Background Few studies have evaluated tuberculosis control in children and adolescents. We used r... more Background Few studies have evaluated tuberculosis control in children and adolescents. We used routine tuberculosis surveillance data to quantify age- and human immunodeficiency virus (HIV)-stratified trends over time and investigate the relationship between tuberculosis, HIV, age, and sex. Methods All 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 tuberculosis was evaluated using multivariable logistic regression. Results Of 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 ...
The International Journal of Tuberculosis and Lung Disease
BACKGROUND Pediatric household contacts (HHCs) of patients with multidrug-resistant TB (MDR-TB) a... more BACKGROUND Pediatric household contacts (HHCs) of patients with multidrug-resistant TB (MDR-TB) are at high risk of infection and active disease. Evidence of caregiver willingness to give MDR-TB preventive therapy (TPT) to children is limited.METHODS This was a cross-sectional study of HHCs of patients with MDR-TB to assess caregiver willingness to give TPT to children aged <13 years.RESULTS Of 743 adult and adolescent HHCs, 299 reported caring for children aged <13 years of age. The median caregiver age was 35 years (IQR 27–48); 75% were women. Among caregivers, 89% were willing to give children MDR TPT. In unadjusted analyses, increased willingness was associated with TB-related knowledge (OR 5.1, 95% CI 2.3–11.3), belief that one can die of MDR-TB (OR 5.2, 95% CI 1.2–23.4), concern for MDR-TB transmission to child (OR 4.5, 95% CI 1.6–12.4), confidence in properly taking TPT (OR 4.5, 95% CI 1.6–12.6), comfort telling family about TPT (OR 5.5, 95% CI 2.1–14.3), and willingnes...
Traditionally paediatric tuberculosis (TB) treatment trials have been limited to phase I/II studi... more Traditionally paediatric tuberculosis (TB) treatment trials have been limited to phase I/II studies evaluating the pharmacokinetics and safety of drugs in children, with assumptions about efficacy made by extrapolating data from adults. However, it is increasingly recognised that in some circumstances, efficacy trials are warranted and required in children. The current treatment for children with multidrug-resistant (MDR)-TB is long and toxic; shorter, safer regimens, using novel agents require urgent evaluation. Given the changing pattern of drug metabolism, disease spectrum and rates of TB disease confirmation with age, decisions around inclusion criteria require careful consideration. The most straightforward MDR-TB efficacy trial would include only children with confirmed MDR-TB and with no additional drug resistance. Given that it may be unclear at the time treatment is initiated whether the diagnosis will ultimately be confirmed and what the final drug resistance profile will ...
Background: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycoba... more Background: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. Methods and Findings To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of 3 children (aged <15 years) who were tre...
Background Limitations in the sensitivity and accessibility of diagnostic tools for childhood tub... more Background Limitations 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 antituberculosis treatment in more children. Methods We analyzed data from a prospective cohort of children <13 years old 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 baseline chest radiographic and Xpert MTB/RIF assay results to the model to develop an algorithm with ≥90% sensitivity in predicting tuberculosis. Results Data from 478 children being evaluated for pulmonary tuberculosis were analyzed (median age, 16.2 months; in...
The International Journal of Tuberculosis and Lung Disease, 2019
SETTING: We conducted a qualitative exploration into the palatability and acceptability of a nove... more SETTING: We conducted a qualitative exploration into the palatability and acceptability of a novel fixed-dose combination (FDC) anti-tuberculosis drug. This study was nested in the SHINE (Shorter treatment for minimal TB in children) trial, which compares the safety and efficacy of treating non-severe drug-susceptible tuberculosis (TB) with a 6 vs. 4 months anti-tuberculosis regimen in children aged 0–16 years. Participants were recruited in Cape Town, South Africa.OBJECTIVE: To describe the palatability and acceptability of a FDC of rifampicin, isoniazid and pyrazinamide among South African children and their caregivers in the SHINE trial.METHODS: We conducted 20 clinic observations of treatment administration, during which we conducted 16 semi-structured interviews with children and their caregivers. Data were organised thematically to report on experiences with administering and ingesting the FDC.RESULTS: Children and caregivers' experiences varied from delight to disgust. In...
