In our study, 224 patients with laboratory-confirmed EV71 infection were enrolled. Approximately one-fourth of the EV71 patients had viremia detected in acute stage of disease. To our knowledge, this is the first study to investigate the correlation between EV71 viremia and the clinical severity of EV71 infection and we found that prolonged viremia was associated with the risk of severe complicated course of EV71 infection.
As for EV71 infection, the classical clinical manifestation, disease course and possible impacts on neurologic and cognitive function has been documented thoroughly in previous studies [4, 21, 22, 28, 29]. In our study, patients with complicated EV71 infection accounted for about 60% of total EV71 cases. Most of them had only myoclonic jerk. Compared to previous epidemiology data [4, 7, 30, 31], the proportion of cases with severe CNS involvement was lower in our cohort. This reduction may be related to different cohorts or different hospital setting.
According to previous retrospective studies, the age of patients is an important risk factor of severe EV71 infection [16, 32]. Our study demonstrated similar tendency, that is, younger children were more vulnerable to have CNS involvement. We also found that children with age under one had a significantly higher rate of viremia, which might be correlated to more complicated clinical manifestations.
Most of the cases with viremia in this study were detected before the third day of disease. This tendency is compatible to the clinical observation about the mean duration of a prodromal stage with fever before the following neurologic complications caused by EV71 . After the third day of disease onset, the proportion of patients with viremia decreased to around one-fourth although the proportion of complicated disease remained at the similar level. No viremia was detected after the seventh day of disease onset even if these patients had persistent clinical symptoms, indicating that the resolution of enterovirus viremia occurred most within seven days and that deterioration of the clinical disease beyond seven days was rare. In animal models, the viral kinetics in the systemic EV71 infection in rhesus monkeys also revealed a similar pattern compared to our study .
Additionally, the percentages of patients with CNS involvement in patients with or without viremia were similar and we did not find the positive correlation between the presence of viremia and the clinical severity of EV71 infection. Viremia is an interesting topic of virus infection and many researchers have taken great efforts to establish correlation between the clinical manifestation and the duration or the magnitude of viremia in several viral diseases. In some viral infections, such as the Epstein–Bar virus and cytomegalovirus disease [33–35], the presence or the magnitude of viremia may be able to predict clinical severity, while in other cases, such as dengue virus, norovirus and hantavirus, the presence of viremia usually only indicated the active stage of disease, but did not absolutely predict the clinical severity [36–39]. The observation in our study suggested that EV71 might be more similar to the later ones.
A possible explanation is that EV71 is considered to be a neurotropic infectious microorganism  and the presence of viremia is not the most crucial step for its severe infection. Viremia may only occur in a certain stage of EV71 infection for a short period and most resolve spontaneously soon afterwards. Another supporting evidence is that the virus can be detected from throat swab and rectal swab [19, 32, 41], which are the primary sites of EV71 infection and it is the cellular tropism that contributes to the clinical presentations and the following complications, for example, myoclonic jerk and other CNS involvement in EV71 infection.
Furthermore, we found that the proportion of detected viremic cases in patients with severe complications (grade 3 to 4) remained similar after the third day of disease while the proportion of viremia decreased in those who had mild diseases (grade 1 to 2). The finding suggested the viremia might persist longer in those who had severe diseases and thus their risk of systemic involvement and complications increased. In addition, the proportion of patients with severe CNS involvement and cardiopulmonary failure increased in those patients whose viremia was detected after the third day of disease. That is to say, a much higher virus burden, prolonged viremic phase or the consequent immunologic reactions might be the principle mechanism of the severe complications of disease rather than viremia alone. Previous studies suggested that the most severe form of EV71 infection causing pulmonary edema might result from the overreaction of immune system and consequent cytokine storm [19, 42]. Besides, a prospective cohort study performed in Sarawak during three EV71 outbreaks over seven years and our previous study [2, 8], showing that a fever for three days or longer was associated with neurological complications, may also support this hypothesis. On the other hand, a previous pathogenesis study performed in rhesus monkey has suggested CNS invasion was correlated with severe CNS diseases with pulmonary edema and the viral loads in the CNS were parallel to the viremia. As a result, a prolonged viremia may increase the viral load in the CNS and is more likely to lead to more severe CNS disease and further cardiopulmonary failure .
Nevertheless, the clinical severity of EV71 infection may be multifactorial and is not determined only by the presence of viremia. Either the different virulence of different genotypes, host factors and other socioeconomic factors [13, 19–22] may contribute to the severe complication and sequelae of EV71 infection as well.
There are some limitations in our study. First, we only collected blood samples for PCR test at one time point in each patient and it is difficult to describe the kinetics and the duration of viremia. A kinetic data could provide more information about the influence of viremia on the clinical manifestation, disease severity and the whole course of EV71 infection. It is also impossible to determine the peak viral load of individuals and this limitation makes it more difficult to clarify the definite relationship between the magnitude of viremia and the clinical manifestation. Second, most patients in our cohort had only uncomplicated disease or myoclonic jerk and the proportion of severe CNS complications or further cardiopulmonary failure was relatively low. Because the epidemics of non-polio enterovirus occurred almost every year in Taiwan, the decreased severity of EV71 infection may result from partial cross-protection from previous enterovirus infection by different serotypes or genotypes . Only 15.6% of patients with EV71 infection in this study had severe complications. The sample size was not large enough to establish the correlation between viremia and severe complications of EV71 infection.