Imperial College London

Dr James A Seddon

Faculty of MedicineDepartment of Infectious Disease

Reader in Global Child Health
 
 
 
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Contact

 

+44 (0)20 7594 3179james.seddon

 
 
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Location

 

235Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

179 results found

Lopez-Varela E, Abulfathi AA, Strydom N, Goussard P, van Wyk AC, Demers AM, Van Deventer A, Garcia-Prats AJ, van der Merwe J, Zimmerman M, Carter CL, Janson J, Morrison J, Reuter H, Decloedt EH, Seddon JA, Svensson EM, Warren R, Savic RM, Dartois V, Hesseling ACet al., 2022, Drug concentration at the site of disease in children with pulmonary tuberculosis, JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, ISSN: 0305-7453

Journal article

Solomons RS, van Toorn R, Cresswell FV, Seddon JAet al., 2022, Update on the Treatment of Pediatric Tuberculous Meningitis., Pediatr Infect Dis J

Journal article

Gunasekera KS, Vonasek B, Oliwa J, Triasih R, Lancioni C, Graham SM, Seddon JA, Marais BJet al., 2022, Diagnostic Challenges in Childhood Pulmonary Tuberculosis-Optimizing the Clinical Approach, PATHOGENS, Vol: 11

Journal article

du Preez K, Jenkins H, Donald P, Solomons R, Graham S, Schaaf S, Starke J, Hesseling A, Seddon Jet al., 2022, Tuberculous meningitis in children: a forgotten public health emergency, Frontiers in Neurology, Vol: 13, Pages: 1-9, ISSN: 1664-2295

Tuberculous meningitis (TBM) remains a major cause of morbidity and mortality in children with tuberculosis (TB), yet there arecurrently no estimates of the global burden of paediatric TBM. Due to frequent non-specific clinical presentation and limited andinadequate diagnostic tests, children with TBM are often diagnosed late or die undiagnosed. Even when diagnosed and treated, 20%of children with TBM die. Of survivors, the majority have substantial neurological disability with significant negative impact onchildren and their families. Surveillance data on this devastating form of TB can help to quantify the contribution of TBM to theoverall burden, morbidity and mortality of TB in children and the epidemiology of TB more broadly.Paediatric TBM usually occurs shortly after primary infection with Mycobacterium tuberculosis and reflects ongoing TBtransmission to children. In this article we explain the public health importance of paediatric TBM, discuss the epidemiology withinthe context of overall TB control and health system functioning and the limitations of current surveillance strategies. We provide aclear rationale for the benefit of improved surveillance of paediatric TBM using a TB care cascade framework to supportmonitoring and evaluation of paediatric TB, and TB control more broadly. Considering the public health implications of a diagnosisof TBM in children, we provide recommendations to strengthen paediatric TBM surveillance and outline how improved surveillancecan help us identify opportunities for prevention, earlier diagnosis and improved care to minimize the impact of TBM on childrenglobally.

Journal article

Turkova A, Wills GH, Wobudeya E, Chabala C, Palmer M, Kinikar A, Hissar S, Choo L, Musoke P, Mulenga V, Mave V, Joseph B, LeBeau K, Thomason MJ, Mboizi RB, Kapasa M, van der Zalm MM, Raichur P, Bhavani PK, McIlleron H, Demers A-M, Aarnoutse R, Love-Koh J, Seddon JA, Welch SB, Graham SM, Hesseling AC, Gibb DM, Crook AMet al., 2022, Shorter treatment for non-severe tuberculosis in African and Indian children, New England Journal of Medicine, Vol: 386, Pages: 911-922, ISSN: 0028-4793

Background:Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen.Methods:We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment.Results:From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, −0.4 percentage points; 95% confidence interval, −2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberc

Journal article

Dodd P, Mafirakureva N, Seddon J, McQuaid Cet al., 2022, The global impact and cost-effectiveness of multidrug- and rifampicin-resistant tuberculosis household contact management in children for 2019: a modelling study, The Lancet Global Health, ISSN: 2214-109X

