Epidemiological trends and sociodemographic factors associated with acute hemorrhagic conjunctivitis in mainland China from 2004 to 2018

Acute hemorrhagic conjunctivitis (AHC) is an acute viral eye disease that was first reported in Ghana in 1969 [1]. It is mainly caused by coxsackievirus A24 variant (CA24v) and human enterovirus type 70 (EV70), and it is characterized by bilateral eye pain, increased secretion, keratitis, and conjunctival congestion, commonly known as "pinkeye" [2]. Generally, the majority of cases present obvious symptoms but result in a favorable prognosis and rarely with severe complications or fatal infections [3‐5]. Due to the rapid onset of symptoms, short incubation period and high infectivity, it usually leads to an outbreak or epidemic in the short term [6].

Since the first occurrence of AHC (caused by CA24v) in Singapore in 1970 [7], it has spread rapidly around the world. In recent decades, more than 10 million AHC cases have been reported worldwide [8], including several large outbreaks in Asia and South America. In 2002, the largest outbreak of AHC was reported in South Korea, with over 1,000,000 cases [9]. In 2014, an unprecedented nationwide outbreak of infectious conjunctivitis occurred in Thailand, which affected more than 300,000 individuals over 3 months [10]. In 2017, it was first reported in Mexico with 10,000 cases and then spread to other neighboring countries in the Caribbean and in South America, resulting in large outbreaks [2]. For instance, over 200,000 cases of AHC occurred in Brazil during the summer of 2017/2018 [13].

The economic and medical burden of conjunctivitis is also noteworthy. In France, during the 13-week epidemic, the estimated cost of the outbreak was €3,341,191 [14]. In the United States, 28% of annual emergency department visits are associated with conjunctivitis, amounting to approximately 560 million dollars in costs [15].

Although there has been no specific estimation of AHC costs in China to date, it still poses a great threat to public health. China has been classified as the most AHC-affected country worldwide [16]. Since the first cases were confirmed in 1971, many AHC cases have regularly appeared [17]. There have been 2 large outbreaks in different provinces. In 2007, the largest AHC epidemic in China was reported in Yunnan, which caused 74,263 cases [5]. Three years later, 69,635 cases caused by CA24v were reported in Guangdong [18]. To date, the AHC incidence ranked fifth among Class C notifiable diseases in 2020 [19].

Several studies have been performed to illustrate the epidemiological characteristics of AHC in China. However, most of the studies performed space–time analysis of AHC in a region-specific manner [20, 21]. Whether epidemiological trends of AHC change during long-term epidemics and what sociodemographic factors contribute to AHC has rarely been studied. Determining these questions is important because it helps to understand the dynamics of AHC and to determine where AHC is severe. Due to the lack of vaccines, identifying the sociodemographic factors associated with AHC could be integrated into the current surveillance system for early warning and risk prevention of AHC. To address these data gaps, we analyzed the long-term trends across time and space for AHC in mainland China using national notifiable infectious surveillance data from 2004 to 2018. We subsequently developed models to estimate the sociodemographic factors associated with AHC incidence.

Understanding the epidemiological distribution and specific spatiotemporal patterns of infectious diseases, also identifying its associated risk factors are the most important task for preventing and controlling infectious diseases [22]. In this study, we illustrate epidemiological trends, hotspots and sociodemographic factors associated with AHC in mainland China from an epidemiological and public health standpoint by using long-term population-based surveillance data. We reported that the epidemiological trends of AHC incidence significantly increased from 2004–2010 but stabilized after 2010. The incidence of AHC has its own characteristics. We found that the burden of AHC was relatively high in South China, particularly in Guangxi, Guangdong and Hainan provinces, and it was significantly increased in low- and middle-income provinces from 2004 to 2018. In addition, there was clear seasonality from August to October and a specific high-risk age group in children. Several sociodemographic factors were identified to be significantly associated with the AHC incidence. These findings will help government develop disease-specific and location-specific interventive measures in the following stage.

