A Cohort Study: Urine Interferon Gamma-Induced Protein 10 As A Non-Sputum Biomarker in Diagnostic and Treatment Monitoring in Patients with Active Pulmonary Tuberculosis
DOI:
https://doi.org/10.52783/jns.v14.2047Keywords:
biomarker, pulmonary tuberculosis, diagnosis, monitoring, urine IP-10Abstract
There are still limitations in the diagnosis of tuberculosis (TB), and developing monitoring tools to predict treatment outcomes for TB patients is important. Sputum collection is not only challenging but also has low sensitivity when used as a diagnostic specimen. Interferon gamma-inducible protein 10 (IP-10) is a potential biomarker of diagnosis and treatment response in tuberculosis. In this study, we measured IP-10 levels in urine samples taken at diagnosis, following the intensive treatment period, and post-treatment from patients with active tuberculosis. This was a comparative observational cohort study on new active pulmonary TB patients who were >18 years old at the TB Clinic of Dr. Hasan Sadikin General Hospital Bandung. IP-10 was measured using enzyme-linked immunosorbent assays in urine samples collected from 39 patients with active TB (26 patients with drug-resistant and 13 patients with drug-sensitive tuberculosis) and 34 healthy adults (73 total individuals). Thirty-nine patients who met the inclusion criteria were followed up until completion of TB treatment. There was a decrease in urine ip-10 levels in both the DR-TB vs DS-TB groups at diagnosis, after the intensive phase, and after treatment. (16.1 vs 13.3 pg/mL; 11.7 vs 8.4 pg/mL; 3.6 vs 3.2 pg/mL). IP-10 in urine has good accuracy with an AUC value of 0.847 in detecting Active TB with a cutoff value of 8.3 pg/mL, sensitivity of 97.4%, specificity of 61.8%, PPV 74.5%, NPV 95.5%, LR+ 2.55, and LR- 0.04. Urine IP-10 levels in active pulmonary TB patients decreased significantly after intensive phase and at the end of treatment (p<0.001), and urine IP-10 levels have the potential as a non-sputum-based marker for treatment-related TB monitoring.
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Global tuberculosis report 2023. Geneva: World Health Organization; 2023. https://www.who.int/teams/global-tuberculosis-programme/tb-reports.
Kim SY, Kim J, Kim DR, Kang YA, Bong S, Lee J, Kim S, Lee NS, Sim B, Cho SN, et al: Urine IP-10 as a biomarker of therapeutic response in patients with active pulmonary tuberculosis. BMC Infect Dis 18: 240, 2018. https://doi.org/10.1186/s12879-018-3144-3 PMID:29843631
Qiu X, Tang Y, Zou R, Zeng Y, Yue Y, Li W, Qu Y and Mu D: Diagnostic accuracy of interferon-gamma-induced protein 10 for differentiating active tuberculosis from latent tuberculosis: A meta-analysis. Sci Rep 9: 11408, 2019. https://doi.org/10.1038/s41598-019-47923-w PMID:31388072
Cannas A, Calvo L, Chiacchio T, Cuzzi G, Vanini V, Lauria FN, Pucci L, Girardi E and Goletti D: IP-10 detection in urine is associated with lung diseases. BMC Infect Dis 10: 333, 2010. https://doi.org/10.1186/1471-2334-10-333 PMID:21092156
van Crevel R, Ottenhoff TH and van der Meer JW: Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev 15: 294-309, 2002. https://doi.org/10.1128/CMR.15.2.294-309.2002 PMID:11932234
Kleinnijenhuis J, Oosting M, Joosten LA, Netea MG and Van Crevel R: Innate immune recognition of Mycobacterium tuberculosis. Clin Dev Immunol 2011: 405310, 2011. https://doi.org/10.1155/2011/405310 PMID:21603213
Yang J, Zhang L, Qiao W, Luo Y. Mycobacterium tuberculosis: Pathogenesis and therapeutic targets. MedComm (2020). 2023 Sep 4;4(5):e353. https://doi.org/10.1002/mco2.353. PMID: 37674971; PMCID: PMC10477518.
