Interferon-g-Inducible Protein 10 for Diagnosis of Tuberculosis in Children

Stefani Candra Firmanti, Rina Triasih, Tri Wibawa, Sofia Mubarika Haryana


BACKGROUND: The diagnosis of tuberculosis (TB) in children is challenging by the absence of a practical gold standard. Interferon (IFN)-ginducible protein 10 (IP-10) is a chemokine that may serve as the leading candidate marker in child TB diagnosis. The aim of this study is to assess the diagnostic value of IP-10 in the diagnosis of TB in children.

METHODS: We recruited eligible symptomatic and asymptomatic children aged <15 years actively by contact investigation and passively from inpatient and outpatient clinics in two hospitals, in Yogyakarta, Indonesia. We conducted clinical examination and chest X-ray in all eligible children. Sputum smear and the rapid molecular TB test were performed in children with TB symptoms. All participants underwent blood sampling for IFN-g Release Assay and IP-10 test.

RESULTS: A total of 79 children were recruited to this study. Twelve children were with TB disease, 16 with latent TB infection (LTBI), 40 were TB-exposed only and 11 were non-TB. Children with evidence of TB infection either with TB disease or LTBI had higher levels of antigen-stimulated IP-10 compared to non-infected children, both TB exposed only and non-TB (p=0.000). A cut-off 408.74 pg/mL for antigen-stimulated IP-10 showed high diagnostic accuracy for diagnosis of TB infection (AUC: 0.97, 95% CI: 0.92-1.00, sensitivity: 92.3%, and specificity: 91.9%). However, the stimulated levels of IP-10 between children with TB disease and LTBI were not significantly different (p=0.268).

CONCLUSION: IP-10 performed well to diagnose TB infection in children. However, it cannot be used to differentiate TB infection from TB disease.

KEYWORDS: IFN-g, IP-10, latent TB, active TB, children

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Oliwa JN, Karumbi JM, Marais BJ, Madhi SA, Graham SM. Tuberculosis as a cause or comorbidity of childhood pneumonia in tuberculosis-endemic areas: a systematic review. Lancet Respir Med. 2015; 3: 235-43, CrossRef.

World Health Organization (WHO). Global tuberculosis report 2017. Geneva: WHO; 2017, article.

Dunn JJ, Starke JR, Revell PA. Laboratory diagnosis of Mycobacterium tuberculosis infection and disease in children. J Clin Microbiol. 2016; 54: 1434-41, CrossRef.

La Manna MP, Orlando V, Li Donni P, Sireci G, Di Carlo P, Cascio A, et al. Identification of plasma biomarkers for discrimination between tuberculosis infection/disease and pulmonary non tuberculosis disease. PLOS ONE. 2018; 13: e0192664, CrossRef.

Holm LL, Rose MV, Kimaro G, Bygbjerg IC, Mfinanga SG, Ravn P, et al. A comparison of Interferon-γ and IP-10 for the diagnosis of tuberculosis. Pediatrics. 2014; 134: e1568-75, CrossRef.

Chegou NN, Detjen AK, Thiart L, Walters E, Mandalakas AM, Hesseling AC, et al. Utility of host markers detected in quantiferon supernatants for the diagnosis of tuberculosis in children in a highburden setting. PLoS ONE. 2013; 8: e64226, CrossRef.

Ruhwald M, Aabye MG, Ravn P. IP-10 release assays in the diagnosis of tuberculosis infection: current status and future directions. Expert Rev Mol Diagn. 2012; 12: 175-87, CrossRef.

Aabye MG, Latorre I, Diaz J, Maldonado J, Mialdea I, Eugen-Olsen J. Dried plasma spots in the diagnosis of tuberculosis: IP-10 release assay on filter paper. Eur Respir J. 2013; 42: 495-503, CrossRef.

Jenum S, Dhanasekaran S, Ritz C, Macaden R, Doherty TM, Grewal HMS. Added value of IP-10 as a read-out of Mycobacterium tuberculosis: Specific immunity in young children. Pediatr Infect Dis J. 2016; 35: 1336-8, CrossRef.

