Epidemiological Characteristics and Risk Factor Analysis of Hand, Foot and Mouth Disease Reinfection Cases in Quzhou, China, 2008-2024

Epidemiological Characteristics and Risk Factor Analysis of Hand, Foot and Mouth Disease Reinfection Cases in Quzhou, China, 2008-2024 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Epidemiological Characteristics and Risk Factor Analysis of Hand, Foot and Mouth Disease Reinfection Cases in Quzhou, China, 2008-2024 Quanjun Fang, Jilai Mao, Shuangqing Wang, Xiaoying Gong, Canjie Zheng, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6903689/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Previous studies on Hand, foot and mouth disease (HFMD) have predominantly focused on primary infections, with limited systematic analysis of the temporal distribution of reinfection and the interplay of multidimensional risk factors. Moreover, conventional analytical approaches, such as logistic regression, have been insufficient in effectively capturing the temporal dynamics of reinfection risk. Methods: In this study, a Cox proportional hazards regression model was employed to analyse the epidemiological characteristics and risk factors associated with HFMD reinfection in Quzhou City from 2008 to 2024, with the aim of informing targeted prevention and control strategies. Results: Between 2008 and 2024, a total of 4,026 cases of HFMD reinfection were reported in Quzhou, corresponding to a reinfection rate of 5.04% (4,026/79,841). Among these, 3,883 cases (96.45%) involved two episodes of infection, 140 cases (3.48%) involved three episodes, and 3 cases (0.07%) experienced four episodes. The timing of onset for the first to third HFMD infections exhibited a bimodal distribution, with peaks occurring in April–June and November–December. The median intervals between successive infections were 1.35 years (interquartile range: 0.82–2.10) between the first and second infections, 1.10 years (0.75–1.81) between the second and third, and 0.82 years between the third and fourth. Cox proportional hazards regression modelling identified age under three years, Scattered children, urban residence, initial infection with Cox A16, and Cox-A16 being the predominant circulating strain in the year of initial infection as significant risk factors for HFMD reinfection. Conclusion: The HFMD reinfection epidemic in Quzhou City between 2008 and 2024 appears to be relatively severe. It is therefore essential to strengthen health education for both parents and childcare institution staff, and to maintain heightened vigilance. Even among children with a history of HFMD infection, parents should remain attentive to the potential recurrence of symptoms. Attention should be focused on diaspora children who experienced their first HFMD episode before the age of three, reside in urban areas, and whose initial infection was caused by Cox A16. The risk of reinfection is heightened when Cox-A16 was the predominant circulating strain in the year of initial infection. Clinical trial number Not applicable. hand foot and mouth disease reinfection epidemiological characteristic risk factors cox regression analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Hand, foot and mouth disease (HFMD) is a notifiable Class C infectious disease primarily affecting children under the age of five 1 . It is caused by a range of enteroviruses, with enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) representing the most prevalent aetiological agents. The majority of patients with HFMD exhibit a mild, self-limiting illness, typically characterised by a vesicular rash on the hands, feet or buttocks, accompanied by oral ulcers or blisters, with or without fever 2 . However, a subset of patients may progress to severe disease, and in extreme cases, the condition can be fatal 3 . Since the 1990s, numerous outbreaks of HFMD have been documented in countries across the Western Pacific region—including Malaysia, Japan, Taiwan and Singapore—and the disease has become an increasingly serious public health issue 4 – 7 . In China, HFMD has occurred annually across much of the country since it was first identified in Shanghai in 1981 8 . In 2008, a major outbreak in Fuyang City, Anhui Province, resulted in 22 fatalities 9 . That same year, the Chinese Ministry of Health classified HFMD as a Category C notifiable infectious disease. In recent years, the average annual number of reported HFMD cases in mainland China has exceeded one million 10 , ranking first among all notifiable infectious diseases 11 . As such, HFMD has emerged as a major public health concern. Vaccination remains the most cost-effective strategy for the prevention of infectious diseases. In 2016, an EV-A71 vaccine was introduced in mainland China, with clinical trials demonstrating an efficacy of 97.4% 12 . However, the vaccine offers protection solely against EV-A71 and does not confer cross-protection against other enteroviruses. Moreover, the antibody response elicited by the EV-A71 vaccine is not lifelong, and reinfection remains possible 13 . Consequently, recurrent cases