Sequential determination of serum viral titers, virus-specific IgG antibodies, and TNF-α, IL-6, IL-10, and IFN-γ levels in patients with Crimean-Congo hemorrhagic fever

BMC Infectious Diseases

Mehmet Sencan⁵  Neziha Yilmaz⁸  Mehmet Bakir⁴  Ilyas Dokmetas⁴  Aynur Engin⁴  Mustafa Gokhan Gozel⁴  Zubeyde Polat⁶  Turabi Gunes¹  Gulderen Karakus¹  Meral Yilmaz¹  Nevcihan Gursoy²  Ayhan Kubar⁷  Nazif Elaldi⁴  Safak Kaya³ 

[1] Cumhuriyet University Medical Faculty Research Center (CUTFAM), Cumhuriyet University, Sivas, Turkey;Department of Food Engineering, Faculty of Engineering, Cumhuriyet University, Sivas, Turkey;Department of Infectious Diseases and Clinical Bacteriology, Training and Research Hospital, Diyarbakir, Turkey;Department of Infectious Diseases and Clinical Bacteriology, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey;Department of Internal Medicine, Section of Haematology, Faculty of Medicine, Cumhuriyet University, Sivas, Turkey;Cumhuriyet University Vocabulary School, Cumhuriyet University, Sivas, Turkey;Department of Clinical Microbiology, Section of Clinical Virology, Gulhane Military Medicine Academy, Ankara, Turkey;Department of Virology, Refik Saydam Hifzissiha Institute, Turkish Ministry of Health, Ankara, Turkey

关键词: Mortality;    DIC;    IFN-γ;    IL-10;    IL-6;    TNF-α;    Specific IgG;    CCHFV titer;    CCHF;   

Others  :  1127281
DOI  :  10.1186/1471-2334-14-416

 received in 2014-02-01, accepted in 2014-07-23,  发布年份 2014

【 摘 要 】

Background

Although there have been a number of studies on the pathogenesis of Crimean-Congo hemorrhagic fever (CCHF) recently, knowledge on this topic is still insufficient. This study aims to reveal the kinetics of serum CCHF virus (CCHFV) titers, serum levels of anti-CCHFV immunoglobulin (Ig)G, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and interferon (IFN)-γ in CCHF patients.

Methods

In total, 31 CCHF cases (11 fatal) were studied. Serum samples were obtained daily from all patients from the time of admission and continued for a 7-day hospitalization period for serologic (ELISA), virologic (real-time PCR), and cytokine (ELISA) analysis.

Results

The mean serum CCHFV titer at admission was 5.5E + 09 copies/mL in fatal cases and 5.7E + 08 copies/mL in survivors (p < 0.001). Compared to survivors, both the mean serum levels of IL-6 and TNF-α at admission were found to be significantly increased in fatal cases. The serum levels of IL-6, TNF-α and serum CCHFV titer at admission were significantly and positively correlated with disseminated intravascular coagulation (DIC) scores (r = 0.626, p = 0.0002; r = 0.461, p = 0.009; and r = 0.625, p = 0.003, respectively). When the data obtained from the sequential determination of CCHFV titer and levels of anti-CCHFV IgG, IL-6, TNF-α, IL-10 and IFN-γ were grouped according to the days of illness, the initial serum CCHFV titer of a fatal patient was 5.5E + 09 (copies/mL) and it was 6.1E + 09 (copies/mL) in a survivor on the 2 day of illness. While significant alterations were observed in all cytokines during the monitoring period, IL-6 levels remained consistently higher in fatal cases and TNF-α levels increased in both in fatal and non-fatal CCHF cases.

Conclusions

The increased CCHFV load and higher concentrations of IL-6 and TNF-α, the presence of DIC, and the absence of CCHFV specific immunity are strongly associated with death in CCHF.

