SUNScholar - Browsing by Author "Seddon, James A."

Browsing by Author "Seddon, James A."

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Assessing 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, Lucy
Background: 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.
Association 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, Mae
ENGLISH 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.
The complex relationship between human immunodeficiency virus infection and death in adults being treated for tuberculosis in Cape Town, South Africa
(BioMed Central, 2015) Osman, Muhammad; Seddon, James A.; Dunbar, Rory; Draper, Heather R.; Lombard, Carl; Beyers, Nulda
Background: Despite recognised treatment strategies, mortality associated with tuberculosis (TB) remains significant. Risk factors for death during TB treatment have been described but the complex relationship between TB and HIV has not been fully understood. Methods: A retrospective analysis of all deaths occurring during TB treatment in Cape Town, South Africa between 2009 and 2012 were done to investigate risk factors associated with this outcome. The main risk factor was HIV status at the start of treatment and its interaction with age, sex and other risk factors were evaluated using a binomial regression model and thus relative risks (RR) are reported. Results: Overall in the 93,133 cases included in the study 4619 deaths (5 %) were recorded. Across all age groups HIV-positive patients were more than twice as likely to die as HIV-negative patients, RR = 2.19 (95 % CI: 2.03–2.37). However in an age specific analysis HIV-positive patients 15–24 and 25–34 years old were at an even higher risk of dying than HIV-negative patients, RR = 4.82 and RR = 3.76 respectively. Gender also modified the effect of HIV- with positive women having a higher risk of death than positive men, RR = 2.74 and RR = 1.94 respectively. Conclusion: HIV carries an increased risk of death in this study but specific high-risk groups pertaining to the impact of HIV are identified. Innovative strategies to manage these high risk groups may contribute to reduction in HIV-associated death in TB patients.
Correction 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 [1] 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.
The current global situation for tuberculous meningitis : epidemiology, diagnostics, treatment and outcomes [version 1; peer review: 2 approved]
(F1000Research, 2019) Seddon, James A.; Tugume, Lillian; Solomons, Regan; Prasad, Kameshwar; Bahr, Nathan C.
ENGLISH ABSTRACT: Tuberculous meningitis (TBM) results from dissemination of M. tuberculosis to the cerebrospinal fluid (CSF) and meninges. Ischaemia, hydrocephalus and raised intracranial pressure frequently result, leading to extensive brain injury and neurodisability. The global burden of TBM is unclear and it is likely that many cases are undiagnosed, with many treated cases unreported. Untreated, TBM is uniformly fatal, and even if treated, mortality and morbidity are high. Young age and human immunodeficiency virus (HIV) infection are potent risk factors for TBM, while Bacillus Calmette–Guérin (BCG) vaccination is protective, particularly in young children. Diagnosis of TBM usually relies on characteristic clinical symptoms and signs, together with consistent neuroimaging and CSF parameters. The ability to confirm the TBM diagnosis via CSF isolation of M. tuberculosis depends on the type of diagnostic tests available. In most cases, the diagnosis remains unconfirmed. GeneXpert MTB/RIF and the next generation Xpert Ultra offer improved sensitivity and rapid turnaround times, and while roll-out has scaled up, availability remains limited. Many locations rely only on acid fast bacilli smear, which is insensitive. Treatment regimens for TBM are based on evidence for pulmonary tuberculosis treatment, with little consideration to CSF penetration or mode of drug action required. The World Health Organization recommends a 12-month treatment course, although data on which to base this duration is lacking. New treatment regimens and drug dosages are under evaluation, with much higher dosages of rifampicin and the inclusion of fluoroquinolones and linezolid identified as promising innovations. The inclusion of corticosteroids at the start of treatment has been demonstrated to reduce mortality in HIV-negative individuals but whether they are universally beneficial is unclear. Other host-directed therapies show promise but evidence for widespread use is lacking. Finally, the management of TBM within health systems is sub-optimal, with drop-offs at every stage in the care cascade.
