Browsing by Author "Hesseling, Anneke C."
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- ItemAnti-Group B Streptococcus antibody in infants born to mothers with human immunodeficiency virus (HIV) infection(Elsevier, 2015-01-29) Le Doare, Kirsty; Allen, Lauren; Kampmann, Beate; Heath, Paul Trafford; Taylor, Stephen; Hesseling, Anneke C.; Gorringe, Andrew; Jones, Christine ElizabethBackground: HIV-exposed uninfected infants have increased infection risk and mortality compared to HIV-unexposed infants. HIV-exposed infants may be at increased risk of invasive GBS disease due to reduced maternal antibody against GBS. Methods: We quantified antibodies that bind to the surface of whole Group B Streptococcus (GBS) of serotypes Ia, Ib, II, III and V using novel flow cytometry assays in South African HIV-infected and non-infected mothers and their uninfected infants. Antibody-mediated complement C3b/iC3b deposition onto GBS of these serotypes was also quantified by a novel flow cytometry assay. Results: Geometric mean concentration (GMC) of both surface-binding anti-GBS antibody and antibody-mediated complement deposition onto GBS were reduced in HIV-infected women (n = 46) compared to HIV-uninfected women (n = 58) for ST1a (surface-binding: 19.3 vs 29.3; p = 0.003; complement deposition: 2.9 vs 5.3 SU/mL; p = 0.003), STIb (24.9 vs 47.6; p = 0.003; 2.6 vs 4.9 SU/mL; p = 0.003), STII (19.8 vs 50.0; p = 0.001; 3.1 vs 6.2 SU/mL; p = 0.001), STIII (27.8 vs 60.1; p = 0.001; 2.8 vs 5.3 SU/mL; p = 0.001) and STV (121.9 vs 185.6 SU/mL; p < 0.001) and in their infants for STIa (complement deposition 9.4 vs 27.0 SU/mL; p = 0.02), STIb (13.4 vs 24.5 SU/mL; p = 0.02), STII (14.6 vs 42.7 SU/mL; p = 0.03), STIII (26.6 vs 62.7 SU/mL; p = 0.03) and STV (90.4 vs 165.8 SU/mL; p = 0.04). Median transplacental transfer of antibody from HIV-infected women to their infants was reduced compared to HIV-uninfected women for GBS serotypes II (0.42 [IQR 0.22–0.59] vs 1.0 SU/mL [0.42–1.66]; p < 0.001), III (0.54 [0.31–1.03] vs 0.95 SU/mL [0.42–3.05], p = 0.05) and V (0.51 [0.28–0.79] vs 0.75 SU/mL [0.26–2.9], p = 0.04). The differences between infants remained significant at 16 weeks of age. Conclusions: Maternal HIV infection was associated with lower anti-GBS surface binding antibody concentration and antibody-mediated C3b/iC3b deposition onto GBS bacteria of serotypes Ia, Ib, II, III and V. This may render these infants more susceptible to early and late onset GBS disease.
- ItemAssessing the impact of multidrug-resistant tuberculosis in children : an exploratory qualitative study(BioMed Central, 2014-08) Franck, Caroline; Seddon, James A.; Hesseling, Anneke C.; Schaaf, H. Simon; Skinner, Donald; Reynolds, LucyBackground: While the prevalence of multidrug-resistant (MDR) tuberculosis (TB) is high among children in the Western Cape of South Africa, the psychosocial implications of treatment for children with MDR-TB remain poorly understood. We sought to explore how MDR-TB and its treatment impact children on an individual, familial, and social level. Methods: Semi-structured interviews were conducted with 20 children and caregivers purposively sampled from a prospective clinical cohort of children. The sample was stratified by age at the start of treatment (children >10 years, and 5-10 years). Caregiver proxy interviews were conducted with younger children, supplemented with child interviews; older children were interviewed directly, supplemented with caregiver proxy interviews. Data were analysed using grounded theory. Results: Findings revealed pill volume and adverse effects produced significant physical, psychological and academic disturbances in children. Adverse effects related to the medication were important obstacles to treatment adherence. While there appear to be no long-lasting effects in younger children, a few older children showed evidence of persisting internalised stigma. Caregivers suffered important treatment-related financial and psychological costs. Community support, notably through the continued involvement of children in strong social networks, promoted resilience among children and their families. Conclusions: We found that the current treatment regimen for childhood MDR-TB has significant psychological, academic, and financial impacts on children and their families. There is a need for psychosocial support of children and caregivers to mitigate the negative effects of community stigma, and to manage the stressors associated with chronic illness.