Journal article

Gureva T, Turkova A, Yablokova E, Smirnova P, Sveshnikova O, Zolotaya O, Nikishova E, Heldal E, Hinderaker S, Seddon JA, Mariandyshev Aet al., 2022, Fluoroquinolone preventive therapy for children exposed to MDR-TB, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 26, Pages: 171-173, ISSN: 1027-3719

Journal article

Lopez-Varela E, Garcia-Prats AJ, Seddon JA, Draper HR, Winckler J, van der Laan L, Palmer M, Burger WA, Schaaf HS, Hesseling ACet al., 2022, Treatment outcomes and safety in children with rifampicin-resistant TB, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 26, Pages: 133-+, ISSN: 1027-3719

Journal article

Palmer M, Gunasekera KS, van der Zalm MM, Morrison J, Schaaf HS, Goussard P, Hesseling AC, Walters E, Seddon JAet al., 2022, The Diagnostic Accuracy of Chest Radiographic Features for Pediatric Intrathoracic Tuberculosis, CLINICAL INFECTIOUS DISEASES, ISSN: 1058-4838

Journal article

Salih R, van Toorn R, Seddon JA, Solomons RSet al., 2022, The impact of hyponatremia on the severity of childhood tuberculous meningitis., Front Neurol, Vol: 12, Pages: 1-9, ISSN: 1664-2295

Introduction: Hyponatremia and/or hypoglycorrhachia are commonly encountered biochemical derangements during the acute stage of childhood tuberculous meningitis (TBM). Few studies have explored the correlation between these derangements and the staging of TBM disease (severity), or explored their role as biomarkers for vascular ischemic events, hydrocephalus, or seizures. Methods: We aimed to identify the prevalence and the correlation between serum hyponatremia (mild, moderate and severe) and/or hypoglycorrhachia in relation to clinical TBM features such as stage of disease, seizures and stroke in children diagnosed with definite and probable TBM, between 1985 and 2015, at Tygerberg Hospital, Cape town, South Africa. Results: The prevalence of hyponatremia was 344 out of 481 (71.5%) patients; 169 (49.1%) had mild hyponatremia, 146 (42.4%) moderate hyponatremia and 29 (8.4%) severe hyponatremia. Children with severe hyponatremia had higher frequency of stroke [odds ratio (OR) 4.36, 95% confidence interval (CI) 1.24-15.35; p = 0.01], brainstem dysfunction (OR 7.37, 95% CI 2.92-18.61; p < 0.01), cranial nerve palsies (OR 2.48, 95% CI 1.04-5.91; p = 0.04) and non-communicating hydrocephalus (OR 2.66, 95% CI 1.09-6.44; p = 0.03). Children with moderate hyponatremia and mild hyponatremia compared to those without hyponatremia similarly were more likely to exhibit signs of brainstem dysfunction (OR 1.91, 95% CI 1.11-3.28; p = 0.02) and hydrocephalus (OR 3.18, 95% CI 1.25-8.09; p = 0.01), respectively. On multivariable analysis only brainstem dysfunction was significantly associated with severe hyponatremia [adjusted odds ratio (aOR) 4.46, 95% CI 1.62-12.30; p < 0.01]. Children with hypoglycorrhachia compared to normoglycorrhachia were more likely to have had longer symptom duration prior to admission (OR 1.87, 95% CI 1.09-3.20; p = 0.02), non-communicating hydrocephalus (OR 1.64, 95% CI 0.99-2.71; p = 0.05), higher cerebrospinal white cell counts (OR 3.00, 95% CI 1.