Wang S, Li Y, Shen Y, Wu J, Gao Y, Zhang S, et al. Screening and identification of a six-cytokine biosignature for detecting TB infection and discriminating active from latent TB. J Transl Med. 2018; 16: 2016, CrossRef.

Latorre I, Díaz J, Mialdea I, Serra-Vidal M, Altet N, Prat C, et al. IP-10 is an accurate biomarker for the diagnosis of tuberculosis in children. J Infect. 2014; 69: 590-9, CrossRef.

Armand M, Chhor V, de Lauzanne A, Guérin-El Khourouj V, Pédron B, Jeljeli M, et al. Cytokine responses to quantiferon peptides in pediatric tuberculosis: A pilot study. J Infect . 2014; 68: 62-70, CrossRef.

Alsleben N, Ruhwald M, Rüssmann H, Marx FM, Wahn U, Magdorf K. Interferon-gamma inducible protein 10 as a biomarker for active tuberculosis and latent tuberculosis infection in children: A case–control study. Scand J Infect Dis. 2012; 44: 256-62, CrossRef.

Lighter J, Rigaud M, Huie M, Peng CH, Pollack H. Chemokine IP-10: an adjunct marker for latent tuberculosis infection in children. Int J Tuberc Lung Dis. 2009; 13: 731-6, PMID.

Ruhwald M, Petersen J, Kofoed K, Nakaoka H, Cuevas LE, Lawson L, et al. Improving T-Cell assays for the diagnosis of latent TB infection: Potential of a diagnostic test based on IP-10. PLoS ONE. 2008; 3(8): e2858, CrossRef.

Petrucci R, Amer NA, Gurgel RQ, Sherchand JB, Doria L, Lama C, et al. Interferon gamma, interferon-gamma-induced-protein 10, and tuberculin responses of children at high risk of tuberculosis infection. Pediatr Infect Dis J. 2008; 27: 1073-7, CrossRef.

Biraro IA, Kimuda S, Egesa M, Cose S, Webb EL, Joloba M, et al. The use of interferon gamma inducible protein 10 as a potential biomarker in the diagnosis of latent tuberculosis infection in Uganda. PLOS ONE. 2016; 11: e0146098, CrossRef.

Syed Ahamed Kabeer B, Paramasivam P, Raja A. Interferon gamma and interferon gamma inducible protein-10 in detecting tuberculosis infection. J Infect. 2012; 64: 573-9, CrossRef.

Goletti D, Raja A, Syed Ahamed Kabeer B, Rodrigues C, Sodha A, Carrara S, et al. Is IP-10 an accurate marker for detecting M. tuberculosis-specific response in HIV-infected persons? PLoS ONE. 2010: 5(9): e12577, CrossRef.

Marais BJ. Well defined symptoms are of value in the diagnosis of childhood pulmonary tuberculosis. Arch Dis Child. 2005; 90: 1162-5, CrossRef.

World Health Organization (WHO). WHO child growth standards: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age; methods and development. Geneva: WHO; 2006, article.

Aabye MG, Eugen-Olsen J, Werlinrud AM, Holm LL, Tuuminen T, Ravn P, et al. A simple method to quantitate IP-10 in dried blood and plasma spots. PLoS ONE. 2012; 7: e39228, CrossRef.

Slight SR, Khader SA. Chemokines shape the immune responses to tuberculosis. Cytokine Growth Factor Rev. 2013; 24: 105-13, CrossRef.

Chegou NN, Heyckendorf J, Walzl G, Lange C, Ruhwald M. Beyond the IFN-g horizon: biomarkers for immunodiagnosis of infection with Mycobacterium tuberculosis. Eur Respir J. 2014; 43: 1472-86, CrossRef.

Syed Ahamed Kabeer B, Sikhamani R, Raja A. Comparison of interferon gamma–inducible protein-10 and interferon gamma–based QuantiFERON TB Gold assays with tuberculin skin test in HIV-infected subjects. Diagn Microbiol Infect Dis. 2011; 71: 236-43, CrossRef.

