Analysis of Epidemiological Characteristics of Scarlet Fever in Zhejiang Province, China, 2004-2018.

OBJECTIVE
The aim of this study was to analyze the trends and epidemiological characteristics of scarlet fever in Zhejiang Province in 2004-2018, intending to provide a basis for targeted prevention and control of this disease.


METHOD
We collated the epidemiological data for cases of scarlet fever from the China Information System for Disease Control and Prevention (CISDCP) in Zhejiang province between 1 January 2004 and 31 December 2018. Descriptive statistical analysis was used to analyze epidemiological characteristics of scarlet fever, whereas the Getis-Ord Gi* statistic was used to determine the hotspot incidence of scarlet fever.


RESULTS
In 2004-2018, a total of 22,194 cases of scarlet fever were reported in Zhejiang Province, with no death reports. The annual average of scarlet fever incidence was 2.82/100,000 (range,1.12 to 6.34/100,000). The male incidence was higher than that among female (χ2 = 999.834, p < 0.05), and a majority of the cases (86.42%) occurred in children aged 3-9 years. Each year, the incidence of scarlet fever in Zhejiang Province appeared two seasonal peaks: the first peak occurred from March to June (the constituent ratio was 49.06%), the second peak was lower than the first one during November and the following January (the constituent ratio was 28.67%). The two peaks were almost in accordance with the school spring semester and autumn-winter semester, respectively. The incidence in the northern regions of the province was generally higher than that in the southern regions. High-value clusters were detected in the central and northern regions, while low-value clusters occurred in the southern regions via the Getis-Ord Gi* statistical analysis.


CONCLUSIONS
The prevalence of scarlet fever in Zhejiang Province showed a marked seasonality variation and mainly clustered in the central and northern regions in 2004-2018. Children under 15 years of age were most susceptible to scarlet fever. Kindergartens and primary schools should be the focus of prevention and control, and targeted strategies and measures should be taken to reduce the incidence.


Introduction
Scarlet fever is an acute respiratory infection caused by group A Beta hemolytic streptococcus, which usually occurs in winter and spring and commonly affects children [1]. Scarlet fever typically spreads in crowds through respiratory droplets or direct contact with the mucus, saliva, or skin of the infected persons. However, some outbreaks of scarlet fever are even found to be food-borne [2]. It is more prevalent in children aged 3-9 years [3], so clustered outbreaks are more common in overcrowded places, such as kindergartens and schools. It is worth noting that currently no vaccine is available to prevent scarlet fever [4]. With antibiotic treatment, scarlet fever can be completely cured, and complications can be prevented.
In recent years, scarlet fever has begun to once again prevail in some countries due to factors such as changes in the virulence of group A streptococcus. In the past decade, many countries and regions such as Australia, the United Kingdom, Poland, South Korea, Hong Kong, and Taiwan have reported scarlet fever epidemics [5][6][7][8][9][10]. The incidence of scarlet fever in the Chinese mainland has also shown a sharp upward trend [11].
Scarlet fever is one of the Class B infectious diseases that must be reported according to the Law of the People's Republic of China on the Prevention and Control of Infectious Diseases [12]. It is also an infectious disease with high incidence and key prevention and control requirements in China. In 2006, about 1000 cases of scarlet fever outbroke in a primary school in Ningbo, Zhejiang Province [2]. In 2011, a large-scale scarlet fever epidemic occurred in Hong Kong [13], with more than 900 cases of scarlet fever and 6 cases of toxic shock syndrome (including 2 deaths). The situation of prevention and control is challenging.
The incidence of scarlet fever in Zhejiang Province has increased since 2004, especially since 2011. In this paper, we presented a descriptive analysis and Getis-Ord Gi* statistical analysis of the spatiotemporal epidemiology of scarlet fever in Zhejiang Province. The results might indicate the transmission trends and confirm the high-risk regions of scarlet fever, providing reliable information for future surveillance and control efforts of scarlet fever in Zhejiang Province. The results are reported as follows.

