Publications
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du Preez K, Seddon JA, Schaaf HS, et al., 2019, Global shortages of BCG vaccine and tuberculous meningitis in children, The Lancet Global Health, Vol: 7, Pages: E28-E29, ISSN: 2214-109X
Seddon JA, Wilkinson R, van Crevel R, et al., 2019, Knowledge gaps and research priorities in tuberculous meningitis., Wellcome Open Res, Vol: 4, ISSN: 2398-502X
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.
Imran D, Hill PC, McKnight J, et al., 2019, Establishing the cascade of care for patients with tuberculous meningitis., Wellcome Open Res, Vol: 4, ISSN: 2398-502X
Meningitis is a relatively rare form of tuberculosis, but it carries a high mortality rate, reaching 50% in some settings, with higher rates among patients with HIV co-infection and those with drug-resistant disease. Most studies of tuberculosis meningitis (TBM) tend to focus on better diagnosis, drug treatment and supportive care for patients in hospital. However, there is significant variability in mortality between settings, which may be due to specific variation in the availability and quality of health care services, both prior to, during, and after hospitalization. Such variations have not been studied thoroughly, and we therefore present a theoretical framework that may help to identify where efforts should be focused in providing optimal services for TBM patients. As a first step, we propose an adjusted cascade of care for TBM and patient pathway studies that might help identify factors that account for losses and delays across the cascade. Many of the possible gaps in the TBM cascade are related to health systems factors; we have selected nine domains and provide relevant examples of systems factors for TBM for each of these domains that could be the basis for a health needs assessment to address such gaps. Finally, we suggest some immediate action that could be taken to help make improvements in services. Our theoretical framework will hopefully lead to more health system research and improved care for patients suffering from this most dangerous form of tuberculosis.
Marais S, Van Toorn R, Chow FC, et al., 2019, Management of intracranial tuberculous mass lesions: how long should we treat for?, Wellcome Open Res, Vol: 4, ISSN: 2398-502X
Tuberculous intracranial mass lesions are common in settings with high tuberculosis (TB) incidence and HIV prevalence. The diagnosis of such lesions, which include tuberculoma and tuberculous abscesses, is often presumptive and based on radiological features, supportive evidence of TB elsewhere and response to TB treatment. However, the treatment response is unpredictable, with lesions frequently enlarging paradoxically or persisting for many years despite appropriate TB treatment and corticosteroid therapy. Most international guidelines recommend a 9-12 month course of TB treatment for central nervous system TB when the infecting Mycobacterium tuberculosis ( M.tb) strain is sensitive to first-line drugs. However, there is variation in opinion and practice with respect to the duration of TB treatment in patients with tuberculomas or tuberculous abscesses. A major reason for this is the lack of prospective clinical trial evidence. Some experts suggest continuing treatment until radiological resolution of enhancing lesions has been achieved, but this may unnecessarily expose patients to prolonged periods of potentially toxic drugs. It is currently unknown whether persistent radiological enhancement of intracranial tuberculomas after 9-12 months of treatment represents active disease, inflammatory response in a sterilized lesion or merely revascularization. The consequences of stopping TB treatment prior to resolution of lesional enhancement have rarely been explored. These important issues were discussed at the 3 rd International Tuberculous Meningitis Consortium meeting. Most clinicians were of the opinion that continued enhancement does not necessarily represent treatment failure and that prolonged TB therapy was not warranted in patients presumably infected with M.tb strains susceptible to first-line drugs. In this manuscript we highlight current medical treatment practices, benefits and disadvantages of different TB treatment durations and the need for evidence-ba
Seddon J, Garcia-Pratts A, Purchase S, et al., 2018, 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), Trials, Vol: 19, ISSN: 1745-6215
