161 results found
van Toorn R, Zaharie S-D, Seddon JA, et al., 2021, The use of thalidomide to treat children with tuberculosis meningitis: A review., Tuberculosis (Edinb), Vol: 130
Much of the morbidity and mortality caused by tuberculous meningitis (TBM) is mediated by a dysregulated immune response. Effective host-directed therapy is therefore critical to improve survival and clinical outcomes. Currently only one host-directed therapy (HDT), corticosteroids, is proven to improve mortality. However, there is no evidence that corticosteroids reduce morbidity and the mechanism of action for mortality reduction is uncertain. Further, it has no proven benefit in HIV co-infected individuals. One promising host-directed therapy approach is to restrict the immunopathology arising from tumour necrosis factor (TNF)-α excess is via TNF-α inhibitors. There are accumulating data on the role of thalidomide, anti-TNF-α monoclonal antibodies (infliximab, adalimumab) and the soluble TNF-α receptor (etanercept) in TBM treatment. Thalidomide was developed nearly seventy years ago and has been a highly controversial drug. Birth defects and toxic adverse effects have limited its use but an improved understanding of its immunological mechanism of action suggest that it may have a crucial role in regulating the destructive host response seen in inflammatory conditions such as TBM. Observational studies at our institution found low dosage adjunctive thalidomide safe in treating tuberculous mass lesions and blindness related to optochiasmatic arachnoiditis, with good clinical and radiological response. In this review, we discuss possible mechanisms of action for thalidomide, based on our clinico-radiologic experience and post-mortem histopathological work. We also propose a rationale for its use in the treatment of certain TBM-related complications.
du Preez K, Osman M, Seddon J, et 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.
Van Zyl KN, Whitelaw AC, Hesseling AC, et 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
Osman M, van Schalkwyk C, Naidoo P, et 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
Chiang S, Brooks M, Jenkins H, et 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.
Dodd P, Yuen C, Jayasooriya S, et 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
Noguera-Julian A, Buonsenso D, Mckenna L, et al., 2021, Availability of fixed-dose, child-friendly formulations of first-line tuberculosis drugs in Europe., Eur Respir J
Manyelo CM, Chegou NN, Seddon JA, et al., 2021, Serum and cerebrospinal fluid host proteins indicate stroke in children with tuberculous meningitis, PLOS ONE, Vol: 16, ISSN: 1932-6203
Basu Roy R, Bakeera-Kitaka S, Chabala C, et 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.
Solomons RS, Nieuwoudt ST, Seddon JA, et al., 2021, Risk factors for ischemic stroke in children with tuberculous meningitis, CHILDS NERVOUS SYSTEM, Vol: 37, Pages: 2625-2634, ISSN: 0256-7040
Osman M, du Preez K, Seddon J, et 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.
Loveday M, Hughes J, Sunkari B, et al., 2021, Maternal and infant outcomes among pregnant women treated for multidrug/rifampicin-resistant tuberculosis in South Africa, Clinical Infectious Diseases, Vol: 72, Pages: 1158-1168, ISSN: 1058-4838
BackgroundData on safety and efficacy of second-line tuberculosis drugs in pregnant women and their infants are severely limited due to exclusion from clinical trials and expanded access programmes.MethodsPregnant women starting treatment for multidrug/rifampicin-resistant (MDR/RR)-tuberculosis at King Dinuzulu Hospital in KwaZulu-Natal, South Africa from 1 January 2013 – 31 December 2017 were included. We conducted a record review to describe maternal treatment and pregnancy outcomes, and a clinical assessment to describe infant outcomes.ResultsOf 108 pregnant women treated for MDR/RR-tuberculosis, 88 (81%) were HIV-infected. Favourable MDR/RR-tuberculosis treatment outcomes were reported in 72 (67%) women. Ninety-nine (91%) of the 109 babies were born alive but, overall, 52 (48%) women had unfavourable pregnancy outcomes. Fifty-eight (54%) women received bedaquiline and 49 (45%) babies were exposed to bedaquiline in utero. Low birthweight was reported in more babies exposed to bedaquiline compared to babies not exposed (45% vs 26%; p=0.034). In multivariate analyses, bedaquiline and levofloxacin, drugs often used in combination, were both independently associated with increased risk of low birthweight. Of the 86 children evaluated at 12 months, 72 (84%) had favourable outcomes; 88% of babies exposed to bedaquiline were thriving and developing normally compared to 82% of the babies not exposed.ConclusionsMDR/RR-tuberculosis treatment outcomes among pregnant women were comparable to non-pregnant adults. Although more babies exposed to bedaquiline were of low birthweight, over 80% had gained weight and were developing normally at one year.