Data Source
The China Information System for Disease Control and Prevention (CISDCP) was initiated in 2004, which is the most comprehensive and macroscopic notifiable disease surveillance system in China [12]. Notifiable infectious disease cases have been reported to this system in real time [14].
The data of scarlet fever cases were extracted all the clinical and laboratory diagnosed cases of scarlet fever from the CISDCP, with the symptom onset date between 1 January 2004 and 31 December 2018 and the current living addresses of the subjects in Zhejiang Province. The diagnosis of scarlet fever is based on the diagnostic criteria issued by the Ministry of Health of the People's Republic of China (WS 282-2008) [15]. The population data of all ages were obtained from the subsystem "Basic Information System" of the CISDCP, which is updated annually.

Study Area
Zhejiang Province, located on the southeast coast of the China, consists of 11 cities, and has moist air, a mild climate, and a developed economy. According to the geographical orientation and landform features, we divided the 11 cities into 5 parts. The central and northern parts of Zhejiang Province are plain areas (the central region: Hangzhou, Shaoxing, and Jinhua; the northern region: Jiaxing and Huzhou), the Southern and Western parts are hilly and mountainous areas (the southern region: Wenzhou, Lishui, and Taizhou; the western region: Quzhou), and the eastern parts are coastal areas (the western region region: Ningbo and Zhoushan). It covers an area of 101,800 km 2 and is one of the most densely populated provinces in China. By 2018, the population has reached up to 56 million, and the population aged 0-14 years was about 7.6 million.

Statistical Methods
The scarlet fever cases were distributed in 11 cities in Zhejiang Province. The descriptive analysis method was used to analyze the incidence, number of cases, and composition ratio of scarlet fever in Zhejiang Province in 2004-2018. The reported incidence rate (R) of scarlet fever cases was calculated by dividing the number of reported scarlet fever cases (C) via the CISDCP by the number of inhabitants (I) registered in local public health facilities (R = C/I). The reported incidence rates were calculated per 100,000 persons. The incidence rates by male or female sex presented as per 100,000 of that sex category. Chi-square test was used to compare count data. A p < 0.05 was considered statistically significant.
The Getis-Ord Gi* statistic was used to determine the hotspot incidence of scarlet fever. The Getis-Ord Gi* statistic belongs to the category of local spatial autocorrelation analysis methods [16,17], which indicated high-value clusters (hot spots) and low-value clusters (cold spots) of scarlet fever in the entire study location. The Gi* statistic can be used as a measure of the degree of spatial clustering. The degree of clustering and its statistical significance is estimated based on a confidence level, according to the Z-scores and p-values. They indicate whether the observed spatial clustering of high or low values is different from the random distribution. If the Z (Gi*) score of the unit area is high and positive with p < 0.05, it indicates a hotspot (a high-value spatial cluster) in this region. On the contrary, if the Z (Gi*) score is low and negative with p < 0.05, it indicates a cold-spot (a low-value spatial cluster). The Z (Gi*) score is higher, the clustering degree is greater. If the Z (Gi*) score is close to zero, it indicates no obvious spatial clustering. Regions with Z-scores > 2.58 are considered to be significant at 99% confidence level (p < 0.01), and they are classified as the highest risk regions. The Z-scores between 1.65-1.96 and 1.96-2.58 are considered to be significant at 90% and 95% confidence levels (p < 0.10, and 0.05), and they are considered as high-risk regions (hot spots). Whereas, Z-scores < −1.65 means low values clusters (cold spots) [18].

Ethical Statement
This study was exempt from institutional review board assessment. Scarlet fever is one of the Class B notifiable infectious diseases. Firstly, policy documents and statistics data related to notifiable disease on public websites of China Health Department, CISDCP, Zhejiang Health Department, and Zhejiang Statistical Bureau were collected and understood. Secondly, data were acquired from secondary sources and analyzed anonymously, therefore no participant was required to provide written informed consent.

General Characteristics of Scarlet Fever
A total of 22,194 cases of scarlet fever were reported in Zhejiang Province during the period of 2004-2018, with no deaths and an average annual incidence rate of 2.82/100,000. There were almost clinically diagnosed cases which accounted for 99.31% (22,040/22,194).