of HFMD are relatively common. Reinfection with HFMD may result not only in more complex clinical presentations, such as atypical rashes and bacterial co-infections, but may also increase the overall disease burden due to variations in the immune response 14 . Epidemiological data indicate a rising trend in HFMD reinfection rates, potentially attributable to pathogen diversity and the transient nature of host immune memory 15 , 16 . For instance, reinfection cases reported in Saudi Arabia suggest that insufficient cross-immunoprotection against different viral serotypes, or antigenic drift, may be key factors driving reinfection 17 . Additionally, host genetic factors and immunosuppressive conditions may affect the risk of reinfection by modulating the efficiency of viral receptor binding or the antibody response 18 , 19 . Previous studies have predominantly focused on primary infections, with limited systematic analyses of the temporal patterns of reinfection and the interplay of multidimensional risk factors. Conventional analytical approaches, such as logistic regression, struggle to effectively capture risks associated with temporal dynamics. There is an urgent need for more robust statistical modelling techniques; however, few survival analysis models capable of handling time-dependent variables have been employed to date. In this study, a Cox proportional hazards regression model was employed, with reinfection as the event of interest and the interval from initial infection to reinfection as the survival time. The effects of multiple factors on survival time were analysed to elucidate the prevalence characteristics of HFMD and identify risk factors for reinfection in Quzhou City between 2008 and 2024. These findings aim to inform strategies for the prevention and control of HFMD. Materials and Methods Data collection HFMD cases were obtained from the Chinese Information System for Disease Control and Prevention (CISDCP), with data extracted based on current address and date of onset, and only cases with verified information were included. The study period was defined by onset dates ranging from 1 January 2008 to 31 December 2024. Data on age, sex, population classification, region, disease severity, and pathogenicity test results were collected for each case. Additionally, pathogenetic findings from previous HFMD sentinel surveillance in Quzhou City were incorporated. Case definitions The diagnostic criteria for HFMD were based on the Clinical Guidelines for Hand, Foot and Mouth Disease (2018 edition), issued by the Chinese Ministry of Health. A clinically diagnosed case was defined by the presence of a vesicular rash on the hands, feet, mouth or buttocks, with or without fever. A laboratory-confirmed case was defined as a clinically diagnosed case accompanied by laboratory evidence of enterovirus infection (EV-A71, CV-A16, or other enteroviruses), confirmed through reverse transcription-polymerase chain reaction or viral isolation. Cases were classified as severe if clinical or laboratory diagnosis revealed the development of neurological complications, cardiopulmonary complications, or both. Cases not meeting these criteria were classified as mild. HFMD reinfection cases were defined as individuals infected with HFMD two or more times during the period from 2008 to 2024. Data Cleaning A total of 80,050 HFMD case records were exported from the system, with 79,841 cases remaining after excluding suspected and duplicate reports. We established criteria for the inclusion and exclusion of HFMD reinfection cases. Inclusion criteria were as follows: (i) identical identity card number; (ii) matching parent’s name and date of birth; (iii) identical telephone number and date of birth. Applying these criteria yielded 5,712, 5,462, and 5,648 case records, respectively. Exclusion criteria were as follows: (i) dissimilar names; (ii) an interval of less than 14 days between onset dates of two mild infections, or less than 23 days between the onset of a severe infection and a subsequent infection 20 ; (iii) differing home addresses across counties (cities or districts). Applying the exclusion criteria resulted in 5,416, 4,952 and 5,286 case records remaining in the three groups, respectively. Duplicate entries across the groups were then consolidated, yielding 4,026 unique cases and a total of 8,198 case records (Fig. 1 ). Methods Descriptive epidemiological methods were employed to analyse the timing of reinfection onset, population distribution, regional distribution, and aetiological characteristics. Cox proportional hazards regression, a widely used method in medical survival analysis, was employed in this study to investigate the risk factors associated with HFMD reinfection. Cumulative risk probabilities were estimated and plotted, and subgroup differences in survival curves were assessed using the log-rank test. In this study, survival time was defined as the interval between the first infection and subsequent reinfection; for individuals with three or four episodes, only the interval between the first and second infections