resistant TB WHO 400 mg strength under-exposes patients with weight <54.9 kg had lower exposure to ethambutol 275 mg tablet strength than those in >55 kg weight bands. Therefore, to balance exposures we proposed an additional 275 mg ethambutol dose. Similarly, our simulations suggest that the multidrug-resistant TB WHO 400 mg strength under-exposes patients with weight <46.9 kg, which could be addressed by increasing the dose by 400 mg. Conclusion: We developed a model for ethambutol and observed that different formulations of ethambutol affected its bioavailability and absorption. Our simulation results indicated that individuals weighing less than 55 kg with drug-susceptible TB and those weighing less than 46 kg with multidrug-resistant TB are at risk of being underdosed. To ensure improved therapeutic outcomes for these individuals, a proposed dose optimization is a more effective solution.
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    Antimycobacterial, Cytotoxic, and Antioxidant Activities of Abietane Diterpenoids Isolated from Plectranthus madagascariensis
    (2021-01-19) Ndjoubi, Kadidiatou O; Sharma, Rajan; Badmus, Jelili A; Jacobs, Ayesha; Jordaan, Audrey; Marnewick, Jeanine; Warner, Digby F; Hussein, Ahmed A
    Medicinal plants of the Plectranthus genus (Lamiaceae) are well known for their ethnomedicinal applications. Plectranthus madagascariensis, which is native to South Africa, is traditionally used in the treatment of respiratory conditions, scabies, and cutaneous wounds. The phytochemical studies of P. madagascariensis led to the isolation of five known royleanone abietanes, namely, 6β,7α-dihydroxyroyleanone (1), 7α-acetoxy-6β-hydroxyroyleanone (2), horminone (3), coleon U quinone (4), and carnosolon (5). The relative configuration of compound 2 was established by X-ray analysis. Compounds 1–4 showed antimycobacterial activity (Minimum inhibitory concentration for 90% inhibition, MIC90 = 5.61–179.60 μM) against Mycobacterium tuberculosis H37Rv. Compound 4 and 5 showed comparable toxicity (Concentration for 50% inhibition, IC50 98.49 μM and 79.77 μM) to tamoxifen (IC50 22.00 μg/mL) against HaCaT cells. Compounds 1–5 showed antioxidant activity through single-electron transfer (SET) and/or hydrogen-atom transfer (HAT) with compound 5 being the most active antioxidant agent. Compounds 3 and 5 were isolated for the first time from P. madagascariensis. The observed results suggest P. madagascariensis as an important ethnomedicinal plant and as a promising source of diterpenoids with potential use in the treatment of tuberculosis and psoriasis.
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    Biomarkers and cell phenotypes in TB patients with minimal or persisting lung inflammation post-anti-TB treatment and ex-vivo atorvastatin immunomodulatory effects on M. tuberculosis-infected PBMC
    (2024) Motaung, Bongani; Guler, Reto; Thienemann, Friedrich; Ozturk, Mumin
    Unresolved lung inflammation post-anti-TB treatment necessitates the evaluation of additional host-directed therapies (HDT). Statins, recognized for their pleiotropic effects, show potential as immunomodulators to reduce post-TB lung inflammation. The ongoing StatinTB clinical trial utilizes a double-blind, randomized, placebo-controlled approach post-anti-TB treatment to assess the safety and efficacy of atorvastatin in reducing post TB lung inflammation. At the end of TB treatment, Mtb culture-negative participants were stratified into minimal (Arm A, Total Lung Glycolysis (TLG) < 50 SUV) or persisting (Arm B/C, TLG ≥ 50 SUV) lung inflammation using Positron Emission Tomography/Computed Tomography (PET/CT) scan. Arm B/C received atorvastatin (40mg/day) or placebo for 12 weeks, and this data remains currently blinded. Study participants were evaluated for hematological, biochemical, and inflammatory parameters where ALP, proBNP, vitamin D, and CRP showed significant increases in Arm B/C compared to Arm A at
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    Catching a glimpse: the visualization of Mycobacterium tuberculosis from TB patient bioaerosols
    (2023) Dinkele, Ryan; Warner, Digby; Gessner, Sophia
    Transmission between hosts is crucial for the success and survival of the obligate human pathogen and aetiological agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb). Despite this, little is known about how and when Mtb is aerosolized nor the key metabolic and morphological determinants driving successful transmission. To address these knowledge gaps, my doctoral research sought to develop a microscopic method for the detection of aerosolized Mtb following liquidcapture within the respiratory aerosol sampling chamber (RASC). This was achieved through the combination of the mycobacterial cell wall probe, 4-N,Ndimethylamino-1,8-naphthalimide-trehalose (DMN-tre), with the arraying of bioaerosol samples on bespoke nanowell devices amenable to fluorescence microscopy. With this method, a median of 14 live Mtb bacilli (range 0-36) were detected in 90% of confirmed TB patients following 60 minutes of bioaerosol sampling. Three distinct DMN-tre staining patterns were identified among aerosolized Mtb, strongly suggestive of metabolic heterogeneity. Moreover, a low proportion of patients produced Mtb in small clumps. These observations highlight the advantages of using microscopy over conventional culture- or molecular-based techniques for probing the metabolic and morphological characteristics of aerosolized Mtb. Applying this method in a second study, we sought to understand how and when Mtb is aerosolized. To this end, we aimed to compare the aerosolization of Mtb and total particulate matter from patients with TB during three respiratory manoeuvres: tidal breathing (TiBr), forced vital capacity (FVC), and cough. Although total particle counts were 4.8-fold greater in cough samples than either TiBr or FVC, all three manoeuvres returned similar rates of positivity for Mtb. No correlation was observed between total particle production and Mtb count. Instead, for total Mtb counts, the variability between individuals was greater than the variability between sampling manoeuvres. Finally, when modelled using 24-hour breath and cough frequencies, our data indicate that TiBr might contribute more than 90% of the daily aerosolized Mtb among symptomatic TB patients. Assuming the number of viable Mtb organisms detected provides a proxy measure of patient infectiousness, this method suggests that TiBr is a significant contributor to TB transmission. In developing a novel platform for the detection of aerosolized Mtb, this work has suggested the need to re-examine old assumptions about Mtb transmission.