Decision-making in the diagnosis of tuberculous meningitis
(Wellcome Open Research, 2020-01-23) Boyles, Tom H.; Lynen, Lutgarde; Seddon, James A.; Tuberculous Meningitis International Research Consortium
ENGLISH ABSTRACT: Tuberculous meningitis (TBM) is the most devastating form of tuberculosis (TB) but diagnosis is difficult and delays in initiating therapy increase mortality. All currently available tests are imperfect; culture of Mycobacterium tuberculosis from the cerebrospinal fluid (CSF) is considered the most accurate test but is often negative, even when disease is present, and takes too long to be useful for immediate decision making. Rapid tests that are frequently used are conventional Ziehl-Neelsen staining and nucleic acid amplification tests such as Xpert MTB/RIF and Xpert MTB/RIF Ultra. While positive results will often confirm the diagnosis, negative tests frequently provide insufficient evidence to withhold therapy. The conventional diagnostic approach is to determine the probability of TBM using experience and intuition, based on prevalence of TB, history, examination, analysis of basic blood and CSF parameters, imaging, and rapid test results. Treatment decisions may therefore be both variable and inaccurate, depend on the experience of the clinician, and requests for tests may be inappropriate. In this article we discuss the use of Bayes' theorem and the threshold model of decision making as ways to improve testing and treatment decisions in TBM. Bayes' theorem describes the process of converting the pre-test probability of disease to the post-test probability based on test results and the threshold model guides clinicians to make rational test and treatment decisions. We discuss the advantages and limitations of using these methods and suggest that new diagnostic strategies should ultimately be tested in randomised trials.
Drug-resistant tuberculosis and advances in the treatment of childhood tuberculosis
(BioMed Central, 2016-11-24) Seddon, James A.; Schaaf, H. Simon
Over the last 10 years, interest in pediatric tuberculosis (TB) has increased dramatically, together with increased funding and research. We have a better understanding of the burden of childhood TB as well as a better idea of how to diagnose it. Our appreciation of pathophysiology is improved and with it investigators are beginning to consider pediatric TB as a heterogeneous entity, with different types and severity of disease being treated in different ways. There have been advances in how to treat both TB infection and TB disease caused by both drug-susceptible as well as drug-resistant organisms. Two completely novel drugs, bedaquiline and delamanid, have been developed, in addition to the use of older drugs that have been re-purposed. New regimens are being evaluated that have the potential to shorten treatment. Many of these drugs and regimens have first been investigated in adults with children an afterthought, but increasingly children are being considered at the outset and, in some instances studies are only conducted in children where pediatric-specific issues exist.
The global burden of tuberculous meningitis in adults : a modelling study
(Public Library of Science, 2021-12) Dodd, Peter J.; Osman, Muhammad; Cresswell, Fiona V.; Stadelman, Anna M.; Lan, Nguyen Huu; Thuong, Nguyen Thuy Thuong; Muzyamba, Morris; Glaser, Lisa; Dlamini, Sicelo S.; Seddon, James A.
Tuberculous meningitis (TBM) is the most lethal form of tuberculosis. The incidence and mortality of TBM is unknown due to diagnostic challenges and limited disaggregated reporting of treated TBM by existing surveillance systems. We aimed to estimate the incidence and mortality of TBM in adults (15+ years) globally. Using national surveillance data from Brazil, South Africa, the United Kingdom, the United States of America, and Vietnam, we estimated the fraction of reported tuberculosis that is TBM, and the case fatality ratios for treated TBM in each of these countries. We adjusted these estimates according to findings from a systematic review and meta-analysis and applied them to World Health Organization tuberculosis notifications and estimates to model the global TBM incidence and mortality. Assuming the case detection ratio (CDR) for TBM was the same as all TB, we estimated that in 2019, 164,000 (95% UI; 129,000–199,000) adults developed TBM globally; 23% were among people living with HIV. Almost 60% of incident TBM occurred in males and 20% were in adults 25–34 years old. 70% of global TBM incidence occurred in Southeast Asia and Africa. We estimated that 78,200 (95% UI; 52,300–104,000) adults died of TBM in 2019, representing 48% of incident TBM. TBM case fatality in those treated was on average 27%. Sensitivity analysis assuming improved detection of TBM compared to other forms of TB (CDR odds ratio of 2) reduced estimated global mortality to 54,900 (95% UI; 32,200–77,700); assuming instead worse detection for TBM (CDR odds ratio of 0.5) increased estimated mortality to 125,000 (95% UI; 88,800–161,000). Our results highlight the need for improved routine TBM monitoring, especially in high burden countries. Reducing TBM incidence and mortality will be necessary to achieve the End TB Strategy targets.