- ItemAssociation between clinical and environmental factors and the gut microbiota profiles in young South African children(Nature Research (part of Springer Nature), 2021) Nel Van Zyl, Kristien; Whitelaw, Andrew C.; Hesseling, Anneke C.; Seddon, James A.; Demers, Anne‑Marie; Newton‑Foot, MaeENGLISH ABSTRACT: Differences in the microbiota in populations over age and geographical locations complicate cross-study comparisons, and it is therefore essential to describe the baseline or control microbiota in each population. This includes the determination of the influence of demographic, clinical and environmental factors on the microbiota in a setting, and elucidates possible bias introduced by these factors, prior to further investigations. Little is known about the microbiota of children in South Africa after infancy. We provide a detailed description of the gut microbiota profiles of children from urban Cape Town and describe the influences of various clinical and environmental factors in different age groups during the first 5 years of life. Prevotella was the most common genus identified in the participants, and after infancy, the gut bacteria were dominated by Firmicutes and Bacteroidetes. In this setting, children exposed to antibiotics and indoor cooking fires were at the most risk for dysbiosis, showing significant losses in gut bacterial diversity.
- ItemCarriage of colistin-resistant Gram-negative bacteria in children from communities in Cape Town (Tuberculosis child multidrug-resistant preventive therapy trial sub-study)(AOSIS, 2021) Snyman, Yolandi; Whitelaw, Andrew C.; Maloba, Motlatji R. B.; Hesseling, Anneke C.; Newton-Foot, MaeENGLISH ABSTRACT: Colistin is a last-resort antibiotic against multidrug-resistant, Gram-negative bacteria. Colistin resistance has been described in the clinical settings in South Africa. However, information on carriage of these bacteria in communities is limited. This study investigated gastrointestinal carriage of colistin-resistant Escherichia coli and Klebsiella spp. and mcr genes in children from communities in Cape Town. Colistin-resistant E. coli was isolated from two participants (4%, 2/50), and mcr-1-mcr-9 genes were not detected. Gastrointestinal carriage of colistin-resistant Enterobacterales was rare; however, continuous extensive surveillance is necessary to determine the extent of carriage and its contribution to resistance observed in clinical settings.
- ItemComplementary surveillance strategies are needed to better characterise the epidemiology, care pathways and treatment outcomes of tuberculosis in children(BioMed Central, 2018-03-23) Du Preez, Karen; Schaaf, H. Simon; Dunbar, Rory; Walters, Elisabetta; Swartz, Alvera; Solomons, Regan; Hesseling, Anneke C.Background: Tuberculosis (TB) in young and HIV-infected children is frequently diagnosed at hospital level. In settings where general hospitals do not function as TB reporting units, the burden and severity of childhood TB may not be accurately reflected in routine TB surveillance data. Given the paucibacillary nature of childhood TB, microbiological surveillance alone will miss the majority of hospital-managed children. The study objective was to combine complementary hospital-based surveillance strategies to accurately report the burden, spectrum and outcomes of childhood TB managed at referral hospital-level in a high TB burden setting. Methods: We conducted a prospective cohort study including all children (< 13 years) managed for TB at a large referral hospital in Cape Town, South Africa during 2012. Children were identified through newly implemented clinical surveillance in addition to existing laboratory surveillance. Data were collected from clinical patient records, the National Health Laboratory Service database, and provincial electronic TB registers. Descriptive statistics were used to report overall TB disease burden, spectrum, care pathways and treatment outcomes. Univariate analysis compared characteristics between children identified through the two hospital-based surveillance strategies to characterise the group of children missed by existing laboratory surveillance. Results: During 2012, 395 children (180 [45.6%] < 2 years) were managed for TB. Clinical surveillance identified 237 (60%) children in addition to laboratory surveillance. Ninety (24.3%) children were HIV co-infected; 113 (29.5%) had weight-for-age z-scores <− 3. Extra-pulmonary TB (EPTB) was diagnosed in 188 (47.6%); 77 (19.5%) with disseminated TB. Favourable TB treatment outcomes were reported in 300/344 (87.2%) children with drugsusceptible and 50/51 (98.0%) children with drug-resistant TB. Older children (OR 1.7; 95% CI 1.0–2.8), children with EPTB (OR 2.3; 95% CI 1.5–3.6) and in-hospital deaths (OR 5.4; 95% CI 1.1–26.9) were more frequently detected by laboratory surveillance. TB/HIV co-infected children were less likely to be identified through laboratory surveillance (OR 0.3; 95% CI 0.2–0.5). Conclusions: The burden and spectrum of childhood TB disease managed at referral hospital level in high burden settings is substantial. Hospital-based surveillance in addition to routine TB surveillance is essential to provide a complete picture of the burden, spectrum and impact of childhood TB in settings where hospitals are not TB reporting units.