Ramakrishnan L: Revisiting the role of the granuloma in tuberculosis. Nat Rev Immunol 12: 352-366, 2012. https://doi.org/10.1038/nri3211 PMID:22517424
Marino S, Myers A, Flynn JL and Kirschner DE: TNF and IL-10 are major factors in modulation of the phagocytic cell environment in lung and lymph node in tuberculosis: A next-generation two-compartmental model. J Theor Biol 265: 586-598, 2010. https://doi.org/10.1016/j.jtbi.2010.05.012 PMID:20510249
Schluger NW: The pathogenesis of tuberculosis: The first one hundred (and twenty-three) years. Am J Respir Cell Mol Biol 32: 251-256, 2005. https://doi.org/10.1165/rcmb.F293 PMID:15778414
Lee JH, Kim B, Jin WJ, Kim HH, Ha H and Lee ZH: Pathogenic roles of CXCL10 signaling through CXCR3 and TLR4 in macrophages and T cells: Relevance for arthritis. Arthritis Res Ther 19: 163, 2017. https://doi.org/10.1186/s13075-017-1353-6 PMID:28724396
Liu M, Guo S, Hibbert JM, Jain V, Singh N, Wilson NO and Stiles JK: CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev 22: 121-130, 2011. https://doi.org/10.1016/j.cytogfr.2011.06.001 PMID:21802343
Petrone L, Cannas A, Aloi F, Nsubuga M, Sserumkuma J, Nazziwa RA, Jugheli L, Lukindo T, Girardi E, Reither K, et al: Blood or Urine IP-10 Cannot Discriminate between Active Tuberculosis and Respiratory Diseases Different from Tuberculosis in Children. BioMed Res Int 2015: 589471, 2015. https://doi.org/10.1155/2015/589471 PMID:26346028
El-emiry FA, Attia GA, Ahmad AY and Sakr BM: Diagnostic value of inducible protein-10 in pulmonary tuberculosis. Egypt J Chest Dis Tuberc 65: 19-225, 2016. https://doi.org/10.1016/j.ejcdt.2015.08.012.
Stefanescu S, Cocoș R, Turcu-Stiolica A, Shelby ES, Matei M, Subtirelu MS, Meca AD, Stanciulescu EC, Popescu SO, Biciusca V, et al: Prediction of Treatment Outcome with Inflammatory Biomarkers after 2 Months of Therapy in Pulmonary Tuberculosis Patients: Preliminary Results. Pathogens 10: 789, 2021. https://doi.org/10.3390/pathogens10070789 PMID:34206598
Syed Ahamed Kabeer B, Raman B, Thomas A, Perumal V and Raja A: Role of QuantiFERON-TB gold, interferon gamma inducible protein-10 and tuberculin skin test in active tuberculosis diagnosis. PLoS One 5: e9051, 2010. https://doi.org/10.1371/journal.pone.0009051 PMID:20140219
Frahm M, Goswami ND, Owzar K, Hecker E, Mosher A, Cadogan E, Nahid P, Ferrari G and Stout JE: Discriminating between latent and active tuberculosis with multiple biomarker responses. Tuberculosis (Edinb) 91: 250-256, 2011. https://doi.org/10.1016/j.tube.2011.02.006 PMID:21393062
Essone PN, Chegou NN, Loxton AG, Stanley K, Kriel M, van der Spuy G, Franken KL, Ottenhoff TH and Walzl G: Host cytokine responses induced after overnight stimulation with novel M. tuberculosis infection phase-dependent antigens show promise as diagnostic candidates for TB disease. PLoS One 9: e102584, 2014. https://doi.org/10.1371/journal.pone.0102584 PMID:25025278
Borgström E, Andersen P, Atterfelt F, Julander I, Källenius G, Maeurer M, Rosenkrands I, Widfeldt M, Bruchfeld J and Gaines H: Immune responses to ESAT-6 and CFP-10 by FASCIA and multiplex technology for diagnosis of M. tuberculosis infection; IP-10 is a promising marker. PLoS One 7: e43438, 2012. https://doi.org/10.1371/journal.pone.0043438 PMID:23144772
Ruhwald M, Dominguez J, Latorre I, Losi M, Richeldi L, Pasticci MB, Mazzolla R, Goletti D, Butera O, Bruchfeld J, et al; TBNET: A multicentre evaluation of the accuracy and performance of IP-10 for the diagnosis of infection with M. tuberculosis. Tuberculosis (Edinb) 91: 260-267, 2011. https://doi.org/10.1016/j.tube.2011.01.001 PMID:21459676
Goletti D, Raja A, Ahamed Kabeer BS, Rodrigues C, Sodha A, Butera O, Carrara S, Vernet G, Longuet C, Ippolito G, et al: IFN-gamma, but not IP-10, MCP-2 or IL-2 response to RD1 selected peptides associates to active tuberculosis. J Infect 61: 133-143, 2010.