Journal article

Ghanaiee RM, Karimi A, Hoseini-Alfatemi SM, Seddon JA, Nasehi M, Tabarsi P, Fahimzad SA, Armin S, Akbarizadeh J, Rahimarbabi E, Azimi Let al., 2022, Household contact investigation for the detection of active tuberculosis and latent tuberculosis: A comprehensive evaluation in two high-burden provinces in Iran., New Microbes New Infect, Vol: 45, ISSN: 2052-2975

BACKGROUND: Systematic evaluation of household contacts of persons with pulmonary tuberculosis (TB) in low- and middle-income countries is recommended by the World Health Organization (WHO). This study recruited adult household contacts of diagnosed TB patients in two high burden provinces of Iran to estimate the prevalence and incidence of active disease and latent TB infection (LTBI) among individuals exposed to TB cases. METHODS: We conducted a cohort study among adults in household contact with a pulmonary TB index case. All subjects were assessed for active disease through evaluation of symptoms. Tuberculin skin test (TST) and QuantiFERON®-TB Gold Plus (QFT-Plus) were used to define LTBI. These tests were performed at the time of the index TB case diagnosis and repeated if the previous result was negative, at three-, 12-, and 18-months post recruitment. In addition, interferon-γ-induced protein-10 (IP-10) concentrations were measured in QFT-Plus supernatants for all participants three months after diagnosing the index case. RESULTS: A total of 451 individuals who had close contact with 95 active TB patients were enrolled in this study. Five (1.1%) contacts were diagnosed with active TB and 285 (63.2%) were identified with LTBI during our study. The incidence rate of LTBI among adult household contacts of TB index cases was 0.44 per person per year. CONCLUSION: The overall rate of LTBI was high. Systematic screening of all household contacts of pulmonary TB should be expanded in Iran to make the timely achievement of the global end TB strategy feasible.

Journal article

Huynh J, Abo Y-N, du Preez K, Solomons R, Dooley K, Seddon Jet al., 2021, Tuberculous meningitis in children: reducing the burden of death and disability, Pathogens, Vol: 11, ISSN: 2076-0817

Tuberculous meningitis disproportionately affects young children. As the most devastating form of tuberculosis, it is associated with unacceptably high rates of mortality and morbidity even if treated. Challenging to diagnose and treat, tuberculous meningitis commonly causes long-term neurodisability in those who do survive. There remains an urgent need for strengthened surveillance, improved rapid diagnostics technology, optimised anti-tuberculosis drug therapy, investigation of new host-directed therapy, and further research on long-term functional and neurodevelopmental outcomes to allow targeted intervention. This review focuses on the neglected field of paediatric tuberculous meningitis and bridges current clinical gaps with research questions to improve outcomes from this crippling disease.

Journal article

Marais BJ, Verkuijl S, Casenghi M, Triasih R, Hesseling AC, Mandalakas AM, Marcy O, Seddon JA, Graham SM, Amanullah Fet al., 2021, Paediatric tuberculosis - new advances to close persistent gaps, INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, Vol: 113, Pages: S63-S67, ISSN: 1201-9712

Journal article

Dodd PJ, Osman M, Cresswell F, Stadelman A, Huu Lan N, Tyhy Thuong Thuong N, Muzyamba M, Glaser L, Dlamini S, Seddon Jet al., 2021, The global burden of tuberculous meningitis in adults: a modelling study, PLOS Global Public Health, Vol: 1, Pages: 1-15, ISSN: 2767-3375

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.

Journal article

Moscibrodzki P, Enane LA, Hoddinott G, Brooks MB, Byron V, Furin J, Seddon JA, Meyersohn L, Chiang SSet al., 2021, The impact of tuberculosis on the well-being of adolescents and young adults, Pathogens, Vol: 10, Pages: 1-17, ISSN: 2076-0817

The health needs of adolescents and young adults (AYAs) have been neglected in tuberculosis (TB) care, control, and research. AYAs, who are distinct from younger children and older adults, undergo dynamic physical, psychological, emotional, cognitive, and social development. Five domains of adolescent well-being are crucial to a successful transition between childhood and adulthood: (1) Good health; (2) connectedness and contribution to society; (3) safety and a supportive environment; (4) learning, competence, education, skills, and employability; and (5) agency and resilience. This review summarizes the evidence of the impact of TB disease and treatment on these five domains of AYA well-being.

