Publications by authors named "Anna M Mandalakas"

66 Publications

Vikela Ekhaya: a novel, community-based, tuberculosis contact management program in a high burden setting.

Clin Infect Dis 2021 Jul 24. Epub 2021 Jul 24.

The Global Tuberculosis Program, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.

Background: The prevention of tuberculosis (TB) in child contacts of TB cases and people living with HIV is a public health priority, but global access to TB preventive therapy (TPT) remains low. In 2019, we implemented Vikela Ekhaya, a novel community-based TB contact management program in Eswatini designed to reduce barriers to accessing TPT.

Methods: Vikela Ekhaya offered differentiated TB and HIV testing for household contacts of TB cases, by utilizing mobile contact management teams to screen contacts, assess their TPT eligibility, and initiate and monitor TPT adherence in participants' homes.

Results: In total, 945 contacts from 244 households were screened for TB symptoms; 72 (8%) contacts reported TB symptoms, and five contacts (0.5%) were diagnosed with prevalent TB. 322 of 330 (98%) eligible asymptomatic household contacts initiated TPT. Of 322 contacts initiating TPT, 248 children initiated 3 months of isoniazid and rifampicin and 74 children and adults living with HIV initiated 6 months of isoniazid; 298 (93%) completed TPT. In clustered logistic regression analyses, unknown HIV status (aOR 5.7, p = 0.023), positive HIV status (aOR 21.1, p = 0.001), urban setting (aOR 5.6, p = 0.006), and low income (aOR 5.9, p =0.001) predicted loss from the cascade of care among TPT eligible contacts.

Conclusion: Vikela Ekhaya demonstrated that community-based TB household contact management is a feasible, acceptable and successful strategy for TB screening and TPT delivery. The results of this study support the development of novel, differentiated, community-based interventions for TB prevention and control.
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http://dx.doi.org/10.1093/cid/ciab652DOI Listing
July 2021

Screening tests for active pulmonary tuberculosis in children.

Cochrane Database Syst Rev 2021 06 28;6:CD013693. Epub 2021 Jun 28.

The Global Tuberculosis Program, Texas Children's Hospital, Section of Global and Immigrant Health, Department of Pediatrics, Baylor College of Medicine , Houston, Texas, USA.

Background: Globally, children under 15 years represent approximately 12% of new tuberculosis cases, but 16% of the estimated 1.4 million deaths. This higher share of mortality highlights the urgent need to develop strategies to improve case detection in this age group and identify children without tuberculosis disease who should be considered for tuberculosis preventive treatment. One such strategy is systematic screening for tuberculosis in high-risk groups.

Objectives: To estimate the sensitivity and specificity of the presence of one or more tuberculosis symptoms, or symptom combinations; chest radiography (CXR); Xpert MTB/RIF; Xpert Ultra; and combinations of these as screening tests for detecting active pulmonary childhood tuberculosis in the following groups. - Tuberculosis contacts, including household contacts, school contacts, and other close contacts of a person with infectious tuberculosis. - Children living with HIV. - Children with pneumonia. - Other risk groups (e.g. children with a history of previous tuberculosis, malnourished children). - Children in the general population in high tuberculosis burden settings.

Search Methods: We searched six databases, including the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, on 14 February 2020 without language restrictions and contacted researchers in the field.

Selection Criteria: Cross-sectional and cohort studies where at least 75% of children were aged under 15 years. Studies were eligible if conducted for screening rather than diagnosing tuberculosis. Reference standards were microbiological (MRS) and composite reference standard (CRS), which may incorporate symptoms and CXR.

Data Collection And Analysis: Two review authors independently extracted data and assessed study quality using QUADAS-2. We consolidated symptom screens across included studies into groups that used similar combinations of symptoms as follows: one or more of cough, fever, or poor weight gain and one or more of cough, fever, or decreased playfulness. For combination of symptoms, a positive screen was the presence of one or more than one symptom. We used a bivariate model to estimate pooled sensitivity and specificity with 95% confidence intervals (CIs) and performed analyses separately by reference standard. We assessed certainty of evidence using GRADE.

Main Results: Nineteen studies assessed the following screens: one symptom (15 studies, 10,097 participants); combinations of symptoms (12 studies, 29,889 participants); CXR (10 studies, 7146 participants); and Xpert MTB/RIF (2 studies, 787 participants). Several studies assessed more than one screening test. No studies assessed Xpert Ultra. For 16 studies (84%), risk of bias for the reference standard domain was unclear owing to concern about incorporation bias. Across other quality domains, risk of bias was generally low. Symptom screen (verified by CRS) One or more of cough, fever, or poor weight gain in tuberculosis contacts (4 studies, tuberculosis prevalence 2% to 13%): pooled sensitivity was 89% (95% CI 52% to 98%; 113 participants; low-certainty evidence) and pooled specificity was 69% (95% CI 51% to 83%; 2582 participants; low-certainty evidence). Of 1000 children where 50 have pulmonary tuberculosis, 339 would be screen-positive, of whom 294 (87%) would not have pulmonary tuberculosis (false positives); 661 would be screen-negative, of whom five (1%) would have pulmonary tuberculosis (false negatives). One or more of cough, fever, or decreased playfulness in children aged under five years, inpatient or outpatient (3 studies, tuberculosis prevalence 3% to 13%): sensitivity ranged from 64% to 76% (106 participants; moderate-certainty evidence) and specificity from 37% to 77% (2339 participants; low-certainty evidence). Of 1000 children where 50 have pulmonary tuberculosis, 251 to 636 would be screen-positive, of whom 219 to 598 (87% to 94%) would not have pulmonary tuberculosis; 364 to 749 would be screen-negative, of whom 12 to 18 (2% to 3%) would have pulmonary tuberculosis. One or more of cough, fever, poor weight gain, or tuberculosis close contact (World Health Organization four-symptom screen) in children living with HIV, outpatient (2 studies, tuberculosis prevalence 3% and 8%): pooled sensitivity was 61% (95% CI 58% to 64%; 1219 screens; moderate-certainty evidence) and pooled specificity was 94% (95% CI 86% to 98%; 201,916 screens; low-certainty evidence). Of 1000 symptom screens where 50 of the screens are on children with pulmonary tuberculosis, 88 would be screen-positive, of which 57 (65%) would be on children who do not have pulmonary tuberculosis; 912 would be screen-negative, of which 19 (2%) would be on children who have pulmonary tuberculosis. CXR (verified by CRS) CXR with any abnormality in tuberculosis contacts (8 studies, tuberculosis prevalence 2% to 25%): pooled sensitivity was 87% (95% CI 75% to 93%; 232 participants; low-certainty evidence) and pooled specificity was 99% (95% CI 68% to 100%; 3281 participants; low-certainty evidence). Of 1000 children, where 50 have pulmonary tuberculosis, 63 would be screen-positive, of whom 19 (30%) would not have pulmonary tuberculosis; 937 would be screen-negative, of whom 6 (1%) would have pulmonary tuberculosis. Xpert MTB/RIF (verified by MRS) Xpert MTB/RIF, inpatient or outpatient (2 studies, tuberculosis prevalence 1% and 4%): sensitivity was 43% and 100% (16 participants; very low-certainty evidence) and specificity was 99% and 100% (771 participants; moderate-certainty evidence). Of 1000 children, where 50 have pulmonary tuberculosis, 31 to 69 would be Xpert MTB/RIF-positive, of whom 9 to 19 (28% to 29%) would not have pulmonary tuberculosis; 969 to 931 would be Xpert MTB/RIF-negative, of whom 0 to 28 (0% to 3%) would have tuberculosis. Studies often assessed more symptoms than those included in the index test and symptom definitions varied. These differences complicated data aggregation and may have influenced accuracy estimates. Both symptoms and CXR formed part of the CRS (incorporation bias), which may have led to overestimation of sensitivity and specificity.

