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. 2019 Apr 25:16:100102.
doi: 10.1016/j.jctube.2019.100102. eCollection 2019 Aug.

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

Eva L Sudbury  1   2 , Larissa Otero  3   4 , Marc Tebruegge  1   5   6 , Nicole L Messina  1   2 , Carlos Seas  3   4 , Martin Montes  3   4 , Julia Rìos  7 , Susie Germano  2 , Kaya Gardiner  2 , Vanessa Clifford  1   2   8 , Eduardo Gotuzzo  3   4 , Nigel Curtis  1   2   8
Affiliations

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

Eva L Sudbury et al. J Clin Tuberc Other Mycobact Dis. .

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-ɣ, IL-1ra, IL-2, IL-13, IP-10, MIP-1β and TNF-α 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-ɣ, with IL-2 achieving positive and negative predictive values of 97.7% and 90.7%, respectively. Furthermore, IL-1ra and TNF-α 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.

Keywords: Cytokine biomarkers; Interferon-gamma release assay; TB-endemic; Tuberculin skin test; Tuberculosis.

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Figures

Fig 1
Fig. 1
Flow diagram outlining the categorisation of study participants.
Fig 2
Fig. 2
IGRA results in relation to TST induration size in study participants.
Fig 3
Fig. 3
Mycobacterial-specific cytokine responses (background-corrected) in participants with probable active TB and LTBI, and sick controls and healthy controls. Tukey whiskers denote the highest and lowest values, excluding outliers.
Fig 4
Fig. 4
Receiver operating characteristic curves for IFN-ɣ, IL-1ra, IL-2, IL-13, IP-10, MIP-1β and TNF-α responses for identifying TB infection. Case values comprised background-corrected cytokine concentrations in participants with LTBI or probable active TB (TB-infected group); control values comprised cytokine concentrations in uninfected participants (sick controls and healthy controls). AUC = area under the curve.
Fig 5
Fig. 5
Receiver operating characteristic curves for IL-1ra and TNF-α responses for the distinction between LTBI and probable active TB. Case values comprised background-corrected cytokine concentrations in participants with probable active TB; control values comprised cytokine concentrations in participants with LTBI. AUC = area under the curve.
See this image and copyright information in PMC

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