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

Eva L Sudbury; Larissa Otero; Marc Tebruegge; Nicole L Messina; Carlos Seas; Martin Montes; Julia Rìos; Susie Germano; Kaya Gardiner; Vanessa Clifford; Eduardo Gotuzzo; Nigel Curtis

doi:10.1016/j.jctube.2019.100102

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

J Clin Tuberc Other Mycobact Dis. 2019 Apr 25:16:100102. doi: 10.1016/j.jctube.2019.100102. eCollection 2019 Aug.

Authors

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 Rìos⁷, Susie Germano², Kaya Gardiner², Vanessa Clifford^{1

2

8}, Eduardo Gotuzzo^{3

4}, Nigel Curtis^{1

2

8}

Affiliations

¹ Department of Paediatrics, The University of Melbourne, Parkville, Australia.
² Murdoch Children's Research Institute, Parkville, Australia.
³ Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.
⁴ Facultad de Medicina, Universidad Peruana Cayetano Heredia, Lima, Peru.
⁵ Department of Infection, Immunity & Inflammation, Great Ormond Street Institute of Child Health, University College London, London, UK.
⁶ Department of Paediatric Infectious Diseases & Immunology, Evelina London Children's Hospital, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
⁷ Dirección de Prevención y Control de Tuberculosis, Ministerio de Salud, Lima, Peru.
⁸ Infectious Diseases Unit, The Royal Children's Hospital Melbourne, Parkville, Australia.

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.