Publications
217 results found
Dodd PJ, Prendergast AJ, Beecroft C, et al., 2017, The impact of HIV and antiretroviral therapy on tuberculosis risk in children: a systematic review and meta-analysis, Thorax, Vol: 72, ISSN: 1468-3296
Background Children (<15 years) are vulnerable to tuberculosis (TB) disease following infection, but no systematic review or meta-analysis has quantified the effects of HIV-related immunosuppression or antiretroviral therapy (ART) on their TB incidence. Objectives Determine the impact of HIV infection and ART on risk of incident TB disease in children.Methods We searched MEDLINE and Embase for studies measuring HIV prevalence in paediatric TB cases (‘TB cohorts’) and paediatric HIV cohorts reporting TB incidence (‘HIV cohorts’). Study quality was assessed using the Newcastle-Ottawa tool. TB cohorts with controls were meta-analysed to determine the incidence rate ratio (IRR) for TB given HIV. HIV cohort data were meta-analysed to estimate the trend in log-IRR versus CD4 percentage, relative incidence by immunological stage, and ART-associated protection from TB.Results 42 TB cohorts and 22 HIV cohorts were included. In the eight TB cohorts with controls, the IRR for TB was 7.9 (95% confidence interval [CI]: 4.5-13.7). HIV-infected children exhibited a reduction in IRR of 0.94 (95% credible interval: 0.83-1.07) per percentage point increase in CD4%. TB incidence was 5.0 (95%CI: 4.0-6.0) times higher in children with severe compared to non-significant immunosuppression. TB incidence was lower in HIV-infected children on ART (hazard ratio: 0.30; 95%CI: 0.21-0.39). Following initiation of ART, TB incidence declined rapidly over 12 months towards a hazard ratio of 0.10 (95%CI: 0.04-0.25).Conclusions HIV is a potent risk factor for paediatric TB, and ART is strongly protective. In HIV-infected children, early diagnosis and ART initiation reduces TB risk.
McAnaw SE, Hesseling AC, Seddon JA, et al., 2016, Pediatric multidrug-resistant tuberculosis clinical trials: challenges and opportunities, International Journal of Infectious Diseases, Vol: 56, Pages: 194-199, ISSN: 1201-9712
On June 17, 2016, RESIST-TB, IMPAACT, Vital Strategies, and New Ventures jointly hosted the Pediatric Multidrug Resistant Tuberculosis Clinical Trials Landscape Meeting in Arlington, Virginia, USA. The meeting provided updates on current multidrug-resistant tuberculosis (MDR-TB) trials targeting pediatric populations and adult trials that have included pediatric patients. A series of presentations were given that discussed site capacity needs, community engagement, and additional interventions necessary for clinical trials to improve the treatment of pediatric MDR-TB. This article presents a summary of topics discussed, including the following: current trials ongoing and planned; the global burden of MDR-TB in children; current regimens for MDR-TB treatment in children; pharmacokinetics of second-line anti-tuberculosis medications in children; design, sample size, and statistical considerations for MDR-TB trials in children; selection of study population, design, and treatment arms for a trial of novel pediatric MDR-TB regimens; practical aspects of pediatric MDR-TB treatment trials; and strategies for integrating children into adult tuberculosis trials. These discussions elucidated barriers to pediatric MDR-TB clinical trials and provided insight into necessary next steps for progress in this field. Investigators and funding agencies need to respond to these recommendations so that important studies can be implemented, leading to improved treatment for children with MDR-TB.
Basu Roy R, Brandt N, Moodie N, et al., 2016, Why the Convention on the Rights of the Child must become a guiding framework for the realization of the rights of children affected by tuberculosis, BMC International Health and Human Rights, Vol: 16, ISSN: 1472-698X
BackgroundUntil recently, paediatric tuberculosis (TB) has been relatively neglected by the broader TB and the maternal and child health communities. Human rights-based approaches to children affected by TB could be powerful; however, awareness and application of such strategies is not widespread. DiscussionWe summarize the current challenges faced by children affected by TB, including: consideration of their family context; the limitations of preventive, diagnostic and treatment options; paucity of paediatric-specific research; failure in implementation of interventions; and stigma. We examine the articles of the Convention on the Rights of the Child (CRC) and relate them to childhood TB. Specifically, we focus on the five core principles of the CRC: children’s inherent right to life and States’ duties towards their survival and development; children’s right to enjoyment of the highest attainable standard of health; non-discrimination; best interests of the child; and respect for the views of the child. We highlight where children’s rights are violated and how a human rights-based approach should be used as a tool to help children affected by TB, particularly in light of the Sustainable Development Goals and their focus on universality and leaving no one behind. SummaryThe article aims to bridge the gap between those providing paediatric TB clinical care and conducting research, and those working in the fields of human rights policy and advocacy to promote a human rights-based approach for children affected by TB based upon the Convention on the Rights of the Child.