Authors' Conclusions: We found that in children who are tuberculosis contacts or living with HIV, screening tests using symptoms or CXR may be useful, but our review is limited by design issues with the index test and incorporation bias in the reference standard. For Xpert MTB/RIF, we found insufficient evidence regarding screening accuracy. Prospective evaluations of screening tests for tuberculosis in children will help clarify their use. In the meantime, screening strategies need to be pragmatic to address the persistent gaps in prevention and case detection that exist in resource-limited settings.
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http://dx.doi.org/10.1002/14651858.CD013693.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237391PMC
June 2021

The Magnitude of Interferon Gamma Release Assay Responses in Children With Household Tuberculosis Contact Is Associated With Tuberculosis Exposure and Disease Status.

Pediatr Infect Dis J 2021 Aug;40(8):763-770

From the Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa.

Background: The clinical utility of the magnitude of interferon gamma (IFNγ) in response to mycobacterial antigens is unknown. We assessed the association between quantitative IFNγ response and degree of Mycobacterium tuberculosis exposure, infection and tuberculosis (TB) disease status in children.

Methods: We completed cross-sectional analysis of children (≤15 years) exposed to an adult with bacteriologically confirmed TB, 2007-2012 in Cape Town, South Africa. IFNγ values were reported as concentrations and spot forming units for the QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB, respectively. Random-effects linear regression was used to investigate the relation between the M. tuberculosis contact score, clinical phenotype (TB diseased, infected, uninfected) and IFNγ▪response as outcome, adjusted for relevant covariates.

Results: We analyzed data from 669 children (median age, 63 months; interquartile range, 33-108 months). A 1-unit increase in M. tuberculosis contact score was associated with an increase of IFNγ 0.60 international unit/mL (95% confidence interval [CI], 0.44-0.76 international unit/mL), and IFNγ spot forming unit 2 counts (95% CI, 1-3). IFNγ response was significantly lower among children with M. tuberculosis infection compared with children with TB disease (β = -1.42; 95% CI, -2.80 to -0.03) for the QFT-GIT, but not for the T-SPOT.TB. This association was strongest among children 2-5 years (β = -2.35 years; 95% CI, -4.28 to -0.42 years) and absent if <2 years.

Conclusions: The magnitude of IFNγ response correlated with the degree of recent M. tuberculosis exposure, measured by QFT-GIT and T-SPOT.TB, and was correlated with clinically relevant TB phenotypes using the QFT-GIT. IFNγ values are not only useful in estimating the risk of M. tuberculosis infection but may also support the diagnosis of TB disease in children.

Discussion: The magnitude of IFNγ response correlated with the degree of recent M. tuberculosis exposure, measured by QFT-GIT and T-SPOT.TB, and was correlated with clinically relevant TB phenotypes using the QFT-GIT. IFNγ values are not only useful in estimating the risk of M. tuberculosis infection but may also support the diagnosis of TB disease in children.
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http://dx.doi.org/10.1097/INF.0000000000003196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277676PMC
August 2021

Perspectives for systems biology in the management of tuberculosis.

Eur Respir Rev 2021 Jun 25;30(160). Epub 2021 May 25.

Research Center Borstel, Borstel, Germany

Standardised management of tuberculosis may soon be replaced by individualised, precision medicine-guided therapies informed with knowledge provided by the field of systems biology. Systems biology is a rapidly expanding field of computational and mathematical analysis and modelling of complex biological systems that can provide insights into mechanisms underlying tuberculosis, identify novel biomarkers, and help to optimise prevention, diagnosis and treatment of disease. These advances are critically important in the context of the evolving epidemic of drug-resistant tuberculosis. Here, we review the available evidence on the role of systems biology approaches - human and mycobacterial genomics and transcriptomics, proteomics, lipidomics/metabolomics, immunophenotyping, systems pharmacology and gut microbiomes - in the management of tuberculosis including prediction of risk for disease progression, severity of mycobacterial virulence and drug resistance, adverse events, comorbidities, response to therapy and treatment outcomes. Application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach demonstrated that at present most of the studies provide "very low" certainty of evidence for answering clinically relevant questions. Further studies in large prospective cohorts of patients, including randomised clinical trials, are necessary to assess the applicability of the findings in tuberculosis prevention and more efficient clinical management of patients.
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http://dx.doi.org/10.1183/16000617.0377-2020DOI Listing
June 2021

Paediatric tuberculosis - new advances to close persistent gaps.

Int J Infect Dis 2021 Mar 11. Epub 2021 Mar 11.

The Indus Hospital, Karachi, Pakistan.

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.
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http://dx.doi.org/10.1016/j.ijid.2021.02.003DOI Listing
March 2021

Predictors of suboptimal adherence to isoniazid preventive therapy among adolescents and children living with HIV.

PLoS One 2020 17;15(12):e0243713. Epub 2020 Dec 17.

Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Global Tuberculosis Program, Section of Global and Immigrant Health, Houston, Texas, United States of America.