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    Conceptualising the right to enjoy benefits of scientific progress and exploring its potential to enhance access to effective diagnosis and treatment of drug-resistant tuberculosis in South Africa
    (2019) Shawa, Remmy Malama; London, Leslie; Coomans, Fons; Cox, Helen
    The lack of access to effective diagnosis and treatment of drug-resistant tuberculosis (DR-TB) remains a persistent global challenge. Human rights arguments for access to treatment mostly focus on the right to health. However, a key challenge in access to effective diagnosis and treatment is the glaring absence of scientific research in neglected diseases such as TB. This thesis sets out to elaborate the right to enjoy the benefits of scientific progress and explore its potential to increase scientific research in DR-TB and consequently enhance access to effective diagnosis and treatment in South Africa. This research project was conducted using three interrelated sub-studies; a legal analysis sub-study which examines the current conceptualisation of the REBSP in international law; a policy analysis sub-study which interrogates South Africa’s legal and policy efforts towards the realisation of the REBSP and access to diagnosis and treatment for DR-TB; and a qualitative sub-study which explores the South African context regarding research and development (R&D) in general, and in DR-TB in particular. The qualitative sub-study included 17 stakeholders who are active in TB R&D, advocacy and policy work, from human rights and research institutions, government agencies, civil society organisations, and donor agencies. This thesis finds that the REBSP essentially ensures two things, namely the production of science and access to the benefits of scientific progress. However, most countries including South Africa have systems, policies and resources aimed at advancing the production of science but lack similar systems, policies and resources to purposely ensure the enjoyment of the benefits from scientific progress. Internationally, there is no clear guidance on the interpretation of the REBSP, making it difficult for states to domesticate it in their national policies and framework laws. A General Comment by a UN human rights monitoring body is therefore urgently needed to secure global consensus on the interpretation of the REBSP. In the meanwhile, South Africa can still draw inspiration for the REBSP and together with the right to health, use it to advance access to DR-TB diagnosis and treatment alongside many other interventions. To enable better access to effective diagnosis and treatment of DR-TB, this thesis recommends that South Africa i) develops systems that would make scientific progress and results accessible, and affordable; ii) removes system and regulatory barriers that hinder the conduct of research or that delay registration of new drugs; iii) monitors and regulates the conduct of third parties and prevent them from exploiting communities; iv) encourages pharmaceutical companies to provide free access to successful treatment and tools in communities where trials are conducted; and v) mobilises financial and technical resources and allocates them to DR-TB researchfrom drug discovery through to implementation science.
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    Correlates of tuberculosis and non-tuberculosis morbidity and immunity in sub-Saharan African HIV-exposed, uninfected infants
    (2024) Iwase, Saori Christina; Jaspan, Heather; Happel, Anna-Ursula
    Background: Perinatal HIV transmission has been considerably reduced due to successful intervention programs. Consequently, there is a growing population of infants who are HIV-exposed but uninfected (iHEU), particularly in sub-Saharan Africa. These infants experience an increased risk of morbidity compared to infants who are HIV-unexposed and uninfected (iHUU), predominantly due to infectious diseases. Although the mechanisms underlying this increased vulnerability remain unclear, it may be associated with their altered immunity and/or gut microbiota. Bacillus Calmette-Guérin (BCG) vaccination is an effective intervention to prevent severe tuberculosis (TB) disease in children. BCG vaccination also enhances heterologous protective immunity against infections through epigenetic reprogramming of innate immune cells (known as “trained innate immunity”). However, whether iHEU receive comparable protection from BCG induced immunity against TB and non-TB infection as iHUU remains elusive. Gut microbiota plays a critical role in immune development during infancy. A close relationship between gut microbiota and vaccine responses has been reported in iHUU, including tetanus toxoid (TT) vaccination. However, a limited number of studies longitudinally investigated the effect of in utero HIV exposure on the gut microbiota, and results are often conflicting. In addition, not many studies have compared the trajectory of gut microbiota between iHEU and iHUU across multiple countries. While several studies have indicated reduced immune responses against TT vaccination in iHEU compared to iHUU, the interplay between HIV exposure, gut microbiota, and vaccine response is largely unexplored. Aims: In this dissertation, we examined three potential contributing factors that may underlie the higher risk of morbidity observed among iHEU in sub-Saharan Africa. The specific aims were to examine whether BCG affords the same protection against TB infection (TBI) and disease in iHEU (corresponds to Aim 1), effect of HIV exposure on longitudinal gut microbiota composition and its association with TT vaccine response (corresponds to Aim 2), and optimization of epigenetic assay protocol, intended for future investigation of BCG-induced histone modifications in iHEU (corresponds to Aim 3). Methods and results: To assess TBI prevalence among iHEU and iHUU, a total of 418 mother-infant pairs from South Africa and Botswana were included. All infants received BCG vaccination at birth as per standard of care. T-SPOT.TB (ELISpot-based interferon-gamma release assay) was performed using cryopreserved peripheral blood mononuclear cells (PBMCs) from infants aged 9-18 months. The prevalence of TBI did not differ by the infant HIV exposure status, with 10 cases (3.4%) among iHEU and four cases (3.2%) among iHUU, none with symptoms of active TB disease. This trend was the same across two different African countries where the burden of HIV and TB is high. However, because of the lower T-SPOT.TB positivity than initially anticipated, we were under powered to conclude the effect. To assess whether gut microbial succession alters immunity in iHEU, we profiled longitudinal gut microbiota composition and associated this with TT vaccine responses in 354 mother-infant pairs from South Africa and Nigeria. Stool samples were collected at 1 and 15 weeks of life, and 16S ribosomal ribonucleic acid (rRNA) gene sequencing was performed. Plasma IgG anti-tetanus antibody titers were measured by enzyme-linked immunosorbent assay (ELISA). The effect of HIV exposure on infant gut microbiota composition was relatively modest compared to the impact of age and geographical factors. However, HIV exposure and specific gut microbes were independently associated with the TT vaccine response at 15 weeks of age. Results for South Africa and Nigeria differed, possibly due to higher maternal anti-tetanus IgG titers and hence infant baseline titers in Nigeria. To optimize an epigenetic assay that can be applied to infant samples, monocytes and natural killer (NK) cells were isolated from cryopreserved PBMCs using fluorescence-activated cell sorting (FACS). Cleavage Under Targets and Tagmentation (CUT&Tag) was optimized for assessing the histone modifications, acetylation of histone H3 at lysine 27 (H3K27Ac), trimethylation of histone H3 at lysine 4 (H3K4me3), and trimethylation of histone H3 at lysine 27 (H3K27me3; also used as a positive control). The optimized protocol was then applied to a subset of infant samples (n = 14; aged between six and seven weeks). Optimal input cell number, polymerase chain reaction (PCR) cycles, and sequencing depth were carefully determined for the CUT&Tag assay. These adjustments were necessary to achieve the assay's feasibility and data quality. The optimized CUT&Tag protocol and fine-tuned data analysis strategy successfully exhibited its capability to analyze multiple histone modifications using only 5,000 infant monocytes or NK cells as an input sample. Conclusions: Prenatal HIV exposure and gut microbiota may independently influence infant TT vaccine response. This supports the existing notion that iHEU exhibit altered immunity. Although previous studies have indicated that iHEU experience a higher risk of infection than iHUU, our data suggested that BCG vaccination was equally protective against TBI, irrespective of HIV exposure status. The optimized CUT&Tag protocol will offer a useful tool for investigating histone modifications using ultra-low input samples. This will be employed in the future study to explore whether iHEU exhibit comparable epigenetic modifications induced by BCG vaccination as for iHUU, providing valuable insight into whether iHEU receive similar non-specific protection from BCG vaccination compared to iHUU.
