Tumor Necrosis Factor-Alpha as Differential Diagnostic Marker for Patients with Fever of Unknown Origin

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Febrile conditions of unidentified origin are still unknown in modern medicine despite the development of diagnostic procedures. There are various agents of long-term temperature encompassing numerous infectious or non-infectious diseases.

The aim of this study was to determine if there was a statistically significant difference in the values of proinflammatory cytokines (IL-1, TNFα, IL-6) in patients who meet the criteria for febrile conditions of unidentified origin, between the group of infectious, malignant, rheumatic, “other” diseases and undiagnosed patients.

The study was conducted in the Immunology laboratory of the Center for Molecular Medicine and Stem Cells Research of the Faculty of Medical Sciences in Kragujevac. Blood samples were taken from patients tested at the Clinic for Infectious Diseases, of the Clinical Center of Kragujevac, in the period from 2014 to 2016. The study included 70 patients.

The measured values of the level of TNFα showed significantly higher values in a group of malignant diseases than in the group of infectious diseases, while the values of IL-1 and IL-6 did not show statistical significance.

TNFα can improve diagnosing in case of patients with an unknown febrile condition, which can shorten the length of the hospital stay and reduce the volume of performance of diagnostic procedures.

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  • 1. Abbas AK Lichtman AH Pillai S. Cellular and molecular immunology. 7th. ed. Philadelphia: Elsevier Saunders; 2012. x 545 p. p.

  • 2. Janeway C. Immunobiology : the immune system in health and disease. 6th ed. New York: Garland Science; 2005. xxiii 823 p. p.

  • 3. Murphy K Travers P Walport M Janeway C. Janeway’s immunobiology. 8th ed. New York: Garland Science; 2012. xix 868 p. p.

  • 4. Hasday JD Thompson C Singh IS. Fever immunity and molecular adaptations. Comprehensive Physiology. 2014;4(1):109-48.

  • 5. Sugimoto Y Narumiya S. Prostaglandin E receptors. The Journal of biological chemistry. 2007;282(16):11613-7.

  • 6. Thelen M Stein JV. How chemokines invite leukocytes to dance. Nature immunology. 2008;9(9):953-9.

  • 7. Yoshimura A Naka T Kubo M. SOCS proteins cytokine signalling and immune regulation. Nature reviews Immunology. 2007;7(6):454-65.

  • 8. Malek TR. The biology of interleukin-2. Annual review of immunology. 2008;26:453-79.

  • 9. Weaver CT Hatton RD Mangan PR Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annual review of immunology. 2007;25:821-52.

  • 10. Feng P Jyotaki M Kim A Chai J Simon N Zhou M et al. Regulation of bitter taste responses by tumor necrosis factor. Brain Behav Immun. 2015;49:32-42.

  • 11. Starkie R Ostrowski SR Jauffred S Febbraio M Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin- induced TNF-alpha production in humans. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2003;17(8):884-6.

  • 12. Aggarwal BB Gupta SC Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later a golden journey. Blood. 2012;119(3):651-65.

  • 13. Balkwill F. Tumour necrosis factor and cancer. Nature reviews Cancer. 2009;9(5):361-71.

  • 14. Petersdorf RG Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine. 1961;40:1-30.

  • 15. Durack DT Street AC. Fever of unknown origin-reexamined and redefined. Current clinical topics in infectious diseases. 1991;11:35-51.

  • 16. Cunha BA. Fever of unknown origin: focused diagnostic approach based on clinical clues from the history physical examination and laboratory tests. Infectious disease clinics of North America. 2007;21(4):1137-87 xi.

  • 17. Ergonul O Willke A Azap A Tekeli E. Revised definition of ‘fever of unknown origin’: limitations and opportunities. The Journal of infection. 2005;50(1):1-5.

  • 18. Finch RG DG Čivljak R. Fever of unknown origin. In: Begovac J BD Lisić M editor. Infectology. Zagreb: Profil International; 2006. p. 123−7.

  • 19. Dinarello CA Gatti S Bartfai T. Fever: links with an ancient receptor. Current biology : CB. 1999;9(4):R147-50.

  • 20. Conti B Tabarean I Andrei C Bartfai T. Cytokines and fever. Frontiers in bioscience: a journal and virtual library. 2004;9:1433-49.

  • 21. Chan-Tack KM CB Bartlett J Sanders CV Talavera F. Fever unknown origin: Medscape from WebMD; 2011 (cited 2012 8 July 2012).

  • 22. M. P. Febrilno stanje nepoznatnog uzroka. In: bolesti Kzi editor. Infektivne bolesti. Beograd: Medicinski fakultet Univerziteta u Beogradu; 2004. p. 387-91.

  • 23. Bosnic D Baresic M Padjen I Balenovic A Zarkovic K Anic B. Fever of unknown origin: large vessel vasculitis diagnosed by PET/CT. Rheumatology international. 2013;33(9):2417-21.

  • 24. Basu S Ranade R. 18-Fluoro-deoxyglucose-PET/Computed Tomography in Infection and Aseptic Inflammatory Disorders: Value to Patient Management. PET clinics. 2015;10(3):431-9.

  • 25. Popovska-Jovičić B Čanović P Gajović O Raković I. and Mijailović Ž. Fever of unknown origin: Most frequent causes in adults patients. Vojnosanit Pregl 2016; 73 (1): 21-25.

  • 26. Aggarwal BB Gupta SC Sung B. Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers. British journal of pharmacology. 2013;169(8):1672-92.

  • 27. Wajant H Pfizenmaier K Scheurich P. Tumor necrosis factor signaling. Cell death and differentiation. 2003;10(1):45-65.

  • 28. Kant S Swat W Zhang S Zhang ZY Neel BG Flavell RA et al. TNF-stimulated MAP kinase activation mediated by a Rho family GTPase signaling pathway. Genes & development. 2011;25(19):2069-78.

  • 29. Raaschou P Simard JF Asker Hagelberg C Askling J. Rheumatoid arthritis anti-tumour necrosis factor treatment and risk of squamous cell and basal cell skin cancer: cohort study based on nationwide prospectively recorded data from Sweden. Bmj. 2016;352:i262.

  • 30. Sandri MT Passerini R Leon ME Peccatori EA Zorzino L Salvatici M Riggio D Cassatella C Cinieri S and Martinelli G. Procalcitonin as a useful marker of infection in hemato-oncological patients with fever. Anticancer research 2008; 28: 3061-3066.

  • 31. Pukac L Kanakaraj P Humphreys R Alderson R Bloom M Sung C Riccobene T Johnson R et al. “HGS-ETR1 a fully human TRAIL-receptor 1 monoclonal antibody induces cell death in multiple tumour types in vitro and in vivo”. British Journal of Cancer 2005; 92 (8): 1430–41. doi:10.1038/sj.bjc.6602487

  • 32. Barrie JR English JC Muller N: Castleman’s disease of the lung: radiographic high-resolution CT and pathologic findings. AJR Am J Roentgenol 1996; 166:1055-1056

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