American journal of respiratory and critical care medicine, Jan 18, 2018
Tuberculosis (TB) has surpassed HIV to become the leading infectious killer of adults globally, c... more Tuberculosis (TB) has surpassed HIV to become the leading infectious killer of adults globally, causing almost 2 million deaths annually. Although this airborne disease has been treatable since 1948, global rates of TB have dropped less than two percent per year; an estimated 10 million incident cases continue to occur annually, including one million in children. While transmission of active disease is an important driver of the epidemic, the seedbed that feeds the epidemic is the more than two billion people estimated to have TB infection, five to ten percent of whom will progress to active disease during their lifetime. While any successful strategy aimed at TB elimination needs to address this reservoir of TB infection worldwide, much remains to be understood about host and pathogen factors that can be used to identify increased risk for progression to disease, and intervened upon to prevent progression from occurring. The Division of AIDS of the National Institute of Allergy and...
Placental antibody transfer is impaired in the context of HIV infection, which may render HIV-exp... more Placental antibody transfer is impaired in the context of HIV infection, which may render HIV-exposed, uninfected infants vulnerable to group B Streptococcus (GBS) disease. The GBS antibody response predominately consists of immunoglobulin G2 (IgG2) antibody. Thus we determined whether concentration and placental transfer of anti-GBS antibody subclasses was altered in HIV-infected compared with HIV-uninfected mothers. A retrospective analysis of anti-GBS antibody subclasses in 38 HIV-infected and 33 HIV-uninfected mothers and their uninfected infants. Sera were analysed using a novel flow cytometric assay that quantified binding of IgG1, IgG2, IgG3 and IgG4 to serotype (ST)Ia, STIII and STV GBS bacteria. IgG2 binding to GBS STIa and V was lower in HIV-infected women compared with HIV-uninfected women. Moreover, IgG2 binding to GBS STIa was also lower in HIV-exposed, uninfected infants compared with unexposed infants. However, there were no statistically significant differences in th...
Background Few studies have evaluated tuberculosis control in children and adolescents. We used r... more Background Few studies have evaluated tuberculosis control in children and adolescents. We used routine tuberculosis surveillance data to quantify age- and human immunodeficiency virus (HIV)-stratified trends over time and investigate the relationship between tuberculosis, HIV, age, and sex. Methods All 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 tuberculosis was evaluated using multivariable logistic regression. Results Of 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 ...
The International Journal of Tuberculosis and Lung Disease
BACKGROUND Pediatric household contacts (HHCs) of patients with multidrug-resistant TB (MDR-TB) a... more BACKGROUND Pediatric household contacts (HHCs) of patients with multidrug-resistant TB (MDR-TB) are at high risk of infection and active disease. Evidence of caregiver willingness to give MDR-TB preventive therapy (TPT) to children is limited.METHODS This was a cross-sectional study of HHCs of patients with MDR-TB to assess caregiver willingness to give TPT to children aged <13 years.RESULTS Of 743 adult and adolescent HHCs, 299 reported caring for children aged <13 years of age. The median caregiver age was 35 years (IQR 27–48); 75% were women. Among caregivers, 89% were willing to give children MDR TPT. In unadjusted analyses, increased willingness was associated with TB-related knowledge (OR 5.1, 95% CI 2.3–11.3), belief that one can die of MDR-TB (OR 5.2, 95% CI 1.2–23.4), concern for MDR-TB transmission to child (OR 4.5, 95% CI 1.6–12.4), confidence in properly taking TPT (OR 4.5, 95% CI 1.6–12.6), comfort telling family about TPT (OR 5.5, 95% CI 2.1–14.3), and willingnes...