Temporal Distribution
In 2004-2018, the reported incidence rate of scarlet fever showed an upward long-term trend (χ 2 trend = 4082.561, p < 0.05) in Zhejiang Province, from 1.12/100,000 in 2004 to 4.08/100,000 in 2018, and the highest annual incidence rate (6.34/100,000) was in 2015 (Figure 1). The incidences of scarlet fever were in a relatively stable state fluctuating from 0.88 to 1.90/100,000 during 2004-2010. The incidence reached 3.57/100,000 in 2011, and thereafter remained 2.22 to 6.34/100,000 (2011-2018). There were reported cases of scarlet fever in Zhejiang Province every month. Each year, the incidence rate of scarlet fever appeared two seasonal peaks. The first peak occurred from March, and gradually reached the summit during April and June. A total of 10,888 cases were reported, accounting for 49.06% (10,888/22,194). The incidence gradually decreased and reached the trough in August. The second peak occurred during November and the following January, with a summit slightly lower than the first one. A total of 6363 cases were reported, accounting for 28.67% (6363 /22,194). Then the trough following it appeared in February ( Figure 1). The incidence of scarlet fever decreased during the school holidays in winter (February) and summer (August).

Spatial Distribution
In 2004-2018, scarlet fever cases were reported in 11 cities throughout the whole province, with the highest reported incidence in Shaoxing (5.41/100,000), Hangzhou (5.39/100,000), Jiaxing (4.38/100,000), Ningbo (2.61/100,000), and Huzhou (2.12/100,000). The top five cities reported cases were in Hangzhou (6341 cases), Shaoxing (3703 cases), Ningbo (2687 cases), Jiaxing (2637 cases), and Taizhou (1843 cases) (Figure 4). Figure 5 demonstrated the clusters of scarlet fever incidence at the district level in Zhejiang Province, 2004-2018. The location and size of high value clusters varied in each year. Generally, the epidemic characteristics of scarlet fever showed the incidence in the northern regions was generally higher than that in the southern regions. The high value clusters were detected in the central and northern regions, while low value clusters occurring in the southern regions via the Getis-Ord Gi* statistical analysis. During the study period, a total of 27 clustering areas were detected by Getis-Ord Gi* analysis, including 23 high-value clustering (hot spots) areas and 4 low-value clustering (cold spots) areas. High-value clustering areas were detected in the northern regions of Zhejiang Province

Discussion
Our research provides a good basis for understanding the epidemiological characteristics of scarlet fever in Zhejiang Province in 2004-2018. The surveillance results showed that the reported incidence rate of scarlet fever varied greatly with time in Zhejiang Province in the past 15 years. Overall, the incidence rate of scarlet fever showed an upward long-term trend from 2004 to 2018, and the highest annual incidence rate was in 2015. In the past 10 years, there were some studies suggesting that scarlet fever was showing a rapid upward trend in other countries [19][20][21]. This study showed that the trend was consistent with the other regions of China [3,11,18]. Some research findings indicated that meteorological factors, as well as air pollutant factors may increase the incidence of scarlet fever [22][23][24][25], such as nitrogen oxide, rainfall, and sunshine hour were significantly associated with scarlet fever incidence. However, the underlying mechanism remained unclear; further studies should be done to explore environmental factors.
This study also showed there were two epidemic peaks each year during the current study period. The two peaks were almost in accordance with the school spring semester (from March to June) and autumn-winter semester (from November to the following January), respectively. This was also similar to the study findings in Guangdong Province, China [26], suggesting that schools may have