Vessiere A, Font H, Gabillard D, et al., 2021, Impact of systematic early tuberculosis detection using Xpert MTB/RIF Ultra in children with severe pneumonia in high tuberculosis burden countries (TB-Speed pneumonia): a stepped wedge cluster randomized trial, BMC Pediatrics, Vol: 21, Pages: 1-12, ISSN: 1471-2431
BackgroundIn high tuberculosis (TB) burden settings, there is growing evidence that TB is common in children with pneumonia, the leading cause of death in children under 5 years worldwide. The current WHO standard of care (SOC) for young children with pneumonia considers a diagnosis of TB only if the child has a history of prolonged symptoms or fails to respond to antibiotic treatments. As a result, many children with TB-associated severe pneumonia are currently missed or diagnosed too late. We therefore propose a diagnostic trial to assess the impact on mortality of adding the systematic early detection of TB using Xpert MTB/RIF Ultra (Ultra) performed on nasopharyngeal aspirates (NPA) and stool samples to the WHO SOC for children with severe pneumonia, followed by immediate initiation of anti-TB treatment in children testing positive on any of the samples.MethodsTB-Speed Pneumonia is a pragmatic stepped-wedge cluster randomized controlled trial conducted in six countries with high TB incidence rate (Côte d’Ivoire, Cameroon, Uganda, Mozambique, Zambia and Cambodia). We will enrol 3780 children under 5 years presenting with WHO-defined severe pneumonia across 15 hospitals over 18 months. All hospitals will start managing children using the WHO SOC for severe pneumonia; one hospital will be randomly selected to switch to the intervention every 5 weeks. The intervention consists of the WHO SOC plus rapid TB detection on the day of admission using Ultra performed on 1 nasopharyngeal aspirate and 1 stool sample. All children will be followed for 3 months, with systematic trial visits at day 3, discharge, 2 weeks post-discharge, and week 12. The primary endpoint is all-cause mortality 12 weeks after inclusion. Qualitative and health economic evaluations are embedded in the trial.DiscussionIn addition to testing the main hypothesis that molecular detection and early treatment will reduce TB mortality in children
Marais BJ, Verkuijl S, Casenghi M, et al., 2021, Paediatric tuberculosis - new advances to close persistent gaps., Int J Infect Dis
Young children are most vulnerable to develop severe forms of tuberculosis (TB) and are over-represented among TB deaths. Almost all children estimated to have died from TB were never diagnosed or offered TB treatment. Improved access to TB preventive treatment (TPT) requires major upscaling of household contact investigation with allocation of adequate resources. Symptom-based screening is often discouraged in adults for fear of generating drug resistance, if TB cases are missed. However, the situation in vulnerable young children is different, as they present minimal risk of drug resistance generation. Further, the perceived need for additional diagnostic evaluation presents a major barrier to TPT access and underlies general reluctance to consider pragmatic decentralised models of care. Widespread roll-out of Xpert MTB/RIF Ultra® represents an opportunity for improved case detection in young children, but attaining full impact will require the use of non-sputum specimens. The new Fujifilm SILVAMP TB LAM® urine assay demonstrated good diagnostic accuracy in HIV-positive and malnourished children, but further validation is required. Given the limited accuracy of all available tests and the excellent tolerance of TB drugs in children, the global community may have to accept some over-treatment if we want to close the persistent case detection gap in young children.