Journal article

Olbrich L, Stockdale L, Basu Roy R, Song R, Cicin-Sain L, Whittaker E, Prendergast AJ, Fletcher H, Seddon JAet al., 2021, Understanding the interaction between cytomegalovirus and tuberculosis in children: The way forward, PLoS Pathogens, Vol: 17, Pages: 1-21, ISSN: 1553-7366

Over 1 million children develop tuberculosis (TB) each year, with a quarter dying. Multiple factors impact the risk of a child being exposed to Mycobacterium tuberculosis (Mtb), the risk of progressing to TB disease, and the risk of dying. However, an emerging body of evidence suggests that coinfection with cytomegalovirus (CMV), a ubiquitous herpes virus, impacts the host response to Mtb, potentially influencing the probability of disease progression, type of TB disease, performance of TB diagnostics, and disease outcome. It is also likely that infection with Mtb impacts CMV pathogenesis. Our current understanding of the burden of these 2 diseases in children, their immunological interactions, and the clinical consequence of coinfection is incomplete. It is also unclear how potential interventions might affect disease progression and outcome for TB or CMV. This article reviews the epidemiological, clinical, and immunological literature on CMV and TB in children and explores how the 2 pathogens interact, while also considering the impact of HIV on this relationship. It outlines areas of research uncertainty and makes practical suggestions as to potential studies that might address these gaps. Current research is hampered by inconsistent definitions, study designs, and laboratory practices, and more consistency and collaboration between researchers would lead to greater clarity. The ambitious targets outlined in the World Health Organization End TB Strategy will only be met through a better understanding of all aspects of child TB, including the substantial impact of coinfections.

Journal article

Purchase S, Batist E, Mmile N, Nkosi S, Workman J, Martinson N, Fairlie L, Schaaf HS, Choo L, McGowan C, Crook AM, Seddon JA, Hesseling ACet al., 2021, Challenges in recruiting children to a multidrug-resistant TB prevention trial, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 25, Pages: 814-822, ISSN: 1027-3719

Journal article

van Toorn R, Zaharie S-D, Seddon JA, van der Kuip M, van Furth AM, Schoeman JF, Solomons RSet al., 2021, The use of thalidomide to treat children with tuberculosis meningitis: A review, TUBERCULOSIS, Vol: 130, ISSN: 1472-9792

Journal article

Noguera-Julian A, Buonsenso D, McKenna L, Seddon JA, Ritz Net al., 2021, Availability of fixed-dose, child-friendly formulations of first-line tuberculosis drugs in Europe, EUROPEAN RESPIRATORY JOURNAL, Vol: 58, ISSN: 0903-1936

Journal article

du Preez K, Osman M, Seddon J, Naidoo P, Schaaf HS, Munch Z, Dunbar R, Mvusi L, Dlamini S, Hesseling Aet al., 2021, The impact of the evolving HIV response on the epidemiology of tuberculosis in South African children and adolescents, Clinical Infectious Diseases, Vol: 73, Pages: e967-e975, ISSN: 1058-4838