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    Effectiveness of different medical interventions implemented when a change in hearing status is detected during ototoxicity monitoring
    (2022) Gangerdine, Kayleen; Ramma, Lebogang; Petersen, Lucretia
    Background: Fourteen thousand (14, 000) people fell ill with Multi-Drug Resistant (MDR) or Rifampicin-Resistant (RR) Tuberculosis (TB) in South Africa (SA) in 2019. Aminoglycosides, which are commonly used anti-tuberculosis drugs in the treatment for RR/MDR-TB patients, are associated with ototoxicity (cochlear or vestibular). Aminoglycoside-induced cochleotoxicity is characterised by permanent, bilateral, highfrequency (HF) sensorineural hearing loss (SNHL). The impact of hearing loss (HL) due to aminoglycoside-induced cochleotoxicity can influence a patient's communication, psychological, physical functioning and overall well-being negatively and lead to a reduced quality of life (QoL). To reduce the risk of aminoglycoside-induced cochleotoxicity, patients' hearing thresholds are monitored (i.e., cochleotoxicity monitoring) when they are being treated with cochleotoxic aminoglycosides. Cochleotoxicity monitoring is performed to detect a significant threshold shift (STS) early and prevent further deterioration of hearing thresholds and avoid hearing loss which may end up affecting frequencies that are important for speech perception. When a STS or hearing loss is detected during cochleotoxicity monitoring, there are various intervention strategies that can be implemented by the treating medical personnel to avoid further deterioration of patient's hearing thresholds. These strategies may include discontinuing the aminoglycoside, changing the aminoglycoside to a less cochleotoxic alternative in the regimen or changing the frequency of administration of the aminoglycoside. This study, therefore, aimed to determine the effectiveness of different strategies used when a STS in hearing occurred during cochleotoxicity monitoring to prevent further deterioration in hearing thresholds. Methodology: A descriptive prospective repeated-measures design was used in this study. Patients who underwent RR/MDR-TB treatment with Kanamycin, a cochleotoxic aminoglycoside, at Brooklyn Chest Tuberculosis Hospital (BCH) between June to December 2016 were recruited to participate in the study. Only patients (n= 69) with normal hearing thresholds (i.e., pure tone average (PTA) at 500 Hz, 1 kHz and 2 kHz ≤ 25 dB HL) at baseline and age 18 – 55 years were included. Patients who were receiving two aminoglycosides, were retreatment patients or had active middle ear (ME) pathology were excluded from this study. Participants were sampled via a purposive sampling strategy. All audiological testing was performed in a sound-treated booth and participants underwent the following types of assessment; baseline, periodic monitoring, and diagnostic assessment (when indicated). The following tests were performed at baseline: case history, otoscopy (OT), tympanometry (TYMP), conventional pure tone audiometry (cPTA) including air conduction (AC) and bone conduction (BC), and ultra-high frequency audiometry (UHFA). Follow-up monitoring assessment occurred monthly if there was no significant change in hearing thresholds, and biweekly if an STS was detected. The ASHA criteria were used to determine STS. The degree of hearing loss was described as mild, moderate, moderately-severe, severe or profound and the type of hearing loss was either conductive, sensorineural, or mixed. Both descriptive and inferential (Chi-squared, Mann-Whitney U and Kruskal-Wallis) statistical tests were used for data analysis. Results: A total of sixty-nine (69) patients who were undergoing treatment for RR/MDR-TB were recruited to participate in this study. Five participants dropped out of the study due to various reasons, therefore, leaving 64 participants in the study. There was 38 males and 26 females. The median age was 31 [range; 18 - 55] years old. An aminoglycoside-induced cochleotoxicity incidence of 90.6% (58/64) was found in this study. There were no statistically significant associations between the occurrence of STS and age (p = 0.487), sex (p = 0.329) and HIV status (p = 0.764). Three types of intervention strategies were used when a participant experienced an STS: (i) discontinue Kanamycin (Strategy A), (ii) modify the frequency of Kanamycin administration (Strategy B), (iii) and leave the regimen unchanged, i.e., no intervention (Strategy C). A smaller proportion of participants, 12 out of 33, experienced further deterioration of hearing thresholds after intervention strategy A (discontinue Kanamycin) was used, when compared to participants who underwent intervention strategies B and C, but the difference was not statistically significant (p = 0.056). Conclusion: This study found a high incidence of cochleotoxicity among patients receiving Kanamycin treatment for RR/MDR-TB. The results showed that discontinuing Kanamycin led to fewer participants developing further deterioration of hearing thresholds, although not statistically significant. There were no statistically significant associations between the occurrence of STS and age, sex, and HIV status. This study had some limitations; only cochlear hearing loss was investigated, participants were not followed up beyond six months, and genetic testing was not performed. Nonetheless, this study revealed that fewer participants had further significant threshold shifts after discontinuing Kanamycin, and for those patients who still receive regimens containing aminoglycosides, these findings are relevant.
