Immunologic Characterization of Cytokine Responses to Enterovirus 71 and Coxsackievirus A16 Infection in Children

Abstract

Viral encephalitis is a serious complication of hand, foot, and mouth disease (HFMD), but characteristics of cytokines response in enterovirus 71 (EV-71) and/or coxsackievirus A16 (CV-A16) associated HFMD with or without viral encephalitis remained unclear.We performed a multigroup retrospective study and compared the serum cytokines concentrations among 16 encephalitis patients infected with EV-71 and CV-A16, 24 encephalitis patients with single EV-71 infection, 34 mild HFMD patients with EV-71 infection, 18 mild HFMD patients with CV-A16 infection, and 39 healthy control subjects.Serum levels of interleukin (IL)-4, IL-5, IL-22, and IL-23 were significantly higher in encephalitis patients than in HFMD-alone patients when adjusting for age and sex; IL-2, tumor necrosis factor (TNF)-α, IL-4, IL-22, and IL-1β were significantly higher in HFMD-alone patients of EV-71 infection than in CV-A16 infected HFMD patients; cerebrospinal fluid level of IL-6 was lower in the EV-71/CV-A16 associated encephalitis than that in the EV-71 alone associated encephalitis patients.Over or low expression of the cytokines cascade in HFMD patients appears to play an important role in the elicitation of the immune response to EV-71 and CV-A16. These data will be used to define a cytokine profile, which might help to recognize HFMD patients with the high risk of developing encephalitis.

Changes of circulating Th22 cells in children with hand, foot, and mouth disease caused by enterovirus 71 infection

“…In the current study, significant differences in plasma levels of IL-22 were observed among HC and, mild and severe patients, which suggested that elevated levels of IL-22 cytokines might play an important role in the pathogenesis of EV71-associated HFMD, which was consistent with previous reports [29]. Subsequent correlation analysis of plasma levels of IL-22 and the frequencies of cTh22 cells further indicated that increased IL-22 levels might be predominantly secreted by cTh22 cells in the patients with EV71-associated HFMD.…”

“…In this study, correlation analysis showed an increase in the plasma levels of IL-17A and the frequencies of cTh17 cells, which also implied that the increased IL-17A expressions might be predominantly produced by cTh17 cells and associated with the pathogenesis of EV71-associated HFMD. Moreover, plasma levels of TNF-α, IL-6 and IL-23 cytokines were significantly higher in the EV71-associated HFMD patients than in HC, particularly in the severe patients, which was consistent with previous reports [4, 29, 30]. These findings indicated that increased plasma levels of cytokines (TNF-α, IL-6 and IL-23) possibly could explain the increased percentages of cTh22 and cTh17 cells and plasma levels of IL-22 and IL-17A in patients with EV71-associated HFMD, particularly in the severe patients.…”

Predicting Severe Enterovirus 71-Infected Hand, Foot, and Mouth Disease: Cytokines and Chemokines

“…The levels of IL-4 among the cases were significantly different and increased from the 2nd day to the 4th day (p < 0:001), especially in the fatal cases accompanied with brainstem encephalitis, neurogenic pulmonary edema, and sepsis [10]. On the other hand, serum levels of IL-4 were significantly higher in the EV71-infected encephalitis patients than those in the HFMD-alone patients when adjusting for age and sex [29]. In this way, it is strongly believed that EV71 infection is associated with higher risk of encephalitis development.…”

“…IL-4 is mainly produced by Th2 cells, mast cells, and basophils, which can promote the proliferation and differentiation of B cells, induce IgG1 and IgE production, facilitate Th0 cells to differentiate into Th2 cells, and so on [28]. The dynamic changes of the IL-4 with the progression of HFMD and its severity have been studied [10,22,29]. The levels of IL-4 among the cases were significantly different and increased from the 2nd day to the 4th day (p < 0:001), especially in the fatal cases accompanied with brainstem encephalitis, neurogenic pulmonary edema, and sepsis [10].…”

Differences in the Levels of Interleukin-1β (IL-1β) and Interleukin-1 Receptor Antagonist (IL-1ra) in Children with Status Epilepticus and Febrile Seizure

“…Zhang and colleagues also showed that HFMD cases with clinical meningoencephalitis caused by viral infection (enterovirus and coxsackie virus) showed higher levels of IL-1β than those without meningoencephalitis [13]. A previous study demonstrated that bacterial meningoencephalitis (meningococcus or pneumococcus) caused an elevation of IL-1β [8].…”