BACKGROUND: The World Health Organization (WHO) estimates tuberculosis (TB) accounted for 40,000 ... more BACKGROUND: The World Health Organization (WHO) estimates tuberculosis (TB) accounted for 40,000 deaths in children living with HIV in 2017. Early detection and treatment of TB reduces mortality in children and adolescents living with HIV (CALHIV). Despite limited evidence, the WHO recommends that CALHIV are actively screened for TB symptoms at every clinical encounter in order to improve TB case detection. As more CALHIV access care and …
Purpose of review The detrimental synergy of colliding HIV and tuberculosis (TB) epidemics is mos... more Purpose of review The detrimental synergy of colliding HIV and tuberculosis (TB) epidemics is most devastating among children and adolescents living with HIV (CALWH) who shoulder a disproportionate burden of all child TB mortality. Recent findings CALWH benefit less from Bacille–Calmette Guerin vaccination than HIV-uninfected children and are not receiving TB preventive therapy despite global recommendations. Further, the predictive utility of most diagnostic tools is reduced in CALWH. Finally, antiretroviral and anti-TB drug interactions continue to complicate cotreatment for children. Despite these challenges, recent data fuel a new awareness of TB as a hidden cause of child mortality and a renewed commitment to TB prevention. New diagnostic approaches using existing tools with novel specimens, such as stool, may improve the diagnosis of TB in CALWH. Further, pharmacokinetic studies and the development of new drug formulations promise better treatment options for CALWH in the near future. Summary With the awareness that TB is the leading cause of mortality among CALWH, comes a responsibility to accelerate research to prevent, diagnose and treat TB in this vulnerable population. In the present, we must adopt evidence-based preventive and treatment strategies to enhance outcomes of CALWH and combating TB.
Delivery of tuberculosis preventive therapy (TPT) for children with household exposure to tubercu... more Delivery of tuberculosis preventive therapy (TPT) for children with household exposure to tuberculosis is a globally supported intervention to reduce the impact of tuberculosis disease (TB) in vulnerable children; however, it is sub-optimally implemented in most high-burden settings. As part of a community-based household contact management program, we evaluated predictors of adherence to community based TPT in children and performed qualitative assessments of caregiver experiences. The Vikela Ekhaya (Protect the Home) project was a community-based household contact management program implemented between 2019 and 2020 in the Hhohho Region of Eswatini. At home visits, contact management teams screened children for TB, initiated TPT when indicated and performed follow-up assessments reviewing TPT adherence. TPT non-adherence was defined as either two self-reported missed doses or a pill count indicating at least two missed doses, and risk factors were evaluated using multivariate clus...
BACKGROUND: The World Health Organization (WHO) estimates tuberculosis (TB) accounted for 40,000 ... more BACKGROUND: The World Health Organization (WHO) estimates tuberculosis (TB) accounted for 40,000 deaths in children living with HIV in 2017. Early detection and treatment of TB reduces mortality in children and adolescents living with HIV (CALHIV). Despite limited evidence, the WHO recommends that CALHIV are actively screened for TB symptoms at every clinical encounter in order to improve TB case detection. As more CALHIV access care and …
This is the first study to compare Mycobacterium tuberculosis DNA extraction techniques from pedi... more This is the first study to compare Mycobacterium tuberculosis DNA extraction techniques from pediatric stool samples for use with sequencing technologies. It provides an important starting point for other researchers to isolate quality DNA for this purpose to further the field and to continue to optimize protocols and approaches.
BACKGROUND Immunity is a critical factor of clinical outcomes after Mycobacterial tuberculosis (M... more BACKGROUND Immunity is a critical factor of clinical outcomes after Mycobacterial tuberculosis (Mtb) infection, however, the lack of identification of immune correlates of protection has prevented development of host directed therapeutics. TB studies have identified incongruous immune responses that can lead to a similar TB disease phenotype. Therefore, instead of envisioning susceptibility to TB to follow a unique path, we sough evidence by which divergent host immunity could result in TB. RESULTS Inspired by multiomics identification of cancer subtypes improving clinical care, we implemented unbiased, RUV clustering from 12 publicly available datasets consisting of data from 717 TB patients and 527 controls, including 12,468 common genes, and identified 4 distinct immune responses among TB patients. The two largest sub-groups displayed divergent metabolic, epigenetic and immune pathways. Cluster A, consisting of 333 TB patients was characterized by increased glycolysis; up-regulat...