was considered. To assess the impact of the predominant strain during the year of initial HFMD infection on the risk of reinfection, data from previous pathogen surveillance in Quzhou City were utilised. EV-A71 was identified as the predominant strain in 2009, 2019, 2022, and 2024; CV-A16 in 2010, 2011, and 2018; while other enterovirus types predominated in the remaining years. The dominant strain in the year of first infection was incorporated into the model analysis as the epidemic strain variable. The six counties (cities and districts) of Quzhou were categorised into urban and rural areas based on geographic distribution, with Kecheng District and Qujiang District classified as urban, and the remaining areas as rural. Cox proportional hazards regression was used to calculate hazard ratios (HR), where an HR greater than 1 indicates that the exposure is a risk factor for the event of interest, while an HR less than 1 suggests a protective effect. Statistical analysis Data were compiled using Microsoft Excel 2010, and statistical analyses were performed using SPSS version 27.0. The HFMD reinfection rate was calculated as follows: reinfection rate = (number of HFMD reinfection cases / total number of HFMD cases) × 100%. Continuous variables were described using medians and interquartile ranges (IQR), while categorical variables were summarised using proportions and rates. The Kaplan–Meier method was applied to stratify and estimate the cumulative risk probability of first HFMD reinfection by sex, age, population type, region, symptom severity, and the predominant strain in the year of initial infection. Differences were assessed using the log-rank test. Cox proportional hazards regression models were utilised for univariate and multivariate analyses of potential risk factors influencing reinfection. A significance level of α = 0.05 was adopted. Results Epidemiological characteristics of reinfection cases Between January 2008 and December 2024, a total of 4,026 cases of HFMD reinfection were reported in Quzhou, representing a reinfection rate of 5.04% (4,026/79,841). Among them, 2,519 were male, with a reinfection rate of 5.41% (2,519/46,552), and 1,507 were female, with a reinfection rate of 4.53% (1,507/33,289). The difference in reinfection rates between sexes was statistically significant (χ² = 31.686, p < 0.001). Most individuals (3,883 cases; 96.45%) experienced two infections, while 140 cases (3.48%) experienced three infections and three cases (0.07%) experienced four infections. By region, the number of reinfection cases was highest in Kecheng District (1,388; 34.48%), followed by Qujiang District (761; 18.90%), Kaihua County (637; 15.82%), Longyou County (494; 12.27%), Changshan County (432; 10.73%), and Jiangshan City (314; 7.80%). The corresponding reinfection rates were 5.68% (1,388/24,451) in Kecheng District, 5.80% (761/13,120) in Qujiang District, 5.31% (637/11,996) in Kaihua County, 4.74% (432/9,113) in Changshan County, 4.12% (494/11,993) in Longyou County, and 3.42% (314/9,168) in Jiangshan City. Severe cases accounted for 0.10% (4/4,026) during the first infection and 0.07% (3/4,026) during the second, with no severe cases reported in the third or fourth infections. All seven severe cases occurred in children. Comparison of the characteristics of cases with first, second, and third to fourth HFMD infections revealed that the median age at infection was 1.72 years (IQR: 1.21–2.64), 3.43 years (IQR: 2.57–4.51), and 3.83 years (IQR: 3.08–5.34), respectively. The intervals between successive infections exhibited a skewed distribution, with median values of 1.35 years (IQR: 0.82–2.10), 1.10 years (IQR: 0.75–1.81), and 0.82 years, respectively. The population classifications were predominantly migrant children (78.07%) for first infections, and children in early childhood care for both second (53.43%) and third to fourth infections (63.51%). The number of severe cases reported was four, three, and zero for first, second, and subsequent infections, respectively. Aetiological test results were dominated by EV-A71 across all episodes, accounting for 65.48%, 47.56%, and 84.62%, respectively (Table 1 , Fig. 2 ). Table 1 Epidemiological characteristics of HFMD reinfection cases in Quzhou, 2008–2024 Characteristic First infection (n = 4026) Second infection (n = 4026) The 3rd to 4th infection (n = 146) n % n % n % Age(years) <0.5 39 0.97 0 0.00 0 0.00 0.5- 555 13.79 20 0.50 0 0.00 1- 1769 43.94 477 11.85 4 2.70 2- 1603 39.82 2833 70.37 99 66.89 5- 59 1.47 677 16.82 43 29.05 ≥ 10 1 0.02 19 0.47 0 0.00 Population classification Scattered children 3143 78.07 1688 41.93 42 28.38 Kindergarten children 875 21.73 2151 53.43 94 63.51 Student 8 0.20 187 4.64 10 6.76 Clinical type Severe 4 0.10 3 0.07 0 0.00 Mild 4022 99.90 4023 99.93 146 100.00 Laboratory results a EV-A71 110 65.48 78 47.56 11 84.62 Cox A16 24 14.29 35 21.34 0 0.00 Other EV 34 20.24 51 31.10 2 15.38 Note: a The number of cases with pathogen detection during the 1st, 2nd, and 3rd to 6th infections was 168, 164, and 13, respectively. Temporal distribution