van Toorn R, Solomons R, Seddon J, et al., 2021, Thalidomide use for complicated central nervous system tuberculosis in children: insights from an observational cohort, Clinical Infectious Diseases, Vol: 72, Pages: e136-e145, ISSN: 1058-4838
BackgroundMuch of the neurological sequelae of central nervous system (CNS) tuberculosis (TB) is due to an excessive cytokine-driven host-inflammatory response. Adjunctive corticosteroids, which reduce cytokine production and thus dampens the inflammation, improve overall survival but do not prevent morbidity. This has prompted investigation of more targeted immunomodulatory agents, including thalidomide.MethodsWe describe a retrospective cohort of 38 children consecutively treated with adjunctive thalidomide for CNS TB-related complications over a 10-year periodResultsThe most common presenting symptom was focal motor deficit (n=16), followed by cranial nerve palsies and cerebellar dysfunction. Three of the 38 children presented with large dural-based lesions, manifesting as epilepsia partialis continua (EPC), 4 presented with blindness secondary to optochiasmatic arachnoiditis whilst two children developed paraplegia due to spinal cord TB mass lesions. Duration of adjunctive thalidomide therapy (3-5 mg/kg/day) varied according to complication type. In children compromised by TB mass lesions, the median treatment duration was 3.9 months (interquartile range [IQR]: 2.0-5.0); whilst in children with optic neuritis it was 2.0 months (IQR: 1.3-7.3) and in EPC it was 1.0 months (IQR: 1-2.5). Satisfactory clinical and radiological response was observed in 37 of the children. None of the children experienced rashes, hepatitis, hematologic derangements or complained of leg cramps.ConclusionThis study is the largest cohort of adult or paediatric patients treated with adjunctive thalidomide for CNS TB-related complications. The drug has proved safe, well tolerated and appears to be clinically efficacious. The potential role of thalidomide or analogues in the treatment of other TBM-related complications requires further exploration.
Ghanaie RM, Karimi A, Azimi L, et al., 2021, Diagnosis of latent tuberculosis infection among pediatric household contacts of Iranian tuberculosis cases using tuberculin skin test, IFN- γ release assay and IFN-γ-induced protein-10., BMC Pediatr, Vol: 21
BACKGROUND: Although the World Health Organization has recommended the diagnosis and prophylactic treatment of latent tuberculous infection (LTBI) in child household contacts of tuberculosis (TB) cases, the national programs in high-burden TB regions rarely implement adequate screening of this high-risk group, mainly because of resource limitations. We aimed to evaluate the prevalence of LTBI among pediatric household contacts of TB cases in two high-burden provinces in Iran. METHODS: We conducted a cohort study in children who had been in household contact with a TB index. All subjects were assessed for active TB disease. For LTBI diagnosis, tuberculin skin test (TST) and QuantiFERON®-TB Gold Plus (QFT-Plus) were performed at the time of the index TB case diagnosis, as well as, 3, 12, and 18 months, if the first results were negative. In addition, interferon-γ-induced protein-10(IP-10) concentrations were measured for all participants. RESULTS: A total of 230 children were enrolled, who had contact with an index TB case. Three contacts were diagnosed with active TB. According to the TST/QFT-Plus results, 104 (45.2%) children were identified with LTBI during our study. Significantly increased IP-10 levels were found in LTBI patients compared to healthy contacts. Accordingly, more than 50% of LTBI contacts and about 10% of healthy contacts were considered as IP-10-positive. CONCLUSION: This study alarmingly illustrates a high prevalence of LTBI among Iranian children exposed to TB cases. We, therefore, emphasize that the children living in close contact with an infectious TB case should be screened effectively and receive prophylactic therapy.
Cresswell F, Davis A, Sharma K, et al., 2021, Recent developments in tuberculous meningitis pathogenesis and diagnostics, Wellcome Open Research, Vol: 4, Pages: 1-26, ISSN: 2398-502X
The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of <150 cells/μL) having higher CSF neutrophils, greater CSF cytokine concentrations and higher mortality than those with CD4+ T-cell counts > 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a “one-size-fits-all” approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens.
