According to World Health Organization (WHO) reports, China is one of the countries with high incidence of HFMD[15]. Since 2008 the outbreak, HFMD has been listed as the type C statutorily notifiable infectious diseases[16] and under constant surveillance. The east coastal cities of China have carried out earlier researches and summarized some regional epidemiological characteristics of HFMD, including the prevalence in children under five years old[17], with a higher incidence in male in local residents, one peak in a year[18], and EV-A71 was the most common causative pathogen[1,7,19].
In recent years, central and western cities of China, like Sichuan and Xinjiang, also have gradually conducted research on HFMD and found obviously regional epidemiological characteristics, such as two peak epidemic seasons in a year[1], and EV-A71 and Cox A16 were considered as the common aetiological agents in local areas[7,21]. Kunming, as a southwest inland city of China, also has made constant surveillance with HFMD for over a decade. A few reports showed the research results of the local incidence of HFMD before 2017, and found that children aged 1-3 and scattered residence were at the highest risk, the ratio of male to female was 1.5:1, a major peak during April to June followed by a autumn peak during October to November, and EV-A71, Cox A16, and other enteroviruses were the most common causative pathogens[22]. These results reflected some regional epidemiological and etiological characteristics of HFMD in Kunming before the vaccination of EV-A71 vaccine, and played a certain role in the prevention and control.
Since 2016, the inactivated monovalent EV-A71 vaccine has been inoculated nationwide in China, which significantly reduces the EV-A71-associated HFMD over 90%[23]. However, due to no cross-protection from the vaccine and the high rate of gene mutation and recombination in other serotypes[24], the prevalence of HFMD remain high, such as Cox A16 replaced EV-A71 in Guangzhou, Shenzhen and Xinjiang; Cox A6 as the dominant serotypes pathogens prevailed in Xiangyang and Sichuan[4,14]. Kunming, from 2017 to 2020, about 600,000 doses of inactivated monovalent EV-A71 vaccines have been vaccinated by the local CDC, and the incidence of EV-A71-associated HFMD has decreased dramatically, 10.4% in 2017 and only 1.3% in 2019. In 2017, other enteroviruses replaced EV-A71 as the predominant serotype pathogen and accounted for 76.2%. However, Cox A6 and Cox A16 showed an increasing trend from 2017 to 2019, with significant outbreaks in 2018 (33.3%) and 2019 (47.2%), respectively. Meanwhile, the peak time was longer than that before vaccination EV-A71 vaccine, the major peak extended for two months from April to August, and the junior peak extended for four months from September to next February. This phenomenon mainly due to the vaccination EV-A71 vaccine impart selective pressure for these other serotypes pathogens to emerge at high proportions[25], and the different enterovirus genotypes with dissimilar activity and transmission characteristics, under the influences of complex social and climatic factors[7,26], which can cause differing scales and peak patterns[27].
In addition, after the COVID-19 outbreak, we found that the incidence of Cox A6 and Cox A10 has increased significantly, and Cox A6 replaced Cox A16 as the predominant serotype pathogens and accounted for 70.8%. From the end of 2019, the junior peak disappeared and presented a platform shape until next February. In 2020, it only presented a single peak, and continued from July to next February. We speculate that the main reasons are as follows. First, the effective personal hygiene propaganda during the epidemic period, such as reducing physical contact, wearing masks and washing hands, which effectively reduced the transmission route of HFMD. Second, public places were closed and children with HFMD were completely isolated at home. Third, the surveillance of population flow has obviously affected the epidemic and outbreak cycle of different pathogens.
In order to further understand the evolutionary dynamics of HFMD enterovirus and enhance the vaccination strategies in Kunming, we introduce the spatial and temporal description of the epidemiological and aetiological characteristics. The spatial-temporal scanning includes geographic information, corrects the non-uniform population density in different places, makes up for the deficiency of the simple epidemiological morbidity comparison, objectively and comprehensively evaluates the abnormal increase and the incidence aggregation area in both time and space dimensions[28].
From 2017 to 2020, by using spatial-temporal scanning, we analyzed the number of cases of HFMD mainly concentrated in Guandu, Xishan, Wuhua, Panlong and Chenggong, and the high incidence of HFMD areas were Guandu, Chenggong and Xishan. Both the number and incidence of HFMD presented outbreak in 2018 and 2019, and continued to increase in Chenggong. Spatial aggregation means that the risk of HFMD is significantly higher in some areas than in others, probably because of more residential and high population density, which can lead to clustered infection. In addition, it is interesting to note that these areas are mainly concentrated near the Panlong river and Dianchi lake, which indicates that the prevalence of HFMD may be associated with the humidity, pollution or other factors related to the lake. Moreover, different pathogens have different spatial and temporal distribution, and which also occurs in the same pathogen. In 2017, other enteroviruses as the predominant serotype pathogens, the areas with high proportion were Shilin, Yiliang and Anning. In 2018, Cox A16 was mainly prevalent in Luquan, Xundian and Fumin; Cox A6 was mainly prevalent in Shilin, Dongchuan and Jinning. In 2019, Cox A16 as the predominant serotype pathogens, the areas with high proportion were Jinning, Yiliang and Chenggong. In 2020, Cox A6 as the predominant serotype pathogens, the areas with high proportion were Luquan, Dongchuan and Anning; Cox A10 was mainly prevalent in Shilin, Songming and Yiliang. Although the annual total incidence of HFMD is directly related to population density, the annual incidence of different enterovirus serotype appears in different regions, which will bring great challenges to the epidemic prevention work of HFMD. It was reported that the epidemics of EV-A71 or Cox A16 circulates in a cyclical pattern of every 2-3 years[29]. Throughout the Kunming after vaccination EV-A71 vaccines, we have noticed that other enteroviruses has decreased significantly since 2018, but by 2019, it has remained stable at 15% to 20%; Cox A16 gradually increased from 2018 and broke out in 2019; Cox A6 broke out regionally in 2018, and gradually increased in 2019; Cox A10 increased since 2018. After the COVID-19 pandemic, Cox A6 broke out throughout the Kunming, Cox A10 broke out regionally, and other enteroviruses remained stable at 20% and surpassed Cox A6. We found that the epidemics and outbreaks of Cox A6 and Cox A16 associated HFMD appeared alternately, and the cycle was only 1 year; Cox A10 and other enteroviruses, although the incidence was not high, they were possible associated potential risk pathogens for outbreaks of HFMD in the next cycle period.
This study has several limitations should be acknowledged. First, HFMD are asymptomatic and self-limiting, thus part cases of HFMD may be ignored through the passive surveillance system, and the actual cases may have been underestimated. Second, we did not test the enterovirus serotypes beyond EV-A71, Cox A16, Cox A6, Cox A10 and other serotypes, because that which had not been dominant in the past based on other studies. Third, we analyzed the association between the spatial and temporal distribution of infectious diseases, but the spread of disease is influenced by a variety of factors, such as meteorological, socioeconomic, health resource and traffic variables. However, due to limited access to data, these factors were not considered in this study.