br Results br Discussion Adult
Discussion Adult hand, foot and mouth disease gets no particular research interest because it has been seen as a sporadic mild viral infection that spontaneously resolved in a few days. However, evidence showed that adults may act as latent enterovirus reservoirs. A serum epidemiological study reported that about half of the adult population in northern Taiwan had BMS 961 receptor against enterovirus, indicating the highly contagious nature of enterovirus (Ho et al., 1999). Consistently, our study showed an increasing incidence rate of adult HFMD since year 2008 (data not shown). Adult patients of HFMD are typically mild or asymptomatic, and few of them will visit the hospital. Our study found the male-to-female ratio of adult patients of HFMD is 7:13 and most of them are housewives or teachers. In this study, 68.3% of the adult patients had children under five years of age, 48.3% had child patients of HFMD in the family (p-value <0.01), and 13.3% had a child diagnosed as recurrent HFMD (p-value-0.02). These findings suggested that adult patients of HFMD have more frequent contact with children, which made them a latent infectious source of HFMD. HFMD most often was caused by a variety of enteroviruses, including EV71, CA16, CA6, CA10 (Pérez-Vélez et al., 2007, WHO, 2011). The pathogenesis of enteroviral infection is not fully elucidated. Cytokines are important cell signaling molecules, which are involved in immune responses, inflammation, and viral infection responses (Paul and Seder, 1994, Fauci, 1996, Premack and Schall, 1996, Yazdanbakhsh et al., 2002, Baxt et al., 2013, Horner and Gale, 2013). Upon viral infection, “signaling cascades” generate pro-inflammatory cytokines through a series of pathways and induce systemic inflammatory responses (Qu et al., 2018, Rajasekaran et al., 2016). Meanwhile, anti-inflammatory cytokines are produced to suppress the excessive inflammatory responses to protect the body from immune damage (Banchereau et al., 2012, Nold et al., 2010). Thus, the balance of pro-inflammatory and anti-inflammatory cytokines are key to the occurrence, development and prognosis of the infectious disease (Arpaia et al., 2013, Josefowicz et al., 2012). Prior studies found dysregulation of cytokines, specifically an imbalance in the level of pro-inflammatory and anti-inflammatory cytokines, in HFMD patients (Lin et al., 2002, Zeng et al., 2013, Ye et al., 2015). Aligned with the previous reports (Lin et al., 2003, Wang et al., 2003), our study found the expression level of 15 cytokines (Eotaxin, HGF, IFN-α2, IFN-γ, IL-2, IL-2Ra, IL-3, IL-5, IL-6, IL-12p40, IL-13, IL-15, IL-18, IP-10, and TNF-α) were significantly elevated compared with those of controls, among which, the expression of IL-6, IL-12p40, Eotaxin, and IFN-α2 were 5 to 10-fold higher than the controls, and the level of TNF-α even increased by 14 times. IL-6 acts as both pro and anti-inflammatory cytokine and is reported to be an inducer of inflammatory responses (Feghali and Wright, 1997). Elevation of IL-6 in our study indicated systemic inflammation development in the adult patients of HFMD. IL-12p40 is important in cell-mediated inflammation and the over-expression of it is reported in the central nervous system (CNS) of multiple sclerosis (MS) patients (Negishi et al., 2012, Benešová et al., 2018). The increased level of IL-12p40 in our study might suggest the risk of CNS complications in adult patients of HFMD, specifically for those who were infected with EV71 (Chang et al., 1999, Wang et al., 2015, Pérez-Vélez et al., 2007). High plasma concentrations of Eotaxin are implicated in allergic response (Lilly et al., 2001, Lamkhioued et al., 1997). EV71-associated severe cases are likely to progress to pulmonary edema (PE), and the high level of Eotaxin might indicate the risk of development of PEs. IFN-α2 is secreted by cells infected by a virus and plays as a key regulator of anti-viral response (Hillyer et al., 2017, Piehler et al., 2000). TNF-α can induce inflammation and fever, and inhibit viral replication (Baxter and Kaufmann, 2016, Lasry et al., 2016). Taken together, these observations indicated elevated inflammation in adult patients of HFMD.