BackgroundMultidrug-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.MethodsThe 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.DiscussionIf the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and th
Seddon J, Chiang S, Esmail H, et al., 2018, The wonder years: what can primary school children teach us about immunity to Mycobacterium tuberculosis?, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
In high burden settings, the risk of infection with Mycobacterium tuberculosis increases throughout childhood due to cumulative exposure. However, the risk of progressing from tuberculosis (TB) infection to disease varies by age. Young children (<5 years) have high risk of disease progression following infection. The risk falls in primary school children (5 to <10 years), but rises again during puberty. TB disease phenotype also varies by age: generally, young children have intrathoracic lymph node disease or disseminated disease, while adolescents (10 to <20 years) have adult-type pulmonary disease. TB risk also exhibits a gender difference: compared to adolescent boys, adolescent girls have an earlier rise in disease progression risk and higher TB incidence until early adulthood. Understanding why primary school children, during what we term the “Wonder Years,” have low TB risk has implications for vaccine development, therapeutic interventions, and diagnostics. To understand why this group is at low risk, we need a better comprehension of why younger children and adolescents have higher risks, and why risk varies by gender. Immunological response to M. tuberculosis is central to these issues. Host response at key stages in the immunopathological interaction with M. tuberculosis influences risk and disease phenotype. Cell numbers and function change dramatically with age and sexual maturation. Young children have poorly functioning innate cells and a Th2 skew. During the “Wonder Years,” there is a lymphocyte predominance and a Th1 skew. During puberty, neutrophils become more central to host response, and CD4+ T cells increase in number. Sex hormones (dehydroepiandrosterone, adiponectin, leptin, oestradiol, progesterone, and testosterone) profoundly affect immunity. Compared to girls, boys have a stronger Th1 profile and increased numbers of CD8+ T cells and NK cells. Girls are more Th2-skewed and elicit more enhanced inflammatory
Garcia-Prats AJ, Rose PC, Draper HR, et al., 2018, Effect of co-administration of lidocaine on the pain and pharmacokinetics of intramuscular amikacin in children with multidrug-resistant tuberculosis: a randomized crossover trial, Pediatric Infectious Disease Journal, Vol: 37, Pages: 1199-1203, ISSN: 0891-3668
BACKGROUND: Currently recommended treatment for multidrug-resistant (MDR) tuberculosis (TB) includes 4-8 months of an injectable medication, which is poorly tolerated. We evaluated the impact of co-administering lidocaine on pain and pharmacokinetics of intramuscular injections of amikacin in children with MDR-TB. METHODS: Children 8-18 years of age, receiving amikacin for MDR-TB treatment in Cape Town, South Africa, were eligible for this randomized crossover trial. Participants received a 15 mg/kg dose of intramuscular amikacin with and without additional lidocaine (0.2-0.4 mg/kg) on different days, and were randomized to the order of the treatments (the sequence). Participants and staff completing evaluations were blinded to sequence. Samples were drawn pre-dose, and at 1, 2, 4, 6 and 8 hours post-dose for measurement of plasma amikacin concentrations. Pain was assessed by participants using the Wong Baker FACES pain scale (0 to 5) pre-dose, immediately after the injection and then at 30 and 60 minutes. Pharmacokinetic measures were calculated using noncompartmental analysis. RESULTS: Twelve children were included, median age 11.5 years (IQR 9.9-13.4y). Participant-reported pain scores immediately after the amikacin injection were lower when lidocaine was co-administered: 1.0 (IQR 0.5-2.0) with lidocaine vs. 2.5 (1.0-4.0) without lidocaine (p=0.004). The median area under the concentration time curve (AUC)0-8 and median maximum plasma concentration (Cmax) of amikacin were 109.0 μg*h/mL (IQR 84.7-121.3) and 36.7 μg/mL (IQR 34.1-40.5) with lidocaine compared to 103.3 μg*h/mL (IQR 81.7-135.0; p=0.814) and 34.1 μg/mL (IQR 35.6-46.4; p=0.638) without lidocaine, respectively. CONCLUSIONS: The co-administration of lidocaine resulted in reduced pain immediately after the injection and did not alter amikacin AUC or Cmax.