Seddon JA, Schaaf HS, 2016, Drug-resistant tuberculosis and advances in the treatment of childhood tuberculosis, Pneumonia, Vol: 8, ISSN: 2200-6133
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.
Marais BJ, Heemskerk AD, Marais SS, et al., 2016, Standardized methods for enhanced quality and comparability of tuberculous meningitis studies, Clinical Infectious Diseases, Vol: 64, Pages: 501-509, ISSN: 1058-4838
Tuberculous meningitis remains a major cause of death and disability in tuberculosis endemic areas, especially in young children and immunocompromised adults. Research aimed at improving outcomes is hampered by poor standardization, which limits study comparison and the generalizability of results. We propose standardized methods for the conduct of tuberculous meningitis clinical research that were drafted at an international tuberculous meningitis research meeting organized by the Oxford University Clinical Research Unit in Vietnam. We propose a core dataset including demographic and clinical information to be collected at study enrolment, important aspects related to patient management and monitoring, and standardized reporting of patient outcomes. The criteria proposed for the conduct of observational and intervention tuberculous meningitis studies should improve the quality of future research outputs, facilitate multi-centre studies and meta-analyses of pooled data, and could provide the foundation for a global tuberculous meningitis data repository.
Garcia-Prats AJ, du Plessis L, Draper HR, et al., 2016, Outcome of culture-confirmed isoniazid-resistant rifampicin-susceptible tuberculosis in children, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 20, Pages: 1469-1476, ISSN: 1027-3719
Smirnova PA, Turkova A, Nikishova EI, et al., 2016, Multidrug-resistant tuberculosis in children in northwest Russia: an observational cohort study, European Respiratory Journal, Vol: 48, Pages: 1496-1499, ISSN: 1399-3003
High proportion of children with MDR-TB had favourable outcome (90%) with early diagnosis and treatment initiation http://ow.ly/2eq5302gWmr
Dodd P, Sismanidis C, Seddon JA, 2016, The global burden of drug-resistant tuberculosis in children: a mathematical model, Lancet Infectious Diseases, Vol: 16, Pages: 1193-1201, ISSN: 1473-3099
Background: Following infection with M. tuberculosis, children are at increased risk of progression to tuberculosis disease; a condition that can be challenging to diagnose. New estimation approaches for children have highlighted the gap between incidence and notifications, and suggest there is much more isoniazid-resistant and multidrug-resistant (MDR) disease than is identified. No work has yet quantified the burden of drug-resistant infection, considered other types of drug-resistance, or accounted for sampling uncertainty. Methods: We combined a mathematical model of tuberculosis in children with an analysis of drug-resistance patterns to produce country-level, regional, and global estimates of drug-resistant infection and disease. We estimated the proportions of tuberculosis cases at a country-level with: isoniazid-monoresistance (HMR), rifampicin mono-resistance, MDR, fluoroquinolone-resistant MDR, second-line injectable resistant MDR, and MDR with resistance to both a fluoroquinolone and a second-line injectable (XDR). Findings: We estimate 850,000 children developed tuberculosis in 2014; 58,000 with HMR-tuberculosis, 25,000 with MDR-tuberculosis, and 1,200 with XDR-tuberculosis. We estimate 67 million children are infected with M. tuberculosis; 5 million with HMR, 2 million with MDR, and 100,000 with XDR. Africa and South-East Asia have the highest numbers of tuberculosis in children, but WHO EMR, EUR and WPR regions also contribute substantially to the burden of drug-resistant tuberculosis due to their much higher proportions of resistance. Interpretation: Far more drug-resistant tuberculosis occurs in children than is diagnosed, and there is a large pool of drug-resistant infection. This has implications for approaches to empiric treatment and preventive therapy in some regions.