BackgroundEvery year, an estimated one million children and young adolescents become ill with tub... more BackgroundEvery year, an estimated one million children and young adolescents become ill with tuberculosis, and around 226,000 of those children die. Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)‐recommended rapid diagnostic test that simultaneously detects Mycobacterium tuberculosis complex and rifampicin resistance. We previously published a Cochrane Review 'Xpert MTB/RIF and Xpert MTB/RIF Ultra assays for tuberculosis disease and rifampicin resistance in children'. The current review updates evidence on the diagnostic accuracy of Xpert Ultra in children presumed to have tuberculosis disease. Parts of this review update informed the 2022 WHO updated guidance on management of tuberculosis in children and adolescents.ObjectivesTo assess the diagnostic accuracy of Xpert Ultra for detecting: pulmonary tuberculosis, tuberculous meningitis, lymph node tuberculosis, and rifampicin resistance, in children with presumed tuberculosis.Secondary objectivesTo investigate potential sources of heterogeneity in accuracy estimates. For detection of tuberculosis, we considered age, comorbidity (HIV, severe pneumonia, and severe malnutrition), and specimen type as potential sources.To summarize the frequency of Xpert Ultra trace results.Search methodsWe searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, three other databases, and three trial registers without language restrictions to 9 March 2021.Selection criteriaCross‐sectional and cohort studies and randomized trials that evaluated Xpert Ultra in HIV‐positive and HIV‐negative children under 15 years of age. We included ongoing studies that helped us address the review objectives. We included studies evaluating sputum, gastric, stool, or nasopharyngeal specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), and fine needle aspirate or surgical biopsy tissue (lymph node tuberculosis). For detecting tuberculosis, reference standards were microbiological (culture) or composite reference standard; for stool, we also included Xpert Ultra performed on a routine respiratory specimen. For detecting rifampicin resistance, reference standards were drug susceptibility testing or MTBDRplus.Data collection and analysisTwo review authors independently extracted data and, using QUADAS‐2, assessed methodological quality judging risk of bias separately for each target condition and reference standard. For each target condition, we used the bivariate model to estimate summary sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We summarized the frequency of Xpert Ultra trace results; trace represents detection of a very low quantity of Mycobacterium tuberculosis DNA. We assessed certainty of evidence using GRADE.Main resultsWe identified 14 studies (11 new studies since the previous review). For detection of pulmonary tuberculosis, 335 data sets (25,937 participants) were available for analysis. We did not identify any studies that evaluated Xpert Ultra accuracy for tuberculous meningitis or lymph node tuberculosis. Three studies evaluated Xpert Ultra for detection of rifampicin resistance. Ten studies (71%) took place in countries with a high tuberculosis burden based on WHO classification. Overall, risk of bias was low.Detection of pulmonary tuberculosisSputum, 5 studiesXpert Ultra summary sensitivity verified by culture was 75.3% (95% CI 64.3 to 83.8; 127 participants; high‐certainty evidence), and specificity was 97.1% (95% CI 94.7 to 98.5; 1054 participants; high‐certainty evidence).Gastric aspirate, 7 studiesXpert Ultra summary sensitivity verified by culture was 70.4% (95% CI 53.9 to 82.9; 120 participants; moderate‐certainty evidence), and specificity was 94.1% (95% CI 84.8 to 97.8; 870 participants; moderate‐certainty evidence).Stool, 6 studiesXpert Ultra summary sensitivity verified by culture was 56.1% (95% CI 39.1 to 71.7; 200 participants; moderate‐certainty evidence), and specificity was 98.0% (95% CI 93.3 to 99.4; 1232 participants; high certainty‐evidence).Nasopharyngeal aspirate, 4 studiesXpert Ultra summary sensitivity verified by culture was 43.7% (95% CI 26.7 to 62.2; 46 participants; very low‐certainty evidence), and specificity was 97.5% (95% CI 93.6 to 99.0; 489 participants; high‐certainty evidence).Xpert Ultra sensitivity was lower against a composite than a culture reference standard for all specimen types other than nasopharyngeal aspirate, while specificity was similar against both reference standards.Interpretation of resultsIn theory, for a population of 1000 children:• where 100 have pulmonary tuberculosis in sputum (by culture):‐ 101 would be Xpert Ultra‐positive, and of these, 26 (26%) would not have pulmonary tuberculosis (false positive); and‐ 899 would be Xpert Ultra‐negative, and of these, 25 (3%) would have tuberculosis (false negative).• where 100 have pulmonary tuberculosis in gastric…