Dodd P, Yuen C, Becerra M, et al., 2018, The potential impact of household contact management on childhood tuberculosis: a mathematical modelling study, The Lancet Global Health, Vol: 6, Pages: e1329-e1338, ISSN: 2214-109X
BackgroundTuberculosis 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.MethodsIn 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.FindingsWe 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.InterpretationHousehold contact management could substantially reduce childhood disease and death
Cruz AT, Garcia-Prats AJ, Furin J, et al., 2018, Treatment of Multidrug-Resistant Tuberculosis Infection in Children, Pediatric Infectious Disease Journal, Vol: 37, Pages: 1061-1064, ISSN: 0891-3668
Seddon JA, Schaff HS, Marais BJ, et al., 2018, Time to act on injectable-free regimens for children with multidrug-resistant tuberculosis, Lancet Respiratory Medicine, Vol: 6, Pages: 662-664, ISSN: 2213-2600
Cruz AT, Garcia-Prats AJ, Furin J, et al., 2018, Treatment of multidrug-resistant tuberculosis infection in children, Pediatric Infectious Disease Journal, Vol: 37, Pages: 831-834, ISSN: 0891-3668
It is estimated that 2 million children (younger than 15 years of age) are infected with multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (TB), known as MDR-TB infection.1 Data on the natural history of TB infection—which are often extrapolated to MDR-TB infection—show that young children (younger than 5 years of age) with TB infection are at high risk (up to 25%) of progressing to TB disease within 2–3 years of exposure, with infants’ risk of progression approaching 50%.2 It is noteworthy that older children and adolescents (10–20 years of age) also have an increased risk of developing TB disease after infection. Most children who develop MDR-TB disease are not diagnosed and started on appropriate therapy; mortality is high. However, even if diagnosed and treated, individuals must tolerate long (up to 18–24 months) courses of therapy with multiple (4–6) second-line drugs associated with far more adverse effects (AEs) than the 6–9 months of treatment with first-line drugs for drug-susceptible (DS)-TB disease. Thus, treatment of MDR-TB infection (often referred to as “preventive therapy”) to prevent progression to disease is critical.
Harausz EP, Garcia-Prats AJ, Law S, et al., 2018, Treatment and outcomes in children with multidrug-resistant tuberculosis: a systematic review and individual patient data meta-analysis, PLoS Medicine, Vol: 15, ISSN: 1549-1277
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 t
Kim S, Seddon JA, Garcia-Prats A, et al., 2018, Statistical considerations for pediatric multidrug-resistant tuberculosis trials, International Journal of Tuberculosis and Lung Disease, Vol: 22, Pages: S34-S39, ISSN: 1027-3719
Inclusion of newly licensed or repurposed drugs in regimens to treat children for multidrug-resistant-tuberculosis may lead to therapy that is shorter than traditional regimens and composed only of oral medications. As an all-oral regimen may be more acceptable and have a better safety profile than current regimens, demonstrating non-inferiority may be satisfactory. To demonstrate non-inferior efficacy it is necessary to set a non-inferiority margin, and the study must have assay sensitivity. Multi-arm multi-stage designs may currently not be appropriate in pediatric trials because of the lack of sensitive and specific intermediate outcomes. However, including an arm with an agent added to ameliorate toxicity would be efficient. Covariates can be used to stratify randomization, define subgroups, and improve efficiency of analysis. Powering or enriching the confirmed-TB subgroup may be important. Primary outcomes using a fixed time point from randomization for all study arms may result in variation in duration post-treatment completion but may be the best choice. While blinding of site personnel and patients may not be possible when regimens differ substantially in drugs and modes of administration, blinding should be maintained for independent endpoint review groups and other personnel. Type I error and family-wise error rates should be tightly controlled.