Hearing 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. Simon
The 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.
The 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.
Impact of systematic early tuberculosis detection using Xpert MTB/RIF Ultra in children with severe pneumonia in high tuberculosis burden countries (TB-Speed pneumonia) : a stepped wedge cluster randomized trial
(BMC (part of Springer Nature), 2021-03-20) Vessiere, Aurelia; Font, Helene; Gabillard, Delphine; Adonis-Koffi, Laurence; Borand, Laurence; Chabala, Chishala; Khosa, Celso; Mavale, Sandra; Moh, Raoul; Mulenga, Veronica; Mwanga-Amumpere, Juliet; Taguebue, Jean-Voisin; Eang, Mao T.; Delacourt, Christophe; Seddon, James A.; Lounnas, Manon; Godreuil, Sylvain; Wobudeya, Eric; Bonnet, Maryline; Marcy, Olivier
Background: In high tuberculosis (TB) burden settings, there is growing evidence that TB is common in children with pneumonia, the leading cause of death in children under 5 years worldwide. The current WHO standard of care (SOC) for young children with pneumonia considers a diagnosis of TB only if the child has a history of prolonged symptoms or fails to respond to antibiotic treatments. As a result, many children with TB-associated severe pneumonia are currently missed or diagnosed too late. We therefore propose a diagnostic trial to assess the impact on mortality of adding the systematic early detection of TB using Xpert MTB/RIF Ultra (Ultra) performed on nasopharyngeal aspirates (NPA) and stool samples to the WHO SOC for children with severe pneumonia, followed by immediate initiation of anti-TB treatment in children testing positive on any of the samples. Methods: TB-Speed Pneumonia is a pragmatic stepped-wedge cluster randomized controlled trial conducted in six countries with high TB incidence rate (Côte d’Ivoire, Cameroon, Uganda, Mozambique, Zambia and Cambodia). We will enrol 3780 children under 5 years presenting with WHO-defined severe pneumonia across 15 hospitals over 18 months. All hospitals will start managing children using the WHO SOC for severe pneumonia; one hospital will be randomly selected to switch to the intervention every 5 weeks. The intervention consists of the WHO SOC plus rapid TB detection on the day of admission using Ultra performed on 1 nasopharyngeal aspirate and 1 stool sample. All children will be followed for 3 months, with systematic trial visits at day 3, discharge, 2 weeks postdischarge, and week 12. The primary endpoint is all-cause mortality 12 weeks after inclusion. Qualitative and health economic evaluations are embedded in the trial. Discussion: In addition to testing the main hypothesis that molecular detection and early treatment will reduce TB mortality in children, the strength of such pragmatic research is that it provides some evidence regarding the feasibility of the intervention as part of routine care. Should this intervention be successful, safe and well tolerated, it could be systematically implemented at district hospital level where children with severe pneumonia are referred.
Knowledge gaps and research priorities in tuberculous meningitis
(Wellcome Open Research, 2019-11-28) Seddon, James A.; Wilkinson, Robert; Van Crevel, Reinout; Figaji, Anthony; Thwaites, Guy E.; Tuberculous Meningitis International Research Consortium
ENGLISH ABSTRACT: Tuberculous meningitis (TBM) is the most severe and disabling form of tuberculosis (TB), accounting for around 1-5% of the global TB caseload, with mortality of approximately 20% in children and up to 60% in persons co-infected with human immunodeficiency virus even in those treated. Relatively few centres of excellence in TBM research exist and the field would therefore benefit from greater co-ordination, advocacy, collaboration and early data sharing. To this end, in 2009, 2015 and 2019 we convened the TBM International Research Consortium, bringing together approximately 50 researchers from five continents. The most recent meeting took place on 1 st and 2 nd March 2019 in Lucknow, India. During the meeting, researchers and clinicians presented updates in their areas of expertise, and additionally presented on the knowledge gaps and research priorities in that field. Discussion during the meeting was followed by the development, by a core writing group, of a synthesis of knowledge gaps and research priorities within seven domains, namely epidemiology, pathogenesis, diagnosis, antimicrobial therapy, host-directed therapy, critical care and implementation science. These were circulated to the whole consortium for written input and feedback. Further cycles of discussion between the writing group took place to arrive at a consensus series of priorities. This article summarises the consensus reached by the consortium concerning the unmet needs and priorities for future research for this neglected and often fatal disease.