- ItemCoronavirus disease 2019 (COVID-19) pharmacologic treatments for children : research priorities and approach to pediatric studies(Oxford University Press, 2020-06) Garcia-Prats, Anthony J.; Salazar-Austin, Nicole; Conway, James H.; Radtke, Kendra; LaCourse, Sylvia M.; Maleche-Obimbo, Elizabeth; Hesseling, Anneke C.; Savic, Rada M.; Nachman, SharonClinical trials of pharmacologic treatments of coronavirus disease 2019 (COVID-19) are being rapidly designed and implemented in adults. Children are often not considered during development of novel treatments for infectious diseases until very late. Although children appear to have a lower risk compared with adults of severe COVID-19 disease, a substantial number of children globally will benefit from pharmacologic treatments. It will be reasonable to extrapolate efficacy of most treatments from adult trials to children. Pediatric trials should focus on characterizing a treatment’s pharmacokinetics, optimal dose, and safety across the age spectrum. These trials should use an adaptive design to efficiently add or remove arms in what will be a rapidly evolving treatment landscape, and should involve a large number of sites across the globe in a collaborative effort to facilitate efficient implementation. All stakeholders must commit to equitable access to any effective, safe treatment for children everywhere.
- ItemCorrection to : The impact of drug resistance on the risk of tuberculosis infection and disease in child household contacts : a cross sectional study(BioMed Central, 2017-11-07) Golla, Vera; Snow, Kathryn; Mandalakas, Anna M.; Schaaf, H. Simon; Du Preez, Karen; Hesseling, Anneke C.; Seddon, James A.Correction: After publication of the original article  the authors noted that the following errors had occurred: The name of the author H. Simon Schaaf had been incorrectly tagged as Simon H. Schaaf. This has been corrected in the author list above. The first p value below Table 1 is listed as p < 0.011, however it should be p < 0.01. An updated version of this table is included with this Correction. The original article has also been corrected.
- ItemCulture-confirmed childhood tuberculosis in Cape Town, South Africa : a review of 596 cases(BioMed Central, 2007-11) Schaaf, H. Simon; Marais, Ben J.; Whitelaw, Andrew; Hesseling, Anneke C.; Eley, Brian; Hussey, Gregory D.; Donald, Peter R.Background: The clinical, radiological and microbiological features of culture-confirmed childhood tuberculosis diagnosed at two referral hospitals are described. Methods: Cultures of Mycobacterium tuberculosis from children less than 13 years of age at Tygerberg and Red Cross Children's Hospitals, Cape Town, South Africa, were collected from March 2003 through February 2005. Folder review and chest radiography were performed and drug susceptibility tests done. Results: Of 596 children (median age 31 months), 330 (55.4%) were males. Of all children, 281 (47.1%) were HIV-uninfected, 133 (22.3%) HIV-infected and 182 (30.5%) not tested. Contact with infectious tuberculosis adults was recorded in 295 (49.5%) children. Missed opportunities for chemoprophylaxis were present in 117/182 (64.3%) children less than 5 years of age. Extrathoracic TB was less common in HIV-infected than in HIV-uninfected children (49/133 vs. 156/281; odds ratio 0.50, 95% confidence interval 0.32–0.78). Alveolar opacification (84/126 vs. 128/274; OR 1.85, 95%CI 1.08–3.19) and cavitation (33/126 vs. 44/274; OR 2.28, 95%CI 1.44–3.63) were more common in HIV-infected than in HIV-uninfected children. Microscopy for acid-fast bacilli on gastric aspirates and sputum was positive in 29/142 (20.4%) and 40/125 (32.0%) children, respectively. Sixty-seven of 592 (11.3%) children's isolates showed resistance to isoniazid and/or rifampicin; 43 (7.3%) were isoniazid-monoresistant, 2 (0.3%) rifampicin-monoresistant and 22 (3.7%) multidrug-resistant. Death in 41 children (6.9%) was more common in HIV-infected children and very young infants. Conclusion: HIV infection and missed opportunities for chemoprophylaxis were common in children with culture-confirmed TB. With cavitating disease and sputum or gastric aspirates positive for acid-fast bacilli, children may be infectious. Transmission of drug-resistant TB is high in this setting.