Kampmann B, Seddon JA, Paton J, et al., 2018, Evaluating UK National Guidance for Screening of Children for TB: A prospective multi-centre study, American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 1058-1064, ISSN: 1073-449X
Rationale and Objective In order to identify infected contacts of tuberculosis (TB) cases, the UK National Institute for Health and Care Excellence (NICE) recommended the addition of interferon-gamma release assays (IGRA) to the tuberculin skin test (TST) in its 2006 TB guidelines. Treatment for TB infection was no longer recommended for children screened TST-positive but IGRA-negative. We carried out a cohort study to evaluate the risk of TB disease in this group. Methods Children exposed to an infectious case of TB in their household were recruited from 11 paediatric TB clinics. TST and IGRA were carried out at baseline, IGRA repeated at 8 weeks and TST repeated if initially negative. Children were treated according to 2006 NICE guidelines and followed for 24 months. Measurements and Main Results Of 431 recruited children 392 completed the study. We diagnosed 48 (12.2%) cases of prevalent TB disease, 105 (26.8%) with TB infection and 239 (60.9%) without TB infection or disease. 18 children aged two years and above had a positive TST but persistently negative IGRA. None received TB infection treatment and none developed TB disease. 90 (26.1%) children qualified for TB infection treatment according to 2006 NICE guidelines. In contrast, 147 (42.7%) children would have qualified under revised NICE guidance, issued in 2016. Conclusions In this low prevalence setting we saw no incident cases of TB disease in children who were TST-positive but IGRA-negative and did not receive treatment for TB infection. Following the latest NICE guidance, significantly more children will require medication.
Schaaf HS, Marais BJ, Carvalho I, et al., 2018, Challenges in childhood tuberculosis, TUBERCULOSIS, Vol: 82, Pages: 234-262, ISSN: 2312-508X
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Schaaf HS, Garcia-Prats AJ, McKenna L, et al., 2017, Challenges of using new and repurposed drugs for the treatment of multidrug-resistant tuberculosis in children, Expert Review of Clinical Pharmacology, Vol: 11, Pages: 233-244, ISSN: 1751-2433
Introduction: New and repurposed antituberculosis drugs are urgently needed to more safely and effectively treat multidrug-resistant (MDR) tuberculosis (TB) in children. Multiple challenges limit timely access to new MDR-TB treatments in children.Areas covered: Diagnosis of MDR-TB in children remains a barrier, with few children with MDR-TB diagnosed and treated. Other barriers to timely access to new and repurposed drugs are discussed, and include delayed initiation of paediatric trials, limited funding for paediatric drug development, fragmented regulatory systems and operational challenges. The status of access to current repurposed and novel drugs is presented.Expert commentary: More timely initiation of paediatric trials is needed and paediatric work should happen and be funded in parallel with each phase of adult trials. Better quality data, increased regulator resources and expertise, harmonization of regulatory requirements across borders/organisations and registration fee waivers would improve registration timelines. Improved diagnosis, recording and reporting will establish better demand. Improved systems for procurement and supply chain management would reduce in-country operational barriers to getting medications to children. The challenges must be addressed to ensure timely and equitable access to new drugs and regimens that are urgently needed for effective, safe and shorter treatment of children with MDR-TB.
