Browsing by Author "Workman, Lesley"
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- ItemOpen AccessAdherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules(BioMed Central Ltd, 2009) le Roux, Stanzi; Cotton, Mark; Golub, Jonathan; le Roux, David; Workman, Lesley; Zar, HeatherBACKGROUND:Tuberculosis contributes significantly to morbidity and mortality among HIV-infected children in sub-Saharan Africa. Isoniazid prophylaxis can reduce tuberculosis incidence in this population. However, for the treatment to be effective, adherence to the medication must be optimized. We investigated adherence to isoniazid prophylaxis administered daily, compared to three times a week, and predictors of adherence amongst HIV-infected children. METHODS: We investigated adherence to study medication in a two centre, randomized trial comparing daily to three times a week dosing of isoniazid. The study was conducted at two tertiary paediatric care centres in Cape Town, South Africa. Over a 5 year period, we followed 324 HIV-infected children aged [greater than or equal to] 8 weeks. Adherence information based on pill counts was available for 276 children. Percentage adherence was calculated by counting the number of pills returned. Adherence [greater than or equal to] 90% was considered to be optimal. Analysis was done using summary and repeated measures, comparing adherence to the two dosing schedules. Mean percentage adherence (per child during follow-up time) was used to compare the mean of each group as well as the proportion of children achieving an adherence of [greater than or equal to] 90% in each group. For repeated measures, percentage adherence (per child per visit) was dichotomized at 90%. A logistic regression model with generalized estimating equations, to account for within-individual correlation, was used to evaluate the impact of the dosing schedule. Adjustments were made for potential confounders and we assessed potential baseline and time-varying adherence determinants. RESULTS: The overall adherence to isoniazid was excellent, with a mean adherence of 94.7% (95% confidence interval [CI] 93.5-95.9); similar mean adherence was achieved by the group taking daily medication (93.8%; 95% CI 92.1-95.6) and by the three times a week group (95.5%; 95% CI 93.8-97.2). Two-hundred and seventeen (78.6%) children achieved a mean adherence of [greater than or equal to] 90%. Adherence was similar for daily and three times a week dosing schedules in univariate (odds ratio [OR] 0.88; 95% CI 0.66-1.17; P = 0.38) and multivariate (adjusted OR 0.85; 95% CI 0.64-1.11; P = 0.23) models. Children from overcrowded homes were less adherent (adjusted OR 0.71; 95% CI 0.54-0.95; P = 0.02). Age at study visit was predictive of adherence, with better adherence achieved in children older than 4 years (adjusted OR 1.96; 95% CI 1.16-3.32; P = 0.01). CONCLUSION: Adherence to isoniazid was excellent regardless of the dosing schedule used. Intermittent dosing of isoniazid prophylaxis can be considered as an alternative to daily dosing, without compromising adherence or efficacy.TRIAL REGISTRATION:Clinical Trials NCT00330304
- ItemOpen AccessComparison of mantoux and tine tuberculin skin tests in BCG-vaccinated children investigated for tuberculosis(Public Library of Science, 2009) Pan, Wenli; Matizirofa, Lyness; Workman, Lesley; Hawkridge, Tony; Hanekom, Willem; Mahomed, Hassan; Hussey, Gregory; Hatherill, MarkBackground: Tuberculin skin tests (TSTs) are long-established screening methods for tuberculosis (TB). We aimed to compare agreement between the intradermal Mantoux and multipuncture percutaneous Tine methods and to quantify risk factors for a positive test result. Methodology/Principal Findings: 1512 South African children younger than 5 years of age who were investigated for tuberculosis (TB) during a Bacille Calmette Guerin (BCG) trial were included in this analysis. Children underwent both Mantoux and Tine tests. A positive test was defined as Mantoux ≥15 mm or Tine ≥ Grade 3 for the binary comparison. Agreement was evaluated using kappa (binary) and weighted kappa (hierarchical). Multivariate regression models identified independent risk factors for TST positivity. The Mantoux test was positive in 430 children (28.4%) and the Tine test in 496 children (32.8%, p<0.0001), with observed binary agreement 87.3% (kappa 0.70) and hierarchical agreement 85.0% (weighted kappa 0.66). Among 173 children culture-positive for Mycobacterium tuberculosis, Mantoux was positive in 49.1% and Tine in 54.9%, p<0.0001 (kappa 0.70). Evidence of digit preference was noted for Mantoux readings at 5 mm threshold intervals. After adjustment for confounders, a positive culture, suggestive chest radiograph, and proximity of TB contact were risk factors for a positive test using both TST methods. There were no independent associations between ethnicity, gender, age, or over-crowding, and TST result. Conclusions/Significance: The Tine test demonstrated a higher positive test rate than the Mantoux, with substantial agreement between TST methods among young BCG-vaccinated children. TB disease and exposure factors, but not demographic variables, were independent risk factors for a positive result using either test method. These findings suggest that the Tine might be a useful screening tool for childhood TB in resource-limited countries.
