Publications by authors named "Anne K Detjen"

17 Publications

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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

Tuberculosis and integrated child health - Rediscovering the principles of Alma Ata.

Int J Infect Dis 2019 03 27;80S:S9-S12. Epub 2019 Feb 27.

Centre for Research Excellence in Tuberculosis and the Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.ijid.2019.02.042DOI Listing
March 2019

The upcoming UN general assembly resolution on tuberculosis must also benefit children.

Lancet Glob Health 2018 05 23;6(5):e485-e486. Epub 2018 Mar 23.

The Indus Hospital, Karachi, Sindh, Pakistan.

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http://dx.doi.org/10.1016/S2214-109X(18)30108-6DOI Listing
May 2018

Re: "It May Be Too Early to Try to Prove the Effect of Deworming on Tuberculin Reactivity".

Pediatr Infect Dis J 2017 02;36(2):241-242

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Section on Global and Immigration Health, Department of Pediatrics, Baylor College of Medicine, Houston, Texas Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Duesseldorf, Germany The International Union Against Tuberculosis and Lung Disease, Paris, France Department of Pediatric Pneumology and Immunology, Charité-Universitätsmedizin, Berlin, Germany, Division of Global Health Equity, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway, Department of Microbiology, Haukeland University Hospital, Bergen, Norway FAM-CRU, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Immunology Research Group, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, MRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Desmond Tutu TB Centre Department of Paediatrics and Child Health Faculty of Medicine and Health Sciences Stellenbosch University Cape Town, South Africa.

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http://dx.doi.org/10.1097/INF.0000000000001408DOI Listing
February 2017

Why the Convention on the Rights of the Child must become a guiding framework for the realization of the rights of children affected by tuberculosis.

BMC Int Health Hum Rights 2016 12 8;16(1):32. Epub 2016 Dec 8.

Centre for International Child Health, Department of Paediatrics 2nd Floor, Medical School Building, St Mary's Campus, Imperial College London, London, W2 1PG, UK.

Background: Until recently, paediatric tuberculosis (TB) has been relatively neglected by the broader TB and the maternal and child health communities. Human rights-based approaches to children affected by TB could be powerful; however, awareness and application of such strategies is not widespread.

Discussion: We summarize the current challenges faced by children affected by TB, including: consideration of their family context; the limitations of preventive, diagnostic and treatment options; paucity of paediatric-specific research; failure in implementation of interventions; and stigma. We examine the articles of the Convention on the Rights of the Child (CRC) and relate them to childhood TB. Specifically, we focus on the five core principles of the CRC: children's inherent right to life and States' duties towards their survival and development; children's right to enjoyment of the highest attainable standard of health; non-discrimination; best interests of the child; and respect for the views of the child. We highlight where children's rights are violated and how a human rights-based approach should be used as a tool to help children affected by TB, particularly in light of the Sustainable Development Goals and their focus on universality and leaving no one behind. The article aims to bridge the gap between those providing paediatric TB clinical care and conducting research, and those working in the fields of human rights policy and advocacy to promote a human rights-based approach for children affected by TB based upon the Convention on the Rights of the Child.
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http://dx.doi.org/10.1186/s12914-016-0105-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5146903PMC
December 2016

Interrupted BCG vaccination is a major threat to global child health.

Lancet Respir Med 2016 04 23;4(4):251-3. Epub 2016 Mar 23.

The University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute, Royal Children's Hospital, Australia.

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http://dx.doi.org/10.1016/S2213-2600(16)00099-0DOI Listing
April 2016

The Effect of Deworming on Tests of Tuberculosis Infection in Children With Recent Tuberculosis Exposure: A Randomized Controlled Trial.

Pediatr Infect Dis J 2016 06;35(6):622-7

From the *Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Stellenbosch University, Stellenbosch, South Africa; †Section on Global and Immigration Health, Department of Pediatrics, Baylor College of Medicine, Houston, Texas; ‡Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Duesseldorf, Germany; §The International Union Against Tuberculosis and Lung Disease, Paris, France; ¶Department of Pediatric Pneumology and Immunology, Charité-Universitätsmedizin, Berlin, Germany; ‖Division of Global Health Equity, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; **Faculty of Medicine and Dentistry, Department of Clinical Science, University of Bergen, Bergen, Norway; ††Department of Microbiology, Haukeland University Hospital, Bergen, Norway; ‡‡FAM-CRU, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Stellenbosch University, Stellenbosch, South Africa; and §§Immunology Research Group, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research and MRC Centre for TB Research, Faculty of Medicine and Health Sciences, Division of Molecular Biology and Human Genetics, Stellenbosch University, Stellenbosch, South Africa.

