Serum Levels of Interleukin-12 and Interferon Gamma in Pediatric Tuberculosis: A Clinico-Microbiological Correlation
Abstract
Objective: The interleukin-12/interferon-γ (IL-12/IFN-γ) pathway is the most validated cytokine pathway regulating Mycobacterium tuberculosis infection. The role of IL-12/IFN-γ axis in protecting against tuberculosis (TB) is exhibited in people having mutations in genes encoding these cytokines. We aimed to study the serum levels of IL-12 and IFN-γ in pediatric tuberculosis and their correlation with clinical and microbiological features.
Material and Methods: A case-control study was conducted on 60 microbiologically confirmed (smear and/or culture and/or cartridge-based nucleic acid amplification test) or clinically diagnosed (based on clinical features and radiography and/or contact history and/or Mantoux test with/without microbiological confirmation) pediatric TB patients ≤12 years. Serum interleukin-12 and interferon-gamma levels were estimated using enzyme-linked immunosorbent assays.Thirty age- and sex-matched controls were also included in the study.
Results: The median IL-12 levels were lower in our pediatric TB patients (488.1 pg/ml) compared to controls (784.8 pg/ml). However, the IFN-γ/IL-12 ratios were significantly higher among the TB patients as compared to the controls. Moreover, the levels of interleukin-12 and interferon gamma were significantly lower in cases with no evidence of TB on chest radiography. IL-12 was significantly lower in patients with hydrocephalus and enlarged ventricles. Higher levels of IL-12 and IFN-γ were associated with positive results by conventional microbiological techniques.
Conclusion: The serum IFN-γ level and the IFN-γ/IL-12 ratio were significantly higher in children with TB compared to the controls in this study. Higher IL-12 and IFN-γ levels as well as IFN-γ/IL-12 ratios were associated with positive results by conventional microbiological techniques. Further studies on larger sample sizes could help evaluate the usefulness of interleukin-12 and interferon-γ as potential markers of severity and prognosis in pediatric TB.
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Raizada N, Sachdeva KS, Swaminathan S, Kulsange S, Khaparde SD, Nair SA, et al. Piloting upfront Xpert MTB/RIF testing on various specimens under programmatic conditions for diagnosis of TB & DR-TB in paediatric population. PLoS One 2015;10:e0140375. doi: 10.1371/journal.pone.0140375.
Kashyap B, Gupta N, Dewan P, Hyanki P, Singh NP. High sensitivity c reactive protein: an adjunct diagnosis in ruling out pediatric tuberculosis. Indian J Clin Biochem 2020;35:211-7. https://doi.org/10.1007/s12291-018-0806-2.
Singh S, Singh A, Prajapati S, Kabra SK, Lodha R, Mukherjee A, et al. Xpert MTB/RIF assay can be used on archived gastric aspirate and induced sputum samples for sensitive diagnosis of paediatric tuberculosis. BMC Microbiol 2015;15:191.
Raizada N, Khaparde SD, Salhotra VS, Rao R, Kalra A, Swaminathan S, et al. Accelerating access to quality TB care for pediatric TB cases through better diagnostic strategy in four major cities of India. PLoS ONE 2018;13:e0193194. https://doi. org/10.1371/journal.pone.0193194.
Zar HJ, Workman LJ, Prins M, Bateman LJ, Mbhele SP, Whitman CB, et al. Tuberculosis diagnosis in children using xpert ultra on different respiratory specimens. Am J Respir Crit Care Med 2019;200:1531-8.
Deveci F, Akbulut HH, Turgut T, Muz MH. Changes in serum cytokine levels in active tuberculosis with treatment. Mediators Inflamm 2005;2005:256-62.
Ramirez-Alejo N, Santos-Argumedo L. Innate defects of the IL-12/IFN-γ axis in susceptibility to infections by mycobacteria and salmonella. J Interferon Cytokine Res 2014;34:307–17.
Kumar P. IFNγ‑producing CD4+ T lymphocytes: the doubleedged swords in tuberculosis. Clin Transl Med 2017;6:1-7.
Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL. Mendelian susceptibility to mycobacterial disease: Genetic, immunological, and clinical features of inborn errors of IFN-γ immunity. Semin Immunol 2014;26:454-70.
Boisson-Dupuis S, Baghdadi JE, Parvaneh N, Bousfiha A, Bustamante J, Feinberg J, et al. IL-12rβ1 deficiency in two of fifty children with severe tuberculosis from Iran, Morocco and Turkey. PLoS One 2011;6:e18524.
Sarrafzadeh SA, Mahloojirad M, Nourizadeh M, Casanova JL, Pourpak Z, Bustamante J, et al. Mendelian susceptibility to mycobacterial disease due to IL-12Rβ1 deficiency in Three Iranian children. Iran J Public Health 2016;45:249–54.
Central TB Division, Government of India. Revised national tuberculosis control programme: technical and operational guidelines for TB Control in India. New Delhi: Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare; 2016;p.1-269.