BackgroundFew studies have evaluated tuberculosis control in children and adolescents. We used routine tuberculosis surveillance data to quantify age- and HIV-stratified trends over time and investigate the relationship between tuberculosis, HIV, age and sex.MethodsAll children and adolescents (0-19 years) routinely treated for drug-susceptible tuberculosis in South Africa and recorded in a de-duplicated national electronic tuberculosis treatment register (2004-2016) were included. Age- and HIV-stratified tuberculosis case notification rates (CNRs) were calculated in four age bands: 0-4, 5-9, 10-14 and 15-19 years. The association between HIV infection, age and sex in children and adolescents with TB was evaluated using multivariable logistic regression.ResultsOf 719,400 children and adolescents included, 339,112 (47%) were 0-4-year-olds. The overall tuberculosis CNR for 0-19-year-olds declined by 54% between 2009 and 2016 (incidence rate ratio [IRR]=0.46, 95% confidence interval [CI] 0.45-0.47). Trends varied by age and HIV, with the smallest reductions (2013-2016) in HIV-positive 0-4-year-olds (IRR=0.90, 95%CI 0.85-0.95) and both HIV-positive (IRR=0.84, 95%CI 0.80-0.88) and HIV-negative (IRR=0.89, 95%CI 0.86-0.92) 15-19-year-olds. Compared to 0-4-year-old males, odds of HIV co-infection among 15-19-year-olds were nearly twice as high in females (adjusted odd’s ratio [aOR]=2.49, 95%CI 2.38-2.60) than in males (aOR=1.35, 95%CI 1.29-1.42).ConclusionsSouth Africa’s national response to the HIV epidemic has made a substantial contribution to the observed declining trends in tuberculosis CNRs in children and adolescents. The slow decline of tuberculosis CNRs in adolescents and young HIV-positive children is concerning. Understanding how tuberculosis affects children and adolescents beyond conventional age bands and by sex, can inform targeted tuberculosis control strategies.

Journal article

Van Zyl KN, Whitelaw AC, Hesseling AC, Seddon JA, Demers A-M, Newton-Foot Met al., 2021, Association between clinical and environmental factors and the gut microbiota profiles in young South African children, SCIENTIFIC REPORTS, Vol: 11, ISSN: 2045-2322

Journal article

Osman M, van Schalkwyk C, Naidoo P, Seddon JA, Dunbar R, Dlamini SS, Welte A, Hesseling AC, Claassens MMet al., 2021, Mortality during tuberculosis treatment in South Africa using an 8-year analysis of the national tuberculosis treatment register, SCIENTIFIC REPORTS, Vol: 11, ISSN: 2045-2322

Journal article

Schaaf HS, Seddon JA, 2021, Management of tuberculous meningitis in children, PAEDIATRICS AND INTERNATIONAL CHILD HEALTH, Vol: 41, Pages: 231-236, ISSN: 2046-9047

Journal article

Chiang S, Brooks M, Jenkins H, Rubenstein D, Seddon J, van de Water B, Lindeborg M, Becerra M, Yuen Cet al., 2021, Concordance of drug resistance profiles between persons with drug-resistant tuberculosis and their household contacts: a systematic review and meta-analysis, Clinical Infectious Diseases, Vol: 73, Pages: 250-263, ISSN: 1058-4838

BackgroundHousehold contacts of patients with drug-resistant tuberculosis are at high risk for being infected with Mycobacterium tuberculosis and for developing tuberculosis disease. To guide regimen composition for the empirical treatment of tuberculosis infection and disease in these household contacts, we estimated drug resistance profile concordance between index patients with drug-resistant tuberculosis and their household contacts.MethodsWe performed a systematic review and meta-analysis of studies published through July 24, 2018 and reported resistance profiles of drug-resistant tuberculosis index and secondary cases within their households. Using a random-effects meta-analysis, we estimated resistance profile concordance, defined as the percentage of secondary cases whose M. tuberculosis strains were resistant to the same drugs as strains from their index cases. We also estimated isoniazid/rifampin concordance, defined as whether index and secondary cases had identical susceptibilities for isoniazid and rifampin only.ResultsWe identified 33 eligible studies, which evaluated resistance profile concordance between 484 secondary cases and their household index cases. Pooled resistance profile concordance was 54.3% (95% confidence interval [CI]: 40.7-67.6, I2=85%). Pooled isoniazid/rifampin concordance was 82.6% (95% CI: 72.3-90.9; I2=73%). Concordance estimates were similar in a sub-analysis of 16 studies from high tuberculosis-burden countries. There were insufficient data to perform a sub-analysis among pediatric secondary cases.ConclusionHousehold contacts of drug-resistant TB patients should receive treatment for TB infection and disease that assumes that they, too, are infected with a drug-resistant M. tuberculosis strain. Whenever possible, drug susceptibility testing should be performed for secondary cases to optimize regimen composition.