Discussion
Our research provides a good basis for understanding the epidemiological characteristics of scarlet fever in Zhejiang Province in 2004-2018. The surveillance results showed that the reported incidence rate of scarlet fever varied greatly with time in Zhejiang Province in the past 15 years. Overall, the incidence rate of scarlet fever showed an upward long-term trend from 2004 to 2018, and the highest annual incidence rate was in 2015. In the past 10 years, there were some studies suggesting that scarlet fever was showing a rapid upward trend in other countries [19][20][21]. This study showed that the trend was consistent with the other regions of China [3,11,18]. Some research findings indicated that meteorological factors, as well as air pollutant factors may increase the incidence of scarlet fever [22][23][24][25], such as nitrogen oxide, rainfall, and sunshine hour were significantly associated with scarlet fever incidence. However, the underlying mechanism remained unclear; further studies should be done to explore environmental factors.
This study also showed there were two epidemic peaks each year during the current study period. The two peaks were almost in accordance with the school spring semester (from March to June) and autumn-winter semester (from November to the following January), respectively. This was also similar to the study findings in Guangdong Province, China [26], suggesting that schools may have played an important role in the spread of scarlet fever. Combined with previous findings that school-age children were the major group with scarlet fever, we can conclude that kindergartens and primary schools should be the focus of surveillance and control of this infectious disease. It is well known that scarlet fever occurs mainly in winter/spring [27,28]. Some researchers believe that seasonal fluctuations of scarlet fever may be attributed to climatic conditions [23,24,29]. It is worth noting that seasonal peaks vary from region to region. This convincing evidence suggested that scarlet fever was more likely to spread in spring and winter than in other seasons, which was consistent with the findings of previous studies and the data of World Health Organization (WHO) [11,27].
The study results showed that children aged 3-9 years (age appropriate for kindergarten or primary school) were the susceptible group of scarlet fever in Zhejiang Province, accounting for 86.43% of the total cases. According to the WHO and the UK Public Health Department, scarlet fever infection is most common among children aged 5-15 [27,28]. Additionally, boys had a consistently higher incidence than girls, suggesting that boys were more prone to infection than girls. Similar results have been reported in some cities China as well as Poland [6,29,30]. Generally, boys participate in more group activities and care less about personal hygiene, which can increase the chances of pathogen exposure. Considering these findings, some conventional measures would be very effective in preventing and controlling scarlet fever. First, teachers and parents should instruct school-age children to wash their hands more often, which would be the best way to prevent this disease [31]. Second, schools should improve their environmental sanitation by disinfecting toys, handrails, desks, etc. [32]. In addition, more physical activities should be organized for children to enhance their health. Public health authorities should implement more effective surveillance for scarlet fever, and strengthen the disinfection efforts so that they may help reduce the risk and harm of scarlet fever epidemics to children.
From map of the incidence, the epidemic characteristics of scarlet fever showed the incidence in the northern regions was generally higher than that in the southern regions in 2004-2018 in Zhejiang Province. Shaoxing, Hangzhou, and Jiaxing were high-incidence regions, so the prevention and control effects of scarlet fever in these areas should be strengthened. Compared with the central and northern regions, the incidence was relatively low in other regions. The clusters of scarlet fever were displayed intuitively and comprehensively by geographic information system in Zhejiang Province. Getisd-ord Gi* statistics showed that high values clustered in the northern and central regions (Jiaxing, Huzhou, Shaoxing, Hangzhou, Jinhua), while rarely occurring in the eastern, western, and southern regions. The hotspot areas of scarlet fever showed a tendency to expand from the northern to the central regions since 2011. More high-value clusters had been detected in the north and central regions, because these areas maybe have similar topography, climate conditions, and other environmental factors which can easily lead to the spread of disease [22,24,25,33]. Further studies should be done to explore on the correlation between different latitudes and the incidence of scarlet fever [34]. These findings may help to guide scarlet fever control programs and targeting the intervention. By reason of information limitations, this study cannot fully consider other factors (such as drug resistance of strains, medical and health conditions, social and economic factors, etc.). Therefore, other key influencing factors of scarlet fever epidemic need to be further studied.

Limitations
Despite the above findings, our research had some limitations. First, as some mild cases may have used family therapies, and some cases of atypical symptoms may have been misdiagnosed, the reported data may underestimate the incidence. Second, case information was acquired from the CISDCP-a passive monitoring system-99.31% of cases were clinically diagnosed cases, and there is no corresponding laboratory testing. Therefore, we could not study the changes of circulating strains in 2004-2018, while this factor exactly played a significance role in explaining the rising incidence of scarlet fever in Zhejiang Province. Third, meteorological factors such as temperature, rainfall, and precipitation may affect scarlet fever epidemics, but we had no access to include such data in our study.

Conclusions
The epidemics of this disease showed obvious seasonal changes and geographic characteristics. Children under the age of 15 were more susceptible to infect scarlet fever, and children aged 3-9 were the main victims. Kindergartens and primary schools should be the focus of surveillance and control of this common disease. The scarlet fever epidemics mainly occurred in the north-central regions of Zhejiang Province.
Author Contributions: J.L. and Q.L. were responsible for the study design. H.W. and Z.D. did the statistical analysis and drafted the initial manuscript. C.W. assisted with the data analysis and interpretation. Q.L. was responsible for data analysis, paper writing, and revision. All authors read and approved the final manuscript.