【 授权许可】

   
2014 Kaya et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Whitehouse CA: Crimean-Congo hemorrhagic fever. Antiviral Res 2004, 64(3):145-160.
• [2]Elaldi N, Bodur H, Ascioglu S, Celikbas A, Ozkurt Z, Vahaboglu H, Leblebicioglu H, Yilmaz N, Engin A, Sencan M, Aydin K, Dokmetas I, Cevik MA, Dokuzoguz B, Tasyaran MA, Ozturk R, Bakir M, Uzun R: Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey. J Infect 2009, 58(3):238-244.
• [3]Ergonul O: Crimean-Congo haemorrhagic fever. Lancet Infect Dis 2006, 6(4):203-214.
• [4]Gunes T, Engin A, Poyraz O, Elaldi N, Kaya S, Dokmetas I, Bakir M, Cinar Z: Crimean-Congo hemorrhagic fever virus in high-risk population. Turkey Emerg Infect Dis 2009, 15(3):461-464.
• [5]Geisbert TW, Jahrling PB: Exotic emerging viral diseases: progress and challenges. Nat Med 2004, 10(12):110-121.
• [6]Schnittler HJ, Feldmann H: Viral Hemorrhagic fever-a vascular disease? Thromb Haemost 2003, 89(6):967-972.
• [7]Burt FJ, Swanepoel R, Shieh WJ, Smith JF, Leman PA, Greer PW, Coffield LM, Rollin PE, Ksiazek TG, Peters CJ, Zaki S: Immunohistochemical and in situ localization of Crimean-Congo hemorrhagic fever (CCHF) virus in human tissues and implications for CCHF pathogenesis. Arch Pathol Lab Med 1997, 121(8):839-846.
• [8]Joubert JR, King JB, Rossouw DJ, Cooper R: A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital: Part III. Clinical pathology and pathogenesis. S Afr Med J 1985, 68(10):722-728.
• [9]Papa A, Bino S, Velo E, Harxhi A, Kota M, Antoniadis A: Cytokine levels in Crimean-Congo hemorrhagic fever. J Clin Virol 2006, 36(4):272-276.
• [10]Ergonul O, Tuncbilek S, Baykam N, Celikbas A, Dokuzoguz B: Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha in patients with Crimean-Congo hemorrhagic fever. J Infect Dis 2006, 193(7):941-944.
• [11]Saksida A, Duh D, Wraber B, Dedushaj I, Ahmeti S, Avsic-Zupanc T: Interacting roles of immune mechanisms and viral load in the pathogenesis of Crimean-Congo hemorrhagic fever. Clin Vaccine Immunol 2010, 17(7):1086-1093.
• [12]Yapar M, Aydogan H, Pahsa A, Besirbellioglu BA, Bodur H, Basustaoglu AC, Guney C, Avci IY, Sener K, Setteh MH, Kubar A: Rapid and quantitative detection of Crimean-Congo hemorrhagic fever virus by one step Real-Time Reverse Transcriptase-PCR. Jpn J Infect Dis 2005, 58(6):358-362.
• [13]Duh D, Saksida A, Petrovec M, Ahmeti S, Dedushaj I, Panning M, Drosten C, Avsic-Zupanc T: Viral load as predictor of Crimean-Congo hemorrhagic fever outcome. Emerg Infect Dis 2007, 13(11):1769-1772.
• [14]Cevik MA, Erbay A, Bodur H, Eren SS, Akinci E, Sener K, Ongürü P, Kubar A: Viral load as a predictor of outcome in Crimean-Congo hemorrhagic fever. Clin Infect Dis 2007, 45(7):e96-e100.
• [15]Wölfel R, Paweska JT, Petersen N, Grobbelaar AA, Leman PA, Hewson R, Georges-Courbot MC, Papa A, Günther S, Drosten C: Virus detection and monitoring of viral load in Crimean-Congo hemorrhagic fever virus patients. Emerg Infect Dis 2007, 13(7):1097-1100.
• [16]Kubar A, Haciomeroglu M, Ozkul A, Bagriacik U, Akinci E, Sener K, Bodur H: Prompt administration of Crimean-Congo hemorrhagic fever (CCHF) virus hyperimmunoglobulin in patients diagnosed with CCHF and viral load monitorization by reverse transcriptase-PCR. Jpn J Infect Dis 2011, 64(5):439-443.
