Epidemiological characteristics and analysis of hand-foot-mouth disease epidemics with EV71 vaccination in Henan Province, China

Abstract

Background: Hand-foot-month disease (HFMD) is an infectious disease occurring primarily in children caused by enteroviruses. HFMD has occurred in various areas in recent years. Many research works on HFMD in different regions have been discussed and published in relevant journals. However, in some large cities, such as Zhengzhou, the epidemiological characteristics and spatiotemporal patterns of individual-level HFMD cases are unclear. The purpose of this work is to investigate the epidemiological characteristics and explore the surveillance data of HFMD in Henan province, to provide appropriate public health measures and strategies for the prevention and treatment of HFMD. Meanwhile, we hope that this work can provide prospective guidance for the analysis of epidemic and etiological study on HFMD following EV71 vaccination in Henan Province.

Methods: All patients with hand-foot-mouth disease admitted to Zhengzhou Children's Hospital in Zhengzhou City, Henan Province were selected using convenient sampling method. Detailed information including the age, occupation, pathogen, location, and gender were recorded to analyze the epidemiological characteristics of HFMD epidemics. Data from individual-level HFMD cases were examined using Local Indicators of Spatial Association (LISA) analysis to identify spatial autocorrelation of HFMD incidence. The results are described in ArcMap10.5.

Results: Before vaccination, a total of 19,512 cases of hand-foot-mouth disease were reported in Zhengzhou Children's Hospital (61% male, 39% female), including 237 severe cases and 2 deaths in 2016. After EV-A71vaccination, the result showed that the number of HMFD patients has decreased. The number of patients with HMFD infection caused by the EV 71 virus has dropped dramatically. HMFD caused by EV 71 virus can be completely controlled within 2 years after vaccination. Results showed that the incidence of HFMD cases showed obvious seasonal distribution, with the highest monthly incidence occurring in 4-7. Most of the pediatric patients were distributed in the <5 age group. Nearly 98.4% of cases were scattered or kindergarten children. The areas with relatively high relative risk are mainly located in Jinshui, Huiji, Guancheng districts of Zhengzhou (the proportion of the population at risk is about 49%), where the incidence of HFMD has a high-high positive spatial autocorrelation. The most likely space-time cluster is located in the north-central area of Jinshui district in Zhengzhou.

Conclusions: EV71 vaccination can effectively prevent and control the number of HMFD patients in Henan province. The main patients with HFMD in Henan Province are preschool children in the <5 age group, and boys are more likely to suffer from HFMD. The peak monthly incidence is mainly concentrated in 4-7. Cities with large population flow like Zhengzhou and Xuchang are the high-incidence cities of HFMD. In particular, northern cities such as Jinshui district and Zhengdong district are the districts with the highest incidence of HFMD.

1. Introduction

Hand-foot-mouth disease (HFMD), first reported in 1958, is an infectious disease that primarily affects the health of infants and preschool children [¹]. The main features of HFMD are fever, rashes or herpes on the hands, feet, mouth and other parts of body. Few patients can be complicated by aseptic meningitis, encephalitis, acute flaccid paralysis, respiratory tract infection, and myocarditis. For some severely ill children with HFMD, death may occur. More than 20 different enteroviruses were associated with HFMD, among which the proportion of severe cases caused by EV71 infection was highest [^2,3,4]. Although effective vaccines for prevention of HFMD infected by EV71 have been developed, the pathogenesis of the disease is also affected by a variety of other pathogens including group Q coxsackievirus (CoxA), echo virus (Echo) pathogens [^5,6]. Thus, it is still a big challenge to completely eradiate HFMD. At present, epidemiological surveillance, risk detection and early warning of HFMD epidemics are still critical issues [⁷].

In recent years, epidemiological cases of HFMD disease have been prevalent in the Asia-Pacific region, especially in East and Southeast Asia [^{8, 9, 10, 11}]. It was reported that the epidemic of HFMD disease occurred all over the China in 2008 [¹² ]. Since 2008, the Ministry of Health of China has classified HFMD disease as a notifiable Category C infectious disease, while it has been included in the surveillance system [¹³]. There are many factors related to the incidence of HFMD, and the prevalence of HFMD in China is affected by the time and space. In addition, social factor is also one of the important factors affecting the epidemiology of the HFMD disease [¹⁴].