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    Environmental health recommendations for Multidrug-Resistant Tuberculosis in low- and middle-income countries: a systematic review
    (2022) Nel, Amy; Rother, Hanna-Andrea; Miller, Mary E
    Despite efforts towards the management and prevention of Tuberculosis (TB) having shown some success, Multidrug-Resistant Tuberculosis (MDR-TB) may potentially compromise these endeavours. MDR-TB has the potential to become the most dominant form of TB in low- and middle-income countries (LMICs). The impact of environmental health factors on the optimization of health of MDR-TB infected individuals, as well as on the prevention of transmission to household contacts, is not well documented. Current Sustainable Development Goals (SDGs) aim to achieve inclusivity, sustainability and resilience, not only through economic and social changes, but also through environmental targets in order to achieve optimal health and well-being for all. However, without appropriate acknowledgment of the environment's influence on outcomes during TB treatment, these targets are potentially unattainable. Establishing the recommendations of environmental health risk factors for individuals living at home with MDR-TB will have important policy implications as well as assist in decision making for those affected with MDR-TB in LMICs, such as South Africa. This systematic review, therefore, sought to identify the environmental health factors in LMICs that affect treatment outcomes for individuals living at home with MDR-TB, to optimize their health during completion of their treatment regimen and prevent transmission to household contacts. Part A outlines the current literature available for such a topic as well as methodology used within the systematic search and analysis of included articles. Prominent environmental health exposure variables of interest that have previously been identified as having a significant role in TB transmission or influencing the well-being of infected individuals, were identified within the literature. These included air pollution, nutrition, migration, urbanization, smoking, alcohol, other substance use and housing. Outcomes of interest included optimization of health and prevention of MDR-TB transmission to household contacts. The article (part B) represents the results from the systematic search as well as the application to current policy recommendations. After screening and reviewing the full text of potential articles for inclusion (N = 87), only thirteen articles were eligible for inclusion into the final sample. All included studies were primary observational studies, examining the relationship between MDRTB and the pre-defined exposures and outcomes in populations ≥13 years of age. Environmental risk factors for household transmission of MDR-TB potentially included malnutrition but showed no significant relationship with overcrowding. There was disagreement as to whether smoking was as a significant predictor of mortality but findings did indicate that smoking did have a negative impact on sputum culture conversion among patients receiving treatment. Other substance use was found to have a significant role in the default of treatment. The use of alcohol was associated with poor treatment outcomes, default of treatment and lack of sputum culture conversion. In terms of household conditions, an association was found between substandard housing conditions and treatment default. Formal housing was associated with a decline in treatment default but a residential address change was associated with defaulting treatment. The results of the review presented contradictory results regarding the risk of mortality and underweight/overweight BMI estimates. The review potentially highlighted vulnerable population groups including gender groups, children and HIV positive individuals. Therefore, this systematic review highlighted the potential relationship between environmental risk factors and optimising the health of individuals on treatment for MDR-TB, as well as the role that promoting environmental health may play in preventing the transmission to household contacts. In conclusion, environmental risk factors should be incorporated into local health system strategies and global policy. This includes WHO targets in TB prevention efforts, as well as in action areas for the attainment of relevant SDGs (e.g. SDG 3 and SDG 5), to address the burden of MDR-TB and decrease MDR-TB transmission in LMICs, effectively and sustainably.
