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Mycobacterium tuberculosis-specific cytokine biomarkers for the diagnosis of childhood TB in a TB-endemic setting.

ABSTRACT: The tuberculin skin test and interferon-gamma release assays have limitations in diagnosing tuberculosis (TB), particularly in children. This study investigated the performance of candidate M. tuberculosis-specific cytokine biomarkers for TB in children in a TB-endemic setting. A total of 237 children with a household contact with smear-positive pulmonary TB were recruited. Importantly, a group of children with illnesses other than TB (sick controls) was included to assess specificity. Median IFN-?, IL-1ra, IL-2, IL-13, IP-10, MIP-1? and TNF-? responses were significantly higher in children with active TB and latent TB infection (LTBI) than in both healthy and sick control children. Three of these cytokines - IL-2, IL-13 and IP-10 - showed better performance characteristics than IFN-?, with IL-2 achieving positive and negative predictive values of 97.7% and 90.7%, respectively. Furthermore, IL-1ra and TNF-? responses differed significantly between active TB and LTBI cases, suggesting that they may be stage-specific biomarkers. Our data indicate that incorporating these biomarkers into future blood-based TB assays could result in substantial performance gains.

SUBMITTER: Sudbury EL

PROVIDER: S-EPMC6830137 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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<i>Mycobacterium tuberculosis</i>-specific cytokine biomarkers for the diagnosis of childhood TB in a TB-endemic setting.

Sudbury Eva L EL Otero Larissa L Tebruegge Marc M Messina Nicole L NL Seas Carlos C Montes Martin M Rìos Julia J Germano Susie S Gardiner Kaya K Clifford Vanessa V Gotuzzo Eduardo E Curtis Nigel N

Journal of clinical tuberculosis and other mycobacterial diseases 20190425

The tuberculin skin test and interferon-gamma release assays have limitations in diagnosing tuberculosis (TB), particularly in children. This study investigated the performance of candidate <i>M. tuberculosis</i>-specific cytokine biomarkers for TB in children in a TB-endemic setting. A total of 237 children with a household contact with smear-positive pulmonary TB were recruited. Importantly, a group of children with illnesses other than TB (sick controls) was included to assess specificity. Me ...[more]

PMID: 31720428

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Project description:IntroductionAs studies of biomarkers of tuberculosis (TB) disease provide hope for a simple, point-of-care test, we aimed to synthesize evidence on biomarkers for diagnosis of TB in children and compare their accuracy to published target product profiles (TPP).MethodsWe conducted a systematic review of biomarkers for diagnosis of pulmonary TB in exclusively paediatric populations, defined as age less than 15 years. PubMed, EMBASE and Web of Science were searched for relevant publications from January 1, 2000 to November 27, 2017. Studies using mixed adult and paediatric populations or reporting biomarkers for extrapulmonary TB were excluded. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) framework. No meta-analysis was done because the published childhood TB biomarkers studies were mostly early stage studies and highly heterogeneous.ResultsThe 29 studies included in this systematic review comprise 20 case-control studies, six cohort studies and three cross-sectional studies. These studies reported diverse and heterogeneous forms of biomarkers requiring different types of clinical specimen and laboratory assays. Majority of the studies (27/29 [93%]) either did not meet the criteria in at least one of the four domains of the QUADAS-2 reporting framework or the assessment was unclear. However, the diagnostic performance of biomarkers reported in 22 studies met one or both of the WHO-recommended minimal targets of 66% sensitivity and 98% specificity for a new diagnostic test for TB disease in children, and/or 90% sensitivity and 70% specificity for a triage test.ConclusionWe found that majority of the biomarkers for diagnosis of TB in children are promising but will need further refining and optimization to improve their performances. As new data are emerging, stronger emphasis should be placed on improving the design, quality and general reporting of future studies investigating TB biomarkers in children.

Project description:BackgroundNew diagnosis tests are urgently needed to address the global tuberculosis (TB) burden and to improve control programs especially in resource-limited settings. An effective in vitro diagnostic of TB based on serological methods would be regarded as an attractive progress because immunoassays are simple, rapid, inexpensive, and may offer the possibility to detect cases missed by standard sputum smear microscopy. However, currently available serology tests for TB are highly variable in sensitivity and specificity. Lipolytic enzymes have recently emerged as key factors in lipid metabolization during dormancy and/or exit of the non-replicating growth phase, a prerequisite step of TB reactivation. The focus of this study was to analyze and compare the potential of four Mycobacterium tuberculosis lipolytic enzymes (LipY, Rv0183, Rv1984c and Rv3452) as new markers in the serodiagnosis of active TB.MethodsRecombinant proteins were produced and used in optimized ELISA aimed to detect IgG and IgM serum antibodies against the four lipolytic enzymes. The capacity of the assays to identify infection was evaluated in patients with either active TB or latent TB and compared with two distinct control groups consisting of BCG-vaccinated blood donors and hospitalized non-TB individuals.ResultsA robust humoral response was detected in patients with active TB whereas antibodies against lipolytic enzymes were infrequently detected in either uninfected groups or in subjects with latent infection. High specifity levels, ranging from 93.9% to 97.5%, were obtained for all four antigens with sensitivity values ranging from 73.4% to 90.5%, with Rv3452 displaying the highest performances. Patients with active TB usually exhibited strong IgG responses but poor IgM responses.ConclusionThese results clearly indicate that the lipolytic enzymes tested are strongly immunogenic allowing to distinguish active from latent TB infections. They appear as potent biomarkers providing high sensitivity and specificity levels for the immunodiagnosis of active TB.

Dataset Information

Mycobacterium tuberculosis-specific cytokine biomarkers for the diagnosis of childhood TB in a TB-endemic setting.

Publications

<i>Mycobacterium tuberculosis</i>-specific cytokine biomarkers for the diagnosis of childhood TB in a TB-endemic setting.

Similar Datasets

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