Gunasekera K, Walters E, van der Zalm M, et al., 2021, Development of a treatment-decision algorithm for HIV-uninfected children evaluated for pulmonary tuberculosis, Clinical Infectious Diseases, Vol: 73, Pages: e904-e912, ISSN: 1058-4838
BackgroundLimitations in the sensitivity and accessibility of diagnostic tools for childhood tuberculosis contribute to the substantial gap between estimated cases and cases notified to national tuberculosis programs. Thus, tools to make accurate and rapid clinical diagnoses are necessary to initiate more children on antituberculosis treatment.MethodsWe analyzed data from a prospective cohort of children <13 years being routinely evaluated for pulmonary tuberculosis in Cape Town, South Africa from March 2012 to November 2017. We developed a regression model to describe the contributions of baseline clinical evaluation to the diagnosis of tuberculosis using standardized, retrospective case definitions. We included results from baseline chest radiography and Xpert MTB/RIF to the model to develop an algorithm with at least 90% sensitivity in predicting tuberculosis.ResultsData from 478 children being evaluated for pulmonary tuberculosis were analyzed (median age: 16.2 months, interquartile range: 9.8-30.9); 242 (50.6%) were retrospectively classified with tuberculosis, of which 104 (43.0%) were bacteriologically-confirmed. The area under the receiver operating characteristic curve for the final model was 0.87. Clinical evidence identified 71.4% of all tuberculosis cases in this cohort, and inclusion of baseline chest radiography results increased the proportion to 89.3%. The algorithm was 90.1% sensitive and 52.1% specific, and maintained a sensitivity of above 90% among children <2 years or with low weight-for-age.ConclusionsClinical evidence alone was sufficient to make most clinical antituberculosis treatment decisions. The use of evidence-based algorithms may improve decentralized, rapid treatment-initiation, reducing the global burden of childhood mortality.
van der Zalm M, Walters E, Classsen M, et al., 2020, High burden of viral respiratory co-infections in a cohort of children with suspected pulmonary tuberculosis, BMC Infectious Diseases, Vol: 20, ISSN: 1471-2334
BackgroundThe presentation of pulmonary tuberculosis (PTB) in young children is often clinically indistinguishable from other common respiratory illnesses, which are frequently infections of viral aetiology. As little is known about the role of viruses in children with PTB, we investigated the prevalence of respiratory viruses in children with suspected PTB at presentation and follow-up.MethodsIn an observational cohort study, children < 13 years were routinely investigated for suspected PTB in Cape Town, South Africa between December 2015 and September 2017 and followed up for 24 weeks. Nasopharyngeal aspirates (NPAs) were tested for respiratory viruses using multiplex PCR at enrolment, week 4 and 8.ResultsSeventy-three children were enrolled [median age 22.0 months; (interquartile range 10.0–48.0); 56.2% male and 17.8% HIV-infected. Anti-tuberculosis treatment was initiated in 54.8%; of these 50.0% had bacteriologically confirmed TB. At enrolment, ≥1 virus were detected in 95.9% (70/73) children; most commonly human rhinovirus (HRV) (74.0%). HRV was more frequently detected in TB cases (85%) compared to ill controls (60.6%) (p = 0.02). Multiple viruses were detected in 71.2% of all children; 80% of TB cases and 60.6% of ill controls (p = 0.07). At follow-up, ≥1 respiratory virus was detected in 92.2% (47/51) at week 4, and 94.2% (49/52) at week 8.ConclusionsWe found a high prevalence of viral respiratory co-infections in children investigated for PTB, irrespective of final PTB diagnosis, which remained high during follow up. Future work should include investigating the whole respiratory ecosystem in combination with pathogen- specific immune responses.
Nash M, Perrin C, Seddon JA, et al., 2020, Access to paediatric formulations for the treatment of childhood tuberculosis, LANCET CHILD & ADOLESCENT HEALTH, Vol: 4, Pages: 855-857, ISSN: 2352-4642
Srivastava S, van Zyl J, Cirrincione K, et al., 2020, Evaluation of ceftriaxone plus avibactam in an intracellular hollow fiber model of tuberculosis: implications for the treatment of disseminated and meningeal tuberculosis in children, The Pediatric Infectious Disease Journal, Vol: 39, Pages: 1092-1100, ISSN: 0891-3668
Background: Ceftazidime-avibactam is an effective agent for the treatment of tuberculosis (TB) but requires frequent administration because of a short half-life. Due to a longer half-life, ceftriaxone could allow intermittent dosing.Methods: First, we identified the MIC of ceftriaxone with 15 mg/L avibactam in 30 clinical Mycobacterium tuberculosis isolates. Next, 2 ceftriaxone exposure-effect studies in the intracellular hollow fiber model of TB (HFS-TB) that mimics disseminated disease in young children, were performed. Ceftriaxone was administered once or twice daily for 28 days to explore percentage of time that the concentration persisted above MIC (%TMIC) ranging from 0 to 100%. In a third HFS-TB experiment, the “double cephalosporin” regimen of ceftazidime-ceftriaxone-avibactam was examined and analyzed using Bliss Independence.Conclusion: The MIC99 of the clinical strains was 32 mg/L, in the presence of 15 mg/L avibactam. Ceftriaxone %TMIC <42 had no microbial effect in the HFS-TB, %TMIC>54% demonstrated a 4.1 log10 colony-forming units per milliliter M. tuberculosis kill, while %TMIC mediating Emax was 68%. The “double cephalosporin” combination was highly synergistic. Monte Carlo experiments of 10,000 subjects identified the optimal ceftriaxone dose as 100 mg/kg twice a day.Conclusion: The combination of ceftriaxone-avibactam at 100 mg/kg could achieve Emax in >90% of children. The ceftriaxone potent activity M. tuberculosis could potentially shorten therapy in children with disseminated TB.