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    Extensively drug-resistant tuberculosis in Africa: prevalence and factors associated: a systematic review and meta-analysis
    (2019) Kosmas, Petrus Ndiiluka; Ncayiyana, Jabulani; Engel, Mark E.
    Background: There is a dearth of information regarding prevalence of extensively drugresistant tuberculosis (XDR-TB) in Africa. Although countries in Africa conduct national tuberculosis surveys on a regular basis, this information has not been systematically reviewed to ascertain the overall prevalence of XDR-TB in Africa. Methods: The study aimed to perform a systematic review and meta-analysis of the prevalence and factors associated with prevalence of pulmonary XDR-TB among adults in Africa. Eligible studies, published between 2006 and 2018, were sourced from various electronic databases including PubMed, Scopus, and Web of Science. Meta-analysis was performed using STATA (version 14.2) statistical software. The protocol of this review was registered with PROSPERO, reg No CRD42018117037. Result: A total of 6242 records were retrieved. Forty-eight studies were screened for eligibility and seven, which varied in terms of country setting and study design, were included. The prevalence of XDR-TB is 4% (95%CI 2-7) among participants tested for second-line anti-TB drug resistance, and 3% (95%1-6) among participants with drug resistant TB. The prevalence of XDR-TB was 7% (95%CI 1-18) among participants with MDR-TB. A few studies reported on the factors associated with the prevalence of XDR-TB. Discussion: The reported prevalence of XDR-TB among participants tested for second-line anti-TB drug resistance is low compared to WHO estimates. The systematic review underscores a dearth of studies depicting the reality regarding the prevalence of XDR-TB in Africa. Policymakers and stakeholders interested in drug-resistant TB should apply prudence when considering XDR-TB prevalence reported for Africa.
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    Factors that influence the utilisation of ototoxicity monitoring services for patients on treatment for drug-resistant tuberculosis
    (2015) Nhokwara, Primrose Tinashe; Rogers, Christine; Ramma, Lebogang
    Multi-drug resistance is increasingly becoming a challenge to tuberculosis control programmes globally. Treatment of multi-drug resistance tuberculosis (MDR-TB) includes aminoglycoside antibiotics which are known to cause hearing loss. Ototoxicity monitoring services are often provided to patients undergoing treatment for MDR-TB for early detection of ototoxic hearing loss to facilitate alerting the patients and relevant medical staff about the presence and progression of any hearing loss. Previously, models of managing patients with MDR-TB required mandatory hospitalization for at least 6 months. This made it relatively easy to monitor the hearing status of patients during their stay in the hospital. However, with recent introduction of policy guidelines that support management of patients with MDR-TB on an outpatients basis, ototoxicity monitoring for these patients will need to be reorganized to align with the new policy guidelines. The extent of the uptake of these services when patients are accessing them as outpatients is however, unknown. This study therefore aimed to describe the patterns of utilisation and explore the barriers and factors that facilitate the use of ototoxicity monitoring services when provided on an outpatient basis in the Cape Town Metropolitan area, Western Cape, South Africa.
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    Gastric lavage procedure animation
    (2010) Daya, Rupesh; Kibel, Maurice; Stent, Stacey
    This resource can be used to illustrate the gastric lavage procedure. Gastric lavage is the standard method of obtaining specimens for Tuberculosis (TB) diagnosis in young children. This animation can be used to demonstrate how this sensitive procedure is performed to medical students.