Traditionally paediatric tuberculosis (TB) treatment trials have been limited to phase I/II studi... more Traditionally paediatric tuberculosis (TB) treatment trials have been limited to phase I/II studies evaluating the pharmacokinetics and safety of drugs in children, with assumptions about efficacy made by extrapolating data from adults. However, it is increasingly recognised that in some circumstances, efficacy trials are warranted and required in children. The current treatment for children with multidrug-resistant (MDR)-TB is long and toxic; shorter, safer regimens, using novel agents require urgent evaluation. Given the changing pattern of drug metabolism, disease spectrum and rates of TB disease confirmation with age, decisions around inclusion criteria require careful consideration. The most straightforward MDR-TB efficacy trial would include only children with confirmed MDR-TB and with no additional drug resistance. Given that it may be unclear at the time treatment is initiated whether the diagnosis will ultimately be confirmed and what the final drug resistance profile will ...
Background: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycoba... more Background: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. Methods and Findings To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of 3 children (aged <15 years) who were tre...
Background Limitations in the sensitivity and accessibility of diagnostic tools for childhood tub... more Background Limitations 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 antituberculosis treatment in more children. Methods We analyzed data from a prospective cohort of children <13 years old 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 baseline chest radiographic and Xpert MTB/RIF assay results to the model to develop an algorithm with ≥90% sensitivity in predicting tuberculosis. Results Data from 478 children being evaluated for pulmonary tuberculosis were analyzed (median age, 16.2 months; in...
The International Journal of Tuberculosis and Lung Disease, 2019
SETTING: We conducted a qualitative exploration into the palatability and acceptability of a nove... more SETTING: We conducted a qualitative exploration into the palatability and acceptability of a novel fixed-dose combination (FDC) anti-tuberculosis drug. This study was nested in the SHINE (Shorter treatment for minimal TB in children) trial, which compares the safety and efficacy of treating non-severe drug-susceptible tuberculosis (TB) with a 6 vs. 4 months anti-tuberculosis regimen in children aged 0–16 years. Participants were recruited in Cape Town, South Africa.OBJECTIVE: To describe the palatability and acceptability of a FDC of rifampicin, isoniazid and pyrazinamide among South African children and their caregivers in the SHINE trial.METHODS: We conducted 20 clinic observations of treatment administration, during which we conducted 16 semi-structured interviews with children and their caregivers. Data were organised thematically to report on experiences with administering and ingesting the FDC.RESULTS: Children and caregivers' experiences varied from delight to disgust. In...
American journal of respiratory and critical care medicine, Jan 18, 2018
Tuberculosis (TB) has surpassed HIV to become the leading infectious killer of adults globally, c... more Tuberculosis (TB) has surpassed HIV to become the leading infectious killer of adults globally, causing almost 2 million deaths annually. Although this airborne disease has been treatable since 1948, global rates of TB have dropped less than two percent per year; an estimated 10 million incident cases continue to occur annually, including one million in children. While transmission of active disease is an important driver of the epidemic, the seedbed that feeds the epidemic is the more than two billion people estimated to have TB infection, five to ten percent of whom will progress to active disease during their lifetime. While any successful strategy aimed at TB elimination needs to address this reservoir of TB infection worldwide, much remains to be understood about host and pathogen factors that can be used to identify increased risk for progression to disease, and intervened upon to prevent progression from occurring. The Division of AIDS of the National Institute of Allergy and...
Placental antibody transfer is impaired in the context of HIV infection, which may render HIV-exp... more Placental antibody transfer is impaired in the context of HIV infection, which may render HIV-exposed, uninfected infants vulnerable to group B Streptococcus (GBS) disease. The GBS antibody response predominately consists of immunoglobulin G2 (IgG2) antibody. Thus we determined whether concentration and placental transfer of anti-GBS antibody subclasses was altered in HIV-infected compared with HIV-uninfected mothers. A retrospective analysis of anti-GBS antibody subclasses in 38 HIV-infected and 33 HIV-uninfected mothers and their uninfected infants. Sera were analysed using a novel flow cytometric assay that quantified binding of IgG1, IgG2, IgG3 and IgG4 to serotype (ST)Ia, STIII and STV GBS bacteria. IgG2 binding to GBS STIa and V was lower in HIV-infected women compared with HIV-uninfected women. Moreover, IgG2 binding to GBS STIa was also lower in HIV-exposed, uninfected infants compared with unexposed infants. However, there were no statistically significant differences in th...
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