BACKGROUND: The World Health Organization (WHO) estimates tuberculosis (TB) accounted for 40,000 ... more BACKGROUND: The World Health Organization (WHO) estimates tuberculosis (TB) accounted for 40,000 deaths in children living with HIV in 2017. Early detection and treatment of TB reduces mortality in children and adolescents living with HIV (CALHIV). Despite limited evidence, the WHO recommends that CALHIV are actively screened for TB symptoms at every clinical encounter in order to improve TB case detection. As more CALHIV access care and …
Purpose of review The detrimental synergy of colliding HIV and tuberculosis (TB) epidemics is mos... more Purpose of review The detrimental synergy of colliding HIV and tuberculosis (TB) epidemics is most devastating among children and adolescents living with HIV (CALWH) who shoulder a disproportionate burden of all child TB mortality. Recent findings CALWH benefit less from Bacille–Calmette Guerin vaccination than HIV-uninfected children and are not receiving TB preventive therapy despite global recommendations. Further, the predictive utility of most diagnostic tools is reduced in CALWH. Finally, antiretroviral and anti-TB drug interactions continue to complicate cotreatment for children. Despite these challenges, recent data fuel a new awareness of TB as a hidden cause of child mortality and a renewed commitment to TB prevention. New diagnostic approaches using existing tools with novel specimens, such as stool, may improve the diagnosis of TB in CALWH. Further, pharmacokinetic studies and the development of new drug formulations promise better treatment options for CALWH in the near future. Summary With the awareness that TB is the leading cause of mortality among CALWH, comes a responsibility to accelerate research to prevent, diagnose and treat TB in this vulnerable population. In the present, we must adopt evidence-based preventive and treatment strategies to enhance outcomes of CALWH and combating TB.
Delivery of tuberculosis preventive therapy (TPT) for children with household exposure to tubercu... more Delivery of tuberculosis preventive therapy (TPT) for children with household exposure to tuberculosis is a globally supported intervention to reduce the impact of tuberculosis disease (TB) in vulnerable children; however, it is sub-optimally implemented in most high-burden settings. As part of a community-based household contact management program, we evaluated predictors of adherence to community based TPT in children and performed qualitative assessments of caregiver experiences. The Vikela Ekhaya (Protect the Home) project was a community-based household contact management program implemented between 2019 and 2020 in the Hhohho Region of Eswatini. At home visits, contact management teams screened children for TB, initiated TPT when indicated and performed follow-up assessments reviewing TPT adherence. TPT non-adherence was defined as either two self-reported missed doses or a pill count indicating at least two missed doses, and risk factors were evaluated using multivariate clus...
BACKGROUND: The World Health Organization (WHO) estimates tuberculosis (TB) accounted for 40,000 ... more BACKGROUND: The World Health Organization (WHO) estimates tuberculosis (TB) accounted for 40,000 deaths in children living with HIV in 2017. Early detection and treatment of TB reduces mortality in children and adolescents living with HIV (CALHIV). Despite limited evidence, the WHO recommends that CALHIV are actively screened for TB symptoms at every clinical encounter in order to improve TB case detection. As more CALHIV access care and …
This is the first study to compare Mycobacterium tuberculosis DNA extraction techniques from pedi... more This is the first study to compare Mycobacterium tuberculosis DNA extraction techniques from pediatric stool samples for use with sequencing technologies. It provides an important starting point for other researchers to isolate quality DNA for this purpose to further the field and to continue to optimize protocols and approaches.
BACKGROUND Immunity is a critical factor of clinical outcomes after Mycobacterial tuberculosis (M... more BACKGROUND Immunity is a critical factor of clinical outcomes after Mycobacterial tuberculosis (Mtb) infection, however, the lack of identification of immune correlates of protection has prevented development of host directed therapeutics. TB studies have identified incongruous immune responses that can lead to a similar TB disease phenotype. Therefore, instead of envisioning susceptibility to TB to follow a unique path, we sough evidence by which divergent host immunity could result in TB. RESULTS Inspired by multiomics identification of cancer subtypes improving clinical care, we implemented unbiased, RUV clustering from 12 publicly available datasets consisting of data from 717 TB patients and 527 controls, including 12,468 common genes, and identified 4 distinct immune responses among TB patients. The two largest sub-groups displayed divergent metabolic, epigenetic and immune pathways. Cluster A, consisting of 333 TB patients was characterized by increased glycolysis; up-regulat...