Morse RM, Myburgh H, Reubi D, et al., 2020, Opportunities for Mobile App-Based Adherence Support for Children With Tuberculosis in South Africa, JMIR MHEALTH AND UHEALTH, Vol: 8, ISSN: 2291-5222
Cox V, McKenna L, Acquah R, et al., 2020, Clinical perspectives on treatment of rifampicin-resistant/multidrug-resistant TB, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 24, Pages: 1134-+, ISSN: 1027-3719
Tucker EW, Marais S, Seddon JA, et al., 2020, International survey reveals opportunities to improve tuberculous meningitis management and the need for standardized guidelines, Open Forum Infectious Diseases, Vol: 7, Pages: 1-14, ISSN: 2328-8957
BackgroundTuberculous meningitis (TBM) is a medical emergency, yet there are no standardized treatment guidelines for the medical or neurosurgical management of these patients and little data on neurocritical care. We conducted an international survey to understand current medical and neurosurgical TBM management and resource availability to provide baseline data needed for future multicenter trials addressing unanswered clinical research questions and the establishment of standardized guidelines.MethodsAn online survey of 77 questions covering medical and neurosurgical TBM management aimed at clinicians/nurses treating TBM was distributed as an anonymous link through email invitation, international organizations’ membership distribution, and direct links on organizational webpages or social media. The survey remained open for 5 months. Data were summarized with frequencies and percentages.ResultsThe survey had 222 responses from 43 countries representing 6 continents. Most respondents were from tertiary care facilities, with broad access to medical and neurosurgical resources. There was significant heterogeneity in general supportive care, and TBM-specific management demonstrated considerable divergence from current standard-of-care practices. The lack of standardized guidelines was identified as a major challenge in TBM management. General and neurocritical care were largely absent. Resources for bedside supportive care and noninvasive monitoring were broadly accessible.ConclusionsThese findings suggest that current TBM management could be improved by the establishment of internationally accepted treatment guidelines based on available evidence, and that numerous centers have resources available to participate in future multicenter trials, even for basic interventions, that may further improve patient outcomes globally.
Reuter A, Seddon JA, Marais BJ, et al., 2020, Preventing tuberculosis in children: A global health emergency, PAEDIATRIC RESPIRATORY REVIEWS, Vol: 36, Pages: 44-51, ISSN: 1526-0542
Donovan J, Cresswell F, Nguyen TTT, et al., 2020, Xpert MTB/RIF ultra for the diagnosis of tuberculous meningitis: a small step forward, Clinical Infectious Diseases, Vol: 71, Pages: 2002-2005, ISSN: 1058-4838
The delayed diagnosis of tuberculous meningitis (TBM) leads to poor outcomes, yet the current diagnostic methods for identifying Mycobacterium tuberculosis in cerebrospinal fluid (CSF) are inadequate. The first comparative study of the new GeneXpert MTB/RIF Ultra (Xpert Ultra) for TBM diagnosis suggested increased sensitivity of Xpert Ultra. Two subsequent studies have shown Xpert Ultra has improved sensitivity, but has insufficient negative predictive value to exclude TBM. Collecting and processing large volumes of CSF for mycobacterial testing are important for optimal diagnostic test performance. But clinical, radiological, and laboratory parameters remain essential for TBM diagnosis and empiric therapy is often needed. We therefore caution against the use of Xpert Ultra as a single diagnostic test for TBM; it cannot be used to “rule out” TBM.