- ItemEffect of Ascaris Lumbricoides specific IgE on tuberculin skin test responses in children in a high-burdensetting : a cross-sectional community-based study(BioMed Central, 2012-09) Van Soelen, Nelda; Mandalakas, Anna M.; Kirchner, H. L.; Walzl, Gerhard; Grewal, Harleen M. S.; Jacobsen, Marc; Hesseling, Anneke C.ABSTRACT:M.tuberculosis (M.tb) is associated with enhanced T helper cell type 1 (Th1) immune responses while helminth infection is associated with T helper cell type 2 (Th2) immune responses. Our aim was to investigate whether helminth infection could influence the ability to generate an appropriate Th1 immune response that is characterized by a positive tuberculin skin test (TST), in M.tb exposed children.MethodsWe completed a community-based, cross sectional household contact tracing study, using matched enrolment of HIV negative children with and without documented household M.tb exposure. We documented demographics, clinical characteristics, HIV status, M.tb exposure (using a standard contact score) and M.tb infection status (TST > = 10 mm). Ascaris lumbricoides-specific IgE was used as proxy for Ascaris infection/exposure.ResultsOf 271 children (median age 4 years (range: 4 months to 15 years)) enrolled, 65 participants (24%) were serum positive for Ascaris IgE. There were 168 (62%) children with a documented household tuberculosis contact and 107 (40%) were (TST) positive overall.A positive TST was associated with increasing age (Odds Ratio (OR) =1.17, p < 0.001), increasing M.tb contact score (OR = 1.17, p < 0.001), previous tuberculosis treatment (OR = 4.8, p = 0.06) and previous isoniazid preventive treatment (OR = 3.16, p = 0.01). A visible bacillus Calmette-Guérin (BCG) scar was associated with reduced odds of being TST positive (OR = 0.42, p = 0.01).Ascaris IgE was not associated with TST status in univariate analysis (OR = 0.9, p = 0.6), but multivariable logistic regression analysis suggested an inverse association between Ascaris IgE status and a positive TST (OR = 0.6, p = 0.08), when adjusted for age, and M.tb contact score. The addition of an age interaction term to the model suggested that the age effect was stronger among Ascaris IgE positive children; the effect of being Ascaris IgE positive significantly reduced the odds of being TST positive amongst younger children while this effect weakened with increasing age.ConclusionsOur preliminary findings highlight a high prevalence of both Ascaris exposure/infection and M.tb infection in children in an urban setting. Helminth exposure/infection may reduce the immune response following M.tb exposure when controlling for epidemiological and clinical covariates. These findings might be relevant to the interpretation of immunological tests of M.tb infection in children.
- ItemFeasibility of identifying household contacts of rifampin-and multidrug-resistant tuberculosis cases at high risk of progression to tuberculosis disease(Oxford University Press, 2020-01) Gupta, Amita; Swindells, Susan; Kim, Soyeon; Hughes, Michael D.; Naini, Linda; Wu, Xingye; Dawson, Rodney; Mave, Vidya; Sanchez, Jorge; Mendoza, Alberto; Gonzales, Pedro; Kumarasamy, Nagalingeswaran; Comins, Kyla; Conradie, Francesca; Shenje, Justin; Fontain, Sandy Nerette; Garcia-Prats, Anthony; Asmelash, Aida; Nedsuwan, Supalert; Mohapi, Lerato; Lalloo, Umesh G.; Ferreira, Ana Cristina Garcia; Mugah, Christopher; Harrington, Mark; Jones, Lynne; Cox, Samyra R.; Smith, Betsy; Shah, N Sarita; Hesseling, Anneke C.; Churchyard, GavinBackground: We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial. Methods: We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings, chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing (tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human immunodeficiency virus (HIV) testing. Results: From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli sputum smears and 43% had cavitary disease; at study entry, 35% remained smear positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs that were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable, and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610 (61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and were TBI positive. Only 21 (2%) HHCs were on preventive therapy. Conclusions: The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel, preventive therapies are urgently needed to inform treatment policy and practice.
