Status of cellular rather than humoral immunity is correlated with clinical outcome of enterovirus 71

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 = 0.04). After EV71 stimulation of peripheral mononuclear cells, there was a significant increase in cellular Th1 cytokine (gamma-interferon) and proinflammatroy cytokines. However, cases with pulmonary edema had significantly lower cellular gamma-interferon (p = 0.04), lower cellular IL-1beta (p = 0.04), lower cellular IL-6 (p = 0.04), lower cellular tumor necrosis factor-alpha response (p = 0.04), and lower cellular macrophage inflammatory protein-1alpha (p = 0.04) response compared with other cases. Their titers of EV71 neutralizing antibodies demonstrated no difference among cases. These results suggest lower EV71-specific cellular response may be associated with immunopathogenesis of EV71-related pulmonary edema.

Figure 1

EV71-specific neutralizing antibody titers among EV71 cases with different severity (EV71 cases with pulmonary edema, EV71 cases with CNS involvement, and uncomplicated EV71 cases). All titers were statistically identical among the three groups (p = 0.567 with Kruskal-Wallis test).

Figure 2

PHA stimulation index among EV71 cases with different severity (EV71 cases with pulmonary edema, EV71 cases with CNS involvement, and uncomplicated EV71 cases). EV71 cases with pulmonary edema had a significantly lower PHA stimulation index (p = 0.04, measured to compare the percentages of a response over the median level of increase of all the EV71 cases by using likelihood ratio χ² test).

Figure 3

Peak enterovirus 71 (EV71) stimulation index among EV71 cases with different severity (EV71 cases with pulmonary edema, EV71 cases with CNS involvement, and uncomplicated EV71 cases). All peak EV71 stimulation index were statistically identical among the three groups (p = 0.31 with Kruskal-Wallis test)

Figure 4

Cellular interferon-γ response after EV71 stimulation at the concentration of 10 μg/mL) among EV71 cases with different severity (EV71 cases with pulmonary edema, EV71 cases with CNS involvement, and uncomplicated EV71 cases). EV71 cases with pulmonary edema had significantly lower interferon-γ response than the other EV71 cases (p = 0.04, measured to compare the percentages of a response over the median level of increase of all the EV71 cases by using likelihood ratio χ² test).