This study identified factors associated with adherence to a 6-month isoniazid preventive therapy (IPT) course among adolescents and children living with HIV. Forty adolescents living with HIV and 48 primary caregivers of children living with HIV completed a Likert-based survey to measure respondent opinions regarding access to care, quality of care, preferred regimens, perceived stigma, and confidence in self-efficacy. Sociodemographic data were collected and adherence measured as the average of pill counts obtained while on IPT. The rates of suboptimal adherence (< 95% adherent) were 22.5% among adolescents and 37.5% among the children of primary caregivers. Univariate logistic regression was used to model the change in the odds of suboptimal adherence. Independent factors associated with suboptimal adherence among adolescents included age, education level, the cost of coming to clinic, stigma from community members, and two variables relating to self-efficacy. Among primary caregivers, child age, concerns about stigma, and location preference for meeting a community-health worker were associated with suboptimal adherence. To determine whether these combined factors contributed different information to the prediction of suboptimal adherence, a risk score containing these predictors was constructed for each group. The risk score had an AUC of 0.87 (95% CI: 0.76, 0.99) among adolescents and an AUC of 0.76 (95% CI: 0.62, 0.90), among primary caregivers suggesting that these variables may have complementary predictive utility. The heterogeneous scope and associations of these variables in different populations suggests that interventions aiming to increase optimal adherence will need to be tailored to specific populations and multifaceted in nature. Ideally interventions should address both long-established barriers to adherence such as cost of transportation to attend clinic and more nuanced psychosocial barriers such as perceived community stigma and confidence in self-efficacy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243713PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746166PMC
February 2021

Tuberculosis prevention in children: a prospective community-based study in South Africa.

Eur Respir J 2021 04 22;57(4). Epub 2021 Apr 22.

Global Tuberculosis Program, Dept of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.

Tuberculosis (TB) preventive therapy reduces TB risk in children. However, the effectiveness of TB preventive therapy in children living in high TB burden settings is unclear.In a prospective observational community-based cohort study in Cape Town, South Africa, we assessed the effectiveness of routine TB preventive therapy in children ≤15 years of age in a high TB and HIV prevalence setting.Among 966 children (median (interquartile range) age 5.07 (2.52-8.72) years), 676 (70%) reported exposure to an adult with TB in the past 3 months and 240 out of 326 (74%) eligible children initiated isoniazid preventive therapy under programmatic guidelines. Prevalent (n=73) and incident (n=27) TB were diagnosed among 100 out of 966 (10%) children. Children who initiated isoniazid preventive therapy were 82% less likely to develop incident TB than children who did not (adjusted OR 0.18, 95% CI 0.06-0.52; p=0.0014). Risk of incident TB increased if children were <5 years of age, living with HIV, had a positive -specific immune response or recent TB exposure. The risk of incident TB was not associated with sex or bacille Calmette-Guérin vaccination status. Number needed to treat (NNT) was lowest in children living with HIV (NNT=15) and children <5 years of age (NNT=19) compared with children of all ages (NNT=82).In communities with high TB prevalence, TB preventive therapy substantially reduces the risk of TB among children who are <5 years of age or living with HIV, especially those with recent TB exposure or a positive -specific immune response in the absence of disease.
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http://dx.doi.org/10.1183/13993003.03028-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060782PMC
April 2021

Transition to dolutegravir is associated with an increase in the rate of BMI change in a cohort of virally suppressed adolescents.

Clin Infect Dis 2020 Oct 29. Epub 2020 Oct 29.

Baylor Children's Foundation-Eswatini, Mbabane, Eswatini.

Background: Antiretroviral therapy (ART) regimens that contain Dolutegravir (DTG) have been associated with increases in body mass index (BMI) in adults. However, this relationship has not been well described in adolescents.

Methods: In a retrospective observational cohort of 460 virally suppressed (< 200 copies/ml) adolescents living with HIV at a clinical site in Eswatini, body mass index (BMI) measurements were analyzed between 1 year prior to the transition to DTG and up to 1 year after DTG transition. Random-effects linear spline models were used to describe the rate of change in BMI before and after the transition to DTG.

Results: In adolescents BMI increased at a rate of 0.3 kg/m 2 per year before DTG transition and increased to a rate of 1.2 kg/m 2 per year after DTG transition. Sex of the adolescent modified the relationship between DTG and rate of BMI change; BMI rate of change was increased by 1.1 kg/m 2 in females and 0.6 kg/m 2 per year after DTG transition in males.

Conclusions: Transition to DTG in virally suppressed adolescents, age 10 to 19, is associated with an increase in the rate of BMI change. Female adolescents may experience a larger change than males. Further investigation is required to elucidate the mechanism that underlies these observations and to assess how DTG impacts BMI in adolescents following longer durations of treatment.
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http://dx.doi.org/10.1093/cid/ciaa1652DOI Listing
October 2020

Distinct Risk Factors for Clinical and Bacteriologically Confirmed Tuberculosis among Child Household Contacts in a High-Burden Setting.

Am J Trop Med Hyg 2020 12 24;103(6):2506-2509. Epub 2020 Sep 24.

The Global Tuberculosis Program, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.

The identification and screening of children at high risk of tuberculosis is essential to the control and prevention of child tuberculosis (TB). BUTIMBA, an active case finding and household contact-tracing project implemented between 2013 and 2015 in Eswatini, evaluated 5,413 contacts of 1,568 index cases, of whom 82 (1.5%) were diagnosed with TB disease. We conducted univariate and multivariate clustered logistic regression analyses of risk factors for any TB diagnosis among child household contacts of TB cases. Children younger than 5 years and children with positive HIV status were more likely to have TB than children aged 5-14 years and children with negative HIV status, respectively (adjusted odds ratio [aOR]: 2.2, < 0.001; aOR: 5.0, < 0.001). Children with one or more TB symptoms were more likely to be diagnosed with TB based on clinical criteria, but less likely to have bacteriologically confirmed TB, highlighting subjectivity in determination of child TB.
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http://dx.doi.org/10.4269/ajtmh.20-0522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695104PMC
December 2020

Design and Evaluation of Risk Assessment Tools to Identify Pediatric Tuberculosis Infection in Bohol, the Philippines, a Low-HIV- and High-TB-Burden Setting.

Am J Trop Med Hyg 2020 11;103(5):1818-1826

Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas.

Identifying children with, or at substantial risk of, infection (TBI) and providing TB preventive therapy (TPT) represent an important, yet challenging, strategy in curbing the global burden of childhood TB. Risk assessment scoring tools, which quantify risks associated with unique factors characterizing an individual, could act as a surrogate measure of TBI risk and guide effective and efficient TPT delivery. We assessed important risk factors of childhood TBI and created risk assessment tools through secondary analysis of data from a large, community-based childhood TB prevalence study in the island province of Bohol in the Philippines, a low-HIV- and high-TB-burden, post-disaster setting. We identified four factors that were statistically associated with acquiring TBI-being 5 years or older, having a known TB contact, having a known TB contact who was either the mother or another primary caregiver, and living in a high-TB-burden municipality. We created 2-item, 4-item, and 9-item scores intended to identify child TBI in this low-resource, low-HIV-, and high-TB-burden setting. In addition to the design, evaluation, and impact analysis of these generalizable and valuable risk assessment tools, our study findings emphasize the necessity of targeting both household and community-associated transmissions of childhood TBI to achieve the global goal to end TB.
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http://dx.doi.org/10.4269/ajtmh.20-0244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646812PMC
November 2020

It Ain't Over Till It's Over: The Triple Threat of COVID-19, TB, and HIV.

