Epidemiological characteristics and analysis of hand-foot-mouth disease epidemics with EV71 vaccination in Henan Province, China
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Epidemiological characteristics and analysis of
hand-foot-mouth disease epidemics with EV71
vaccination in Henan Province, China
Chunlan Song
Department of Emergency Medicine，Children's Hospital Affiliated of Zhengzhou University, Henan
Children's Hospital Zhengzhou Children's Hospital, Zhengzhou
Xue Zhang
Department of Emergency Medicine，Children's Hospital Affiliated of Zhengzhou University, Henan
Children's Hospital Zhengzhou Children's Hospital, Zhengzhou
Peng Li
Department of Emergency Medicine，Children's Hospital Affiliated of Zhengzhou University, Henan
Children's Hospital Zhengzhou Children's Hospital, Zhengzhou
Ke Yuan
National Joint Engineering Research Center for Infection Diseases and Cancer Diagnosis, Changsha
Junhao Cui
Department of Emergency Medicine，Children's Hospital Affiliated of Zhengzhou University, Henan
Children's Hospital Zhengzhou Children's Hospital, Zhengzhou
Yangji Wang
Department of Emergency Medicine，Children's Hospital Affiliated of Zhengzhou University, Henan
Children's Hospital Zhengzhou Children's Hospital, Zhengzhou
Shuqin Fu
Department of Emergency Medicine，Children's Hospital Affiliated of Zhengzhou University, Henan
Children's Hospital Zhengzhou Children's Hospital, Zhengzhou
Wanying Li
Department of Emergency Medicine，Children's Hospital Affiliated of Zhengzhou University, Henan
Children's Hospital Zhengzhou Children's Hospital, Zhengzhou
Lizhong Dai ( lizhongd@sansure.com.cn )
National Joint Engineering Research Center for Infection Diseases and Cancer Diagnosis, Changsha
Research Article
Keywords: Hand-foot-month disease,epidemiological characteristics,spatial autocorrelation,EV71
vaccination, Henan Province
Page 1/25
Posted Date: June 17th, 2022
DOI: https://doi.org/10.21203/rs.3.rs-1683296/v1
License: This work is licensed under a Creative Commons Attribution 4.0 International License.
Read Full License
Page 2/25
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
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
Page 4/252.1 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.
Page 5/25Number Percentage (%) Gender Male 11823 61% Female 7689 39% Age 0-2 13173 67.5% 2-5 5747 29.46% 6-14 589 3.02% >14 4 0.02% Severe case Yes 237 1% No 19275 99% Death 2
Jiyuan city 21 0.11%
Jiaozuo city 150 0.77%
Kaifeng city 112 0.57%
Lankao city 13 0.07%
Luyi city 37 0.19%
Luoyang city 24 0.12%
Luohe city 26 0.13%
Nanyang city 45 0.23%
Pingdingshan city 39 0.2%
Puyang city 10 0.05%
Ruzhou city 96 0.49%
Sanmenxia city 11 0.06%
Shangqiu city 84 0.43%
Xincaixian city 9 0.05%
Xinxiang city 576 2.95%
Xinyang city 38 0.19%
Xuchang city 579 2.97%
Yongcheng city 7 0.04%
Changyuanxian city 11 0.06%
Zhengzhou city 16965 86.95%
Zhoukou city 387 1.98%
Zhumadian city 138 0.71%
Other province 35 0.18%
Monthly HFMD incidence
2016
Jan 306 1.57%
Feb 152 0.78%
Mar 486 2.49%
Apr 2243 11.5%
Page 7/25May 4744 24.31%
Jun 3756 19.25%
Jul 2371 12.15%
Aug 1774 9.09%
Sep 1323 6.78%
Oct 895 4.59%
Nov 971 4.98%
Dec 468 2.40%
2015
Jan 1 0.005%
Dec 22 0.11%
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
Page 8/25district) 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
Page 9/25showed 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.
Page 10/25Month Age(year) Number
2016
Jan 0-5 298
6-14 8
>14 0
Total 306
Feb 0-5 145
6-14 7
>14 0
Total 152
Mar 0-5 478
6-14 8
>14 0
Total 486
Apr 0-5 2195
6-14 48
>14 0
Total 2243
May 0-5 4563
6-14 181
>14 0
Total 4744
Jun 0-5 3637
6-14 119
>14 0
Total 3756
Jul 0-5 2291
6-14 77
>14 3
Page 11/25Total 2371
Aug 0-5 1726
6-14 48
>14 0
Total 1774
Sep 0-5 1286
6-14 36
>14 1
Total 1323
Oct 0-5 872
6-14 23
>14 0
Total 895
Nov 0-5 948
6-14 23
>14 0
Total 971
Dec 0-5 458
6-14 10
>14 0
Total 468
2015
Dec 0-5 22
6-14 1
>14 0
Total 23
Table 3
Gender difference analysis of HFMD cases among different age groups.
Page 12/25Age Male(n) Female(n)
0-2 7846 5330
3-5 3167 2130
6-14 359 230
>14 4 0
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
Page 13/25Location Number Percentage (%)
Zhongyuan district 1504 8.87%
Erqi district 1050 6.18%
Jinshui district 5474 32.27%
Huiji district 1571 9.26%
Guancheng district 1348 7.95%
Shangjie district 67 0.39%
Gongyi country 39 0.23%
Xinzheng country 588 3.46%
Dengfeng country 47 0.28%
Xinmi country 397 2.34%
Xingyang country 386 2.28%
Zhongmu country 781 4.6%
Jishukaifa district 1249 7.35%
Zhengdong district 2335 13.76%
Hangkonggang district 279 1.64%
Others 438 2.58%
Total 16965 100%
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
Page 14/25Since 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.
Year Number of HFMD Severe case Death case PE(+) EV71(+) Cox A16(+)
2016 19,512 237 2 98 168 24
2017 10242 75 2 95 29 54
2018 15977 150 0 124 0 3
2019 10090 6 0 40 2 34
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 theprevention 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
Page 16/25HFMD 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.
Page 17/25Acknowledgements: Not applicable.
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Figures
Page 20/25Figure 1
The location of Henan province in China. (The author drew this map by ArcGIS10.5 software)
Page 21/25Figure 2
Age distribution of HFMD cases in Zhengzhou Children's Hospital in 2016.
Page 22/25Figure 3
Monthly HFMD incidence in Zhengzhou Children's Hospital in 2016.
Page 23/25Figure 4
Spatial difference and spatiotemporal distribution of HFMD incidence in Henan province in 2016. (The
author drew this map by ArcGIS10.5)
Page 24/25Figure 5
Local Indicators of Spatial Association (LISA) cluster maps for Zhengzhou HFMD incidence. (The author
drew this map by ArcGIS10.5)
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