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    High levels of multidrug resistant tuberculosis in new and treatment-failure patients from the Revised National Tuberculosis Control Programme in an urban metropolis (Mumbai) in Western India
    (BioMed Central Ltd, 2009) D'souza, Desiree TB; Mistry, Nerges F; Vira, Tina N; Dholakia, Yatin; Hoffner, Sven; Pasvol, Geoffrey; Nicol, Mark; Wilkinson, Robert J
    BACKGROUND: India, China and Russia account for more than 62% of multidrug resistant tuberculosis (MDRTB) globally. Within India, locations like urban metropolitan Mumbai with its burgeoning population and high incidence of TB are suspected to be a focus for MDRTB. However apart from sporadic surveys at watched sites in the country, there has been no systematic attempt by the Revised National Tuberculosis Control Programme (RNTCP) of India to determine the extent of MDRTB in Mumbai that could feed into national estimates. Drug susceptibility testing (DST) is not routinely performed as a part of programme policy and public health laboratory infrastructure, is limited and poorly equipped to cope with large scale testing. METHODS: From April 2004 to January 2007 we determined the extent of drug resistance in 724 {493 newly diagnosed, previously untreated and 231 first line treatment failures (sputum-smear positive at the fifth month after commencement of therapy)} cases of pulmonary tuberculosis drawn from the RNTCP in four suboptimally performing municipal wards of Mumbai. The observations were obtained using a modified radiorespirometric Buddemeyer assay and validated by the Swedish Institute for Infectious Disease Control, Stockholm, a supranational reference laboratory. Data was analyzed utilizing SPSS 10.0 and Epi Info 2002. RESULTS: This study undertaken for the first time in RNTCP outpatients in Mumbai reveals a high proportion of MDRTB strains in both previously untreated (24%) and treatment-failure cases (41%). Amongst new cases, resistance to 3 or 4 drug combinations (amplified drug resistance) including isoniazid (H) and rifampicin (R), was greater (20%) than resistance to H and R alone (4%) at any point in time during the study. The trend for monoresistance was similar in both groups remaining highest to H and lowest to R. External quality control revealed good agreement for H and R resistance (k = 0.77 and 0.76 respectively). CONCLUSION: Levels of MDRTB are much higher in both previously untreated and first line treatment-failure cases in the selected wards in Mumbai than those projected by national estimates. The finding of amplified drug resistance suggests the presence of a well entrenched MDRTB scenario. This study suggests that a wider set of surveillance sites are needed to obtain a more realistic view of the true MDRTB rates throughout the country. This would assist in the planning of an adequate response to the diagnosis and care of MDRTB.
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    HIV viral load as an independent risk factor for tuberculosis in South Africa: collaborative analysis of cohort studies
    (2017) Fenner, Lukas; Atkinson, Andrew; Boulle, Andrew; Fox, Matthew P; Prozesky, Hans; ZYrcher, Kathrin; Ballif, Marie; Furrer, Hansjakob; Zwahlen, Marcel; Davies, Mary-Ann; Egger, Matthias
    Introduction: Chronic immune activation due to ongoing HIV replication may lead to impaired immune responses against opportunistic infections such as tuberculosis (TB). We studied the role of HIV replication as a risk factor for incident TB after starting antiretroviral therapy (ART).
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    The Invisible Story: Underground Health Narratives of Women in Mining
    (2017) Mutendi, Mutsawashe; Macdonald, Helen
    This dissertation may be read on several different levels. At its most accessible, it is a detailed ethnographic description of how ‘women in mining’ negotiate the daily terrain of caregiving and being exposed to highly contagious and resistant diseases that are associated with mining, which could potentially adversely affect their day-to-day lives, wellbeing and family relations. At its most analytical, it utilises Nixon’s concept of ‘slow violence’ by carefully charting the challenges that a female mineworker faces; having to provide for her family even in the most difficult situations, and sometimes at the expense of her own health. Hence, ‘women in mining’ are situated in a web of connections that exist between working underground and being caregivers in their homes; while at risk of transmitting tuberculosis (TB) and acquiring reproductive health related problems. This dissertation illustrates the tactics and coping strategies that women in mining employ, and argues that they ‘make a plan’ to minimise the negative social consequences of ill health.
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    Medicine and the Arts Week 2 - In dialogue about children's voices
    (2015-01-21) Levine, Susan; Callaghan, Nina; Abney, Kate; Hendricks, Marc
    In this video, Associate Professor Susan Levine pose questions to Dr. Hendricks, Dr. Kate Abney, as well as Nina Callaghan in an attempt to unlock some of the synergies that brings their various perspectives into focus. Marc Hendricks is asked how doctors take care of themselves in dealing with the deaths, illness and victories of their patients’ stories. Kate talks about how she has used art as part of her research methodology and discusses how the issue of time surfaced in her work at the TB hospital. Nina provides an example of a child she had worked with. This is the fifth video in Week 2 of the Medicine and the Arts Massive Open Online Course.
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    Medicine and the Arts Week 2 - Me and TB: children's accounts of tuberculosis and the clinic
    (2015-01-21) Abney, Kate
    In this video, medical anthropologist Kate Abney shares some of the stories told by young patients in the tuberculosis (TB) wards of hospitals across South Africa’s Western Cape where she worked. She describes how she has helped to facilitate storytelling among young TB patients through art. This is the third video in Week 2 of the Medicine and the Arts Massive Open Online Course.
