Status of Cellular Rather Than Humoral Immunity is Correlated with Clinical Outcome of Enterovirus 71

Abstract

ABSTRACT:We valuated specific cellular and humoral immune response of cases of enterovirus 71 (EV71) infection and correlated immune response with clinical outcome. After obtaining informed consent, we enrolled 30 EV71 cases including 7 cases with brainstem encephalitis plus pulmonary edema, 12 cases of CNS (CNS) involvement and 11 uncomplicated cases. We measured antibodies specific to EV71, lymphocyte proliferation response and EV71-stimulated cellular response of Th1/Th2 cytokines and chemokines. The 7 EV71 cases involving brainstem encephalitis plus pulmonary edema had a significantly lower phytohemagglutinin stimulation index than other cases (p ϭ 0.04). After EV71 stimulation of peripheral mononuclear cells, there was a significant increase in cellular Th1 cytokine (␥-interferon) and proinflammatroy cytokines. However, cases with pulmonary edema had significantly lower cellular ␥-interferon reported from the United States, Europe, Australia, Japan, Brazil and Malaysia (1-10), since it was originally characterized from a 1969 California outbreak (1). Before 1998, there were three large outbreaks with dozens of fatal cases occurring in Bulgaria, Hungary, and Malaysia (l975, l978, and 1997, respectively) (3,5,10). The largest and most severe EV71 epidemic to date occurred in Taiwan in 1998 (11-16). A total of 129,106 cases of hand-foot-and-mouth disease and herpangina (HFMD/HA) were reported (15). Severe neurologic complications and/or pulmonary edema were reported in 405 cases, and 78 children died (15).Most EV71 fatalities were cases of fulminant pulmonary edema (15). However, EV71 infection causes very diverse symptoms, ranging from none (about 71%) to fatality (about 0.05%) (17,18). It remains unknown why different hosts of the same EV71 infection have such a range of clinical outcomes (17,18). Perhaps this range is related to virulence or load of the virus, or particular host factors. To date no relationship has been found between EV71 genotypes and clinical outcome (19,20), and EV71 virulence factors have not been clarified. It is possible that host factors, especially host immune response, may be of ultimate importance to clinical outcome.To clarify severe EV71 infection pathogenesis, we investigated factors of cellular versus humoral immune response and correlated this with clinical outcome. SUBJECTS AND METHODS Subjects. After National Taiwan University Hospital Research EthicsCommittee approved this study and informed parental consent was obtained, 30 EV71 cases of different severity were enrolled. EV71 infection was confirmed by positive EV71 isolation and/or positive EV71 specific IgM at the onset of their disease.The CNS involvement was indicated in four types of cases. Those with aseptic meningitis had headache and irritability along with cerebrospinal fluid (CSF) pleocytosis (Ͼ5 leukocytes/L) and without an altered level of consciousness. The second type of cases involved encephalitis had altered level of consciousness plus cerebrospinal fluid (CSF) pleocytosis. Poliomyelitislike syndrome was ...

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