Seddon JA, Johnson S, Palmer M, et al., 2020, Multidrug-resistant tuberculosis in children and adolescents: current strategies for prevention and treatment, EXPERT REVIEW OF RESPIRATORY MEDICINE, Vol: 15, Pages: 221-237, ISSN: 1747-6348
Sartoris G, Seddon JA, Rabie H, et al., 2020, Abdominal Involvement in Children With Bacteriologically Confirmed Tuberculosis A Five-year Experience From Cape Town, South Africa, PEDIATRIC INFECTIOUS DISEASE JOURNAL, Vol: 39, Pages: 914-919, ISSN: 0891-3668
McArdle A, Keane D, Seddon J, et al., 2020, Vitamin D deficiency is associated with tuberculosis disease in British children, International Journal of Tuberculosis and Lung Disease, Vol: 24, Pages: 782-788, ISSN: 1027-3719
Background53Basic science, epidemiological and interventional research supports a link between vitamin D and 54tuberculosis immunity, infection and disease. We evaluated the association between vitamin D 55levels and tuberculosis (TB) infection and disease in UK children recruited to the NIHR IGRA Kids 56Study (NIKS).57Methods58Children presenting between 2011-2014 were eligible if they had history of exposure to an adult 59case with sputum smear/culture-positive TB, or were referred and diagnosed with TB disease. 60Children were assessed at baseline and 6-8 weeks for immunological evidence of TB infection (IGRA 61and/or tuberculin skin test) and evidence of TB disease. Some centres routinely measured total 25-62hydroxy vitamin D levels.63Results64166 children were included. Median 25-hydroxy vitamin D levels were higher in uninfected children 65(45.5 nmol/l) compared to those with infection (36.2 nmol/l) and disease (20.0 nmol/l). The 66difference between TB infection and disease was statistically significant (p<0.001). By logistic 67regression, lower vitamin D levels were associated with TB disease among participants with 68infection/disease, with no evidence of confounding by age, sex, BCG status, ethnicity, non-contact 69referral, season or centre.70Conclusion71Children with TB disease had lower vitamin D levels than children with infection. Implications for 72prevention and treatment remain to be established.
Ganmaa D, Uyanga B, Zhou X, et al., 2020, Vitamin D supplements and prevention of tuberculosis infection and disease, New England Journal of Medicine, Vol: 383, Pages: 359-368, ISSN: 0028-4793
BACKGROUND: Vitamin D metabolites support innate immune responses to Mycobacterium tuberculosis. METHODS: We randomly assigned children who had negative results for Mycobacterium tuberculosis infection, using the QuantiFERON-TB Gold In-tube assay (QFT), to receive a weekly oral dose of 14,000 IU vitamin D3 or placebo over 3 years. The primary outcome was the proportion of children having a positive QFT result at 3 years. Secondary outcomes included end-study vitamin D status and incidence of tuberculosis disease, acute respiratory infections and adverse events.RESULTS: 8851 participants underwent randomization (4418 to vitamin D, 4433 to placebo), of whom 95.6% had baseline serum 25-hydroxyvitamin D concentrations <20 ng/mL. Mean end-study 25-hydroxyvitamin D concentration in participants randomized to vitamin D vs. placebo was 31.0 vs. 10.7 ng/mL (95% CI for difference, 19.9 to 20.6 ng/mL), and 147 participants in the vitamin D group vs. 134 participants in the placebo group tested positive by QFT (adjusted risk ratio [aRR] 1.10, 95% CI 0.87 to 1.38, P=0.42). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and 25 children in the placebo group (aRR 0.87, 95% CI 0.49 to 1.55). 29 participants randomized to vitamin D and 34 randomized to placebo were hospitalized for treatment of acute respiratory infections (aRR 0.86, 95% CI 0.52 to 1.40). Incidence of adverse events did not differ significantly between study arms.CONCLUSIONS: Vitamin D supplementation did not reduce risk of tuberculosis infection, tuberculosis disease or acute respiratory infections among vitamin D-deficient schoolchildren in Mongolia.
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