Therefore, it is urgent to get a comprehensive understanding of the epidemiological characteristics and temporal and spatial distribution of HFMD disease in a timely manner, allowing for disease prevention and control in advance for relevant departments and authorities against the key populations and regions [¹⁵].Compared with conventional methods, spatiotemporal analysis can not only explore the disease location and time, but also help public health authorities to conduct timely surveillance and intervention of HFMD by identifying when and where the incidence rate is highest. A real-time spatiotemporal surveillance system will help to identify high-risk areas and population clusters, and them formulate and implement appropriate regional public health intervention strategies to prevent and control outbreaks of HFMD. In previous studies, it has been used to study the gathering area of HFMD clusters, such as Sichuan, Beijing, Shandong [^16,17,18,19]. However, it is reported that previous studies on the spatiotemporal distribution of HFMD in Zhengzhou are limited, and a comprehensive understanding of the spatiotemporal characteristics of HFMD has not been established. In addition, due to the influence of geographical location, economic conditions, social factors and climatic conditions, the spatial and temporal distribution characteristics of HFMD show some differences for different regions [²⁰]. Therefore, in this work, we aimed to study the surveillance data of HFMD in Zhengzhou city to provide appropriate public health measures and strategies for the prevention and treatment of HFMD disease. Meanwhile, we hope to provide a foundation for prospective environmental surveillance of the study area through this work.

2. Materials and methods

2.1 General information

All patients with hand-foot-mouth disease who were admitted to Zhengzhou Children's Hospital were selected as the research objects, and were randomly divided into group A and group B according to the hospitalization conditions. There was no significant difference in the general conditions of the two groups of children. The detailed information is listed in Tab.1. The study was approved by the hospital ethics committee.

Table 1

Statistics of children with hand-foot-mouth disease in Zhengzhou Children's Hospital.

2.2 Inclusion criteria

The inclusion criteria for this study are as follows: (1) The family of the child fully understood the research process and signed the informed consent; (2) The child was diagnosed with hand-foot-mouth disease according to the 2010 edition of the "Guidelines for the Diagnosis and Treatment of Hand-Foot-Mouth Disease" [²¹]; (3) The child had fever symptoms [²²].

2.3 Exclusion criteria

The exclusion criteria for pediatric patients in this study are as follows: (1) Mental problems or inability to communicate with others; (2) Suffering from other organic diseases; (3) Coma [²³]; (4) Combined with genetic diseases or brain damage [²⁴]; (5) Past history A history of epilepsy and other diseases [²⁵].

2.4 Methods

2.4.1 Study area

Zhengzhou is the capital city of Henan Province of China, located between latitude 34°16′N and 34°58′N, and longitude 112°42′E and 114°14′E (Fig.1). Zhengzhou city has a warm temperate monsoon climate with four distinct seasons and an annual average temperature of 14.4°C. Zhengzhou city consists of 6 districts (Zhongyuan district, Erqi district, Jinshui district, Huiji district, Guancheng district, Shangjie district) and 6 countries (Gongyi country, Xinzheng country, Dengfeng country, Xinmi country, Xingyang country, Zhongmu country) covering an area of 7446 km², with a permanent resident population of 7.082 million [²⁶].

 2.4.2 Data sources and visualization

Daily reported HFMD cases from Zhengzhou Children's Hospital were recorded and analyzed. All HFMD cases were reported online to the Infectious Disease Surveillance System within 24 hours of diagnosis, and were based on the unified diagnostic criteria issued by the Chinese Ministry of Health [²⁷]. The basic information was recorded and input such as age, gender, symptom date, place of residence, etc. [²⁸]

Excel 2016 and R 4.0.2 were used to analyze and process the underlying data, OpenGeoDa for spatial autocorrelation analysis and SaTScan 9.6 for spatiotemporal cluster analysis. The administrative codes of residence address of HFMD cases will be recorded matched to the map codes of the country, and the results will be shown in ArcGIS 10.5 via combined with the map of cases [²⁹].

3. Results

Epidemiological characteristics

Demographic characteristics

A total of 19,512 HFMD cases were reported in Zhengzhou Children's Hospital, including 237 severe cases and 2 deaths in 2016. The highest monthly incidence is between May and July (see Tab.1). The majority of HFMD cases are in the 0-5 year age group (96.97%, 18920 cases) in Fig.2. Most patients with HFMD are scattered children (75.5%) or kindergarten preschool children (22.9%). The remaining cases (1.6%) are students and adults. In the analysis of 290 laboratory genotyped cases, the proportions of cases infected by Cox A16, EV71 and other enterovirus infections are 8.28%, 57.93% and 33.79%, respectively. Therefore, the main causative viruses are EV71 and other enteroviruses, which is different from the previous work by Wang's group [⁷]. 