Zhang’s study reported that higher mean temperature, relative humidity and precipitation were associated with an increased risk of AHC [45]. Meteorological conditions in South China were also characterized by risk factors of high temperature, high relative humidity, and abundant rainfall, especially during summer, which were suitable for the growth and reproduction of intestinal viruses [46]. Therefore, in those high burden key provinces, strengthening epidemic surveillance by monitoring before the epidemic season, timely assessment and early warning of the epidemic development trend are critical for the prevention and control of AHC. This finding revealed that the AHC incidence increased from 2004–2010 but stabilized after 2010. Since 2004, China has established a notifiable infectious disease surveillance/reporting system with continuous standardization and maturity [22]. It has greatly promoted the prevention and control of 40 kinds of infectious diseases in China, including AHC. During the study period, there were two peaks of AHC incidence, in 2007 and 2010 [17]. Since 1971, Cox24v has been the major pathogen of AHC in China [47]. The outbreaks caused by CA24v are usually more widespread than those caused by EV70 [9]. From 1986 to 1988, CA24v caused epidemics in Beijing, Shanghai, and Guangzhou[48]. In 2007–2008, it was also responsible for outbreaks of AHC in Zhejiang, Yunnan and Guangdong [33, 49]. Two years later, the intensity of the outbreak in China caused by CA24v was significantly higher than that in 2007 and presented spatial–temporal clusters. G4-c3, G4-c5a and c5b of CA24v were the predominant strains in China from 2004 to 2014. They cocirculated and coevolved in southern and eastern China [16]. The genetic diversity of virus type alternation and antigen variation, lack of cross-protection between different genotypes, and poor immune persistence after infection may have resulted in random outbreaks of AHC [12]. In addition, the incidence of AHC was significantly increased in low- and middle-income provinces during the study period. Lower-income provinces are usually characterized by low immune systems, poor living environments, and poor knowledge of epidemic prevention measures, which might cause AHC to spread easily [50]. Regarding the AAPC, the provinces with higher increasing rates are also noticeable. Continuous surveillance to monitor genotypes and the emergence of new strains for the development of prevention and control strategies is necessary.

Children are usually the most frequently infected group [51]. In addition to school children, our results indicated that young children age 0–3 years are still worth studying. The absence of protective antibodies against enterovirus, low immunity and lack of basic hygiene knowledge in young children, along with poor knowledge of AHC among their parents (kindergarten teachers), leading to the inability to rapidly identify the main clinical symptoms, may result in higher risk [18, 52]. Therefore, health education should address hand-eye hygiene and improve the ability of parents (kindergarten teachers) to recognize the symptoms of conjunctivitis at an early stage.

Our results also provide insights into the relationship between sociodemographic factors and AHC, whose results emphasize the necessity of incorporating these parameters into the current surveillance system for early warning of AHC. Regions with high birth rates and populations aged 0–14 (% of the total population) contribute to high AHC incidence, echoing the results of high-risk age groups in the above discussion. China is rapidly becoming more urbanized, with low- and middle-income provinces experiencing the most striking social structure changes, which are also related to high AHC incidence, similar to other infectious diseases [31, 53, 54]. In addition to urbanization, passenger traffic greatly increases the risks of infectious disease spread, also including AHC [53]. Finally, yet importantly, regions with low per capita gross domestic products are at high risk of AHC, which may be characterized by poor sanitation permitting these causative agents to spread quickly [18, 50], echoing the results of the trends of AAPC subgroups by income. Those findings emphasize the necessity of incorporating these parameters into the current surveillance system for early warning of AHC. Characteristics related to the high incidence of AHC can also be applied to the prevention and control of AHC in other countries. Public health authorities should strengthen the surveillance of AHC in regions with these characteristics. Simultaneously, before the high-risk season, it is important to publicize and educate the public on the prevention and control of AHC, especially in high-risk groups. These efforts can help them understand the transmission and prevention methods of AHC, lend attention to personal eye hygiene, and form good hygiene habits and self-protection awareness. In addition, the infected should seek medical treatment as soon as possible and avoid going to public places, such school, nursery, factory, or natatorium [32].

This study has several limitations. First, in surveillance data, underreporting is a common problem. However, the dataset on the basis of the notifiable infectious disease reporting system used in this study was the most complete dataset currently available. Second, the sociodemographic factors identified in our study were only correlated with AHC, and a causal relationship was not proven. Further investigation is needed to determine the causality to provide a more precise basis when formulating targeted prevention policies. Last, this research only involved study site in China, more related-researches in different countries are also encouraged, then to provide more scientific evidence for prevent and control AHC, as well as other infectious diseases in future.

AHC has a clear regional, population, and seasonal distribution in China during 2004–2018. The burden of AHC was high in South China, and children between the ages of 0–3 were at high risk, while the seasonal peak of AHC prevalence was from August to October. After 2010, the AHC incidence remained stable; however, in low- and middle-income provinces, the AHC incidence continuously increased. Regions with a high birth rate, population ages 0–14 (% of the total population), urban population (% of the total population), passenger traffic and low per capita gross domestic product are at high risk of AHC. In the future, public health policy and resource priority for AHC in regions with these characteristics are necessary.