Journal article

McArdle AJ, Vito O, Patel H, Seaby EG, Shah P, Wilson C, Broderick C, Nijman R, Tremoulet AH, Munblit D, Ulloa-Gutierrez R, Carter MJ, De T, Hoggart C, Whittaker E, Herberg JA, Kaforou M, Cunnington AJ, Levin Met al., 2021, Treatment of multisystem inflammatory syndrome in children, New England Journal of Medicine, Vol: 385, Pages: 11-22, ISSN: 0028-4793

BACKGROUNDEvidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.METHODSWe performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.RESULTSData were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.CONCLUSIONSWe found n

Journal article

Dodd P, Yuen C, Jayasooriya S, van der Zalm M, Seddon Jet al., 2021, Quantifying the global number of tuberculosis survivors: a modelling study, Lancet Infectious Diseases, Vol: 21, Pages: 984-992, ISSN: 1473-3099

Background: People who survive tuberculosis continue to experience clinical and societal consequences after recovery, including increased risks of recurrent tuberculosis, premature death, reduced lung function, and ongoing stigma. We aimed to describe the magnitude of this issue by estimating the number of tuberculosis survivors, who could be amenable to intervention. Methods: We estimated the number of people who developed tuberculosis during 1980-2019 and survived until 2020. Numbers surviving treatment were based on country-level data on tuberculosis case notifications reported to the World Health Organization (WHO), excluding people who died during treatment. Numbers surviving untreated tuberculosis were based on the difference between WHO country-level incidence estimates and notifications, with published age-and HIV-stratified case fatality ratios applied. Post-tuberculosis life tables were developed for each country-year, using United Nations World Population Prospects 2019 mortality rates and published post-tuberculosis mortality hazard ratios. Findings: Between 1980 and 2019 we estimate that 363 (95% uncertainty interval [UI] 287 -438) million people developed tuberculosis, of whom 172 (95%UI 169 -174) million were treated. Individuals who developed tuberculosis since 1980 experienced a total of 3.5 (95%UI 3.0 -3.9) billion life-years post-tuberculosis, with survivors of paediatric tuberculosis contributing 12% (95%UI 7 -17%) of these life-years. We estimate that 155 (95%UI 138 -171) million tuberculosis survivors were alive in 2020. The South-East Asia region had the largest proportion of tuberculosis survivors (47%). We estimate that 27 (95%UI 26 -29) million tuberculosis survivors alive in 2020 were treated within the past 5 years. Interpretation: The number of tuberculosis survivors alive today is over ten times the estimated annual tuberculosis incidence. Interventions to alleviate respiratory morbidity, screen for and prevent recurrent tuberculos

Journal article

Manyelo CM, Chegou NN, Seddon JA, Snyders CI, Mutavhatsindi H, Manngo PM, Walzl G, Stanley K, Solomons RSet al., 2021, Serum and cerebrospinal fluid host proteins indicate stroke in children with tuberculous meningitis, PLoS One, Vol: 16, Pages: 1-18, ISSN: 1932-6203

IntroductionStroke is a common complication in children with tuberculous meningitis (TBM). Host proteins may give us insight into the mechanisms of stroke in TBM and serve as biomarkers for detection of stroke, however, they have not been widely explored. In this study, we compared the concentrations of cerebrospinal fluid (CSF) and serum proteins between children who had TBM-related stroke and children with TBM without stroke.MethodsWe collected CSF and serum from 47 children consecutively admitted to the Tygerberg Academic Hospital in Cape Town, South Africa between November 2016, and November 2017, on suspicion of having TBM. A multiplex platform was used to measure the concentrations of 69 host proteins in CSF and serum from all study participants.ResultsAfter classification of study participants, 23 (48.9%) out of the 47 study participants were diagnosed with TBM, of which 14 (60.9%) demonstrated radiological arterial ischemic infarction. The levels of lipocalin-2, sRAGE, IP-10/ CXCL10, sVCAM-1, MMP-1, and PDGF-AA in CSF samples and the levels of D-dimer, ADAMTS13, SAA, ferritin, MCP-1/ CCL2, GDF-15 and IL-13 in serum samples were statistically different between children who had TBM-related stroke and children with TBM without stroke. After correcting for multiple testing, only the levels of sVCAM-1, MMP-1, sRAGE, and IP-10/ CXCL10 in CSF were statistically different between the two groups. CSF and serum protein biosignatures indicated stroke in children diagnosed with TBM with up to 100% sensitivity and 88.9% specificity.ConclusionSerum and CSF proteins may serve as biomarkers for identifying individuals with stroke amongst children diagnosed with TBM at admission and may guide us to understand the biology of stroke in TBM. This was a pilot study, and thus further investigations in larger studies are needed.