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    Newer and novel sputum versus non-sputum-based tools for the diagnosis of active tuberculosis in different patient sub-populations
    (2025) Esmail, Aliasgar; Dheda, Keertan
    Background Pulmonary tuberculosis (PTB) has a spectrum of presentation ranging from sub clinical/minimally symptomatic disease on one end, usually in community-based patients, to overt symptomatic TB with hospitalisation on the severe end of the spectrum. This spectrum of sub-clinical and clinical presentation of TB along with the site of TB (pulmonary vs. Extra-pulmonary TB) generate a number of sub-populations. Current diagnostic tools are not a ‘one size fits all' and have important differential limitations in these patient sub-populations including those with pauci-bacillary disease (e.g., in HIV-infected patients, minimally symptomatic patients with low burden disease in the community, and in patients with extra-pulmonary TB). Thus, the overarching objective of this PhD was to evaluate the diagnostic performance of frontline tests, including the newer and more sensitive Xpert Ultra and urine LAM in key active TB patient sub-populations (wherein data are limited). The main themes and sub-populations included in my thesis are as follows: 1) Hospitalised HIV-Infected patients (patients in the severe end of PTB spectrum): To determine the optimal and most cost-efficient diagnostic strategy incorporating sputum and LAM (lipoarabinomannan) for the detection of TB (chapter 1). 2) Smear-negative TB: Independent confirmation on the performance of the more sensitive Xpert Ultra (Cepheid MTB/RIF Ultra) in sputum archived samples (chapter 2). 3) Community-based minimally symptomatic patients (patient in the non-severe end of the PTB spectrum): Evaluation of point-of-care (POC) sputum Xpert Ultra for detection of TB in minimally symptomatic/at-risk population for TB and its impact in detecting potentially infectious patients (chapter 3). 4) Extra-pulmonary TB (TB serositis): Evaluation on the performance of conventional diagnostic tools, including Xpert Ultra in tuberculous pericarditis (chapter 4) and pleuritis (chapter 5) compared to a novel immunodiagnostic tool (IRISA-TB). Methods (sub-populations are underlined) In Chapter 1, I describe an evaluation of an algorithm that describes the optimal & cost efficient strategy to combine sputum GeneXpert and urine LAM (tests that are recommended by the WHO) in a hospitalized HIV-infected sub-population: This comprised a post-hoc analysis of 561 HIV-infected sputum-expectorating patients that was part of a larger parent trial. 5 different diagnostic strategies using sputum culture as a reference standard were explored (Xpert alone, LAM alone, sequential Xpert followed by LAM and vice versa [LAM in Xpert-negative patients and Xpert in LAM-negative patients], and both tests concurrently [LAM + Xpert]). A cost-consequence analysis was also performed. In Chapter 2, I evaluated the performance of GeneXpert Ultra in 272 selected and well characterized archived sputum samples including 104 patients with smear negative TB and 102 non-TB with a history of previous TB to accentuate and evaluate the clinical significance of trace readouts (i.e., a readout that usually corresponds to the detection of a very small amount of TB DNA). Assay-specific limit-of-detection (LOD) experiments were conducted using serial dilutions of Mycobacterium tuberculosis H37Rv to confirm the assay's detection threshold. In In Chapter 3, I evaluated the diagnostic performance of point-of-care (POC) Xpert Ultra for the detection of TB in minimally symptomatic community-based sub-population: 5,274 participants were rapidly screened to enrol 584 patients with suspected pulmonary TB from peri-urban high burden communities of Cape Town, South Africa. The utility of POC-Xpert Ultra in detecting likely infectious patients was also specifically evaluated. In Chapter 4, I described the diagnostic performance of pericardial fluid unstimulated interferon gamma (measured using the novel IRISA-TBTM test) and compared it to other same-day tests including Xpert Ultra and adenosine deaminase (ADA) in 99 South African patients with suspected pericardial TB using a composite reference standard including pericardial fluid, pericardial tissue TB culture, pericardial tissue histopathology and response to TB treatment. Similarly, In Chapter 5, I described the diagnostic performance of pleural fluid unstimulated interferon gamma (measured using the novel IRISA-TBTM test) and compared to other same-day tests including Xpert Ultra and adenosine deaminase (ADA) in 207 individuals from Cape Town, South Africa and Vellore, India. A composite reference standard including pleural fluid, pleural tissue TB culture, pericardial tissue histopathology and response to TB treatment was used to define the composite reference standard for TB. Results: Chapter 1: In the HIV-infected hospitalised patient sub-population, the incremental yield of LAM over Xpert was 29.6% (45/152) and that of Xpert over LAM was 75% (84/11). The incremental yield of LAM increased with decreasing CD4 count. The costs per TB case diagnosed were similar for the sequential and concurrent strategies ($1,617 to $1,626). Chapter 2: Xpert Ultra had a lower sputum-specific LOD compared to that of the G4 version of Xpert MTB/RIF (9 vs. 184 cfu/mL). 94% in both forms of EPTB in chapters 4 & 5. Conclusions: Overall, the performance of currently available diagnostic tools varied in different subpopulations due to differential mycobacterial load, the compartment interrogated, patient phenotype (e.g. HIV-infected), testing strategy, and clinical context (e.g. hospitalized versus community-based). Main findings from each chapter as summarized as follows: Main conclusion in chapter 1: Xpert-Ultra had a considerably lower limit-of-detection compared to older Xpert-MTB/RIF assay, however, trace-readouts in the context of previous TB, reduced the specificity of the assay slight (<5%). A third of the trace results (3/9) were likely false positive. Main conclusion in chapter 2: In sputum-expectorating hospitalized patients with advanced HIV and access to both Xpert and LAM, concurrent testing with sputum Xpert and urine LAM may be the best and most cost-effective strategy for diagnosing TB in this sub-population. Main conclusion in chapter 3: POC-Xpert Ultra, when used as part of a community-based ACF, missed ~50% of patients with culture-positive TB. However, Xpert detected almost all likely infectious cases. Main conclusions in chapters 4 & 5: Conventional TB diagnostic tests performed poorly in pericardial and pleural TB. IRISA-TBTM, a novel same-day immunodiagnostic test, outperformed Xpert Ultra for the diagnosis of pericardial and pleural TB. These data have implications for the clinical utility of newer diagnostic tools in patient sub-populations from TB and HIV endemic settings.