- ItemOpen AccessDoes helminth treatment reduce the risk of active tuberculosis in a cohort of children from high tuberculosis risk population who have been vaccinated with BCG at birth?(2009) Workman, Lesley; Ehrlich, Rodney; Little, Francesca; Hatherill, Mark[Background] Research in adults and older children has shown an association between Mycobacterium tuberculosis and helminth infection, with those infected with helminths at greater risk of tuberculosis. This association is believed to be on the basis that chronic helminth infection can result in a functional impairment of the immune response that is necessary to clear or control infection by Mycobacterium tuberculosis (Elias et al. 2001; Rook et al. 2006; Fincham 2001). It is thus possible that the introduction of regular deworming programmes in a vulnerable population of children under the age of five years could assist their immune systems to ward off tuberculosis infection and reduce the risk of tuberculosis disease in such a population. A randomised controlled trial to compare two methods of administering bacille Camlette-Guerin (BCG) vaccination to newborns from a high tuberculosis risk population provided an opportunity to test this hypothesis in a sub-study. [Objective] The objective of this study is to determine if young children in a high-risk tuberculosis population who have been vaccinated with BCG at birth and have been treated for helminth infection are at lower risk of tuberculosis disease than children who have been vaccinated with BCG at birth but not treated for helminth infection. [Method] A case control study nested within a cohort recruited for a separate randomised control trial to compare two methods of administering BCG vaccination was carried out. Children who presented to their local clinic or hospital with symptoms of tuberculosis or a history of exposure to tuberculosis were admitted to a case verification (CV) ward for investigation of tuberculosis. Investigation of tuberculosis included a detailed history, including past helminth treatment, physical examination, tuberculin skin test, chest radiograph, gastric washing and induced sputum for culture of tuberculosis and clinical examination. A diagnostic algorithm was developed by specialist physicians and biostatisticians to classify the children into one of five tuberculosis categories. A total of 510 children (median age 18.13 months) were included in the primary analysis of this case control study. Those defined as cases were the 328 classified as "definite or probable TB" and 182, classified as "not TB", comprised the control group. Those classified as "possible TB" or "unlikely TB" were excluded. A secondary analysis was performed that included the 337 children who had been classified as "unlikely TB" with the controls resulting in a total of 847 children (median age 18.37 months). The 328 children classified as "definite or probable TB" were defined as cases and the 519 classified as "unlikely or not TB" comprised the control group. Univariate analysis was used to explore a possible relationship between tuberculosis and helminth treatment using all the variables in the sub-study (n=510 primary analysis; n=847 secondary analysis). For both the primary and secondary analysis a multivariate logistic regression model was built using a reduced sample that had a complete set of data for all the variables: primary analysis (n=435); secondary analysis (n=724). This final model was then fitted on a more complete sample as the final variables selected had fewer missing data for the observations: primary analysis (n=493); secondary analysis (n=822). [Result] A total of 35.69% of the study sample in the primary analysis had been treated for helminth infection. The proportion of children who had been treated for helminth infection was similar in the cases and controls (35.98% and 35.16% respectively). Univariate