Publications
217 results found
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.
McArdle AJ, Vito O, Patel H, et 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
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
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, 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.
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.
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
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 PEDIATRICS, Vol: 21
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Seddon JA, Johnson S, Palmer M, et al., 2021, 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
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- Citations: 15
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.
Schaaf HS, Seddon JA, 2021, Childhood Tuberculosis, Essential Tuberculosis, Pages: 229-243, ISBN: 9783030667054
Children constitute approximately 11% of the global tuberculosis (TB) burden each year. Diagnosing TB in children can be challenging; bacteriological confirmation is often not possible and symptoms are frequently non-specific. Making a diagnosis therefore requires the synthesis and combination of varying sources of evidence. While the ultimate goal of a bacteriological confirmed diagnosis can be elusive, all efforts should be made to collect samples to identify Mycobacterium tuberculosis. Effective treatment regimens are available for both drug-susceptible and drug-resistant TB in children with good outcomes if appropriate regimens are started early. However, several treatment challenges remain, such as optimal dosing of first-and second-line drugs, shorter treatment regimens (for drug-susceptible and drug-resistant TB, and TB meningitis), availability of child-friendly formulations and dosing and safety studies for new TB medications and regimens. Preventing TB is central to reducing the global TB burden. Providing effective TB preventive treatment to child contacts of both drug-susceptible and drug-resistant TB source cases therefore should be a high priority, and effective preventive therapy regimens are available. Several novel preventive regimens have recently been developed which require further evaluation in young children.
Whittaker E, Welch SB, Cohen J, et al., 2021, Tuberculosis in Children Adolescents, Tuberculosis in Clinical Practice, Pages: 115-141, ISBN: 9783030755089
Children adolescents represent an important component of the overall tuberculosis (TB) epidemic. Following exposure to an infectious case of TB subsequent infection, young children pubertal adolescents have a high risk of progression to TB disease. The disease manifestations change with age; the youngest children often have paucibacillary disease, either localised to lymph nodes or disseminated through the body as miliary TB or TB meningitis. As children enter adolescence, they are more likely to develop multibacillary disease have typical features of adult TB, such as cavities. The diagnosis of TB in young children can be challenging, microbiological confirmation is frequently not possible, due to the paucibacillary nature of the disease as well as the challenges in obtaining respiratory specimens. The clinician must therefore assemble pieces of evidence to support the diagnosis, including symptoms, signs, immunological tests, radiology. The treatment of TB infection disease in children adolescents are broadly similar to adults. However, important differences include drug dosages, the need for child-friendly formulations, specific issues for adherence support other areas such as impact on schooling, child protection. Childhood TB needs to be addressed as part of any TB programme services need to be tailored to the specific needs of children adolescents of all ages. If this is undertaken, the potential for a future TB-free generation is possible.
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.
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.
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
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- Citations: 5
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
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- Citations: 6
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.
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
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- Citations: 10
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
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- Citations: 6
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.
Sartoris G, Seddon JA, Rabie H, et al., 2020, Abdominal Involvement in Children With Bacteriologically Confirmed Tuberculosis <i>A Five</i>-<i>year Experience From Cape Town</i>, <i>South Africa</i>, PEDIATRIC INFECTIOUS DISEASE JOURNAL, Vol: 39, Pages: 914-919, ISSN: 0891-3668
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- Citations: 3
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.
Schaaf HS, du Preez K, Kruger M, et al., 2020, Bacille Calmette-Guerin (BCG) vaccine and the COVID-19 pandemic: responsible stewardship is needed, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 24, Pages: 732-734, ISSN: 1027-3719
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Ghanaie R, Karimi A, Azimi L, et al., 2020, Prevalence and Diagnosis of Latent Tuberculosis Infection Among Pediatric Household Contacts of Iranian Tuberculosis Cases
<jats:title>Abstract</jats:title> <jats:p><jats:bold>Background:</jats:bold> 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.<jats:bold>Methods:</jats:bold> We conducted a cohort study in children who had been in household contact with a TB index. All subjects were assessed for active disease through evaluation of symptoms and if active disease was suspected were investigated by chest radiograph and bacilli detection in sputum or nasogastric lavage. 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 in QFT-Plus supernatants for all participants. <jats:bold>Results:</jats:bold> 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.<jats:bold>Conclusion:</jats:bold> 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.</jats:p>
Rohlwink U, Chow F, Wasserman S, et al., 2020, Standardized approaches for clinical sampling and endpoint ascertainment in tuberculous meningitis studies [version 2; peer review: 2 approved], Wellcome Open Research, Vol: 4, ISSN: 2398-502X
Tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, has poorly understood immunopathology and high mortality and morbidity despite antituberculous therapy. This calls for accelerated clinical and basic science research in this field. As TBM disproportionally affects poorer communities, studies are often performed in resource-limited environments, creating challenges for data collection and harmonisation. Comparison of TBM studies has been hampered by variation in sampling strategies, study design and choice of study endpoints. Based on literature review and expert consensus, this paper provides firstly, practical recommendations to enable thorough diagnostic, pathophysiological and pharmacokinetic studies using clinical samples, and facilitates better data aggregation and comparisons across populations and settings. Secondly, we discuss clinically relevant study endpoints, including neuroimaging, functional outcome, and cause of death, with suggestions of how these could be applied in different designs for future TBM studies.
Chiang SS, Park S, White EI, et al., 2020, Using changes in weight-for-age z score to predict effectiveness of childhood tuberculosis therapy, Journal of the Pediatric Infectious Diseases Society, Vol: 9, Pages: 150-158, ISSN: 2048-7193
Background: International guidelines recommend monitoring weight as an indicator of therapeutic response in childhood tuberculosis (TB) disease. This recommendation is based on observations in adults. In the current study, we evaluated the association between weight change and treatment outcome, the accuracy of using weight change to predict regimen efficacy, and whether successfully treated children achieve catch-up weight gain. Methods: We enrolled children treated for drug-susceptible TB disease (group 1) and multidrug-resistant TB disease (group 2) in Peru. We calculated the change in weight-for-age z score (ΔWAZ) between baseline and the end of treatment months 2-5 for group 1, and between baseline and months 2-8 for group 2. We used logistic regression and generalized estimating equation models to evaluate the relationship between ΔWAZ and outcome. We plotted receiver operating characteristic curves to determine the accuracy of ΔWAZ for predicting treatment failure or death. Results: Groups 1 and 2 included 100 and 94 children, respectively. In logistic regression, lower ΔWAZ in months 3-5 and month 7 was associated with treatment failure or death in groups 1 and 2, respectively. In generalized estimating equation models, children in both groups who experienced treatment failure or death had lower ΔWAZ than successfully treated children. The ΔWAZ predicted treatment failure or death with 60%-90% sensitivity and 60%-86% specificity in months 2-5 for group 1 and months 7-8 for group 2. All successfully treated children-except group 2 participants with unknown microbiologic confirmation status-achieved catch-up weight gain. Conclusions: Weight change early in therapy can predict the outcome of childhood TB treatment.
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