of reinfection cases There was a clear seasonal pattern in the onset of all first to third infections, displaying a bimodal distribution. The first peak of incidence occurred between April and June, accounting for 38.28%, 50.17%, and 49.32% of cases, respectively; the second peak occurred between November and December, comprising 19.92%, 14.90%, and 12.33% of cases, respectively (Fig. 3 ). The fourth infection was reported in three cases, with onset occurring in April, June, and July, respectively. Pathogenetic features of reinfection cases Among the reinfection cases, 54 had laboratory confirmation for both the first and second infections. EV-A71, CV-A16, and other enterovirus types were all capable of causing recurrent infections. The highest proportion of cases involved EV-A71 on both occasions (66.67%), followed by reinfection with CV-A16 after an initial EV-A71 infection (12.96%) and other enterovirus types following EV-A71 infection (11.11%) (Table 2 ). There were 13 confirmed cases of third infection, among which 11 were caused by EV-A71 (with both first and second infections confirmed, comprising 5 cases of EV-A71, 5 cases of CV-A16, and 1 case of other enterovirus types), and 1 case was caused by other enterovirus types (with both first and second infections clinically diagnosed). All fourth infections were clinically diagnosed cases. Table 2 Aetiology of First and Second Infections in Reinfected HFMD Cases in Quzhou, 2008–2024 Virus of First Infection Virus of Second Infection n % EV-A71 EV-A71 36 66.67 EV-A71 CV-A16 7 12.96 EV-A71 Other EV 6 11.11 CV-A16 CV-A16 2 3.70 CV-A16 Other EV 1 1.85 Other EV EV-A71 1 1.85 Other EV CV-A16 1 1.85 Note: EV-A71, enterovirus A71; CV- A16, coxsackievirus A 16. Among the reinfection cases, 54 had laboratory confirmation for both the first and second infections The hazard of HFMD reinfection The risk of reinfection was significantly elevated within 20 months following the initial HFMD infection, with 25.41% (1,023/4,026) of cases reinfected within 10 months and 62.47% (2,515/4,026) reinfected within 20 months. The cumulative hazard probability curves for HFMD reinfection, stratified by six factors—sex, population category, symptom severity, age group, place of residence, and the predominant strain in the year of first infection—indicated a higher risk of reinfection among children under 3 years of age, scattered children, those living in urban areas, and individuals whose first infection occurred during a year when CV-A16 was the predominant circulating strain (Fig. 4 ). Cox proportional hazards regression analyses, adjusted for relevant covariates, indicated that age group, population classification, region of residence, and the predominant enterovirus strain during the year of primary infection were all significantly associated with the risk of HFMD reinfection, even after accounting for potential confounding variables. Notably, children aged ≥ 3 years exhibited a substantially lower risk of reinfection compared with those aged < 3 years (HR = 0.312, 95% CI: 0.286–0.339). Compared with scattered children, those in kindergarten care and school students had a significantly lower risk of reinfection (HR = 0.124, 95% CI: 0.101–0.151; and HR = 0.743, 95% CI: 0.689–0.801, respectively) (Table 3 ). Table 3 Cox proportional hazards regression analysis of factors influencing HFMD reinfection in Quzhou, 2008–2024 Characteristic Single-variable analysis Multivariable analysis HR 95%CI P HR 95%CI P Gender Female Male 1.038 0.974–1.106 0.253 1.020 0.957–1.087 0.539 Age(Years) <3 ≥ 3 0.237 0.219–0.256 <0.001 0.312 0.286–0.339 <0.001 Population classification Scattered children Kindergarten children 0.485 0.454–0.518 <0.001 0.743 0.689–0.801 <0.001 Student 0.081 0.067–0.098 <0.001 0.124 0.101–0.151 <0.001 Region Rural Urban 1.265 1.188–1.346 <0.001 1.119 1.051–1.191 <0.001 Clinical type Severe Mild 1.201 0.387–3.727 0.751 1.106 0.245–3.339 0.658 Prevalent strain in year of first infection EV-A71 CV-A16 3.183 2.701–3.751 <0.001 2.391 2.025–2.822 <0.001 Other EV 1.590 1.484–1.704 <0.001 1.367 1.274–1.467 <0.001 Laboratory results a EV-A71 CV-A16 2.517 1.323–5.412 0.012 Other EV 0.504 0.342–1.256 0.283 Note: a Among the 4,026 reinfection cases, only 168 were confirmed by laboratory testing. Consequently, the ‘pathogen’ variable contains numerous missing values and was excluded from the multivariate analysis. Discussion HFMD is a common infectious illness in children, responsible for numerous clinical cases annually and posing a risk of mortality in severe instances 21 . In recent years, parental awareness and preventative measures against HFMD have steadily improved; however, reinfection continues to pose a significant threat to children’s health 22 . The reinfection rate of HFMD in Quzhou was 5.04%, exceeding the 1.93% reported in Wuhan between 2008 and 2015 23 and the 3.25% nationwide during the same period 20 , yet remaining lower than the 6.01% observed in Wuxi from 2008 to 2016 24 . The observed differences may be attributed to variations in the temporal scope of the analysis, the