Among all HFMD cases, 11,823 were male and 7,689 were female. The gender ratio (male/female) was 1.54. The 0-5 year age group had the highest incidence of HFMD in 2016. The time of onset of HFMD cases varied among different age groups, but the difference was not significant (Tab.2), and the 0-5 age group had the highest incidence in May (4563, 23.4%), while the incidence cases reached their lowest value in February (0.7%). Among them, the incidence of the age group of >14 years old only appeared in July and September. In addition, the gender ratio of HFMD cases also varied among different age groups (in Tab.3). For the 0-14 year age group, male patients with HMFD are generally higher than female patients. However, for the >14 age group, all HFMD patients are male. Overall, the incidence of HFMD is significantly higher in male than in female, which is consistent with previous reports [⁷]. In Fig.3, the result showed that the incidence of HFMD cases showed obvious seasonal distribution, with the peak incidence in 2016 occurring in summer (between April and July). 

Table 2

 Monthly HFMD incidence and seasonal analysis among different age groups.

Table 3

 Gender difference analysis of HFMD cases among different age groups.

Demographic characteristics

In 2016, the HFMD patients in Henan Province were mainly distributed in Zhengzhou, Xuchang, and Xinxiang, among which Zhengzhou accounted for the highest proportion, reaching about 87%. Figure 4 shows the distribution of HFMD incidence in Henan Province. From Figure 4, we can see that the high incidence area of HFMD in 2016 was mainly concentrated in the center of Zhengzhou, and the epidemic spread radially and quickly spread to the whole province, especially the northern regions. The incidence of 

Table 4

 The regional autocorrelation analysis of HFMD in Zhengzhou city, Henan Province

 the southeastern regions was lower, especially in Xinxiang, Shangqiu and Zhoukou areas. In addition, there were also significant differences in the incidence of HFMD between provincial cities (Table 4). A Local Indicators of Spatial Association (LISA) analysis of the incidence of HFMD in 2016 identified distinct patterns of spatial associations in the prevalence of HFMD (Figure 5). High-High and Low-Low modes indicate clusters of similar values for HFMD incidence, while Low-High and High-Low indicate spatial outliers. The results in Figure 5 showed that the incidence of HFMD in urban and rural areas in northern Zhengzhou has a High-High positive spatial autocorrelation, while the incidence of HFMD in urban and rural areas in northwestern Zhengzhou has a stable Low-Low positive spatial autocorrelation. The towns with negative spatial associations are mainly distributed in the south and northeast of Zhengzhou.

Analysis of HMFD cases after EV71 vaccination 

Since the second half of 2016, we have implemented vaccination against hand, foot and mouth disease for residents in Henan. In this study, we conducted a comparative analysis of HFMD cases before and after vaccination, and the detailed data are recorded in Table 5. The results of this study showed that the total number of HFMD patients decreased one year after vaccination, and the proportion of EV71 positive patients decreased from 0.86% to 0.28%. After 2 years of EV71 vaccination, EV71-positive patients were fully controlled, achieving complete clearance. In the third year of vaccination, the total number of HFMD infections continued to decline, but a small number of EV71-positive patients appeared. This result showed that EV71 vaccination is time-sensitive. Certainly, this result may also be due to the fact that the number of cases collected by Zhengzhou Children’s Hospital is not comprehensive enough, resulting in deviations in the experimental results. In addition, in this work, we found that after the EV71 vaccine, the number of severe patients and death cases also decreased. Therefore, EV71 vaccination can effectively prevent and control HFMD, and can reduce the cases of severe patients and death cases.

Table 5

 Analysis of HFMD cases before and after EV71 vaccination.

4. Discussion

HFMD is a common infectious disease that has emerged in many countries since the 1970s [³⁰]. To date, HFMD is also an important public health problem in mainland China, and it has been designated as a Class C notifiable infectious disease after the outbreak of spring in 2008 [¹³]. Therefore, a comprehensive understanding of the epidemiological characteristics of HFMD is crucial for formulating scientific and effective prevention and control strategies. In our ³¹study, we found that most of the pediatric patients were distributed in the <5 age group. This result suggested that the specific age group (<5) should be targeted objects for HFMD control and prevention. In addition, it was found that males had higher rates of incidence, severe cases, and mortality with HFMD than females, suggesting that certain factors at the host genetic level, host immune status, and/or behavioral patterns increase male susceptibility. However, this could also be due to reporting bias. Significant imbalances in prevalence rate among different age groups were found. Nearly 90% of cases with HFMD were concentrated in the <5 age group, which is consistent with previous reported studies [^31,32]. According to the demographic characteristics of HFMD, children in the <5 age group, especially children from 6 months to 3 years old, are the key objects for prevention and control of HFMD, which is also the targeted objects for the EV71 vaccine that has been developed [⁴]. 