Levofloxacin 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.
Mortality 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.
Opportunities 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, Graeme
ENGLISH 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.
Potential effect of household contact management on childhood tuberculosis : a mathematical modelling study
(Elsevier, 2018) Dodd, Peter J.; Yuen, Courtney M,; Becerra, Mercedes C.; Revill, Paul; Jenkins, Helen E.; Seddon, James A.
Summary Background Tuberculosis is recognised as a major cause of morbidity and mortality in children, with most cases in children going undiagnosed and resulting in poor outcomes. Household contact management, which aims to identify children with active tuberculosis and to provide preventive therapy for those with HIV or those younger than 5 years, has long been recommended but has very poor coverage globally. New guidelines include widespread provision of preventive therapy to children with a positive tuberculin skin test (TST) who are older than 5 years. Methods In this mathematical modelling study, we provide the first global and national estimates of the impact of moving from zero to full coverage of household contact management (with and without preventive therapy for TST-positive children older than 5 years). We assembled data on tuberculosis notifications, household structure, household contact co-prevalence of tuberculosis disease and infection, the efficacy of preventive therapy, and the natural history of childhood tuberculosis. We used a model to estimate households visited, children screened, and treatment courses given for active and latent tuberculosis. We calculated the numbers of tuberculosis cases, deaths, and life-years lost because of tuberculosis for each intervention scenario and country. Findings We estimated that full implementation of household contact management would prevent 159 500 (75% uncertainty interval [UI] 147 000–170 900) cases of tuberculosis and 108 400 (75% UI 98 800–116 700) deaths in children younger than 15 years (representing the loss of 7 305 000 [75% UI 6 663 000–7 874 000] life-years). We estimated that preventing one child death from tuberculosis would require visiting 48 households, screening 77 children, giving 48 preventive therapy courses, and giving two tuberculosis treatments versus no household contact management. Interpretation Household contact management could substantially reduce childhood disease and death caused by tuberculosis globally. Funding and research to optimise its implementation should be prioritised.
Protecting children in low-income and middle-income countries from COVID-19
(BMJ, 2020) Ahmed, Salahuddin; Mvalo, Tisungane; Akech, Samuel; Agweyu, Ambrose; Baker, Kevin; Bar-Zeev, Naor; Campbell, Harry; Checkley, William; Chisti, Mohammod Jobayer; Colbourn, Tim; Cunningham, Steve; Duke, Trevor; English, Mike; Falade, Adegoke G.; Fancourt, Nicholas S. S.; Ginsburg, Amy S.; Graham, Hamish R.; Gray, Diane M.; Gupta, Madhu; Hammitt, Laura; Hesseling, Anneke C.; Hooli, Shubhada; Johnson, Abdul-Wahab B. R.; King, Carina; Kirby, Miles A.; Lanata, Claudio F.; Lufesi, Norman; Mackenzie, Grant A.; McCracken, John P.; Moschovis, Peter P.; Nair, Harish; Oviawe, Osawaru; Pomat, William S.; Santosham, Mathuram; Seddon, James A.; Thahane, Lineo Keneuoe; Wahl, Brian; Van der Zalm, Marieke; Verwey, Charl; Yoshida, Lay-Myint; Zar, Heather J.; Howie, Stephen R. C.; McCollum, Eric D.
A saving grace of the COVID-19 pandemic in high-income and upper middle-income countries has been the relative sparing of children. As the disease spreads across low-income and middle-income countries (LMICs), long-standing system vulnerabilities may tragically manifest, and we worry that children will be increasingly impacted, both directly and indirectly. Drawing on our shared child pneumonia experience globally, we highlight these potential impacts on children in LMICs and propose actions for a collective response.