Am J Trop Med Hyg 2020 10;103(4):1348-1349

Baylor College of Medicine and Texas Children's Hospital, Houston, Texas.

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http://dx.doi.org/10.4269/ajtmh.20-1089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543805PMC
October 2020

Xpert MTB/RIF and Xpert MTB/RIF Ultra assays for active tuberculosis and rifampicin resistance in children.

Cochrane Database Syst Rev 2020 08 27;8:CD013359. Epub 2020 Aug 27.

The Global Tuberculosis Program, Texas Children's Hospital, Section of Global and Immigrant Health, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

Background: Every year, at least one million children become ill with tuberculosis and around 200,000 children die. Xpert MTB/RIF and Xpert Ultra are World Health Organization (WHO)-recommended rapid molecular tests that simultaneously detect tuberculosis and rifampicin resistance in adults and children with signs and symptoms of tuberculosis, at lower health system levels. To inform updated WHO guidelines on molecular assays, we performed a systematic review on the diagnostic accuracy of these tests in children presumed to have active tuberculosis.

Objectives: Primary objectives • To determine the diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for (a) pulmonary tuberculosis in children presumed to have tuberculosis; (b) tuberculous meningitis in children presumed to have tuberculosis; (c) lymph node tuberculosis in children presumed to have tuberculosis; and (d) rifampicin resistance in children presumed to have tuberculosis - For tuberculosis detection, index tests were used as the initial test, replacing standard practice (i.e. smear microscopy or culture) - For detection of rifampicin resistance, index tests replaced culture-based drug susceptibility testing as the initial test Secondary objectives • To compare the accuracy of Xpert MTB/RIF and Xpert Ultra for each of the four target conditions • To investigate potential sources of heterogeneity in accuracy estimates - For tuberculosis detection, we considered age, disease severity, smear-test status, HIV status, clinical setting, specimen type, high tuberculosis burden, and high tuberculosis/HIV burden - For detection of rifampicin resistance, we considered multi-drug-resistant tuberculosis burden • To compare multiple Xpert MTB/RIF or Xpert Ultra results (repeated testing) with the initial Xpert MTB/RIF or Xpert Ultra result SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and the International Standard Randomized Controlled Trials Number (ISRCTN) Registry up to 29 April 2019, without language restrictions.

Selection Criteria: Randomized trials, cross-sectional trials, and cohort studies evaluating Xpert MTB/RIF or Xpert Ultra in HIV-positive and HIV-negative children younger than 15 years. Reference standards comprised culture or a composite reference standard for tuberculosis and drug susceptibility testing or MTBDRplus (molecular assay for detection of Mycobacterium tuberculosis and drug resistance) for rifampicin resistance. We included studies evaluating sputum, gastric aspirate, stool, nasopharyngeal or bronchial lavage specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), fine needle aspirates, or surgical biopsy tissue (lymph node tuberculosis).

Data Collection And Analysis: Two review authors independently extracted data and assessed study quality using the Quality Assessment of Studies of Diagnostic Accuracy - Revised (QUADAS-2). For each target condition, we used the bivariate model to estimate pooled sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We assessed certainty of evidence using the GRADE approach.

Main Results: For pulmonary tuberculosis, 299 data sets (68,544 participants) were available for analysis; for tuberculous meningitis, 10 data sets (423 participants) were available; for lymph node tuberculosis, 10 data sets (318 participants) were available; and for rifampicin resistance, 14 data sets (326 participants) were available. Thirty-nine studies (80%) took place in countries with high tuberculosis burden. Risk of bias was low except for the reference standard domain, for which risk of bias was unclear because many studies collected only one specimen for culture. Detection of pulmonary tuberculosis For sputum specimens, Xpert MTB/RIF pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 64.6% (55.3% to 72.9%) (23 studies, 493 participants; moderate-certainty evidence) and 99.0% (98.1% to 99.5%) (23 studies, 6119 participants; moderate-certainty evidence). For other specimen types (nasopharyngeal aspirate, 4 studies; gastric aspirate, 14 studies; stool, 11 studies), Xpert MTB/RIF pooled sensitivity ranged between 45.7% and 73.0%, and pooled specificity ranged between 98.1% and 99.6%. For sputum specimens, Xpert Ultra pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 72.8% (64.7% to 79.6%) (3 studies, 136 participants; low-certainty evidence) and 97.5% (95.8% to 98.5%) (3 studies, 551 participants; high-certainty evidence). For nasopharyngeal specimens, Xpert Ultra sensitivity (95% CI) and specificity (95% CI) were 45.7% (28.9% to 63.3%) and 97.5% (93.7% to 99.3%) (1 study, 195 participants). For all specimen types, Xpert MTB/RIF and Xpert Ultra sensitivity were lower against a composite reference standard than against culture. Detection of tuberculous meningitis For cerebrospinal fluid, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 54.0% (95% CI 27.8% to 78.2%) (6 studies, 28 participants; very low-certainty evidence) and 93.8% (95% CI 84.5% to 97.6%) (6 studies, 213 participants; low-certainty evidence). Detection of lymph node tuberculosis For lymph node aspirates or biopsies, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 90.4% (95% CI 55.7% to 98.6%) (6 studies, 68 participants; very low-certainty evidence) and 89.8% (95% CI 71.5% to 96.8%) (6 studies, 142 participants; low-certainty evidence). Detection of rifampicin resistance Xpert MTB/RIF pooled sensitivity and specificity were 90.0% (67.6% to 97.5%) (6 studies, 20 participants; low-certainty evidence) and 98.3% (87.7% to 99.8%) (6 studies, 203 participants; moderate-certainty evidence).

Authors' Conclusions: We found Xpert MTB/RIF sensitivity to vary by specimen type, with gastric aspirate specimens having the highest sensitivity followed by sputum and stool, and nasopharyngeal specimens the lowest; specificity in all specimens was > 98%. Compared with Xpert MTB/RIF, Xpert Ultra sensitivity in sputum was higher and specificity slightly lower. Xpert MTB/RIF was accurate for detection of rifampicin resistance. Xpert MTB/RIF was sensitive for diagnosing lymph node tuberculosis. For children with presumed tuberculous meningitis, treatment decisions should be based on the entirety of clinical information and treatment should not be withheld based solely on an Xpert MTB/RIF result. The small numbers of studies and participants, particularly for Xpert Ultra, limits our confidence in the precision of these estimates.
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http://dx.doi.org/10.1002/14651858.CD013359.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078611PMC
August 2020

DNA hypermethylation during tuberculosis dampens host immune responsiveness.