- ItemHealth system determinants of tuberculosis mortality in South Africa : a causal loop model(BMC (part of Springer Nature), 2021-04-26) Osman, Muhammad; Karat, Aaron S.; Khan, Munira; Meehan, Sue-Ann; Von Delft, Arne; Brey, Zameer; Charalambous, Salome; Hesseling, Anneke C.; Naidoo, Pren; Loveday, MarianBackground: Tuberculosis (TB) is a major public health concern in South Africa and TB-related mortality remains unacceptably high. Numerous clinical studies have examined the direct causes of TB-related mortality, but its wider, systemic drivers are less well understood. Applying systems thinking, we aimed to identify factors underlying TB mortality in South Africa and describe their relationships. At a meeting organised by the ‘Optimising TB Treatment Outcomes’ task team of the National TB Think Tank, we drew on the wide expertise of attendees to identify factors underlying TB mortality in South Africa. We generated a causal loop diagram to illustrate how these factors relate to each other. Results: Meeting attendees identified nine key variables: three ‘drivers’ (adequacy & availability of tools, implementation of guidelines, and the burden of bureaucracy); three ‘links’ (integration of health services, integration of data systems, and utilisation of prevention strategies); and three ‘outcomes’ (accessibility of services, patient empowerment, and socioeconomic status). Through the development and refinement of the causal loop diagram, additional explanatory and linking variables were added and three important reinforcing loops identified. Loop 1, ‘Leadership and management for outcomes’ illustrated that poor leadership led to increased bureaucracy and reduced the accessibility of TB services, which increased TBrelated mortality and reinforced poor leadership through patient empowerment. Loop 2, ‘Prevention and structural determinants’ describes the complex reinforcing loop between socio-economic status, patient empowerment, the poor uptake of TB and HIV prevention strategies and increasing TB mortality. Loop 3, ‘System capacity’ describes how fragmented leadership and limited resources compromise the workforce and the performance and accessibility of TB services, and how this negatively affects the demand for higher levels of stewardship. Conclusions: Strengthening leadership, reducing bureaucracy, improving integration across all levels of the system, increasing health care worker support, and using windows of opportunity to target points of leverage within the South African health system are needed to both strengthen the system and reduce TB mortality. Further refinement of this model may allow for the identification of additional areas of intervention.
- ItemHearing loss in patients on treatment for drug-resistant tuberculosis(European Respiratory Society, 2012-06) Seddon, James A.; Godfrey-Faussett, Peter; Jacobs, Kayleen; Ebrahim, Adam; Hesseling, Anneke C.; Schaaf, H. SimonThe treatment of drug‐resistant (DR) tuberculosis (TB) necessitates the use of second‐line injectable anti‐TB drugs which are associated with hearing loss. Hearing loss affects communication and for children the development of language and social skills. This article describes the pathophysiology of hearing loss and the testing methodologies that can be employed. It is the first paper to systematically review the literature regarding hearing loss in those treated for DR‐TB. In the studies identified, the methodology used to test for and to classify hearing loss is inconsistent and children and those with HIV are poorly represented. The review describes existing guidelines and suggests management strategies when hearing loss is found. It describes the challenges of testing hearing in the developing world contexts where the majority of patients with DR‐TB are treated. Finally it makes the recommendation that a standardised testing methodology and classification system be used.