Blauenfeldt T, Wagner D, Aabye M, Heyckendorf J, Lange B, Lange C, Ernst M, Ravn P, Duarte R, Morais C, et al: Thermostability of IFN-γ and IP-10 release assays for latent infection with Mycobacterium tuberculosis: A TBnet study. Tuberculosis (Edinb) 98: 7-12, 2016. https://doi.org/10.1016/j.tube.2015.04.013 PMID:27156612
Jacobs R, Malherbe S, Loxton AG, Stanley K, van der Spuy G, Walzl G and Chegou NN: Identification of novel host biomarkers in plasma as candidates for the immunodiagnosis of tuberculosis disease and monitoring of tuberculosis treatment response. Oncotarget 7: 57581-57592, 2016. https://doi.org/10.18632/oncotarget.11420 PMID:27557501
Azab NY, Elmahallawy I, Sharara G and Abdel-Atti E: The utility of the interferon gamma-inducible protein-10 (IP-10) level in bronchoalveolar lavage and blood in the diagnosis of tuberculosis. Egypt J Chest Dis Tuberc 62: 629-634, 2013. https://doi.org/10.1016/j.ejcdt.2013.08.009.
Hong JY, Jung GS, Kim H, Kim YM, Lee HJ, Cho SN, Kim SK, Chang J and Kang YA: Efficacy of inducible protein 10 as a biomarker for the diagnosis of tuberculosis. Int J Infect Dis 16: e855-e859, 2012. https://doi.org/10.1016/j.ijid.2012.07.013 PMID:22959355
Luo J, Zhang M, Yan B, Li F, Guan S, Chang K, Jiang W, Xu H, Yuan T, Chen M, et al: Diagnostic performance of plasma cytokine biosignature combination and MCP-1 as individual biomarkers for differentiating stages Mycobacterium tuberculosis infection. J Infect 78: 281-291, 2019. https://doi.org/10.1016/j.jinf.2018.10.017 PMID:30528869
La Manna MP, Orlando V, Li Donni P, Sireci G, Di Carlo P, Cascio A, Dieli F and Caccamo N: Identification of plasma biomarkers for discrimination between tuberculosis infection/disease and pulmonary non tuberculosis disease. PLoS One 13: e0192664, 2018. https://doi.org/10.1371/journal.pone.0192664 PMID:29543810
Nonghanphithak D, Reechaipichitkul W, Namwat W, Naranbhai V and Faksri K: Chemokines additional to IFN-γ can be used to differentiate among Mycobacterium tuberculosis infection possibilities and provide evidence of an early clearance phenotype. Tuberculosis (Edinb) 105: 28-34, 2017. https://doi.org/10.1016/j.tube.2017.04.005 PMID:28610785
Biraro IA, Kimuda S, Egesa M, Cose S, Webb EL, Joloba M, Smith SG, Elliott AM, Dockrell HM and Katamba A: The Use of Interferon Gamma Inducible Protein 10 as a Potential Biomarker in the Diagnosis of Latent Tuberculosis Infection in Uganda. PLoS One 11: e0146098, 2016. https://doi.org/10.1371/journal.pone.0146098 PMID:26771653
Wergeland I, Pullar N, Assmus J, Ueland T, Tonby K, Feruglio S, Kvale D, Damås JK, Aukrust P, Mollnes TE, et al: IP-10 differentiates between active and latent tuberculosis irrespective of HIV status and declines during therapy. J Infect 70: 381-391, 2015. https://doi.org/10.1016/j.jinf.2014.12.019 PMID:25597826