Seddon JA, Weld E, Simon S, et al., 2017, Conducting efficacy trials in children with multidrug-resistant tuberculosis: what is the rationale and how should they be done?, International Journal of Tuberculosis and Lung Disease, ISSN: 1027-3719
Traditionally paediatric tuberculosis (TB) treatment trials have been limited to phase I/II studies evaluating the pharmacokinetics and safety of drugs in children, with assumptions about efficacy made by extrapolating data from adults. However, it is increasingly recognised that in some circumstances, efficacy trials are warranted and required in children. The current treatment for children with multidrug-resistant (MDR)-TB is long and toxic; shorter, safer regimens, using novel agents require urgent evaluation. Given the changing pattern of drug metabolism, disease spectrum and rates of TB disease confirmation with age, decisions around inclusion criteria require careful consideration. The most straightforward MDR-TB efficacy trial would include only children with confirmed MDR-TB and with no additional drug resistance. Given that it may be unclear at the time treatment is initiated whether the diagnosis will ultimately be confirmed and what the final drug resistance profile will be, this presents a unique challenge in children. Recruiting only these children would however limit the generalizability of such a trial since, in reality, the majority of children with TB do not have bacteriologically confirmed disease. Given the good existing treatment outcomes with current routine regimens for children with MDR-TB, conducting a superiority trial may not be the optimal design. Demonstrating non-inferiority of efficacy but superiority with regard to safety, would be an alternative strategy. Using standardized control and experimental MDR-TB treatment regimens is challenging given the wide spectrum of paediatric disease. However, using variable regimens would make interpretation challenging. A paediatric MDR-TB efficacy trial is urgently needed, and with global collaboration and capacity building, is highly feasible.
Golla V, Snow K, Mandalakas AM, et al., 2017, Correction to: The impact of drug resistance on the risk of tuberculosis infection and disease in child household contacts: a cross sectional study., BMC Infectious Diseases, Vol: 17, ISSN: 1471-2334
After publication of the original article [1] the authors noted that the following errors had occurred.
Reuter A, Tisile P, von Delft D, et al., 2017, The devil we know: is the use of injectable agents for the treatment of MDR-TB justified?, International Journal of Tuberculosis and Lung Disease, Vol: 21, Pages: 1114-1126, ISSN: 1027-3719
For decades, second-line injectable agents (IAs) have been the cornerstone of treatment for multidrug-resistant tuberculosis (MDR-TB). Although evidence on the efficacy of IAs is limited, there is an expanding body of evidence on the serious adverse events caused by these drugs. Here, we present the results of a structured literature review of the safety and efficacy of IAs. We review the continued widespread use of these agents in the context of therapeutic alternatives—most notably the newer TB drugs, bedaquiline and delamanid—and from the context of human rights, ethics and patient-centered care. We conclude that there is limited evidence of the efficacy of IAs, clear evidence of the risks of these drugs, and that persons living with MDR-TB should be informed about these risks and provided with access to alternative therapeutic options.
Kodama C, Lange B, Olaru I, et al., 2017, Mycobacterium tuberculosis transmission from patients with drug-resistant compared to drug-susceptible tuberculosis: a systematic review and meta-analysis, European Respiratory Journal, Vol: 50, ISSN: 1399-3003
Achar J, Hewison C, Cavalheiro A, et al., 2017, Off-label use of bedaquiline in children and adolescents with drug-resistant tuberculosis, Emerging Infectious Diseases, Vol: 23, Pages: 1711-1713, ISSN: 1080-6059
Limited information on the use of bedaquiline in children and adolescents has resulted in restriction of its use to adults. This report describes 27 children and adolescents aged <18 years who received bedaquiline during treatment for drug-resistant TB. We report good treatment responses and no cessation due to adverse effects.
Cox H, Reuter A, Furin J, et al., 2017, Prevention of hearing loss in patients with multidrug-resistant tuberculosis., Lancet, Vol: 390, Pages: 934-934, ISSN: 0140-6736
In their Lancet Review, Blake S Wilson and colleagues (July 10)1 describe the growing global burden of hearing loss caused by a range of possible factors. The use of ototoxic medication is a considerable contributor to hearing loss for both children and adults. The authors suggest a primary prevention strategy for reducing hearing loss, which includes the use of ototoxic drugs only when no alternatives are available and only for serious conditions.