BackgroundEvery year, an estimated one million children and young adolescents become ill with tub... more BackgroundEvery year, an estimated one million children and young adolescents become ill with tuberculosis, and around 226,000 of those children die. Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)‐recommended rapid diagnostic test that simultaneously detects Mycobacterium tuberculosis complex and rifampicin resistance. We previously published a Cochrane Review 'Xpert MTB/RIF and Xpert MTB/RIF Ultra assays for tuberculosis disease and rifampicin resistance in children'. The current review updates evidence on the diagnostic accuracy of Xpert Ultra in children presumed to have tuberculosis disease. Parts of this review update informed the 2022 WHO updated guidance on management of tuberculosis in children and adolescents.ObjectivesTo assess the diagnostic accuracy of Xpert Ultra for detecting: pulmonary tuberculosis, tuberculous meningitis, lymph node tuberculosis, and rifampicin resistance, in children with presumed tuberculosis.Secondary objectivesTo investigate potential sources of heterogeneity in accuracy estimates. For detection of tuberculosis, we considered age, comorbidity (HIV, severe pneumonia, and severe malnutrition), and specimen type as potential sources.To summarize the frequency of Xpert Ultra trace results.Search methodsWe searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, three other databases, and three trial registers without language restrictions to 9 March 2021.Selection criteriaCross‐sectional and cohort studies and randomized trials that evaluated Xpert Ultra in HIV‐positive and HIV‐negative children under 15 years of age. We included ongoing studies that helped us address the review objectives. We included studies evaluating sputum, gastric, stool, or nasopharyngeal specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), and fine needle aspirate or surgical biopsy tissue (lymph node tuberculosis). For detecting tuberculosis, reference standards were microbiological (culture) or composite reference standard; for stool, we also included Xpert Ultra performed on a routine respiratory specimen. For detecting rifampicin resistance, reference standards were drug susceptibility testing or MTBDRplus.Data collection and analysisTwo review authors independently extracted data and, using QUADAS‐2, assessed methodological quality judging risk of bias separately for each target condition and reference standard. For each target condition, we used the bivariate model to estimate summary sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We summarized the frequency of Xpert Ultra trace results; trace represents detection of a very low quantity of Mycobacterium tuberculosis DNA. We assessed certainty of evidence using GRADE.Main resultsWe identified 14 studies (11 new studies since the previous review). For detection of pulmonary tuberculosis, 335 data sets (25,937 participants) were available for analysis. We did not identify any studies that evaluated Xpert Ultra accuracy for tuberculous meningitis or lymph node tuberculosis. Three studies evaluated Xpert Ultra for detection of rifampicin resistance. Ten studies (71%) took place in countries with a high tuberculosis burden based on WHO classification. Overall, risk of bias was low.Detection of pulmonary tuberculosisSputum, 5 studiesXpert Ultra summary sensitivity verified by culture was 75.3% (95% CI 64.3 to 83.8; 127 participants; high‐certainty evidence), and specificity was 97.1% (95% CI 94.7 to 98.5; 1054 participants; high‐certainty evidence).Gastric aspirate, 7 studiesXpert Ultra summary sensitivity verified by culture was 70.4% (95% CI 53.9 to 82.9; 120 participants; moderate‐certainty evidence), and specificity was 94.1% (95% CI 84.8 to 97.8; 870 participants; moderate‐certainty evidence).Stool, 6 studiesXpert Ultra summary sensitivity verified by culture was 56.1% (95% CI 39.1 to 71.7; 200 participants; moderate‐certainty evidence), and specificity was 98.0% (95% CI 93.3 to 99.4; 1232 participants; high certainty‐evidence).Nasopharyngeal aspirate, 4 studiesXpert Ultra summary sensitivity verified by culture was 43.7% (95% CI 26.7 to 62.2; 46 participants; very low‐certainty evidence), and specificity was 97.5% (95% CI 93.6 to 99.0; 489 participants; high‐certainty evidence).Xpert Ultra sensitivity was lower against a composite than a culture reference standard for all specimen types other than nasopharyngeal aspirate, while specificity was similar against both reference standards.Interpretation of resultsIn theory, for a population of 1000 children:• where 100 have pulmonary tuberculosis in sputum (by culture):‐ 101 would be Xpert Ultra‐positive, and of these, 26 (26%) would not have pulmonary tuberculosis (false positive); and‐ 899 would be Xpert Ultra‐negative, and of these, 25 (3%) would have tuberculosis (false negative).• where 100 have pulmonary tuberculosis in gastric…
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