The HFMD epidemics in China during 2008-2009 share many similarities with previous large outbreaks in the Asia-Pacific area.14,15
Preschool children, particularly the 1.0–2.9 years old, had the highest risk of acquiring HFMD, whereas infants had the greatest risk of severe complication and death. Males were more susceptible to disease and complications. EV71 was responsible for the majority of severe complications and deaths, whereas CA16 usually caused only mild symptoms. We found that temperature and wind speed were important, and relative humidity and precipitation were mild, risk modifiers for aggregate human-to-human transmission. The favorable effect of high relative humidity for viral transmission has been previously documented for polioviruses.16
Despite the enormous numbers of cases, the reported annual attack rates, 0.38 and 0.89 per thousand in 2008 and 2009, are lower than 6.1 per thousand in Taiwan’s 1998 outbreak and 3.5+ per thousand in Singapore’s outbreaks during 2002 and 2005–2007.14,17
Ho et al. reported 0.083 per thousand for the proportion of severe cases and 19.3% for the severe case fatality ratio among people under 15 years of age in the 1998 epidemic of Taiwan,14
while the corresponding figures are 0.090 per thousand and 2.6% among children under 10 years of age in 2009 in mainland China. The gap in the severe case fatality ratio could result from better treatment options for Chinese patients ten years after the outbreak in Taiwan or from the difference in the definition of severe cases. The EV71 lineages differ between the two outbreaks, C2 in Taiwan and C4 in China, but we are not aware of any systematic comparison of the virulence between different lineages of EV71. The proportions of EV71 among lab-confirmed severe cases were similar (around 80%) in the 1998 outbreak of Taiwan and the 2008–2009 outbreaks of China.
We found that severe cases and infant cases are associated with longer delay in diagnosis. Extremity rash or oral ulcers appeared less frequently in severe cases than in mild cases, and neurological complications are not specific to enteroviruses, both of which might have contributed to the delay in diagnosis. It is possible that the delay in diagnosis had in turn contributed to further deterioration of the disease to cardiorespiratory complications or even death in China. Such deterioration, if occurred, often progressed fast, generally in three to five days.18
The delay in diagnosis in infants was likely related to the fact that infants have a higher baseline body temperature and are thus more tolerant with fever, and that they can not really communicate their discomfort to their parents. A timely diagnosis may be a key to lowering the high mortality rate in infants, which may be achieved by educational campaigns about monitoring signs of HFMD among parents of newborns. The reason for the longer delay in diagnosis in Guangdong province compared to the rest of China is much less obvious. Guangdong province has been traditionally more industrialized than other regions, with a large volume of migrant labor workers from rural areas of inland provinces. This subpopulation has a relatively low economic status and hygienic conditions, and medical services are likely to be less accessible to them. This conjecture may be verified by collecting socioeconomic, hygienic and behavioral data from cases in the future.
HFMD was moderately transmissible with the estimated local effective R between 1.4 and 1.6 during the peak season. The estimates for the basic reproductive number R0
for polioviruses, another family of enterovirus, range from 5 to 15,16
but these estimates were based on serosurveillance data and are not comparable to our estimates for the local effective R. The dominance of local transmission suggests that more information about risk determinants is hidden within prefectures and warrants future analysis at a finer spatial scale such as counties or townships. The lack of finer spatial resolution data for risk factors limited our analysis to the prefecture level.
While most cases were younger than six years of age, our analysis revealed a strong effect of school closure on the epidemic. A plausible explanation is that substantial asymptomatic infections occurred among young school children during school mixing, and these asymptomatic children further transmitted the disease to their younger siblings or neighbors at home. If this speculation is true, the re-opening of schools after the summer break may partially account for the second rise of the epicurve in September. This speculation is partially supported by a serosurvey study in Taiwan which found that nearly 70% of EV71 seropositive children under six years of age were asymptomatic and the New York virus watch program in the 1960s which found that > 40% children of ≥ 5 years infected with Coxsackie viruses had no illness.7,19
Adults were found to have high proportions of asymptomatic EV71 infection in Taiwan5
or of detectable EV71 antibodies in Germany.20,21
Future serosurvey studies are needed in China to confirm the role of asymptomatic infections among school children and adults in the epidemics. These people are possible targets for vaccine design as they generally have much better immune response than preschool children.
Neither asymptomatic infections nor under-reporting of symptomatic cases are explicitly considered in our model due to the lack of information. Under-reporting is possible if, for example, overwhelmed medical facilities tended to adopt more strict diagnosis criteria. Ignoring unobserved infections, asymptomatic or unreported, will not bias the estimates of aggregate human-to-human transmissibility under the assumptions that (1) unobserved cases are as infectious as observed symptomatic cases, and (2) the probability of not being observed given infection does not changes over time or space (online supplementary materials
). However, the effect of a risk factor can be biased if the probability of not being observed differs across the levels of the risk factor. For example, infected adults may be more likely than children to be asymptomatic or less likely to seek medical care, which is a potential source of bias for the age effect on transmissibility.
It is more rational to model the transmission process of each type of enterovirus separately with appropriate consideration of inter-pathogen interaction. This may be pursued after the completion of the virological confirmation of local specimens in the national laboratories of Chinese CDC. On the other hand, the estimated transmission rates can be interpreted as the averages over the co-circulating pathogens, and the estimated risk ratios have the interpretation of average effects if the true risk ratios are similar across pathogens (online supplementary materials
Our model fits the incidence of HFMD well for most of the year except for the peak weeks in April and May of 2009, suggesting that there are unknown risk factors that drove the epidemic to the peak in such a short time. To inform prevention and control strategies, it is crucial to identify these underlying risk factors through field studies. Some insights may be provided by conducting a case-control study that samples subjects over the duration of an outbreak and across spatial regions, traces exposure history of each subject, and performs environmental sampling of the viruses.
The aggregated nature of our data means that we are estimating average effects for risk factors collected at the population level, and so the results may not reflect the effects of these factors at the individual level, due to the “ecological fallacy”.22,23
For example, the estimated effects of the climate indices at the prefecture level may not reflect the effects at the township level. However, the age and gender effects based on our model can be interpreted as individual-level effects because each age-gender stratum of each prefecture was modeled as an transmission unit.
Following the large outbreaks in 2008 and 2009, the incidence of HFMD continued to rise during 2010 in the Western Pacific region, particularly in China, Japan, South Korea and Singapore.24
Despite the fact that HFMD is an ongoing threat to regional health and can potentially become an emerging threat to global health, there appears to be a lack of studies and plans for intervention strategies. Our quantification of the population-level transmissibility and the effects of risk factors using surveillance data provides a basis for the use of mathematical or statistical models to evaluate the effectiveness of possible intervention strategies. The epidemiological hypotheses generated by our analyses need to be addressed by both the collection of more information in surveillance questionaires and the implementation of appropriate field studies.