- ItemIdentification of subclinical tuberculosis in household contacts using exposure scores and contact investigations(BMC (part of Springer Nature), 2020-01-31) Bekken, Gry K.; Ritz, Christian; Selvam, Sumithra; Jesuraj, Nelson; Hesseling, Anneke C.; Doherty, T. M.; Grewal, Harleen M. S.; Vaz, Mario; Jenum, SynneBackground: The goal of tuberculosis elimination put forward in the End TB Strategy prioritizes diagnosis and treatment of incipient and subclinical TB, recently defined by key stakeholders as “asymptomatic, early pre-clinical disease during which pathology evolves”. Regarded as indicative of a high risk of TB progression, considerable efforts have been made to identify these cases through exploration of biomarkers. The present study aimed to evaluate simple scoring systems for TB exposure as screening tools for subclinical TB, the only identifiable of the incipient and subclinical disease states, in a contact investigation (CI) setting of low HIV-prevalence. Methods: Nested within a large prospective study in household contacts (HHCs) of smear positive pulmonary TB cases in South-India conducted 2010–2012, we assessed 1) the association between the Tuberculosis Contact Score (TCS) and the Infectivity Score, with established tools for Mycobacterium tuberculosis (Mtb) infection, corrected for established TB risk factors, and 2) the capability of the TB exposure scores to identify subclinical TB defined by Mtbculture positivity in sputum or gastric aspirate (subjects < 5 years) specimen. Results: Of 525 HHCs, 29 were Mtb-culture positive and 96.6% of these asymptomatic. The TCS and the Infectivity Score associated with positive Tuberculin Skin Test and QuantiFeron TB-Gold In-tube assay (QFT) results in multivariate analyses (TCS: ORTST 1.16, 95% CI: 1.01, 1.33; ORQFT 1.33 95% CI: 1.16, 1.51. Infectivity Score: ORTST 1.39, 95% CI: 1.10, 1.76; ORQFT 1.41 95% CI: 1.16, 1.71). The Infectivity Score showed a moderate capability to identify subclinical TB (AUC of 0.61, 95% CI: 0.52, 0.70). Conclusions: Although our results did not identify an easily applicable screening tool for subclinical TB, the present study indicates that focusing on TB-related symptoms in CI settings may be of limited value for early identification of HHCs with high risk for TB progression.
- ItemThe impact of drug resistance on the risk of tuberculosis infection and disease in child household contacts : a cross sectional study(Biomed Central, 2017-08-29) Golla, Vera; Snow, Kathryn; Mandalakas, Anna M.; Schaaf, Simon H.; Du Preez, Karen; Hesseling, Anneke C.; Seddon, James A.ENGLISH SUMMARY : Background: The relative fitness of organisms causing drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) is unclear. We compared the risk of TB infection and TB disease in young child household contacts of adults with confirmed DS-TB and MDR-TB. Methods: In this cross-sectional analysis we included data from two community-based contact cohort investigation studies conducted in parallel in Cape Town, South Africa. Children <5 years of age with household exposure to an infectious TB case were included between August 2008 to June 2011. Children completed investigation for TB infection (tuberculin skin test) and TB disease (symptom evaluation, chest radiograph, bacteriology) in both studies using standard approaches. The impact of MDR-TB exposure on each covariate of TB infection and TB disease was assessed using univariable and multivariable logistic regression. Results: Of 538 children included, 312 had DS-TB and 226 had MDR-TB exposure. 107 children with DS-TB exposure had TB infection (34.3%) vs. 101 (44.7%) of children with MDR-TB exposure (adjusted Odds Ratio [aOR]: 2.05; 95% confidence interval [CI]: 1.34–3.12). A total of 15 (6.6%) MDR-TB vs. 27 (8.7%) DS-TB child contacts had TB disease at enrolment (aOR: 0.43; 95% CI: 0.19–0.97). Conclusions: Our results suggest a higher risk of TB infection in child contacts with household MDR-TB vs. DS-TB exposure, but a lower risk of TB disease. Although potentially affected by residual confounding or selection bias, our results are consistent with the hypothesis of impaired virulence in MDR-TB strains in this setting.