Risk factors for infection and disease in child contacts of multidrug-resistant tuberculosis : a cross-sectional study
(BioMed Central, 2013-08) Seddon, James A.; Hesseling, Anneke C.; Godfrey-Faussett, Peter; Fielding, Katherine; Schaaf, H. Simon
Background: Young children exposed to Mycobacterium tuberculosis have a high risk of disease progression following infection. This study aimed to determine risk factors for M. tuberculosis infection and disease in children following exposure to adults with multidrug-resistant (MDR) tuberculosis (TB). Methods: Cross-sectional study; all children aged < 5 years, routinely referred per local guidelines to the provincial specialist MDR-TB clinic, Western Cape Province, South Africa, following identification as contacts of adult MDR-TB source cases, were eligible for enrolment from May 2010 through April 2011. Demographic, clinical and social characteristics were collected. All children underwent HIV and tuberculin skin testing. Results: Of 228 children enrolled (median age: 30 months), 102 (44.7%) were classified as infected. Of these, 15 (14.7%) had TB disease at enrolment. Of 217 children tested for HIV, 8 (3.7%) were positive. In adjusted analysis, child’s age (AOR: 1.43; 95% CI: 1.13-1.91; p = 0.002) and previous TB treatment history (AOR: 2.51; 95% CI: 1.22-5.17; p = 0.01) were independent risk factors for infection. Increasing age of the MDR-TB source case (AOR: 0.67; 95% CI: 0.45-1.00; p = 0.05) was protective and source case alcohol use (AOR: 2.59; 95% CI: 1.29-5.22; p = 0.007) was associated with increased odds of infection in adjusted analysis. Decreasing age of the child (p = 0.01) and positive HIV status (AOR: 25.3; 95% CI: 1.63-393; p = 0.01) were associated with prevalent TB disease. Conclusion: A high proportion of children exposed to MDR-TB are infected or diseased. Early contact tracing might provide opportunities to prevent the progression to TB disease in children identified as having been exposed to MDR-TB.
Treatment and outcomes in children with multidrug-resistant tuberculosis : a systematic review and individual patient data meta-analysis.
(Public Library of Science, 2018-07-11) Harausz, Elizabeth P.; Garcia-Prats, Anthony J.; Law, Stephanie; Schaaf, H. Simon; Kredo, Tamara; Seddon, James A.; Menzies, Dick; Turkova, Anna; Achar, Jay; Amanullah, Farhana; Barry, Pennan; Becerra, Mercedes; Chan, Edward D.; Chan, Pei Chun; Chiotan, Domnica Ioana; Crossa, Aldo; Drobac, Peter C.; Fairlie, Lee; Falzon, Dennis; Flood, Jennifer; Gegia, Medea; Hicks, Robert M.; Isaakidis, Petros; Kadri, S. M.; Kampmann, Beate; Madhi, Shabir A.; Marais, Else; Mariandyshev, Andrei; Mendez-Echevarria, Ana; Moore, Brittany Kathryn; Nargiza, Parpieva; Ozere, Iveta; Padayatchi, Nesri; Ur-Rehman, Saleem; Rybak, Natasha; Santiago-Garcia, Begona; Shah, N. Sarita; Sharma, Sangeeta; Shim, Tae Sun; Skrahina, Alena; Soriano-Arandes, Antoni; Van Den Boom, Martin; Van Der Werf, Marieke J.; Van Der Werf, Tjip S.; Williams, Bhanu; Yablokova, Elena; Yim, Jae-Joon; Furin, Jennifer; Hesseling, Anneke C.
Background: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. Methods and findings: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%±19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%±48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15± 20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0±8.3, p = 0.041 and aOR 5.9, 95% CI 1.7±20.5, p = 0.007, respectively). These findings for high-dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multidrug regimens, only observational cohort studies were available for inclusion, and treatment decisions were based on the clinician's perception of illness, with resulting potential for bias. Conclusions: This study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children. Our findings of individual drug effects on treatment outcome should be further evaluated.
Tuberculous meningitis : new tools and new approaches required [version 1; peer review: not peer reviewed]
(F1000Research, 2019) Seddon, James A.; Thwaites, Guy E.; Tuberculous Meningitis International Research Consortium
ENGLISH ABSTRACT: Tuberculous meningitis is the most severe form of tuberculosis and causes widespread mortality and morbidity. Understanding of the epidemiology and pathogenesis is incomplete, and the optimal diagnosis and treatment are poorly defined. To generate research collaboration and coordination, as well as to promote sharing of ideas and advocacy efforts, the International Tuberculous Meningitis Research Consortium was formed in 2009. During the most recent meeting of this group in Lucknow, India, in March 2019, the Consortium decided to bring together key articles on tuberculous meningitis in one supplement. The supplement covers recent scientific updates, expert perspectives on specific clinical challenges, consensus statements on how to conduct research, and a set of priorities for future investigation.

Browsing by Author "Seddon, James A."

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