J Clin Invest 2020 06;130(6):3113-3123

Global Tuberculosis Program, Texas Children's Hospital, Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

Mycobacterium tuberculosis (M. tuberculosis) has coevolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to improve outcomes and potentially shorten existing therapy will require identification of the full complement by which host immunity is inhibited. Perturbation of host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV, lymphocytic choriomeningitis virus (LCMV), and schistosomiasis to evade host immunity. Here, we evaluated the DNA methylation status of patients with tuberculosis (TB) and their asymptomatic household contacts and found that the patients with TB have DNA hypermethylation of the IL-2/STAT5, TNF/NF-κB, and IFN-γ signaling pathways. We performed methylation-sensitive restriction enzyme-quantitative PCR (MSRE-qPCR) and observed that multiple genes of the IL-12/IFN-γ signaling pathway (IL12B, IL12RB2, TYK2, IFNGR1, JAK1, and JAK2) were hypermethylated in patients with TB. The DNA hypermethylation of these pathways was associated with decreased immune responsiveness with decreased mitogen-induced upregulation of IFN-γ, TNF, IL-6, CXCL9, CXCL10, and IL-1β production. The DNA hypermethylation of the IL-12/IFN-γ pathway was associated with decreased IFN-γ-induced gene expression and decreased IL-12-inducible upregulation of IFN-γ. This study demonstrates that immune cells from patients with TB are characterized by DNA hypermethylation of genes critical to mycobacterial immunity resulting in decreased mycobacteria-specific and nonspecific immune responsiveness.
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http://dx.doi.org/10.1172/JCI134622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260034PMC
June 2020

Prevalence of Tuberculosis in Children After Natural Disasters, Bohol, Philippines.

Emerg Infect Dis 2019 10;25(10):1884-1892

In 2013, a severe earthquake and typhoon affected Bohol, Philippines. To assess the postdisaster risk for emergence of Mycobacterium tuberculosis infection in children, we conducted a cross-sectional multistage cluster study to estimate the prevalence of tuberculin skin test (TST) positivity and tuberculosis (TB) in children from 200 villages in heavily affected and less affected disaster areas. Of the 5,476 children we enrolled, 355 were TST-positive (weighted prevalence 6.4%); 16 children had active TB. Fourteen (7%) villages had >20% TST-positive prevalence. Although prevalence did not differ significantly between heavily affected and less affected areas, living in a shelter with >25 persons approached significance. TST positivity was independently associated with older age, prior TB treatment, known contact with a person with TB, and living on a geographically isolated island. We found a high TST-positive prevalence, suggesting that national programs should consider the differential vulnerability of children and the role of geographically isolated communities in TB emergence.
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http://dx.doi.org/10.3201/eid2510.190619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759243PMC
October 2019

Diagnosis and clinical outcomes of extrapulmonary tuberculosis in antiretroviral therapy programmes in low- and middle-income countries: a multicohort study.

J Int AIDS Soc 2019 09;22(9):e25392

Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland.

Introduction: Extrapulmonary tuberculosis (EPTB) is difficult to confirm bacteriologically and requires specific diagnostic capacities. Diagnosis can be especially challenging in under-resourced settings. We studied diagnostic modalities and clinical outcomes of EPTB compared to pulmonary tuberculosis (PTB) among HIV-positive adults in antiretroviral therapy (ART) programmes in low- and middle-income countries (LMIC).

Methods: We collected data from HIV-positive TB patients (≥16 years) in 22 ART programmes participating in the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium in sub-Saharan Africa, Asia-Pacific, and Caribbean, Central and South America regions between 2012 and 2014. We categorized TB as PTB or EPTB (EPTB included mixed PTB/EPTB). We used multivariable logistic regression to assess associations with clinical outcomes.

Results And Discussion: We analysed 2695 HIV-positive TB patients. Median age was 36 years (interquartile range (IQR) 30 to 43), 1102 were female (41%), and the median CD4 count at TB treatment start was 114 cells/μL (IQR 40 to 248). Overall, 1930 had PTB (72%), and 765 EPTB (28%). Among EPTB patients, the most frequently involved sites were the lymph nodes (24%), pleura (15%), abdomen (11%) and meninges (6%). The majority of PTB (1123 of 1930, 58%) and EPTB (582 of 765, 76%) patients were diagnosed based on clinical criteria. Bacteriological confirmation (using positive smear microscopy, culture, Xpert MTB/RIF, or other nucleic acid amplification tests result) was obtained in 897 of 1557 PTB (52%) and 183 of 438 EPTB (42%) patients. EPTB was not associated with higher mortality compared to PTB (adjusted odd ratio (aOR) 1.0, 95% CI 0.8 to 1.3), but TB meningitis was (aOR 1.9, 95% CI 1.0 to 3.1). Bacteriological confirmation was associated with reduced mortality among PTB patients (aOR 0.7, 95% CI 0.6 to 0.8) and EPTB patients (aOR 0.3 95% CI 0.1 to 0.8) compared to TB patients with a negative test result.

Conclusions: Diagnosis of EPTB and PTB at ART programmes in LMIC was mainly based on clinical criteria. Greater availability and usage of TB diagnostic tests would improve the diagnosis and clinical outcomes of both EPTB and PTB.
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http://dx.doi.org/10.1002/jia2.25392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737289PMC
September 2019

Development of a Tool for Health Screening and Assessment in Orphanages in Lesotho.

Am J Trop Med Hyg 2019 05;100(5):1290-1293

Department of Pediatrics, Baylor College of Medicine, Houston, Texas.

In low- and middle-income countries that have high burdens of disease, simple interventions such as health screenings can have a significant impact on health outcomes. Among vulnerable children, orphans in particular, deaths are often caused by conditions preventable through early identification and provision of basic health and nutritional needs. After consulting local preventative care guidelines and medical providers, a health screening tool for use in orphanages was created. This tool was used to screen children in two orphanages in Lesotho. Overall, the tool was found to be easy, efficient, and valuable in identifying both preventable and immediately treatable conditions in orphans. As a result, orphans with long-term medical needs were linked to community-based providers by developing individualized care plans in collaboration with orphanage colleagues. This preventative tool offers a screening strategy that directly aligns with the United Nations Agency for Development's Sustainable Development Goals and helps to advance the goal of universal health coverage.
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http://dx.doi.org/10.4269/ajtmh.18-0853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493929PMC
May 2019

Immunologic-based Diagnosis of Latent Tuberculosis Among Children Younger Than 5 Years of Age Exposed and Unexposed to Tuberculosis in Tanzania.

Pediatr Infect Dis J 2019 04;38(4):333-339

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

Background: Childhood tuberculosis (TB) is acquired after exposure to an infectious TB case, often within the household. We prospectively screened children 6-59 months of age, exposed and unexposed to an infectious TB case within the same household, for latent tuberculosis infection (LTBI), in Dar es Salaam, Tanzania.

