Abstract
Background:
Distinguishing latent tuberculosis (LTB) from tuberculosis (TB) disease may be challenging in children. Here, we analyzed cytokine profiles that can distinguish the two infection stages in a nonendemic country (France).
Methods:
Immunocompetent children with LTB (n = 6) or TB disease (n = 8) (median age: 6.2 and 5.7 years, respectively) were analyzed. Four young uninfected children were included as controls. A Luminex assay evaluated cytokine responses to Mycobacterium tuberculosis antigens.
Results:
Poor interleukin-4 (IL-4) and IL-10 responses precluded analysis of these cytokines. Interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-2, and T-helper type 1 (Th1) cytokines and IL-5, IL-13, T-helper type 2 (Th2) cytokines were simultaneously induced by antigens in 14/14 infected but 0/4 uninfected children. Th1 cytokine levels were similar in LTB and TB disease: IFN-γ: 12,254 and 10,495 pg/ml; IL-2: 2,097 and 1,869 pg/ml; and TNF-α: 1,020 and 2,875 pg/ml, respectively. Th2 cytokine levels were similar and even higher in LTB than in TB disease: IL-5: 23 and 10 pg/ml; IL-13: 284 and 109 pg/ml, respectively. Positive correlation of cytokine levels, whether Th1 or Th2, was observed. Higher (P = 0.008) TNF-α/IL-2 ratios distinguished 6/8 active TB disease cases from 6/6 LTB cases.
Conclusion:
TNF-α/IL-2 ratio may discriminate TB disease from LTB in immunocompetent children. Larger studies in TB endemic settings must verify these results.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
WHO report. Global tuberculosis control 2011. WHO, 2011. (http://www.who.int/tb/publications/global_report/2011/gtbr11_full.pdf.)
Feja K, Saiman L . Tuberculosis in children. Clin Chest Med 2005;26:295–312, vii.
Stenger S . Immunological control of tuberculosis: role of tumour necrosis factor and more. Ann Rheum Dis 2005;64:Suppl 4:iv24–8.
Ferrara G, Losi M, D’Amico R, et al. Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study. Lancet 2006;367:1328–34.
van de Vosse E, Hoeve MA, Ottenhoff TH . Human genetics of intracellular infectious diseases: molecular and cellular immunity against mycobacteria and salmonellae. Lancet Infect Dis 2004;4:739–49.
Rook GA . Th2 cytokines in susceptibility to tuberculosis. Curr Mol Med 2007;7:327–37.
Lalor MK, Smith SG, Floyd S, et al. Complex cytokine profiles induced by BCG vaccination in UK infants. Vaccine 2010;28:1635–41.
Wilkinson KA, Wilkinson RJ . Polyfunctional T cells in human tuberculosis. Eur J Immunol 2010;40:2139–42.
Harari A, Rozot V, Enders FB, et al. Dominant TNF-a+ Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease. Nat Med 2011;17:372–6.
Soares AP, Scriba TJ, Joseph S, et al. Bacillus Calmette-Guérin vaccination of human newborns induces T cells with complex cytokine and phenotypic profiles. J Immunol 2008;180:3569–77.
Jasmer RM, Nahid P, Hopewell PC . Clinical practice. Latent tuberculosis infection. N Engl J Med 2002;347:1860–6.
Debord C, De Lauzanne A, Gourgouillon N, et al. Interferon-gamma release assay performance for diagnosing tuberculosis disease in 0- to 5-year-old children. Pediatr Infect Dis J 2011;30:995–7.
Al-Attiyah R, Madi N, El-Shamy AS, Wiker H, Andersen P, Mustafa A . Cytokine profiles in tuberculosis patients and healthy subjects in response to complex and single antigens of Mycobacterium tuberculosis. FEMS Immunol Med Microbiol 2006;47:254–61.
Ottenhoff TH, Verreck FA, Hoeve MA, van de Vosse E . Control of human host immunity to mycobacteria. Tuberculosis (Edinb) 2005;85:53–64.
Turner J, Gonzalez-Juarrero M, Ellis DL, et al. In vivo IL-10 production reactivates chronic pulmonary tuberculosis in C57BL/6 mice. J Immunol 2002;169:6343–51.
Lin PL, Flynn JL . Understanding latent tuberculosis: a moving target. J Immunol 2010;185:15–22.
Lighter-Fisher J, Peng CH, Tse DB . Cytokine responses to QuantiFERON® peptides, purified protein derivative and recombinant ESAT-6 in children with tuberculosis. Int J Tuberc Lung Dis 2010;14:1548–55.
Chegou NN, Black GF, Kidd M, van Helden PD, Walzl G . Host markers in QuantiFERON supernatants differentiate active TB from latent TB infection: preliminary report. BMC Pulm Med 2009;9:21.
Sutherland JS, Adetifa IM, Hill PC, Adegbola RA, Ota MO . Pattern and diversity of cytokine production differentiates between Myco-bacterium tuberculosis infection and disease. Eur J Immunol 2009;39:723–9.
Biselli R, Mariotti S, Sargentini V, et al. Detection of interleukin-2 in addition to interferon-gamma discriminates active tuberculosis patients, latently infected individuals, and controls. Clin Microbiol Infect 2010;16:1282–4.
Pantaleo G, Harari A . Functional signatures in antiviral T-cell immunity for monitoring virus-associated diseases. Nat Rev Immunol 2006;6:417–23.
Team RDC . A Language and Environment for Statistical Computing. R Fundation for Statistical Computing, Vienna, Austria, 2011. (http://www.r-project.org/links.html).
Tobias J, Sander O, Beerenwinkel N, Lengauer RT. 2009. ROCR: Visualizing the performance of scoring classifiers. R package version 0.0-4. (http://CRAN.R-project.org/package=ROCR.).
Acknowledgements
We thank Guylaine Boiry, Anne-Marie Courchinoux, Pricilia Egremonte, Elodie Geneletti, and Judith Tholle for excellent technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gourgouillon, N., de Lauzanne, A., Cottart, CH. et al. TNF-α/IL-2 ratio discriminates latent from active tuberculosis in immunocompetent children: a pilot study. Pediatr Res 72, 370–374 (2012). https://doi.org/10.1038/pr.2012.89
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/pr.2012.89
This article is cited by
-
Cytokine and Chemokine Concentrations as Biomarkers of Feline Mycobacteriosis
Scientific Reports (2018)
-
Novel T-Cell Assays for the Discrimination of Active and Latent Tuberculosis Infection: The Diagnostic Value of PPE Family
Molecular Diagnosis & Therapy (2015)
-
Diagnostic accuracy of IL-2 for the diagnosis of latent tuberculosis: a systematic review and meta-analysis
European Journal of Clinical Microbiology & Infectious Diseases (2014)