Dodd P, Yuen C, Sismanidis C, et al., 2017, The global burden of tuberculosis mortality in children: amathematical modelling study, Lancet Global Health, Vol: 5, Pages: e898-e906, ISSN: 2214-109X
BackgroundTuberculosis in children is increasingly recognised as an important component of the global tuberculosis burden, with an estimated 1 million cases in 2015. Although younger children are vulnerable to severe forms of tuberculosis disease, no age-disaggregated estimates of paediatric tuberculosis mortality exist, and tuberculosis has never been included in official estimates of under-5 child mortality. We aimed to produce a global mortality burden estimate in children using a complementary approach not dependent on vital registration data.MethodsIn this mathematical modelling study, we estimated deaths in children younger than 5 years and those aged 5–14 years for 217 countries and territories using a case-fatality-based approach. We used paediatric tuberculosis notification data and HIV and antiretroviral treatment estimates to disaggregate the WHO paediatric tuberculosis incidence estimates by age, HIV, and treatment status. We then applied systematic review evidence on corresponding case-fatality ratios.FindingsWe estimated that 239 000 (95% uncertainty interval [UI] 194 000–298 000) children younger than 15 years died from tuberculosis worldwide in 2015; 80% (191 000, 95% UI 132 000–257 000) of these deaths were in children younger than 5 years. More than 70% (182 000, 140 000–239 000) of deaths occurred in the WHO southeast Asia and Africa regions. We estimated that 39 000 (17%, 23 000–73 000) paediatric tuberculosis deaths worldwide were in children with HIV infections, with 31 000 (36%, 19 000–59 000) in the WHO Africa region. More than 96% (230 000, 185 000–289 000) of all tuberculosis deaths occurred in children not receiving tuberculosis treatment.InterpretationTuberculosis is a top ten cause of death in children worldwide and a key omission from previous analyses of under-5 mortality. Almost all these deaths occur in children not on tuberculosis treatment, implying substantial scope to reduce this burden.
Osman M, Lee K, Du Preez K, et al., 2017, Excellent treatment outcomes in children treated for tuberculosis under routine operational conditions in Cape Town, Clinical Infectious Diseases, Vol: 65, Pages: 1444-1452, ISSN: 1537-6591
BackgroundTuberculosis (TB) remains a leading cause of death in children globally. It is recognized that human immunodeficiency virus (HIV) infection increases the risk of developing TB, but our understanding of the impact of HIV on risk of mortality for children treated for TB is limited. We aimed to identify predictors of mortality in children treated for drug-susceptible TB.MethodsA retrospective analysis of all children (<15 years of age) routinely treated between 2005 and 2012 for drug-susceptible TB in Cape Town was conducted using the programmatic electronic TB treatment database. Survival analysis using Cox regression was used to estimate hazard ratios for death. Logistic regression was used to estimate the odds of unfavorable outcomes.ResultsOf 29519 children treated for and notified with TB over the study period, <1% died during TB treatment and 89.5% were cured or completed treatment. The proportion of children with known HIV status increased from 13% in 2005 to 95% in 2012. Children aged <2 years had an increased hazard of death (adjusted hazard ratio [aHR], 3.13; 95% confidence interval [CI], 1.78–5.52) and greater odds of unfavorable outcome (adjusted odds ratio [aOR], 1.44; 95% CI, 1.24–1.66) compared with children aged 10–14 years. HIV-infected children had increased mortality compared to HIV-negative children (aHR, 6.85; 95% CI, 4.60–10.19) and increased odds of unfavorable outcome (aOR, 2.01; 95% CI, 1.81–2.23). Later year of TB treatment was a protective predictor for both mortality and unfavorable outcome.ConclusionsWe demonstrate a dramatic improvement in HIV testing in children with TB over time and excellent overall treatment outcomes. HIV infection and young age were associated with increased risk of death and unfavorable outcome.
Turkova A, Tebruegge M, Brinkmann F, et al., 2017, Management of child MDR-TB contacts across countries in the WHO European Region: a survey of current practice, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 21, Pages: 774-777, ISSN: 1027-3719
The World Health Organization European Region has one of the highest rates of multidrug-resistant tuberculosis (MDR-TB) in the world, resulting in many vulnerable children being exposed each year. Evidence for preventive therapy following MDR-TB exposure is limited and current guidance is conflicting. An internet-based survey was performed to determine clinical practice in this region. Seventy-two clinicians from 25 countries participated. Practices related to screening and decision-making were highly variable. Just over half provided preventive therapy for children exposed to MDR-TB; the only characteristic associated with provision was practice within the European Union (adjusted OR 4.07, 95%CI 1.33–12.5).