• [17]Levi M, de Jonge E, Meijers J: The diagnosis of disseminated intravascular coagulation. Blood Rev 2002, 16(4):217-223.
• [18]Swanepoel R, Gill DE, Shepherd AJ, Leman PA, Mynhardt JH, Harvey S: The clinical pathology of Crimean-Congo hemorrhagic fever. Rev Infect Dis 1989, 11(4):794-800.
• [19]Tignor GH, Hanham CA: Ribavirin efficacy in an in vivo model of Crimean-Congo hemorrhagic fever virus (CCHF) infection. Antiviral Res 1993, 22(4):309-325.
• [20]Shepherd AJ, Swanepoel R, Leman PA: Antibody response in Crimean-Congo hemorrhagic fever. Rev Infect Dis 1989, 11(4):801-806.
• [21]Akinci E, Bodur H, Leblebicioglu H: Pathogenesis of Crimean-Congo hemorrhagic Fever. Vector Borne Zoonotic Dis 2013, 13(7):429-437.
• [22]Feldmann H, Bugany H, Mahner F, Klenk HD, Drenckhahn D, Schnittler HJ: Filovirus-induced endothelial leakage triggered by infected monocytes/macrophages. J Virol 1996, 70(4):2208-2214.
• [23]Papa A, Bino S, Llagami A, Brahimaj B, Papadimitriou E, Pavlidou V, Velo E, Cahani G, Hajdini M, Pilaca A, Harxhi A, Antoniadis A: Crimean-Congo hemorrhagic fever in Albania, 2001. Eur J Clin Microbiol Infect Dis 2002, 21(8):603-606.
• [24]Zelova H, Hosek J: TNF-α signalling and inflammation: interactions between old acquaintances. Inflamm Res 2013, 62(7):641-651.
• [25]Levi M: Pathogenesis and treatment of disseminated intravascular coagulation in the septic patient. J Crit Care 2001, 16(4):167-177.
• [26]Trotter L: Disseminated intravascular coagulation in the neonatal period. Newborn and Infant Nursing Reviews 2004, 4(4):176-180.
• [27]Levi M, de Jonge E, van der Poll T: Plasma and plasma components in the management of disseminated intravascular coagulation. Best Pract Res Clin Haematol 2006, 19(1):127-142.
• [28]Mammen EF: Disseminated intravascular coagulation. Clin Lab Sci 2000, 13(4):239-245.
• [29]Libraty DH, Young PR, Pickering D, Endy TP, Kalayanarooj S, Green S, Vaughn DW, Nisalak A, Ennis FA, Rothman AL: High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis 2002, 186(8):1165-1168.
• [30]Green S, Vaughn DW, Kalayanarooj S, Nimmannitya S, Suntayakorn S, Nisalak A, Rothman AL, Ennis FA: Elevated plasma IL-10 levels in acute dengue correlate with disease severity. J Med Virol 1999, 59(3):329-334.
• [31]Villinger F, Rollin PE, Brar SS, Chikkala NF, Winter J, Sundstrom JB, Zaki SR, Swanepoel R, Ansari AA, Peters CJ: Markedly elevated levels of interferon (IFN)-gamma, IFN-alpha, interleukin (IL)-2, IL-10, and tumor necrosis factor-alpha associated with fatal Ebola virus infection. J Infect Dis 1999, 179(Suppl1):S188-S191.
• [32]Kelso A: Cytokines: Principles and prospects. Immunol Cell Biol 1998, 76(4):300-317.
• [33]Andersson I, Karlberg H, Mousavi-Jazi M, Martínez-Sobrido L, Weber F, Mirazimi A: Crimean-Congo hemorrhagic fever virus delays activation of the innate immune response. J Med Virol 2008, 80(8):1397-1404.
• [34]Bereczky S, Lindegren G, Karlberg H, Akerström S, Klingström J, Mirazimi A: Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice. J Gen Virol 2010, 91(Pt 6):1473-1477.
• [35]Zivcec M, Safronetz D, Scott D, Robertson S, Ebihara H, Feldmann H: Lethal Crimean-Congo Hemorrhagic Fever virus infection in interferon α/β receptor knockout mice is associated with high viral loads, pro-inflammatory responses and coagulopathy. J Infect Dis 2013, 207(12):1909-1921.