- ItemInclusion of key populations in clinical trials of new antituberculosis treatments : current barriers and recommendations for pregnant and lactating women, children, and HIV-infected persons(Public Library of Science, 2019) Gupta, Amita; Hughes, Michael D.; Garcia-Prats, Anthony J.; McIntire, Katherine; Hesseling, Anneke C.ENGLISH ABSTRACT: Pregnant women, children < 15 years old and, HIV-infected persons contribute approximately 20% of the global tuberculosis (TB) burden, with an estimated 216,000, 1,000,000, and 1,040,000 cases each year, respectively, yet these populations are currently largely excluded from TB clinical trials, leading to suboptimal treatment and poor access to new therapeutics. • Special considerations in these populations include specific TB disease spectrum and severity, lower sensitivity of commonly used TB diagnostic tests, potential differential drug dosing and treatment responses, drug–drug interactions, and challenges in acquiring high-quality data through clinical trials. • To counter the automatic exclusion of pregnant and lactating women that currently pervades the TB trial landscape, early discussions among trialists, pharmaceutical companies, maternal–child clinical experts, ethicists, and regulatory bodies are needed to address risks, benefits, and compelling rationale for inclusion. Reconsenting women when pregnancy occurs on a trial to allow continuation of study drug by informed choice is a practical and valuable approach to expand the currently limited evidence base. • Children tend to have less severe, often paucibacillary TB disease and may respond better to treatment than adults. Consequently, trials of shorter, less intense TB treatment regimens in children are needed; pharmacokinetic and safety studies should be initiated earlier and involve age groups in parallel rather than in an age-de-escalation approach. More rapid development of child-friendly drug formulations is needed. • All HIV-infected populations, including those with advanced disease, who are likely to be the intended population of the TB therapy, should be involved in Phase IIb and/or Phase III trials, as appropriate, to maximize knowledge of treatment, toxicities, drug– drug interactions, and outcomes.
- ItemLevofloxacin versus placebo for the prevention of tuberculosis disease in child contacts of multidrug-resistant tuberculosis : study protocol for a phase III cluster randomised controlled trial (TB-CHAMP)(BMC (part of Springer Nature), 2018-12-20) Seddon, James A.; Garcia-Prats, Anthony J.; Purchase, Susan E.; Osman, Muhammad; Demers, Anne-Marie; Hoddinott, Graeme; Crook, Angela M.; Owen-Powell, Ellen; Thomason, Margaret J.; Turkova, Anna; Gibb, Diana M.; Fairlie, Lee; Martinson, Neil; Schaaf, H. Simon; Hesseling, Anneke C.Background: Multidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment. Methods: The tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged < 5 years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged < 5 years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15–20 mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18–24 months with all children followed for 18 months after treatment. Qualitative and health economic evaluations are embedded in the trial. Discussion: If the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy.
- ItemMorbidity and mortality up to 5 years post tuberculosis treatment in South Africa : a pilot study(Elsevier, 2019) Osman, Muhammad; Welte, Alex; Dunbar, Rory; Brown, Rosemary; Hoddinott, Graeme; Hesseling, Anneke C.; Marx, Florian M.Background: A high risk of tuberculosis (TB), chronic lung disease, and mortality have been reported among people with a history of previous TB treatment, but data from high-incidence settings remain limited. The aim of this study was to characterize general morbidity and mortality among adults who had successfully completed TB treatment in the past 5 years in a high-incidence setting in South Africa. Methods: Adults ( 18 years) who had completed treatment for pulmonary TB between 2013 and 2017 were randomly selected from TB treatment registers. Household visits were conducted to locate and interview former TB (FTB) patients, and bacteriological testing for TB was offered. Additional data sources were used to ascertain the vitality status of FTB patients who could not be located. Results: Addresses were located for 200 of the 223 FTB patients sampled and 89 FTB patients were contacted of whom 51 agreed to be interviewed. Approximately half reported persistent respiratory symptoms, such as shortness of breath and wheezing, and repeated lung infections. One (3.6%) of 28 patients who provided a sputum sample had culture-positive TB and another two were currently on re-treatment for TB. Fifteen deaths post treatment were ascertained, resulting in a standardized mortality ratio of 3.8 (95% confidence interval 2.3–6.3) after successful TB treatment relative to the general population. Conclusions: In this high-incidence setting, locating and interviewing FTB patients was challenging. The study findings are consistent with a high rate of respiratory disease, including recurrent TB, and substantially elevated mortality among FTB patients.