Background: Helminth infestations are associated with T-helper cell type 2 (Th2) immune responses, leading to suppression of Th1 responses required to control Mycobacterium tuberculosis infection. We hypothesized that deworming after documented M. tuberculosis exposure might improve Th1 immune responses.

Methods: This was a randomized controlled trial comparing the effect of early versus delayed (after 3 months) deworming on tuberculin skin testing (TST) and Quantiferon-Gold-in-tube responses among children from a setting with a known high burden of M. tuberculosis and helminth co-infection in Cape Town, South Africa. Children aged 6 to 15 years with documented M. tuberculosis exposure were enrolled. Ascaris lumbricoides status was measured by Ascaris-specific IgE and stool microscopy.

Results: A total of 250 children (mean age, 9.6 years) were enrolled; 11.9% (27/227) were Ascaris stool microscopy positive and 54.2% (135/249) were Ascaris stool and/or IgE positive (Ascaris status). In univariable analysis, deworming at enrollment was not associated with a negative TST at 3 months (odds ratio, 0.61; 95% confidence interval, 0.35-1.07; P = 0.08). In stratified analysis, children with a positive Ascaris status were more likely to be TST negative at 3 months if dewormed early (odds ratio, 0.49; 95% confidence interval, 0.23-1.04; P = 0.06). In multivariable analysis, deworming was not associated with TST status (adjusted odds ratios, 0.62; 95% confidence interval, 0.34-1.10; P = 0.10). There was no association between deworming and Quantiferon-Gold-in-tube status.

Conclusions: Deworming in children with recent M. tuberculosis exposure is associated with a trend toward a negative TST result. Timing of deworming might influence interpretation of TST in settings with high burdens of tuberculosis and helminths.
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http://dx.doi.org/10.1097/INF.0000000000001115DOI Listing
June 2016

Editorial Commentary: Improving Children's Access to New Tuberculosis Diagnostic Tools Starts With the Collection of Appropriate Specimens.

Clin Infect Dis 2016 May 7;62(9):1169-71. Epub 2016 Feb 7.

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

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http://dx.doi.org/10.1093/cid/ciw042DOI Listing
May 2016

Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children: An Update.

Clin Infect Dis 2015 Oct;61Suppl 3:S179-87

Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, MRC Unit on Child and Adolescent Health, University of Cape Town, South Africa.

Consensus case definitions for childhood tuberculosis have been proposed by an international expert panel, aiming to standardize the reporting of cases in research focusing on the diagnosis of intrathoracic tuberculosis in children. These definitions are intended for tuberculosis diagnostic evaluation studies of symptomatic children with clinical suspicion of intrathoracic tuberculosis, and were not intended to predefine inclusion criteria into such studies. Feedback from researchers suggested that further clarification was required and that these case definitions could be further improved. Particular concerns were the perceived complexity and overlap of some case definitions, as well as the potential exclusion of children with acute onset of symptoms or less severe disease. The updated case definitions proposed here incorporate a number of key changes that aim to reduce complexity and improve research performance, while maintaining the original focus on symptomatic children suspected of having intrathoracic tuberculosis. The changes proposed should enhance harmonized classification for intrathoracic tuberculosis disease in children across studies, resulting in greater comparability and the much-needed ability to pool study results.
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http://dx.doi.org/10.1093/cid/civ581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583568PMC
October 2015

Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in children: a systematic review and meta-analysis.

Lancet Respir Med 2015 Jun 24;3(6):451-61. Epub 2015 Mar 24.

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

Background: Microbiological confirmation of childhood tuberculosis is rare because of the difficulty of collection of specimens, low sensitivity of smear microscopy, and poor access to culture. We aimed to establish summary estimates for sensitivity and specificity of of the Xpert MTB/RIF assay compared with microscopy in the diagnosis of pulmonary tuberculosis in children.

Methods: We searched for studies published up to Jan 6, 2015, that used Xpert in any setting in children with and without HIV infection. We systematically reviewed studies that compared the diagnostic accuracy of Xpert MTB/RIF (Xpert) with microscopy for detection of pulmonary tuberculosis and rifampicin resistance in children younger than 16 years against two reference standards-culture results and culture-negative children who were started on anti-tuberculosis therapy. We did meta-analyses using a bivariate random-effects model.