Latorre I, Díaz J, Mialdea I, Serra-Vidal M, Altet N, Prat C, Díez N, Escribano A, Casas I, Rodrigo C, et al: IP-10 is an accurate biomarker for the diagnosis of tuberculosis in children. J Infect 69: 590-599, 2014. https://doi.org/10.1016/j.jinf.2014.06.013 PMID:24975172
Jeong YH, Hur YG, Lee H, Kim S, Cho JE, Chang J, Shin SJ, Lee H, Kang YA, Cho SN, et al: Discrimination between active and latent tuberculosis based on ratio of antigen-specific to mitogen-induced IP-10 production. J Clin Microbiol 53: 504-510, 2015. https://doi.org/10.1128/JCM.02758-14 PMID:25428147
Zhao Y, Yang X, Zhang X, Yu Q, Zhao P, Wang J, Duan C, Li J, Johnson H, Feng X, et al: IP-10 and RANTES as biomarkers for pulmonary tuberculosis diagnosis and monitoring. Tuberculosis (Edinb) 111: 45-53, 2018. https://doi.org/10.1016/j.tube.2018.05.004 PMID:30029914
Strzelak A, Komorowska-Piotrowska A, Borowa A, Krasińska M, Feleszko W and Kulus M: IP-10 for the Diagnosis and Treatment Monitoring of Tuberculosis in Children. Diagnostics (Basel) 14: 177, 2024. https://doi.org/10.3390/diagnostics14020177 PMID:38248054
Dheda K, Van-Zyl Smit RN, Sechi LA, Badri M, Meldau R, Symons G, Khalfey H, Carr I, Maredza A, Dawson R, et al: Clinical diagnostic utility of IP-10 and LAM antigen levels for the diagnosis of tuberculous pleural effusions in a high burden setting. PLoS One 4: e4689, 2009. https://doi.org/10.1371/journal.pone.0004689 PMID:19277111
Sutherland JS, Garba D, Fombah AE, Mendy-Gomez A, Mendy FS, Antonio M, Townend J, Ideh RC, Corrah T and Ota MO: Highly accurate diagnosis of pleural tuberculosis by immunological analysis of the pleural effusion. PLoS One 7: e30324, 2012. https://doi.org/10.1371/journal.pone.0030324 PMID:22295081
Fu X, Yang B, Lao S, Fan Y and Wu C: Human memory-like NK cells migrating to tuberculous pleural fluid via IP-10/CXCR3 and SDF-1/CXCR4 axis produce IFN-γ in response to Bacille Calmette Guerin. Clin Immunol 148: 113-123, 2013. https://doi.org/10.1016/j.clim.2013.04.003 PMID:23685221.
Elabscience. Human IP-10/CXCL10 (Interferon Gamma Induced Protein 10kDa) ELISA Kit. 2021 [cited 11 Sept 2024]. https://u2.elabscience.com/PDF/Cate61/E-EL-H0050-Elabscience.pdf
García-Basteiro AL, Mambuque E, den Hertog A, Saavedra B, Cuamba I, Oliveras L, Blanco S, Bulo H, Brew J, Cuevas LE, et al: IP-10 Kinetics in the First Week of Therapy are Strongly Associated with Bacteriological Confirmation of Tuberculosis Diagnosis in HIV-Infected Patients. Sci Rep 7: 14302, 2017. https://doi.org/10.1038/s41598-017-13785-3 PMID:29084992
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