Singh V, Mahto D. Antitubercular drugs and RNTCP guidelines for childhood tuberculosis. In: Gupta P, Menon PSN, Ramji S, Lodha R, editors. PG Textbook of pediatrics: Infections and systemic disorders. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers; 2018;p.1348.
Forbes BA, Sahm DF, Weissfeld AS. Mycobacteria and other bacteria with unusual growth requirements. In: Forbes BA, Sahn DF, Weissfeld AS, editors. Bailey & Scott’s Diagnostic Microbiology. 13th ed. Missouri: Mosby Elsevier; 2014;p.484-512.
Central TB Division, Government of India. Revised national tb control programme training manual for Mycobacterium tuberculosis culture and drug susceptibility testing [homepage on the Internet]. New Delhi: Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare; 2009 [cited 2017 Jan 28]. Available from: http://www. tbcindia.nic.in/showfile.php?lid=2991
World Health organization. The WHO child growth standards [homepage on the Internet]. Geneva: WHO; 2006 [2022 Nov 16]. Available from: https://www.who.int/tools/child-growthstandards/ standards
Crevel RV, Karyadi E, Netea MG, Verhoef H, Nelwan RHH, West CE, et al. Decreased plasma leptin concentrations in tuberculosis patients are associated with wasting and inflammation. J Clin Endocrinol Metab 2002;87:758-63. https:// doi.org/10.1210/jcem.87.2.8228
Kumar NP, Anuradha R, Andrade BB, Suresh N, Ganesh R, Shankar J, et al. Circulating biomarkers of pulmonary and extrapulmonary tuberculosis in children. Clin Vaccine Immunol 2013;20:704-11.
Liu WD, Lu JR. Serum levels of IL-12, TGF beta1 and IgE in children with asthma. Zhongguo Dang Dai Er Ke Za Zhi 2008;10:146-8.
Mustafa T, Brokstad KA, Mfinanga SG,Wiker HG. Multiplex Analysis of Pro- or Anti-inflammatory serum cytokines and chemokines in relation to gender and age among tanzanian tuberculous lymphadenitis patients. Tuberc Res Treat 2015; 2015:561490
Romani L, Puccetti P, Bistoni F. Interleukin-12 in infectious diseases. Clin Microbiol Rev 1997;10:611-36. doi: 10.1128/ CMR.10.4.611.
Selvaraj P, Alagarasu K, Harishankar M, Vidyarani M, Rajeswari ND, Narayanan PR. Cytokine gene polymorphisms and cytokine levels in pulmonary tuberculosis. Cytokine 2008;43:26-33.
Abhimanyu, Mangangcha IR, Jha P, Arora K, Mukerji M, Banavaliker JN, et al. Differential serum cytokine levels are associated with cytokine gene polymorphisms in north Indians with active pulmonary tuberculosis. Infect Genet Evol 2011;11:1015–22.
Morahan G, Kaur G, Singh M, Rapthap CC, Kumar N, Katoch K, et al. Association of variants in the IL12B gene with leprosy and tuberculosis. Tissue Antigens 2007;69(Suppl 1):234-6.
Kumar NP, Moideen K, Banurekha VV, Nair D, Babu S. Plasma proinflammatory cytokines are markers of disease severity and bacterial burden in pulmonary tuberculosis. Open Forum Infect Dis 2019;6:ofz257. https://doi.org/10.1093/ofid/ofz257.
Mendez-Samperio P. Role of interleukin-12 family cytokines in the cellular response to mycobacterial disease. Int J Infect Dis 2010;14:e366-71.
Hamza T, Barnett JB, Li B. Interleukin 12 a key immunoregulatory cytokine in infection applications. Int J Mol Sci 2010;11:789-806.
Sack U, Burkhardt U, Borte M, Schadlich H, Berg K, Emmrich F. Age-dependent levels of select immunological mediators in sera of healthy children. Clin Diagn Lab Immunol 1998;5:28–32.
Shaviya N, Budambula V, Webale MK, Were T. Circulating Interferon-Gamma levels are associated with low body weight in newly diagnosed Kenyan non-substance using tuberculosis individuals. Interdiscip Perspect Infect Dis 2016;2016:9415364.
Hussain S, Afzal N, Javaid K, Ullah MI, Ahmad T, Saleem-Uz- Zaman. Level of interferon gamma in the blood of tuberculosis patients. Iran J immunol 2010;7:240-6.
Nie W, Wang J,Wei Jing, Shi W, Wang Q, Huang X, et al. Value of serum cytokine biomarkers TNF-α, IL-4, sIL-2R and IFN-γ for use in monitoring bacterial load and anti-tuberculosis treatment progress. Cytokine X 2020;2;100028.
Rohlwink UK, Mauff K, Wilkinson KA, Enslin N, Wegoye E, Wilkinson RJ, et al. Biomarkers of cerebral injury and inflammation in pediatric tuberculous meningitis. Clin Infect Dis 2017;65:1298–307.
Sharma SK, Mitra DK, Balamurugan A, Pandey RM, Mehra NK. Cytokine polarization in miliary and pleural tuberculosis. J Clin Immunol 2002;22:345-52.
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