Findings: We identified 15 studies including 4768 respiratory specimens in 3640 children investigated for pulmonary tuberculosis. Culture tests were positive for tuberculosis in 12% (420 of 3640) of all children assessed and Xpert was positive in 11% (406 of 3640). Compared with culture, the pooled sensitivities and specificities of Xpert for tuberculosis detection were 62% (95% credible interval 51-73) and 98% (97-99), respectively, with use of expectorated or induced sputum samples and 66% (51-81) and 98% (96-99), respectively, with use of samples from gastric lavage. Xpert sensitivity was 36-44% higher than was sensitivity for microscopy. Xpert sensitivity in culture-negative children started on antituberculosis therapy was 2% (1-3) for expectorated or induced sputum. Xpert's pooled sensitivity and specificity to detect rifampicin resistance was 86% (95% credible interval 53-98) and 98% (94-100), respectively.

Interpretation: Compared with microscopy, Xpert offers better sensitivity for the diagnosis of pulmonary tuberculosis in children and its scale-up will improve access to tuberculosis diagnostics for children. Although Xpert helps to provide rapid confirmation of disease, its sensitivity remains suboptimum compared with culture tests. A negative Xpert result does not rule out tuberculosis. Good clinical acumen is still needed to decide when to start antituberculosis therapy and continued research for better diagnostics is crucial.

Funding: WHO, Global TB Program of Texas Children's Hospital.
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http://dx.doi.org/10.1016/S2213-2600(15)00095-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756280PMC
June 2015

Importance of tuberculosis control to address child survival.

Lancet 2014 May 24;383(9928):1605-7. Epub 2014 Mar 24.

Institute for International Programs, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

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http://dx.doi.org/10.1016/S0140-6736(14)60420-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503686PMC
May 2014

Utility of host markers detected in Quantiferon supernatants for the diagnosis of tuberculosis in children in a high-burden setting.

PLoS One 2013 15;8(5):e64226. Epub 2013 May 15.

DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.

Background: The diagnosis of childhood tuberculosis (TB) disease remains a challenge especially in young and HIV-infected children. Recent studies have identified potential host markers which, when measured in Quantiferon (QFT-IT) supernatants, show promise in discriminating between Mycobacterium tuberculosis (M.tb) infection states. In this study, the utility of such markers was investigated in children screened for TB in a setting with high TB incidence.

Methodology And Principal Findings: 76 children (29% HIV-infected) with or without active TB provided blood specimens collected directly into QFT-IT tubes. After overnight incubation, culture supernatants were harvested, aliquoted and frozen for future immunological research purposes. Subsequently, the levels of 12 host markers previously identified as potential TB diagnostic markers were evaluated in these supernatants for their ability to discriminate between M.tb infection and disease states using the Luminex platform. Of the 76 children included, 19 (25%) had culture confirmed TB disease; 26 (46%) of the 57 without TB had positive markers of M.tb infection defined by a positive QFT-IT test. The potentially most useful analytes for diagnosing TB disease included IFN-α2, IL-1Ra, sCD40L and VEGF and the most useful markers for discriminating between QFT-IT positive children as TB or latent infection included IL-1Ra, IP-10 and VEGF. When markers were used in combinations of four, 84% of all children were accurately classified into their respective groups (TB disease or no TB), after leave-one-out cross validation.

Conclusions: Measurement of the levels of IFN-α2, IL-1Ra, sCD40L, IP-10 and VEGF in QFT-IT supernatants may be a useful method for diagnosing TB disease and differentiating between active TB disease and M.tb infection in children. Our observations warrant further investigation in larger well-characterized clinical cohorts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064226PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655018PMC
January 2014

Laryngeal involvement in two severe cases of childhood tuberculosis.

Pediatr Infect Dis J 2009 Dec;28(12):1136-8

Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.

Laryngeal tuberculosis in children is seldom reported in the literature. We present 2 children from Cape Town, South Africa who had disseminated tuberculosis involving the cervical lymph nodes and the larynx. The cases emphasize the pathophysiology, the clinical picture, the bronchoscopic appearance, and the response to therapy in laryngeal tuberculosis.
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http://dx.doi.org/10.1097/INF.0b013e3181ac7b26DOI Listing
December 2009

Mycobacterium tuberculosis-specific CD4+, IFNgamma+, and TNFalpha+ multifunctional memory T cells coexpress GM-CSF.