Methods: We collected medical data and clinical specimens (to evaluate for helminths, TB and HIV coinfections) and performed physical examinations at enrollment and at 3-month and 6-month follow-up surveys. LTBI was assessed using QuantiFERON-TB Gold (QFT) at enrollment and at 3 months.

Results: In total, 301 children had complete data records (186 with TB exposure and 115 without known TB exposure). The median age of children was 26 months (range: 6-58); 52% were females, and 4 were HIV positive. Eight children (3%) developed TB during the 6-month follow-up. We found equal proportions of children with LTBI among those with and without exposure: 20% (38/186) versus 20% (23/115) QFT-positive, and 2% (4/186) versus 4% (5/115) indeterminate QFT. QFT conversion rate was 7% (22 children) and reversion 8% (25 children). Of the TB-exposed children, 72% initiated isoniazid preventive therapy, but 61% of parents/caregivers of children with unknown TB exposure and positive QFT refused isoniazid preventive therapy.

Conclusions: In this high burden TB setting, TB exposure from sources other than the household was equally important as household exposure. Nearly one third of eligible children did not receive isoniazid preventive therapy. Evaluation for LTBI in children remains an important strategy for controlling TB but should not be limited to children with documented TB exposure.
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http://dx.doi.org/10.1097/INF.0000000000002131DOI Listing
April 2019

Evaluation of the QuantiFERON-Tuberculosis Gold Plus Assay in Children with Tuberculosis Disease or Following Household Exposure to Tuberculosis.

Am J Trop Med Hyg 2019 03;100(3):540-543

Baylor College of Medicine, Houston, Texas.

Interferon-gamma release assays are increasingly used in children to establish evidence of tuberculosis (TB) infection and to assist in the diagnosis of TB disease. The QuantiFERON-TB Gold In-Tube assay is being phased out in favor of a next-generation test, the QuantiFERON-TB Gold Plus (QFT-Plus) assay. The QFT-Plus assay is designed with two antigen tubes to differentially stimulate CD4 and CD8 T cells. The performance of this assay has been documented extensively in adults but has not yet been evaluated in children. Here, we compare the performance of the two assays in a cohort of 46 children exposed to TB and 12 children diagnosed with TB disease in Eswatini. The tests demonstrated excellent concordance in both TB disease (100% agreement, Cohen's kappa = 1) and TB infection (96% agreement, Cohen's kappa = 0.91). Most of the children with household exposure tested negative for TB infection by both tests, indicating the ongoing need for new tests for TB infection that can be easily implemented in TB high-burden settings at minimal cost.
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http://dx.doi.org/10.4269/ajtmh.18-0674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402910PMC
March 2019

Schistosomiasis Induces Persistent DNA Methylation and Tuberculosis-Specific Immune Changes.

J Immunol 2018 07 11;201(1):124-133. Epub 2018 May 11.

Department of Pathology, Baylor College of Medicine, Houston, TX 77030.

Epigenetic mechanisms, such as DNA methylation, determine immune cell phenotype. To understand the epigenetic alterations induced by helminth coinfections, we evaluated the longitudinal effect of ascariasis and schistosomiasis infection on CD4 T cell DNA methylation and the downstream tuberculosis (TB)-specific and bacillus Calmette-Guérin-induced immune phenotype. All experiments were performed on human primary immune cells from a longitudinal cohort of recently TB-exposed children. Compared with age-matched uninfected controls, children with active and infection had 751 differentially DNA-methylated genes, with 72% hypermethylated. Gene ontology pathway analysis identified inhibition of IFN-γ signaling, cellular proliferation, and the Th1 pathway. Targeted real-time quantitative PCR after methyl-specific endonuclease digestion confirmed DNA hypermethylation of the transcription factors , , , , , , and and cytokines or cytokine receptors , , (TNF receptor), and ( < 0.001; Sidak-Bonferroni). Functional blockage of the IFN-γ signaling pathway was confirmed, with helminth-infected individuals having decreased upregulation of IFN-γ-inducible genes (Mann-Whitney < 0.05). Hypomethylation of the IL-4 pathway and DNA hypermethylation of the Th1 pathway was confirmed by Ag-specific multidimensional flow cytometry demonstrating decreased TB-specific IFN-γ and TNF and increased IL-4 production by CD4+ T cells (Wilcoxon signed-rank < 0.05). In -infected individuals, these DNA methylation and immune phenotypic changes persisted at least 6 mo after successful deworming. This work demonstrates that helminth infection induces DNA methylation and immune perturbations that inhibit TB-specific immune control and that the duration of these changes are helminth specific.
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http://dx.doi.org/10.4049/jimmunol.1800101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008220PMC
July 2018

Diagnostic and Treatment Monitoring Potential of A Stool-Based Quantitative Polymerase Chain Reaction Assay for Pulmonary Tuberculosis.

Am J Trop Med Hyg 2018 08 19;99(2):310-316. Epub 2018 Apr 19.

The Global TB Program, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas.

A quantifiable, stool-based, () test has potential complementary value to respiratory specimens. Limit of detection (LOD) was determined by spiking control stool. Clinical test performance was evaluated in a cohort with pulmonary tuberculosis (TB) ( = 166) and asymptomatic household TB child contacts ( = 105). Stool-quantitative polymerase chain reaction (qPCR) results were compared with sputum acid-fast bacilli (AFB) microscopy, GeneXpert MTB/RIF (Xpert MTB/RIF), and cultures. In stool-spiking studies, the LOD was 96 colony-forming units/50 mg of stool (95% confidence interval [CI]: 84.8-105.6). Among specimens collected within 72 hours of antituberculosis treatment (ATT) initiation, stool qPCR detected 22 of 23 (95%) of culture-positive cases. Among clinically diagnosed cases that were Xpert MTB/RIF and culture negative, stool qPCR detected an additional 8% (3/37). Among asymptomatic, recently TB-exposed participants, stool PCR detected in two of 105 (1.9%) patients. Two months after ATT, the quantitative burden in femtogram per microliters decreased (Wilcoxon signed-rank < 0.001) and persistent positive stool PCR was associated with treatment failure or drug resistance (relative risk 2.8, CI: 1.2-6.5; = 0.012). Stool-based qPCR is a promising complementary technique to sputum-based diagnosis. It detects and quantifies low levels of stool DNA, thereby supporting adjunct diagnosis and treatment monitoring in pulmonary TB.
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http://dx.doi.org/10.4269/ajtmh.18-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090360PMC
August 2018

High Incidence of Tuberculosis Infection in HIV-exposed Children Exiting an Isoniazid Preventive Therapy Trial.

Pediatr Infect Dis J 2018 10;37(10):e254-e256

Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa.