In this work, the results showed that the prevalence of HFMD had seasonal distribution. In 2016, there were two peaks of incidence of HFMD cases in summer and autumn respectively, and summer is the main incidence period (from April to July), followed by autumn (between October and November). While severe cases only showed one peak of incidence of HFMD cases in summer (from April to July). According to epidemiological and etiological surveillance, the experimental results showed that EV71 was the main enterovirus causing HFMD in confirmed severe, especially in death cases. This may be due to the fact that the basic reproductive capacity of EV71 is higher than that of Cox A16 and other enterovirus [³³]. In our study, we found that the number of HFMD cases infected by other enteroviruses was higher than that of CoxA16, which is different from previous reports. The possible reason is that the number of selected HFMD cases was insufficient when we performed laboratory virus analysis on the cases, which is also the limitation of this study. Vaccination can effectively prevent and control HMFD. The best preventive time for EV71 vaccination is 2 years after vaccination. The number of HMFD patients in Henan Province decreased after vaccination with EV-A71. The number of patients with HMFD infection caused by EV 71 virus has dropped dramatically. HMFD caused by EV 71 virus can be completely controlled within 2 years after vaccination. Therefore, regular vaccination of children with EV 71 can effectively prevent and control HFMD.

According to our study, the spatial distribution of the incidence of HFMD has also differences in different cities. We found that the most likely cluster was located in the capital city (Zhengzhou), which is consistent with previous report [³⁴]. The city with the second highest number of HFMD epidemics is Xuchang, a tourism city. These results suggested that cities with large migrant population have higher risks of HFMD epidemics. The number of HFMD incidence in Xinxiang has greatly increased, becoming the third most susceptible city to HFMD, while the number of HFMD cases in Luoyang has decreased sharply. This finding in our work is quite different from previous reports [³⁴]. In addition, our analysis of HFMD cases in Zhengzhou, a high-incidence city, found that the HFMD incidence in north area was generally higher than those in south area. The incidence of HFMD in urban and rural areas in northern Zhengzhou has a High-High positive spatial autocorrelation, while the incidence of HFMD in urban and rural areas in northwestern Zhengzhou has a stable Low-Low positive spatial autocorrelation. The towns with negative spatial associations are mainly distributed in the south and northeast of Zhengzhou. Therefore, special research about spatial analysis is worth carrying out in order to better understand the etiology of HFMD, so as to formulate more targeted and effective prevention and treatment strategies. It is worth noting that Jinshui district and Zhengdong district are the main HFMD epidemic areas, and it is recommended to strengthen the monitoring and prevention work in these areas. Certainly, some other countries and cities like Zhongyuan district, Erqi district, Huiji district, Guancheng district and Jishukaifa district should also arouse our great attention. 

Conclusion

HFMD mainly threatens children under the age of 5, and the prevention and control of HFMD in Henan Province should focus on preschool children of the ＜5 age group, especially boys. The monthly peak of incidence is mainly concentrated in 4-7. The high incidence area of HFMD in Henan Province was mainly concentrated in Zhengzhou City, and the epidemic spread radially and quickly spread to the whole province. The highest HFMD incidence was concentrated in cities with large population flow such as Zhengzhou City and Xuchang City. In the spatial cluster distribution of Zhengzhou, a high-incidence city, the northern cities such as Jinshui district and Zhengdong district are the areas with the highest incidence of HFMD. The incidence of HFMD in northern urban and rural areas showed a High-High positive spatial autocorrelation, and the incidence of HFMD in urban and rural areas in the northwest of Zhengzhou showed a stable Low-Low positive spatial autocorrelation. The towns with negative spatial associations are mainly distributed in the south and northeast of Zhengzhou. EV71 vaccination can effectively prevent and control the number of HMFD patients. EV71 vaccination had the best preventive effect after the second year of vaccination. It is suggested to invest more manpower and resources in EV71 vaccination in the northern towns of Zhengzhou City, and early control and prevention for high-incidence areas will effectively control the number of patients with hand, foot and mouth disease in Henan Province.

Declarations

Ethics approval and consent to participate: The family of the child fully understood the research process and signed the informed consent. And all methods were performed in accordance with the relevant guidelines and regulation. This study had been approved by the ethics committee of Zhengzhou Children's Hospital.

Consent for publication: All authors have read and agreed to the published version of the manuscript.

Availability of data and material: The primary data to support the results of this study are available at reasonable request to the corresponding author.

Competing interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Funding:This work was supported by Science and technology project of Henan Province (LHGJ20190920).

Authors' contributions: Chunlan Song and Ke Yuan wrote the paper, Chunlan Song and Li zhong Dai guided the writing of the paper and reviewed the manuscript, Xue Zhang, Peng Li, Junhao Cui collected the clinical information, Xue Zhang, Yangji Wang, Shuqin Fu analyzed the age and gender information , Xue Zhang, Peng Li, Wanying Li,Ke Yuan analyzed Local Indicators of Spatial Association map . All authors have read and agreed to the published version of the manuscript.

Acknowledgements: Not applicable.

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