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

Abstract

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)-alpha, interleukin (IL)-6, IL-10, and interferon (IFN)-gamma 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-alpha at admission were found to be significantly increased in fatal cases. The serum levels of IL-6, TNF-alpha 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-alpha, IL-10 and IFN-gamma 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-alpha levels increased in both in fatal and non-fatal CCHF cases. Conclusions: The increased CCHFV load and higher concentrations of IL-6 and TNF-alpha, the presence of DIC, and the absence of CCHFV specific immunity are strongly associated with death in CCHF.