| ObjectionOutbreaks and epidemics of enterovirus 71 (EV71) infection have occurred around the world. EV71 usually causes relatively benign and self-limited hand,foot and mouth disease and herpangina in children.It can also cause severe infection of the central nervous system(CNS).The CNS manifestations include aseptic meningitis, encephalitis, brain stem encephalitis(BE),encephalomyelitis, a poliomyelitis-like syndrome. It can also result in fatal pulmonary edema(PE)in minority patients. Definite pathogenesis of PE is unclear. Studies postulated that PE may result from excessive stimulation of the sympathetic nerve,originating from viral brainstem lesions or increased pulmonary vascular permeability as the result of a systemic inflammatory response caused by the excessive release of cytokines, or a combination of both responses.Previous studies have shown that PE is associated with extensive inflammatory responses, including significantly elevated levels of cotykines or pre-inflammatory cotykines,such as interleukin[IL]-6,tumor necrosis factor[TNF]-a, IL-1β,IL-10,IL-13,and interferon[IFN]-γin peripheral blood or cerebrosoinal fluid of patients,as well as the depletion of CD4+T cells and CD8+T cells and natural killer [NK] cells,which suggests variance of cotykines piays an important role in the pathogenesis of critical EV71 infection patients.IL-18 is a pleiotropic cytokine with numerous functions. IL-18 stimulates Thl-mediated immune responses through the induction of IFN-γ. In addition, IL-18 induces inflammatory cytokines, such as TNF-αand IL-1, Fas-ligand [FasL] and several chemokines. On the contrary, IL-18 and T cell receptor-mediated stimulation could induce naive CD4+ T cells to develop into Th2-cells in vitro. Excessive release of IL-18 can cause immune function disorder by promoting over-release of proinflammary and anti-inflammary cytokines,recuiting neutrophils and causing lymphocytic apoptosis,which result in acute organ injury. Previous studies have shown IL-18 is highly expressed in patients and experimental models of arthritis and sepsis, and causes tissue damage by inducing IFN-γor recruiting neutrophils, incluing lung injury.The variance and role of IL-18 in EV71 infection is not still reported.In our study,we assayed variance of levels of serum IL-18 in severe evterovirus 71(EV71) cases with different severity of the disease in order to explore the role and significance of IL-18 in EV71 infection.Materials and MethodsForty-eight patients with confirmed EV71 infection by feces virus nucleic acid assay were admitted to the Kai Feng Children's Hospital, Henan during the period of May through June 2009. Among patients, there were 26 men and 22 women, and their mean age was 1.96±0.67 years. The patients were stratified into three groups according to critical degree of enterovirs 71 infection:central nervous system disease (CNSD) group (n=20); autonomic nervous system dysregulation (ANSD) group (n=23); and pulmonary edema (PE) group (n=5). Among 20 patients in CNSD group, there were 13 men and 7 women, and their mean age was 2.37±0.99 years. Among 23 patients in ANSD group, there were 10 men and 13 women, and their mean age was 1.64±0.77 years. Among 5 patients in PE group, there were 3 men and 2 women,and their mean age was 1.70±1.37 years. Fifteen age-matched healty children were selected as normal control(NC) group.Among 15 children in NC group, there were 8 men and 7 women, and their mean age was 2.08±0.64 years.Serums for IL-18 determination from patients were harvested from centrifuged peripheral venous blood samples soon after admission to the hospital or respectively on the 1st,2nd,4th day after the mechanical ventilation and were stored at-70℃until analyed. The levels of serum IL-18 from patients and control subjects were measured by enzyme-linked inmunosorbent assay method(ELISA).Results(1) Year,gander,and clinical materials comparison among groups1) Year and ganderThere were no significant difference in year (2.08±0.64 vs.1.96±0.97, Mann-Whitney U test p=0.27) and gander (P>0.05) between patients and control subjects. Year is smaller in ANSD group than that in CNSD (P<0.05). There are no significant difference in gander ratio among CNSD group, ANSD group and PE group (P=0.36)2) Clinical materialsThere were no significant difference in duration of fever before hospitalization among CNSD group, ANSD group and PE group (P=0.43).Total white blood cell (WBC)count from peripheral blood gradually increased with aggravation of the disease. Total WBC count in PE group was higher than that in CNSD group (P< 0.05). Total WBC count in PE group was higher than that in ANSD group (P=0.08), and total WBC count in ANSD group was higher than that in CNSD group (P=0.07), but there were no statistical difference. Lymphcyte count gradually decreased with aggravation of the disease. Lymphcyte count in PE group was lower than that in ANSD group (P<0.05), and lymphcyte count in ANSD group was lower than that in CNSD group (P<0.005. Neutrophil count has a contrary variance tendency,compared with lymphcyte count. Neutrophil count in PE group was higher than that in ANSD group (P<0.05), and neutrophil count in ANSD group was higher than that in CNSD group (P<0.005). Blood glucose level in PE group was higher than that in ANSD group (P<0.05), and blood glucose level in ANSD group is higher than that in CNSD group (P<0.05). Cerebrospinal fluid (CSF) leukocyte count did not differ among CNSD group, ANSD group and PE group (P=0.14)(2) The levels of serum IL-181) The levels of serum IL-18 in PE group were extremely higher than those in ANSD group (P<0.005), CNSD group (P<0.005) and NC group(P<0.005). The levels of serum IL-18 in ANSD group were higher when compared with those in NC group and CNSD group,but there were no statistical difference (P>0.05).2) Variance of serum IL-18 at different time pointsThe levels of serum IL-18 gradually decreased with the alleviation of disease. In PE group, The levels of serum IL-18 on the 1st day were higher than those on the 2nd day and the 4th day after the mechanical ventilation (P<0.005) and the levels of serum IL-18 on the 2nd day were higher than those on the 4th day after the mechanical ventilation (P<0.05). In ANSD group, The levels of serum IL-18 on 1st day were higher than those on the 2nd day and the 4th day after the mechanical ventilation (P< 0.005), and the levels of serum IL-18 on the 2nd day were higher than those on the 4th day after the mechanical ventilation (P< 0.05)Conclusion(1) IL-18 can play an important role in the pathogenesis of fatal EV71-ralated PE.(2) Dynamic assay of serum IL-18 levels in patients with EV71 infection can faciliate evaluation of severity of the disease.Significant elevation of serum IL-18 levels suggested the desease was critical and prognosis was bad.(3) Elevations of WBC count, neutrophil count and blood glucose level suggested the desease was critical. |
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