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    Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome
    (Lippincott, Williams & Wilkins, 2010) Meintjes, Graeme; Wilkinson, Robert J; Morroni, Chelsea; Pepper, Dominique J; Rebe, Kevin; Rangaka, Molebogeng X; Oni, Tolu; Maartens, Gary
    Objective: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of antiretroviral therapy in resource-limited countries. We aimed to assess whether a 4 week course of prednisone would reduce morbidity in patients with paradoxical TB-IRIS without excess adverse events. Design: A randomised double blind placebo-controlled trial of prednisone (1.5mg/kg/day for 2 weeks then 0.75mg/kg/day for 2 weeks). Patients with immediately life-threatening TB-IRIS manifestations were excluded. Methods: The primary combined endpoint was days of hospitalization and outpatient therapeutic procedures, which were counted as one hospital day. Results: 110 participants were enrolled (55 to each arm). The primary combined endpoint was more frequent in the placebo than the prednisone arm (median hospital days 3 (IQR 0-9) and 0 (IQR 0-3) respectively; p=0.04). There were significantly greater improvements in symptoms, Karnofsky score, and quality of life (MOS-HIV) in the prednisone versus the placebo arm at 2 and 4 weeks, but not at later timepoints. Chest radiographs improved significantly more in the prednisone arm at weeks 2 (p=0.002) and 4 (p=0.02). Infections on study medication occurred in more participants in prednisone than placebo arm (27 vs 17 respectively; p=0.05), but there was no difference in severe infections (2 vs 4 respectively; p=0.40). Isolates from 10 participants were found to be resistant to rifampicin after enrollment. Conclusions: Prednisone reduced the need for hospitalisation and therapeutic procedures, and hastened improvements in symptoms, performance and quality of life. It is important to investigate for drug-resistant tuberculosis and other causes for deterioration before administering glucocorticoids.
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    Reconstitution of antimycobacterial immune responses in HIV-infected children receiving HAART
    (2006) Kampmann, B; Tena, G; Nicol, MP; Levin, M; Eley, BS
    Objective: Recent epidemiological studies in adults suggest that HAART can prevent the development of tuberculosis in HIV-infected individuals, but the mechanisms are incompletely understood and no data exist in children. We investigated whether changes in mycobacterial-specific immune responses can be demonstrated in children after commencing antiretroviral therapy. Design: We measured mycobacterial growth in vitro using a novel whole-blood assay employing reporter-gene tagged bacillus Calmette–Guérin (BCG) in a prospective cohort study in the tuberculosis-endemic environment of South Africa. Key cytokines were measured in supernatants collected from the whole-blood assay using cytometric bead array. Patients: A cohort of 15 BCG-vaccinated HIV-infected children was evaluated prospectively for in-vitro antimycobacterial immune responses before and during the first year of HAART. All children had advanced HIV disease. Nine children completed all study timepoints. Results: Before HAART, blood from children showed limited ability to restrict the growth of mycobacteria in the functional whole-blood assay. The introduction of HAART was followed by rapid and sustained reconstitution of specific antimycobacterial immune responses, measured as the decreased growth of mycobacteria. IFN-γ levels in culture supernatants did not reflect this response; however, a decline in TNF-α was observed. Conclusion: This is the first study using a functional in-vitro assay to assess the effect of HAART on immune responses to mycobacteria in HIV-infected children. Our in-vitro data mirror the in-vivo observation of decreased susceptibility to tuberculosis in HIV-infected adults receiving antiretroviral agents. This model may be useful for further characterizing immune reconstitution after HAART.
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    The clinical significance of the erythrocyte sedimentation rate with special reference to pulmonary tuberculosis
    (1947) Wiles, Frank Joseph
    There are few subjects in medicine, about which there is more controversy than the Erythrocyte Sedimentation Rate. Some authorities place great ·reliance on test while others have discarded it as having no practical importance. There is little agreement as regards either the methods of estimation and interpretation or the clinical value of the test. This thesis will deal only with practical considerations. Theories as to the mechanism of sedimentation will not be discussed.