- ItemMortality during tuberculosis treatment in South Africa using an 8-year analysis of the national tuberculosis treatment register(Nature, 2021-08) Osman, Muhammad; Van Schalkwyk, Cari; Naidoo, Pren; Seddon, James A.; Dunbare, Rory; Dlamini, Sicelo S.; Welte, Alex; Hesseling, Anneke C.; Claassens, Mareli M.In 2011, the South African HIV treatment eligibility criteria were expanded to allow all tuberculosis (TB) patients lifelong ART. The impact of this change on TB mortality in South Africa is not known. We evaluated mortality in all adults (≥ 15 years old) treated for drug-susceptible TB in South Africa between 2009 and 2016. Using a Cox regression model, we quantified risk factors for mortality during TB treatment and present standardised mortality ratios (SMR) stratified by year, age, sex, and HIV status. During the study period, 8.6% (219,618/2,551,058) of adults on TB treatment died. Older age, male sex, previous TB treatment and HIV infection (with or without the use of ART) were associated with increased hazard of mortality. There was a 19% reduction in hazard of mortality amongst all TB patients between 2009 and 2016 (adjusted hazard ratio: 0.81 95%CI 0.80–0.83). The highest SMR was in 15–24-year-old women, more than double that of men (42.3 in 2016). Between 2009 and 2016, the SMR for HIV-positive TB patients increased, from 9.0 to 19.6 in women, and 7.0 to 10.6 in men. In South Africa, case fatality during TB treatment is decreasing and further interventions to address specific risk factors for TB mortality are required. Young women (15–24-year-olds) with TB experience a disproportionate burden of mortality and interventions targeting this age-group are needed.
- ItemOperational challenges in managing Isoniazid Preventive Therapy in child contacts : a high-burden setting perspective(2011-07-08) Van Wyk, Susan S.; Reid, Anthony J.; Mandalakas, Anna M.; Enarson, Donald A.; Beyers, Nulda; Morrison, Julie; Hesseling, Anneke C.Abstract Background The study was conducted at a high TB-HIV burden primary health community clinic in Cape Town, South Africa. We describe the management of children under five years of age in household contact with a smear and/or culture-positive adult TB case. Methods This study was a record review of routinely-collected programme data. Results A total of 1094 adult TB case folders were reviewed. From all identified contacts, 149 children should have received IPT based on local guidelines; in only 2/149 IPT was initiated. Management of child contacts of sputum smear and/or culture-positive compared to sputum-negative TB patients were similar. Conclusions IPT delivery to children remains an operational challenge, especially in high TB-HIV burden communities. A tool to improve IPT management and targeting sputum smear and/or culture-positive TB child contacts may overcome some of these challenges and should be developed and piloted in such settings.
- ItemOpportunities for mobile app–based adherence support for children with tuberculosis in South Africa(JMIR Publications, 2020) Morse, Rachel M.; Myburgh, Hanlie; Reubi, David; Archey, Ava E.; Busakwe, Leletu; Garcia-Prats, Anthony J.; Hesseling, Anneke C.; Jacobs, Stephanie; Mbaba, Sharon; Meyerson, Kyla; Seddon, James A.; Van Der Zalm, Marieke M.; Wademan, Dillon T.; Hoddinott, GraemeENGLISH ABSTRACT: Tuberculosis is the number one infectious cause of death globally. Young children, generally those younger than 5 years, are at the highest risk of progressing from tuberculosis infection to tuberculosis disease and of developing the most severe forms of tuberculosis. Most current tuberculosis drug formulations have poor acceptability among children and require consistent adherence for prolonged periods of time. These challenges complicate children’s adherence to treatment and caregivers’ daily administration of the drugs. Rapid developments in mobile technologies and apps present opportunities for using widely available technology to support national tuberculosis programs and patient treatment adherence. Pilot studies have demonstrated that mobile apps are a feasible and acceptable means of enhancing children’s treatment adherence for other chronic conditions. Despite this, no mobile apps that aim to promote adherence to tuberculosis treatment have been developed for children. In this paper, we draw on our experiences carrying out research in clinical pediatric tuberculosis studies in South Africa. We present hypothetical scenarios of children’s adherence to tuberculosis medication to suggest priorities for behavioral and educational strategies that a mobile app could incorporate to address some of the adherence support gaps faced by children diagnosed with tuberculosis. We argue that a mobile app has the potential to lessen some of the negative experiences that children associate with taking tuberculosis treatment and to facilitate a more positive treatment adherence experience for children and their caregivers.