Journal article

Basu Roy R, Bakeera-Kitaka S, Chabala C, Gibb DM, Huynh J, Mujuru H, Sankhyan N, Seddon JA, Sharma S, Singh V, Wobudeya E, Anderson STet al., 2021, Defeating paediatric tuberculous meningitis: applying the WHO "Defeating Meningitis by 2030: Global Roadmap"., Microorganisms, Vol: 9, Pages: 1-18, ISSN: 2076-2607

Children affected by tuberculous meningitis (TBM), as well as their families, have needs that lie at the intersections between the tuberculosis and meningitis clinical, research, and policy spheres. There is therefore a substantial risk that these needs are not fully met by either programme. In this narrative review article, we use the World Health Organization (WHO) "Defeating Meningitis by 2030: global roadmap" as a starting point to consider key goals and activities to specifically defeat TBM in children. We apply the five pillars outlined in the roadmap to describe how this approach can be adapted to serve children affected by TBM. The pillars are (i) prevention; (ii) diagnosis and treatment; (iii) surveillance; (iv) support and care for people affected by meningitis; and (v) advocacy and engagement. We conclude by calling for greater integration between meningitis and TB programmes at WHO and at national levels.

Journal article

Solomons RS, Nieuwoudt ST, Seddon JA, van Toorn Ret al., 2021, Risk factors for ischemic stroke in children with tuberculous meningitis, CHILDS NERVOUS SYSTEM, Vol: 37, Pages: 2625-2634, ISSN: 0256-7040

Journal article

Osman M, du Preez K, Seddon J, Dunbar R, Dlamini S, Welte A, Naidoo P, Hesseling A, Claassens Met al., 2021, Mortality in South African children and adolescents routinely treated for tuberculosis, Pediatrics, Vol: 147, Pages: 1-1, ISSN: 0031-4005

BackgroundIn South Africa, tuberculosis (TB) is a leading cause of death among those <20 years. We describe changes in TB mortality amongst children and adolescents in South Africa over a 13-year period, identify risk factors for mortality, and estimate excess TB-related mortality.MethodsRetrospective analysis of all patients <20 years routinely recorded in the national electronic drug-susceptible TB treatment register (2004-2016). We developed a multivariable Cox regression model for predictors of mortality and used estimates of mortality among the general population to calculate standardized mortality ratios (SMR).ResultsBetween 2004-16, 729,463 children and adolescents were recorded on TB treatment; 84.0% had treatment outcomes and 2.5% (18,539) died during TB treatment. The case fatality ratio (CFR) decreased from 3.3% in 2007, to 1.9% in 2016. In the multivariable Cox regression model, age 0-4, 10-14 and 15-19 years (compared to age 5-9 years) was associated with increased risk of mortality, as was HIV infection, previous TB treatment and extrapulmonary involvement. The SMR of 15-19-year-old females was more than double that of males the same age (55.3 vs 26.2). Among 10-14-year-olds and those HIV-positive, SMRs increased over time.ConclusionsMortality in South African children and adolescents treated for TB is declining but remains considerable, with 2% dying during 2016. Adolescents (10-19 years) and those people living with HIV have the highest risk of mortality and greatest SMRs. Interventions to reduce mortality during TB treatment, specifically targeting those at highest risk, are urgently needed.

Journal article

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