Hand, foot, and mouth (HFMD) disease is an infectious disease caused by a group of enteroviruses [1
], mainly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71), and recently, coxsackievirus A6 (CVA6) is playing a more important role [2
]. HFMD is typically characterized by fever, skin eruptions on hands, feet, buttocks, and vesicles/ulcer in the mouth. Most HFMD cases are mild and self-limited; however, some cases rapidly develop serious complications, such as meningitis and encephalitis, which can be fatal [3
]. Enteroviruses are spread by various routes of transmission, including direct contact fluid from blisters, through the gastrointestinal tract, and the respiratory tract.
As one of the most serious epidemic areas, China was heavily burdened with HFMD. It was estimated that the incidence of HFMD was 1.2 per 1000 person years in the 2010–2012 period in China, and the disease was responsible for 500–900 reported deaths every year, mainly in children [4
]. The 2016 Chinese yearbook of health statistics showed that incidence of HFMD ranked the first in the list of 39 notifiable infectious diseases, followed by tuberculosis and hepatitis. Chongqing is the largest municipality under direct control of the national government in China, located in the southwestern part of China. Previous studies about HFMD were mainly focused on characteristics of hospitalized cases [5
], and lack of geographic information; therefore, the epidemiological characteristics and spatial–temporal patterns of HFMD in Chongqing were still unclear. EV71 vaccines have been licensed by the Chinese Food and Drug Administration in 2015, but not widely used in Chongqing yet.
We conducted this study to present the most comprehensive and updated epidemiological evidence of HFMD, and to detect spatial–temporal clusters in Chongqing, China, from 2009 to 2016.
Chongqing, the largest municipality under direct control of the national government in China, has experienced a continuous increase in incidence of HFMD from 2009 to 2016. The incidence was much higher than the national incidence, as well as that in many countries or regions over the same time period [4
The epi-curve of HFMD in Chongqing exhibited a phenomenon of increasing incidence in a two-year cycle, similar to other provinces in China [9
], which was not the same as the epidemic pattern in Taiwan [10
], Singapore [11
], Malaysia [12
], and Japan [13
], where it was shown that the epidemic pattern of HFMD occurred every 3 to 4 years. Besides, HFMD showed semiannual peaks of activity in Chongqing, which was also commonly observed in other southern provinces in China [4
] and other countries, such as Vietnam [15
], and Singapore [11
], but different from annual epidemics in Japan [4
]. Several factors have been proposed to explain the different seasonal patterns of HFMD in different regions, including the temperature, humidity, other meteorological factors, host susceptibility, population density, birth rate, and the environmental conditions [16
]. In order to better understand the influential factors of HFMD and predict future occurrence of HFMD in Chongqing, future studies including these indicators should be considered in this area.
Even though strategies and measurements, such as symptoms surveillance in the gate of kindergartens and primary schools, timely isolation of cases, and daily disinfecting of toys and environment, were brought up for intervening the transmission of HFMD in Chongqing and all over China, the number of cases still increased in this seven-year period, which might be attributed to several influential factors, including improvement of the awareness of HFMD among the physicians in hospital and the parents of children, which might lead to the increase in the number of hospital visits, diagnoses, and reporting; these measures were not strictly complied with, since some facilities such as private kindergartens want to make profits by keeping more children in, and did not isolate the HFMD-infected child by sending him/her home, which will lead to sustained transmission of HFMD in kindergartens, and they might not disinfect the toys or environment regularly according to guidelines for reducing cost.
The observed age profile of infection in this study showed sharp discordance among the different age groups. More than 90% of cases were concentrated in children less than five years old, and especially those under three years old; the median age of severe cases was younger than mild cases, in line with some other reports [4
]. One of the important explanations of discordance among the different age groups was that the levels of antibodies against enteroviruses were increased by age, because of asymptomatic infection [29
]. Consistent with previous studies [4
], males were more frequently infected than females, and so was the ratio of severe cases; this phenomenon may be related to some factors including male susceptibility at the host genetic level, host immune status, behavior pattern, and it may also be due to reporting bias [4
The districts/counties with high-incidence showing clustering were consisted of the main urban districts and northeast counties, according to incidence rates comparison or spatial–temporal cluster analysis. Several possible explanations were the density of population, the suitable meteorological conditions, the socioeconomic status, availability of health care, and the diagnosis level in these regions, which needed to be further researched.
Regarding the etiology, in line with previous reports [4
], EV71 was the major causative agent of severe cases of HFMD. One of the most important explanations might be that EV71 is more virulent than other enteroviruses. Thus, the serological distribution of the enteroviruses can be a predictor for the early warning of epidemics of fatal cases, and we also consider that the principal and most promising strategy of controlling and preventing severe and fatal HFMD cases is to prevent EV71 circulation in children through mass EV71 vaccination [32
Given the public health impact and epidemiological characteristic of HFMD in Chongqing, and EV71, with which vaccines for prevention can decrease the fraction of total HFMD cases [32
], integrated strategies and measurements are recommended, including improving awareness of the importance of hand-washing for preventing HFMD, regularly cleaning and disinfecting the toys, appliances, and environment in kindergartens [7
], timely isolation of the patient, and allowing the child to come back kindergarten only if recovered.
To the best of our knowledge, this is the most comprehensive study of HFMD up to now in Chongqing, China. The findings can be helpful for the control and prevention of HFMD epidemics in this area. Moreover, our results will serve as a pre-vaccination baseline against which future interventions can be evaluated.
Some limitations of this study deserve mention. First, only 6.7% of the reported HFMD cases were tested for the pathogens associated with the infection, due to that the purpose of laboratory testing is to determine the predominant virus circulation in Chongqing, rather than to verify each case with HFMD. Second, we did not determine the serotype enteroviruses beyond CVA16 and EV71, especially CVA6, which was observed to have increased dramatically in recent years [33
]; further studies are needed to identify other enteroviruses in future, and then accelerate the development of vaccines against those pathogens, which will play an important role in the prevention of HFMD. Third, the HFMD surveillance system has only been operated for around eight years; a longer time for trend analysis is probably needed in future, and this surveillance system is a passive information collecting system, and might be underreporting HFMD cases, especially mild cases, which could lead to underestimation of the incidence rate.