Seddon JA, Makhene MK, 2016, Harnessing novel quantitative pharmacology approaches to optimize the treatment of children with tuberculosis, Clinical Infectious Diseases, Vol: 63, Pages: S61-S62, ISSN: 1058-4838
Gumbo T, Makhene MK, Seddon JA, 2016, Partnerships to design novel regimens to treat childhood tuberculosis, Sui Generis: the road ahead, Clinical Infectious Diseases, Vol: 63, Pages: S110-S115, ISSN: 1058-4838
There has been a recent expansion of preclinical models to predict the efficacy of regimens to treat adults with tuberculosis. Despite increasing global interest in childhood tuberculosis, these same tools have not been employed to develop pediatric regimens. Children differ from adults in bacillary burden, spectrum of disease, the metabolism and distribution of antituberculosis drugs, and the toxicity experienced. The studies documented in this series describe a proof-of-concept approach to pediatric regimen development. We propose a program of investigation that would take this forward into a systematic and comprehensive method to find optimal drug combinations to use in children, ideal exposures, and required dosing. Although the number of possible drug combinations is extensive, a series of principles could be employed to select likely effective regimens. Regimens should avoid drugs with overlapping toxicity or linked mechanisms of resistance and should aim to include drugs with different mechanisms of action and ones that are able to target different subpopulations of mycobacteria. Finally drugs should penetrate into body sites necessary for treating pediatric disease. At an early stage, this body of work would need to engage with regulatory agencies and bodies that formulate guidelines, so that once regimens and dosages are identified, translation into clinical studies and clinical practice can be rapid. The development of child-friendly drug formulations would need to be carried out in parallel so that pharmacokinetic studies can be undertaken as formulations are created. Significant research and development would be required and a wide range of stakeholders would need to be engaged. The time is right to consider a more thoughtful and systematic approach toward identifying, testing, and comparing combinations of drugs for children with tuberculosis.
Seddon JA, 2016, Two sizes do not fit all: the terms infection and disease are inadequate for the description of children with tuberculosis, Archives of Disease in Childhood, Vol: 101, Pages: 594-595, ISSN: 0003-9888
Seddon JA, Paton J, Nademi Z, et al., 2016, The impact of BCG vaccination on tuberculin skin test responses in children is age dependent: evidence to be considered when screening children for tuberculosis infection, Thorax, Vol: 71, Pages: 932-939, ISSN: 1468-3296
Background Following exposure to TB, contacts are screened to target preventive treatment at those at high risk of developing TB. The UK has recently revised its recommendations for screening and now advises a 5 mm tuberculin skin test (TST) cut-off irrespective of age or BCG status. We sought to evaluate the impact of BCG on TST responses in UK children exposed to TB and the performance of different TST cut-offs to predict interferon γ release assay (IGRA) positivity.Methods Children <15 years old were recruited from 11 sites in the UK between January 2011 and December 2014 if exposed in their home to a source case with sputum smear or culture positive TB. Demographic details were collected and TST and IGRA undertaken. The impact of BCG vaccination on TST positivity was evaluated in IGRA-negative children, as was the performance of different TST cut-offs to predict IGRA positivity.Results Of 422 children recruited (median age 69 months; IQR: 32–113 months), 300 (71%) had been vaccinated with BCG. BCG vaccination affected the TST response in IGRA-negative children less than 5 years old but not in older children. A 5 mm TST cut-off demonstrated good sensitivity and specificity in BCG-unvaccinated children, and an excellent negative predictive value but was associated with low specificity (62.7%; 95% CI 56.1% to 69.0%) in BCG-vaccinated children. For BCG-vaccinated children, a 10 mm cut-off provided a high negative predictive value (97.7%; 95% CI 94.2% to 99.4%) with the positive predictive value increasing with increasing age of the child.Discussion BCG vaccination had little impact on TST size in children over 5 years of age. The revised TST cut-off recommended in the recent revision to the UK TB guidelines demonstrates good sensitivity but is associated with impaired specificity in BCG-vaccinated children.
Seddon JA, 2016, Knowing how many children to find is the first step in finding them, Public Health Action, Vol: 6, Pages: 52-52, ISSN: 2220-8372
Berry C, Yates TA, Seddon JA, et al., 2016, Efficacy, safety and tolerability of linezolid for the treatment of XDR-TB: a study in China, European Respiratory Journal, Vol: 47, Pages: 1591-1592, ISSN: 1399-3003
Swaminathan A, du Cros P, Seddon JA, et al., 2016, Treating children for drug-resistant tuberculosis in Tajikistan with Group 5 medications, International Journal of Tuberculosis and Lung Disease, Vol: 20, Pages: 474-478, ISSN: 1815-7920
BACKGROUND: Management of extensively drug-resistant tuberculosis (XDR-TB) and pre-XDR-TB is challenging, as effective drugs are lacking. Group 5 anti-tuberculosis drugs have an unclear role in the treatment of drug-resistant TB, and in children the efficacy, safety and effects of long-term use are not well described. We present clinical outcomes and adverse effects of a cohort of children with XDR-TB or pre-XDR-TB treated with Group 5 drugs in Tajikistan.METHODS: We conducted a retrospective analysis of eight children treated with one or more of the Group 5 drugs available under the Tajikistan National TB Programme—linezolid, amoxicillin-clavulanate, clofazimine and clarithromycin—given in combination with first- and second-line drugs. Time to sputum culture conversion, clinical outcomes and adverse effects were evaluated.RESULTS: Two children were cured, one completed treatment, four achieved favourable interim outcomes and one died. Adverse effects attributable to linezolid that required drug cessation occurred in one child; adverse effects of the other Group 5 drugs were insignificant or absent, requiring no regimen changes.CONCLUSION: Group 5 drugs can contribute to effective regimens in children with XDR and pre-XDR-TB. With proper monitoring and aggressive management of adverse effects, their safety profile might be acceptable, even in long-term use.