logistic regression showed no association between tuberculosis and treatment for helminth infection: [odds ratio (OR) 1.04; 95% confidence interval (CI) 0.71 - 1.51]. Multivariate analysis adjusted for the effect of nutritional status, recorded as height for age z score (haz), number of occupants sharing the same dwelling as the child, gender and birth site showed a similar result: (OR 1.03; 95% CI 0.69 " 1.53). The OR is very close to 1 with a 95% CI that includes 1, which indicates that there is not a statistically significant association between tuberculosis and helminth treatment. In the secondary analysis, a total of 38.61% of the study sample had been treated for helminth infection. In this analysis the proportion of children who had been treated for helminth infection showed a difference between the cases and controls (35.98% and 40.27% respectively). Univariate logistic regression showed a 17% relative reduction in tuberculosis odds but this was not a statistically significant result: (OR 0.83; 95% CI 0.63 " 1.11). Multivariate analysis adjusted for the effect of haz, number of children sharing the same dwelling as the child and gender, showed a similar result: (OR 0.85; 95% CI 0.63 " 1.15). [Conclusion] The primary analysis of this observational study does not support the hypothesis that helminth treatment reduces the risk of tuberculosis disease in young children in a high-risk tuberculosis population. Although the secondary analysis showed a 15% relative reduction in tuberculosis odds after adjusting for the effect of haz, number of occupants sharing the same dwelling as the child and gender, this was not a statistically significant result. [Final Conclusion] This study does not support the hypothesis that helminth treatment reduces the risk of tuberculosis disease in young children in a high-risk tuberculosis population.
- ItemOpen AccessHuman rhinovirus infection in young African children with acute wheezing(BioMed Central Ltd, 2011) Smuts, Heidi; Workman, Lesley; Zar, HeatherBACKGROUND:Infections caused by human rhinoviruses (HRVs) are important triggers of wheezing in young children. Wheezy illness has increasingly been recognised as an important cause of morbidity in African children, but there is little information on the contribution of HRV to this. The aim of this study was to determine the role of HRV as a cause of acute wheezing in South African children. METHODS: Two hundred and twenty children presenting consecutively at a tertiary children's hospital with a wheezing illness from May 2004 to November 2005 were prospectively enrolled. A nasal swab was taken and reverse transcription PCR used to screen the samples for HRV. The presence of human metapneumovirus, human bocavirus and human coronavirus-NL63 was assessed in all samples using PCR-based assays. A general shell vial culture using a pool of monoclonal antibodies was used to detect other common respiratory viruses on 26% of samples. Phylogenetic analysis to determine circulating HRV species was performed on a portion of HRV-positive samples. Categorical characteristics were analysed using Fisher's Exact test. RESULTS: HRV was detected in 128 (58.2%) of children, most (72%) of whom were under 2 years of age. Presenting symptoms between the HRV-positive and negative groups were similar. Most illness was managed with ambulatory therapy, but 45 (35%) were hospitalized for treatment and 3 (2%) were admitted to intensive care. There were no in-hospital deaths. All 3 species of HRV were detected with HRV-C being the most common (52%) followed by HRV-A (37%) and HRV-B (11%). Infection with other respiratory viruses occurred in 20/128 (16%) of HRV-positive children and in 26/92 (28%) of HRV-negative samples. CONCLUSION: HRV may be the commonest viral infection in young South African children with acute wheezing. Infection is associated with mild or moderate clinical disease.