Young HIV-exposed children are at high risk for TB infection. We performed QuantiFERON-TB Gold among HIV-exposed children in South Africa at enrolment and 1-year follow-up. The incidence of TB infection was high for HIV+ (11 cases per 100 child-years) and HIV-exposed uninfected children (15 cases per 100 child-years). QuantiFERON-TB Gold may identify HIV-exposed children at risk for TB disease progression.
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http://dx.doi.org/10.1097/INF.0000000000001946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095832PMC
October 2018

T-SPOT.TB Performance in Routine Pediatric Practice in a Low TB Burden Setting.

Pediatr Infect Dis J 2018 04;37(4):292-297

Background: The T-SPOT.TB, an interferon-gamma release assay, is an indirect test of Mycobacterium tuberculosis infection. Due to sparse and conflicting evidence, the use of interferon-gamma release assay is limited in young and HIV-infected children. We determined the prevalence of invalid, borderline, positive and negative results and associations with key demographic variables during routine pediatric use in a low tuberculosis burden setting.

Methods: For pediatric samples received at Oxford Diagnostic Laboratories between 2010 and 2015, the associations between initial test outcome and demographics were estimated by bivariate analysis and logistic regression.

Results: A total of 44,289 samples (median age 12.5 years; interquartile range 7.7-15.5), including 5057 samples (11.6%) from children under 5 years old, were received from 46 U.S. states, Washington, DC and Puerto Rico. A total of 592 samples (1.3%) could not be tested. T-SPOT.TB positivity was strongly correlated (r = 0.60; P < 0.0001) with state TB incidence. Compared with negative results, positive results were more likely in samples from older children (P < 0.0001), public health clinics (P < 0.0001) and rural locations (P = 0.005). Although infrequent (0.6%), invalid results were more common in samples collected at HIV clinics (odds ratio = 2.5, 95% confidence interval: 1.3-4.9) and from younger children (P = 0.03). These invalid results were more likely due to a robust nil (negative) control response rather than a weak mitogen (positive) control response.

Conclusions: The T-SPOT.TB test correlated strongly with well-recognized risk factors for tuberculosis infection and provided evaluable results in 98% of children. To optimize the impact of testing on clinical decision making and patient outcomes, local epidemiology and individual patient risk should be considered when incorporating IGRAs into pediatric guidelines.
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http://dx.doi.org/10.1097/INF.0000000000001792DOI Listing
April 2018

Correction to: The impact of drug resistance on the risk of tuberculosis infection and disease in child household contacts: a cross sectional study.

BMC Infect Dis 2017 11 7;17(1):713. Epub 2017 Nov 7.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Box 241, Cape Town, PO, 8000, South Africa.

After publication of the original article [1] the authors noted that the following errors had occurred.
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http://dx.doi.org/10.1186/s12879-017-2806-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674833PMC
November 2017

Schistosoma, other helminth infections, and associated risk factors in preschool-aged children in urban Tanzania.

PLoS Negl Trop Dis 2017 Nov 6;11(11):e0006017. Epub 2017 Nov 6.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

Background: Despite the high prevalence of helminth infections among preschool-aged children, control programs in sub-Saharan countries primarily focus on school-aged populations. We assessed the prevalence of helminth infections and determined risk factors for infection among preschool-aged children in the urban setting of Dar es Salaam, Tanzania.

Methodology: Starting in October 2015, we conducted a 12-month prospective study among tuberculosis (TB)-exposed children under the age of 5 years and unexposed controls from neighboring households. At the time of recruitment, we collected medical histories, assessed development and cognitive functions, and performed medical examinations. We performed full blood cell counts and screened for HIV and malaria. Point-of-care circulating cathodic antigen (POC-CCA), urine filtration, Kato-Katz, FLOTAC, and Baermann tests were employed to detect helminth infections in urine and stool. Helminth infections were stratified for Schistosoma and other helminths to identify risk factors, using logistic regression.

Principal Findings: We included 310 children with a median age of 26 months (inter quartile range 17-42 months) in the study. Among these, 189 were TB-exposed and 121 TB-unexposed. Two thirds of the children were anemic (hemoglobin level <11 g/dl) and the HIV prevalence was 1.3%. Schistosoma spp. was the predominant helminth species (15.8%; 95% confidence interval [CI] 12.1-20.3%). Other helminth infections were less frequent (9.0%, 95% CI 6.3-12.8%). Poor hygiene, use of household water sources, and TB-exposure were not associated with helminth infection. Development and cognitive scores did not significantly differ in helminth-infected and uninfected peers, but hemoglobin levels were significantly lower in helminth-infected children (10.1 g/dl vs. 10.4 g/dl, p = 0.027).

Conclusions/significance: In Dar es Salaam, a city with more than 4 million inhabitants, the prevalence of Schistosoma spp. infection among preschool-aged children was unexpectedly high. Setting-specific interventions that target preschool-aged children and urban settlements should be considered to reduce the transmission of Schistosoma and other helminth infections and to improve children's health.
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http://dx.doi.org/10.1371/journal.pntd.0006017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697890PMC
November 2017

The impact of drug resistance on the risk of tuberculosis infection and disease in child household contacts: a cross sectional study.

BMC Infect Dis 2017 08 29;17(1):593. Epub 2017 Aug 29.

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, 8000, Cape Town, South Africa.

Background: The relative fitness of organisms causing drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) is unclear. We compared the risk of TB infection and TB disease in young child household contacts of adults with confirmed DS-TB and MDR-TB.

Methods: In this cross-sectional analysis we included data from two community-based contact cohort investigation studies conducted in parallel in Cape Town, South Africa. Children <5 years of age with household exposure to an infectious TB case were included between August 2008 to June 2011. Children completed investigation for TB infection (tuberculin skin test) and TB disease (symptom evaluation, chest radiograph, bacteriology) in both studies using standard approaches. The impact of MDR-TB exposure on each covariate of TB infection and TB disease was assessed using univariable and multivariable logistic regression.

Results: Of 538 children included, 312 had DS-TB and 226 had MDR-TB exposure. 107 children with DS-TB exposure had TB infection (34.3%) vs. 101 (44.7%) of children with MDR-TB exposure (adjusted Odds Ratio [aOR]: 2.05; 95% confidence interval [CI]: 1.34-3.12). A total of 15 (6.6%) MDR-TB vs. 27 (8.7%) DS-TB child contacts had TB disease at enrolment (aOR: 0.43; 95% CI: 0.19-0.97).

Conclusions: Our results suggest a higher risk of TB infection in child contacts with household MDR-TB vs. DS-TB exposure, but a lower risk of TB disease. Although potentially affected by residual confounding or selection bias, our results are consistent with the hypothesis of impaired virulence in MDR-TB strains in this setting.
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http://dx.doi.org/10.1186/s12879-017-2668-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576070PMC
August 2017

Tuberculosis-making predictions, especially about the future.

Lancet Infect Dis 2017 11 18;17(11):1106-1107. Epub 2017 Aug 18.