Cytokine 2008 Aug 7;43(2):143-8. Epub 2008 Jul 7.

Department of Immunology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117 Berlin, Germany.

Multifunctional T cells expressing several cytokines in parallel are thought to play a crucial role in protection against different infections. To characterize T cell cytokine patterns associated with disease and protection in Mycobacterium tuberculosis infection we determined the expression of IFNgamma, IL-2, TNFalpha, and GM-CSF in T cell subpopulations from children with tuberculosis (TB) and healthy latently M. tuberculosis-infected children (LTBI) after short-term in vitro restimulation. We identified CD4(+) effector memory T cells (T(EM)) as the major source of all measured cytokines after antigen-specific restimulation. T(EM) from children with TB expressed higher proportions of IFNgamma, TNFalpha, and IL-2 after Mtb restimulation while no differences were detected for GM-CSF between both study groups. GM-CSF secretion strongly depended on antigen-specific stimulation. Analyses of multiple cytokine patterns revealed that the majority of GM-CSF-positive M. tuberculosis-specific memory T cells coexpressed IFNgamma and TNFalpha therefore showing a characteristic feature of multifunctional T cells. We conclude that children with active TB possess higher proportions of IFNgamma-, TNFalpha-, and/or IL-2-positive T(EM) than children with LTBI while GM-CSF coexpression reveals a novel subpopulation within CD4(+) memory T cells not increased in children with active TB.
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http://dx.doi.org/10.1016/j.cyto.2008.05.002DOI Listing
August 2008

Proposed management of childhood tuberculosis in low-incidence countries.

Eur J Pediatr 2008 Aug 10;167(8):927-38. Epub 2008 May 10.

Department of Pediatric Pulmonology and Allergy, Chest Clinic Heckeshorn, Helios Klinikum Emil von Behring, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany.

The incidence of childhood tuberculosis continues to decline in central Europe, but due to migration from high incidence countries paediatricians will still be confronted with it. The management of childhood tuberculosis in low-incidence, high-income countries differs from most high-incidence countries. The primary measures for preventing the transmission of tuberculosis to children are the detection of adult source cases, detection of latent TB infection (LTBI) in children by history, tuberculin skin testing and, if necessary and recommended, interferon-gamma release assays. Children with LTBI should receive preventive therapy. The inclusion of tuberculosis in the differential diagnosis of unclear pulmonary and extrapulmonary disease remains important, and tuberculosis has to be managed according to international standards.
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http://dx.doi.org/10.1007/s00431-008-0730-1DOI Listing
August 2008

Clonal expansion of CD8+ effector T cells in childhood tuberculosis.

J Immunol 2007 Jul;179(2):1331-9

Department of Immunology, Max Planck Institute for Infection Biology, University Hospital Charité, Berlin, Germany.

The role of CD8(+) T cells in human tuberculosis (TB) remains elusive. We analyzed the T cell repertoire and phenotype in 1) children with active TB (< or =4 years), 2) healthy latently Mycobacterium tuberculosis-infected children, and 3) noninfected age-matched (tuberculin skin test-negative) controls. Ex vivo phenotyping of T cell subpopulations by flow cytometry revealed a significant increase in the proportion of CD8(+)CD45RO(-)CD62L(-)CD28(-)CD27(-) effector T cells (T(EF)) in the peripheral blood of children with active TB (22.1 vs 9.5% in latently M. tuberculosis-infected children, vs 8.5% in tuberculin skin test-negative controls). Analyses of TCR variable beta-chains revealed markedly skewed repertoires in CD8(+) T(EF) and effector memory T cells. Expansions were restricted to single TCR variable beta-chains in individual donors indicating clonal growth. CDR3 spectratyping and DNA sequencing verified clonal expansion as the cause for CD8(+) effector T cell enrichment in individual TB patients. The most prominent enrichment of highly similar T(EF) clones (>70% of CD8(+) T(EF)) was found in two children with active severe TB. Therefore, clonal expansion of CD8(+) T(EF) occurs in childhood TB with potential impact on course and severity of disease.
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http://dx.doi.org/10.4049/jimmunol.179.2.1331DOI Listing
July 2007
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