| Summary: | 博士 === 國立成功大學 === 臨床醫學研究所 === 94 === Enterovirus 71 (EV71) brainstem encephalitis (BE) is a complication clinically characterized by fever, hand-foot-and-mouth disease (HFMD), and myoclonus jerk after the infection. High neurovirulence and fatalities with a rapid course from BE to pulmonary edema (PE) were noted. The first part of this study was designed to determine whether there is a quantitative relationship of specific cytokine in the cerebrospinal fluid (CSF) among various severity of EV71 BE, and compared to those echovirus meningitis (EM). Mean CSF glucose, total protein and lactate levels were significantly increased in associated with EV71 BE severity. CSF interleukin (IL)-1b, IL-6 and interferon (IFN)-g were significantly higher in patients of stage IIIb than in patients of stage II. In comparison with patients of stage II, CSF IL-6 and IFN-g were also significantly higher in patients of stage IIIa. Higher CSF IFN-g and lower IL-1b were in patients of stage IIIb than in EM. There is distinct pattern of the CNS inflammation among children with various severity of EV71 BE and EM. The pathogenesis of PE may be related to brainstem lesions and/or systemic inflammatory response syndrome and the release of cytokines. To elucidate the role of systemic inflammatory responses in the pathogenesis of EV71 BE and its fatal complication, PE, we analyzed the laboratory findings, cytokine, and immunophenotypes of patients with EV71 BE. Leukocytosis and thrombocytosis were significantly more frequent among patients with PE. A significant elevation of plasma IL-10, IL-13, and IFN-g levels were observed in patients of stage IIIb. Patients of stage IIIb also had lower circulating CD4+ T cells, CD8+ T cells, and natural killer (NK) cells. An extensive peripheral inflammatory response appears to be responsible for the pathogenesis of EV71 PE. Both systemic and CNS inflammatory responses are involving in the pathogenesis of EV71 PE. The third part of this study was designed to evaluate the potential therapeutic effect of milrinone, a phosphodiesterase (PDE) inhibitor, in the treatment of patients with EV71 PE (stage IIIb). Patients were divided into groups treated before and after the introduction of milrinone therapy. The mortality was lower in the milrinone-treated vs. nontreated group. Sympathetic tachycardia was decreased in patients treated with milrinone compared to controls. A marked decrease in IL-13 was observed in milrinone-treated patients compared to controls. There was a significant reduction in white blood cell and platelet counts in milrinone-treated patients compared to controls. Milrinone therapy may provide a useful therapeutic approach for this highly lethal disorder. We also performed the study to determine the changes in cytokine profiles associated with administration of intravenous immunoglobulin (IVIG) in patients of stage IIIa and stage IIIb. Plasma levels of IFN-g, IL-6, IL-8, IL-10, and IL-13 levels significantly decreased in patients stage IIIb after administration of IVIG. Plasma levels of IL-6 and IL-8 were significantly decreased in patients of stage IIIa after administration of IVIG. All the satage IIIa patients were survived without deteriorated to stage IIIb. These findings suggest that IVIG might be considered to have a therapeutic role in stage IIIa EV71 BE. In summary, both systemic and CNS inflammatory responses have participate in the pathogenesis of EV71 BE. The peripheral inflammatory responses can be attenuate by milrinone and IVIG. Milrinone and IVIG therapy may provide a useful therapeutic approach for complicated EV71 BE.
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