Department of Global Health and Amsterdam Institute for Global Health and Development, Academic Medical Centre, Amsterdam, Netherlands.

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http://dx.doi.org/10.1016/S1473-3099(17)30492-9DOI Listing
November 2017

Child contact management in high tuberculosis burden countries: A mixed-methods systematic review.

PLoS One 2017 1;12(8):e0182185. Epub 2017 Aug 1.

Global TB Program, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.

Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. Considering the World Health Organization recommendation to implement child contact management (CCM) for TB, we conducted a mixed-methods systematic review to summarize CCM implementation, challenges, predictors, and recommendations. We searched the electronic databases of PubMed/MEDLINE, Scopus, and Web of Science for studies published between 1996-2017 that reported CCM data from high TB-burden countries. Protocol details for this systematic review were registered on PROSPERO: International prospective register of systematic reviews (#CRD42016038105). We formulated a search strategy to identify all available studies, published in English that specifically targeted a) population: child contacts (<15 years) exposed to TB in the household from programmatic settings in high burden countries (HBCs), b) interventions: CCM strategies implemented within the CCM cascade, c) comparisons: CCM strategies studied and compared in HBCs, and d) outcomes: monitoring and evaluation of CCM outcomes reported in the literature for each CCM cascade step. We included any quantitative, qualitative, mixed-methods study design except for randomized-controlled trials, editorials or commentaries. Thirty-seven studies were reviewed. Child contact losses varied greatly for screening, isoniazid preventive therapy initiation, and completion. CCM challenges included: infrastructure, knowledge, attitudes, stigma, access, competing priorities, and treatment. CCM recommendations included: health system strengthening, health education, and improved preventive therapy. Identified predictors included: index case and clinic characteristics, perceptions of barriers and risk, costs, and treatment characteristics. CCM lacks standardization resulting in common challenges and losses throughout the CCM cascade. Prioritization of a CCM-friendly healthcare environment with improved CCM processes and tools; health education; and active, evidence-based strategies can decrease barriers. A focused approach toward every aspect of the CCM cascade will likely diminish losses throughout the CCM cascade and ultimately decrease TB related morbidity and mortality in children.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182185PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538653PMC
October 2017

Tuberculosis Treatment Outcomes Among HIV/TB-Coinfected Children in the International Epidemiology Databases to Evaluate AIDS (IeDEA) Network.

J Acquir Immune Defic Syndr 2017 Jun;75(2):156-163

*Vanderbilt Institute for Global Health, Nashville, TN; †Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN; ‡Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN; §Vanderbilt Tuberculosis Center, Nashville, TN; ‖Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; ¶Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN; #Children's Hospital 1, Ho Chi Minh City, Vietnam; **University of Ghana School of Medicine and Dentistry, Accra, Ghana; ††Department of Pediatrics and Child Health, Rahima Moosa Mother and Child Hospital, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; ‡‡Masaka Regional Referral Hospital, Masaka, Uganda; §§The Ohio State University, College of Public Health, Columbus, OH; ‖‖Department of Pediatrics, Baylor College of Medicine, Houston, TX; ¶¶Centre for Infectious Disease Epidemiology and Research, University of Cape Town, Cape Town, South Africa; ##Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; ***Swiss Tropical and Public Health Institute, Basel, Switzerland; †††University of Basel, Basel, Switzerland; and ‡‡‡Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

Introduction: Management of tuberculosis (TB) is challenging in HIV/TB-coinfected children. The World Health Organization recommends nucleic acid amplification tests for TB diagnosis, a 4-drug regimen including ethambutol during intensive phase (IP) of treatment, and initiation of antiretroviral therapy (ART) within 8 weeks of TB diagnosis. We investigated TB treatment outcomes by diagnostic modality, IP regimen, and ART status.

Methods: We conducted a retrospective cohort study among HIV/TB-coinfected children enrolled at the International Epidemiology Databases to Evaluate AIDS treatment sites from 2012 to 2014. We modeled TB outcome using multivariable logistic regression including diagnostic modality, IP regimen, and ART status.

Results: Among the 386 HIV-infected children diagnosed with TB, 20% had microbiologic confirmation of TB, and 20% had unfavorable TB outcomes. During IP, 78% were treated with a 4-drug regimen. Thirty-one percent were receiving ART at the time of TB diagnosis, and 32% were started on ART within 8 weeks of TB diagnosis. Incidence of ART initiation within 8 weeks of TB diagnosis was higher for those with favorable TB outcomes (64%) compared with those with unfavorable outcomes (40%) (P = 0.04). Neither diagnostic modality (odds ratio 1.77; 95% confidence interval: 0.86 to 3.65) nor IP regimen (odds ratio 0.88; 95% confidence interval: 0.43 to 1.80) was associated with TB outcome.

Discussion: In this multinational study of HIV/TB-coinfected children, many were not managed as per World Health Organization guidelines. Children with favorable TB outcomes initiated ART sooner than children with unfavorable outcomes. These findings highlight the importance of early ART for children with HIV/TB coinfection, and reinforce the need for implementation research to improve pediatric TB management.
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http://dx.doi.org/10.1097/QAI.0000000000001335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429189PMC
June 2017

Clinical Application of Interferon-γ Release Assays for the Prevention of Tuberculosis in Countries with Low Incidence.

Pathog Immun 2016 4;1(2):308-329. Epub 2016 Jan 4.

Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany.

Despite global efforts to control tuberculosis (TB) the estimated number of people who developed TB worldwide increased to an all-time record of more than 10 million in 2015. The goal of the World Health Organization (WHO) to reduce the global incidence of TB to less than 100 cases per million by 2035, cannot be reached unless TB prevention is markedly improved. There is a need for an improved vaccine that better protects individuals who are exposed to from infection and active disease compared to the current Bacille Calmette Guérin (BCG) vaccine. In the absence of such a vaccine, prevention relies on infection control measures and preventive chemotherapy for people with latent infection with (LTBI), who have the highest risk of progression to active TB. During the past decade, interferon-γ release assays (IGRAs) have increasingly replaced the tuberculin skin test as screening tools for the diagnosis of LTBI in countries with a low incidence of TB. Despite recent WHO guidelines on the management of LTBI, the definition of groups at risk for TB remains controversial, and the role of IGRAs for TB prevention in low-incidence countries remains uncertain. We reviewed the scientific literature and provide recommendations for the use of IGRAs for LTBI diagnosis in low-incidence countries. These recommendations are based on the number of patients needing treatment in order to prevent one case of TB. As the positive predictive value of IGRAs for the development of TB is sub-optimal, research must focus on the identification of alternative biomarkers that offer better predictive ability in order to substantially reduce the number needing treatment while improving the prevention of TB and improving the effectiveness of targeted preventive chemotherapy.
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http://dx.doi.org/10.20411/pai.v1i2.173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315027PMC
January 2016
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