- ItemOpen AccessMaking data map-worthy—enhancing routine malaria data to support surveillance and mapping of Plasmodium falciparum anti-malarial resistance in a pre-elimination sub-Saharan African setting: a molecular and spatiotemporal epidemiology study(2022-06-29) Kagoro, Frank M.; Allen, Elizabeth; Mabuza, Aaron; Workman, Lesley; Magagula, Ray; Kok, Gerdalize; Davies, Craig; Malatje, Gillian; Guérin, Philippe J; Dhorda, Mehul; Maude, Richard J; Raman, Jaishree; Barnes, Karen IBackground Independent emergence and spread of artemisinin-resistant Plasmodium falciparum malaria have recently been confirmed in Africa, with molecular markers associated with artemisinin resistance increasingly detected. Surveillance to promptly detect and effectively respond to anti-malarial resistance is generally suboptimal in Africa, especially in low transmission settings where therapeutic efficacy studies are often not feasible due to recruitment challenges. However, these communities may be at higher risk of anti-malarial resistance. Methods From March 2018 to February 2020, a sequential mixed-methods study was conducted to evaluate the feasibility of the near-real-time linkage of individual patient anti-malarial resistance profiles with their case notifications and treatment response reports, and map these to fine scales in Nkomazi sub-district, Mpumalanga, a pre-elimination area in South Africa. Results Plasmodium falciparum molecular marker resistance profiles were linked to 55.1% (2636/4787) of notified malaria cases, 85% (2240/2636) of which were mapped to healthcare facility, ward and locality levels. Over time, linkage of individual malaria case demographic and molecular data increased to 75.1%. No artemisinin resistant validated/associated Kelch-13 mutations were detected in the 2385 PCR positive samples. Almost all 2812 samples assessed for lumefantrine susceptibility carried the wildtype mdr86ASN and crt76LYS alleles, potentially associated with decreased lumefantrine susceptibility. Conclusion Routine near-real-time mapping of molecular markers associated with anti-malarial drug resistance on a fine spatial scale provides a rapid and efficient early warning system for emerging resistance. The lessons learnt here could inform scale-up to provincial, national and regional malaria elimination programmes, and may be relevant for other antimicrobial resistance surveillance.
- ItemOpen AccessSafety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial(2019-06-24) Raman, Jaishree; Allen, Elizabeth; Workman, Lesley; Mabuza, Aaron; Swanepoel, Hendrik; Malatje, Gillian; Frean, John; Wiesner, Lubbe; Barnes, Karen IAbstract Background To reduce onward falciparum malaria transmission, the World Health Organization recommends adding single low-dose (SLD) primaquine to artemisinin-based combination treatment in low transmission areas. However, uptake of this recommendation has been relatively slow given concerns about whether individual risks justify potential community benefit. This study was undertaken to generate comprehensive local data on the risk–benefit profile of SLD primaquine deployment in a pre-elimination area in South Africa. Methods This randomized, controlled open-label trial investigated adding a single low primaquine dose on day 3 to standard artemether–lumefantrine treatment for uncomplicated falciparum malaria. Efficacy, safety and tolerability of artemether–lumefantrine and primaquine treatment were assessed on days 3, 7, 14, 28 and 42. Lumefantrine concentrations were assayed from dried blood spot samples collected on day 7. Results Of 217 patients screened, 166 were enrolled with 140 randomized on day 3, 70 to each study arm (primaquine and no primaquine). No gametocytes were detected by either microscopy or PCR in any of the follow-up samples collected after randomization on day 3, precluding assessment of primaquine efficacy. Prevalence of the CYP2D6*4, CYP2D6*10 and CYP2D6*17 mutant alleles was low with allelic frequencies of 0.02, 0.11 and 0.16, respectively; none had the CYP2D6*4/*4 variant associated with null activity. Among 172 RDT-positive patients G6PD-genotyped, 24 (14%) carried the G6PD deficient (A−) variant. Median haemoglobin concentrations were similar between treatment arms throughout follow-up. A third of participants had a haemoglobin drop > 2 g/dL; this was not associated with primaquine treatment but may be associated with G6PD genotype [52.9% (9/17) with A− genotype vs. 31% (36/116) with other genotypes (p = 0.075)]. Day 7 lumefantrine concentrations and the number and nature of adverse events were similar between study arms; only one serious adverse event occurred (renal impairment in the no primaquine arm). The artemether–lumefantrine PCR-corrected adequate clinical and parasitological response rate was 100%, with only one re-infection found among the 128 patients who completed 42-day follow-up. Conclusions Safety, tolerability, CYP2D6 and G6PD variant data from this study support the deployment of the WHO-recommended SLD primaquine without G6PD testing to advance malaria elimination in South African districts with low-intensity residual transmission. Trial registration Pan African Clinical Trial Registry, PACTR201611001859416. Registered 11 November 2016, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=1859