Swaminathan A, du Cros P, Seddon JA, et al., 2017, Peripheral neuropathy in a diabetic child treated with linezolid for multidrugresistant tuberculosis: a case report and review of the literature, BMC INFECTIOUS DISEASES, Vol: 17, ISSN: 1471-2334
Background:Extensively drug-resistant (XDR) tuberculosis (TB) and multidrug resistant (MDR)-TB with additional resistance to injectable agents or fluoroquinolones are challenging to treat due to lack of available, effective drugs. Linezolid is one of the few drugs that has shown promise in treating these conditions. Long-term linezolid use is associated with toxicities such as peripheral and optic neuropathies. Diabetes mellitus (DM), especially when uncontrolled, can also result in peripheral neuropathy. The global burden of DM is increasing, and DM has been associated with a three-fold increased risk of developing TB disease. TB and DM can be a challenging combination to treat. DM can inhibit the host immune response to tuberculosis infection; and TB and some anti-TB drugs can worsen glycaemic control. A child experiencing neuropathy that is a possible complication of both DM and linezolid used to treat TB has not been reported previously. We report peripheral neuropathy in a 15-year-old boy with type 1 DM, diagnosed with MDR-TB and additional resistance to injectable TB medications.Case presentation:The boy was treated with a linezolid-based regimen, but after 8 months developed peripheral neuropathy. It was unclear whether the neuropathy was caused by the DM or the linezolid therapy. He had clinical improvement following cessation of linezolid and was declared cured following 21 months of treatment. Following completion of treatment, nerve conduction studies demonstrated significant improvement in neuropathy.Conclusions:To the best of our knowledge, this is the first case of peripheral neuropathy reported in a diabetic child on long-term linezolid therapy for tuberculosis. This case study underlines the importance of stringent follow-up for side effects of linezolid, especially when associated with co-morbidity such as DM that increases the chances of adverse effects. The presence of both DM and TB should alert a physician to strive for optimal glycaemic control
Seddon JA, Gie RP, 2017, If you look, you will find: time to challenge the childhood tuberculosis paradigm, International Journal of Tuberculosis and Lung Disease, Vol: 21, Pages: 602-602, ISSN: 1027-3719
Harausz EP, Garcia-Prats AJ, Seddon JA, et al., 2017, New and repurposed drugs for pediatric multidrug-resistant tuberculosis practice-based recommendations, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 1300-1310, ISSN: 1535-4970
It is estimated that 33,000 children develop multidrug-resistant tuberculosis (MDR-TB) each year. In spite of these numbers, children and adolescents have limited access to the new and repurposed MDR-TB drugs. There is also little clinical guidance for the use of these drugs and for the shorter MDR-TB regimen in the pediatric population. This is despite the fact that these drugs and regimens are associated with improved interim outcomes and acceptable safety profiles in adults. This review fills a gap in the pediatric MDR-TB literature by providing practice-based recommendations for the use of the new (delamanid and bedaquiline) and repurposed (linezolid and clofazimine) MDR-TB drugs and the new shorter MDR-TB regimen in children and adolescents.
Seddon JA, Makhene MK, Gumbo T, 2017, Old Antibiotics for Tuberculosis Reply, CLINICAL INFECTIOUS DISEASES, Vol: 64, Pages: 983-984, ISSN: 1058-4838
Basu Roy R, Seddon JA, 2017, Linezolid for children with tuberculous meningitis: more evidence required, Pediatric Infectious Disease Journal, Vol: 36, Pages: 439-439, ISSN: 1532-0987
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