Marais BJ, Seddon JA, Detjen AK, et al., 2016, Interrupted BCG vaccination is a major threat to global child health, Lancet Respiratory Medicine, Vol: 4, Pages: 251-253, ISSN: 2213-2619
Bahr NC, Marais S, Caws M, et al., 2016, GeneXpert MTB/Rif to Diagnose Tuberculous Meningitis: Perhaps the First Test but not the Last, Clinical Infectious Diseases, Vol: 62, Pages: 1133-1135, ISSN: 1537-6591
Seddon JA, Graham SM, 2016, Childhood TB: can the End TB Strategy deliver?, TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, Vol: 110, Pages: 155-157, ISSN: 0035-9203
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- Citations: 5
Yuen CM, Amanullah F, Dharmadhikari A, et al., 2015, Turning off the tap: stopping tuberculosis transmission through active case-finding and prompt effective treatment, LANCET, Vol: 386, Pages: 2334-2343, ISSN: 0140-6736
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- Citations: 101
Seddon JA, Jenkins HE, Liu L, et al., 2015, Counting children with tuberculosis: why numbers matter, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 19, Pages: S9-S16, ISSN: 1027-3719
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- Citations: 47
Furin J, Mafukidze A, Brigden G, et al., 2015, A bitter pill to swallow: the need for better medications for drug-resistant tuberculosis in children, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 19, Pages: S55-S60, ISSN: 1027-3719
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- Citations: 12
Seddon JA, Kampmann B, 2015, HIV and tuberculosis in children: biology meets epidemiology, LANCET HIV, Vol: 2, Pages: E506-E507, ISSN: 2352-3018
Achar J, Berry C, Herboczek K, et al., 2015, Multidrug-resistant tuberculosis in child successfully treated with 9-month drug regimen, Emerging Infectious Diseases, Vol: 21, Pages: 2105-2106, ISSN: 1080-6059
Shah T, Williams B, Langer D, et al., 2015, A retrospective analysis of paediatric tuberculosis diagnosis in London: room for improvement?, ARCHIVES OF DISEASE IN CHILDHOOD, Vol: 100, Pages: 1097-1098, ISSN: 0003-9888
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- Citations: 1
Kranzer K, Elamin WF, Cox H, et al., 2015, A systematic review and meta-analysis of the efficacy and safety of <i>N</i>-acetylcysteine in preventing aminoglycoside-induced ototoxicity: implications for the treatment of multidrug-resistant TB, THORAX, Vol: 70, Pages: 1070-1077, ISSN: 0040-6376
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- Citations: 42
Seddon JA, McKenna L, Shah T, et al., 2015, Recent Developments and Future Opportunities in the Treatment of Tuberculosis in Children, CLINICAL INFECTIOUS DISEASES, Vol: 61, Pages: S188-S199, ISSN: 1058-4838
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- Citations: 7
Garcia-Prats AJ, Draper HR, Thee S, et al., 2015, Pharmacokinetics and Safety of Ofloxacin in Children with Drug-Resistant Tuberculosis, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 59, Pages: 6073-6079, ISSN: 0066-4804
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- Citations: 13
du Cros P, Swaminathan A, Bobokhojaev OI, et al., 2015, Challenges and solutions to implementing drug-resistant tuberculosis programmes for children in Central Asia, PUBLIC HEALTH ACTION, Vol: 5, Pages: 99-102, ISSN: 2220-8372
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- Citations: 3
Osman M, Seddon JA, Dunbar R, et al., 2015, The complex relationship between human immunodeficiency virus infection and death in adults being treated for tuberculosis in Cape Town, South Africa, BMC Public Health, Vol: 15, ISSN: 1471-2458
BackgroundDespite 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. MethodsA 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. ResultsOverall in the 93,133 cases included in the study 4,619 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. ConclusionHIV 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.
Seddon JA, 2015, THE BURDEN OF CHILDHOOD TUBERCULOSIS - IMPLICATIONS FOR PREVENTION AND MANAGEMENT, PEDIATRIC PULMONOLOGY, Vol: 50, Pages: S2-S3, ISSN: 8755-6863
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