Whittaker E, Gordon A, Kampmann B. Is IP-10 a better biomarker for active and latent tuberculosis in children than IFNγ? PLoS ONE. 2008; 3: e3901, CrossRef.

Guo SJ, Jia LQ, Hu QJ, Long HY, Pang CS, Wen FQ. Diagnostic accuracy of interferon gamma-induced protein 10 for tuberculosis: a meta-analysis. Int J Clin Exp Med. 2014; 7(1): 93-100, PMID.

Firoozeh A, Khaledi A, Rezaee SA, Ghazvini K. Diagnostic accuracy of IP-10 biomarker for Mycobacterium tuberculosis: A systematic review. Der Pharmacia Lettre. 2016; 8: 294-8, article.

Venturini E, Remaschi G, Berti E, Montagnani C, Galli L, de Martino M, et al. What steps do we need to take to improve diagnosis of tuberculosis in children? Expert Rev Anti Infect Ther. 2015; 13: 907-22, CrossRef.

Frahm M, Goswami ND, Owzar K, Hecker E, Mosher A, Cadogan E, et al. Discriminating between latent and active tuberculosis with multiple biomarker responses. Tuberculosis. 2011; 91: 250-6, CrossRef.

Yao X, Liu Y, Liu Y, Liu W, Ye Z, Zheng C, et al. Multiplex analysis of plasma cytokines/chemokines showing different immune responses in active TB patients, latent TB infection and healthy participants. Tuberculosis. 2017; 107: 88-94, CrossRef.

You E, Kim MH, Lee WI, Kang SY. Evaluation of IL-2, IL-10, IL-17 and IP-10 as potent discriminative markers for active tuberculosis among pulmonary tuberculosis suspects. Tuberculosis. 2016; 99: 100-8, CrossRef.

Jeong YH, Hur YG, Lee H, Kim S, Cho JE, Chang J, et al. Discrimination between active and latent tuberculosis based on ratio of antigen-specific to mitogen-induced IP-10 production. J Clin Microbiol. 2015; 53: 504-10, CrossRef.

Liu M, Guo S, Hibbert JM, Jain V, Singh N, Wilson NO, et al. CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev. 2011; 22: 121-30, CrossRef.

Blauenfeldt T, Petrone L, del Nonno F, Baiocchini A, Falasca L, Chiacchio T, et al. Interplay of DDP4 and IP-10 as a Potential Mechanism for Cell Recruitment to Tuberculosis Lesions. Front Immunol. 2018; 9: 1456, CrossRef.

Amanatidou V, Critselis E, Trochoutsou A, Soldatou A, Benetatou K, Spyridis N, et al. Interferon gamma inducible protein-10 in the diagnosis of paediatric tuberculosis infection in a low TB incidence country. Int J Tuberc Lung Dis. 2015; 19: 1463-9, CrossRef.

Petrone L, Cannas A, Aloi F, Nsubuga M, Serumkuma J, Nazziwa RA, et al. Blood or urine IP-10 cannot discriminate between active tuberculosis and respiratory diseases different from tuberculosis in children. BioMed Res Int. 2015; 2015: 589471, CrossRef.

Tebruegge M, Dutta B, Donath S, Ritz N, Forbes B, Camacho-Badilla K, et al. Mycobacteria-specific cytokine responses detect tuberculosis infection and distinguish latent from active tuberculosis. Am J Respir Crit Care Med. 2015; 192: 485-99, CrossRef.

Clifford V. Improving diagnostic tests for tuberculosis: mycobacterial antigen-stimulated cytokine biomarkers for diagnosis and monitoring therapy [Dissertation]. Melbourne: The University of Melbourne; 2017, article.

Tuuminen T, Salo E, Kotilainen H, Ruhwald M. Evaluation of the filter paper IP-10 tests in school children after exposure to tuberculosis: a prospective cohort study with a 4-year follow-up. BMJ Open. 2012; 2: e001751, CrossRef.


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