criteria used to define reinfection, and regional factors such as geographic location, economic status, and population density. These findings also indicate that the reinfection rate of HFMD in Quzhou remains high, emphasising the urgent need for further research into the risk of reinfection. The HFMD reinfection rate varied across counties, cities and districts within Quzhou City, ranging from 3.42–5.80%. This suggests potential spatial heterogeneity in reinfection rates, the underlying causes of which require further investigation. HFMD reinfections predominantly involved two episodes, with cases of three or more infections being less common, consistent with previous studies 20 , 23 . Multiple HFMD infections predominantly occurred in children aged under four years, with median ages of 3.43 and 3.83 years for the second and third infections, respectively. Correspondingly, the population categories for the first to third infections were primarily composed of children living in scattered settings for the initial infection, followed by those in early childhood care for the second and third infections. A marked seasonality was evident in the onset of HFMD reinfection cases, with the seasonal patterns of the first, second and third infections being largely consistent. The primary peak in incidence occurred between April and June, consistent with the findings of Tian et al 25 . However, this study also identified a secondary peak during November–December. Xu et al 26 reported that the incidence of HFMD was positively associated with ambient temperature, with the strongest correlation observed within the 25.0–27.5 ℃ range. From the perspective of the temporal interval between reinfections, the median duration between successive HFMD episodes exceeded one year, consistent with findings from Fujian Province 27 . This underscores the importance of disseminating relevant health education to parents and emphasising the need for vigilance in preventing reinfection within two years of the initial episode. HFMD reinfection can be attributed to a diverse range of enteroviruses. Reinfection with EV-A71, Cox A16, or other enterovirus types may occur following an initial EV-A71 infection, and in some instances, homologous reinfection has been observed. The underlying reasons may be attributed, firstly, to the failure of some patients to develop effective humoral immunity following HFMD virus infection 28 ; and secondly, to the limited or absent cross-immunity between different enterovirus types 29 . However, the high proportion of recurrent EV-A71 infections following initial EV-A71 infection may be attributable to the fact that EV-A71 testing is primarily conducted in Quzhou City, and therefore, the results may not be generalisable. Furthermore, the incidence of reinfection was higher when the initial infection was caused by Cox A16 or when Cox A16 was the predominant strain in the year of first infection. This finding aligns with studies conducted nationwide 20 , as well as in Wuhan City 23 and Anhui Province 30 , and may be related to differences in the shedding rates of various subtypes. A review indicated that EV-A71 exhibits slower viral shedding and requires a longer period for complete clearance by the host compared with Cox A16. This prolonged clearance may contribute to the development of more durable immunity against EV-A71 and consequently a reduced risk of reinfection 31 . In this study, it was observed that while reinfection could occur following a severe initial infection, subsequent episodes did not progress to severe disease. Conversely, cases where the first infection was mild could still result in reinfection with progression to severe disease. This phenomenon may be related to the viral subtype and warrants further investigation. Both univariate and multivariate analyses indicated that the risk of hand, HFMD reinfection was significantly associated with demographic factors, including age, area of residence and population classification. Notably, being under three years of age, residing in urban settings, and belonging to the Scattered children emerged as independent risk factors for reinfection. In a systematic study, Luo et al 32 reported that neonatal antibody levels against EV-A71 and CV-A16 declined to their lowest point by one year of age, followed by a gradual increase, peaking at approximately four years of age. Zhang et al 33 observed that organismal immunity to enteroviruses in children increases progressively with age. Consequently, reinfection with HFMD is more likely to be observed in children under three years of age. This study identified a relatively higher risk of reinfection among children residing in urban areas compared to their rural counterparts. This finding contrasts with the commonly held assumption that superior urban sanitation correlates with a reduced risk of reinfection. It may be attributable to enhanced access to and utilisation of healthcare services among urban populations, greater parental awareness regarding the importance of seeking medical care, and consequently, a higher likelihood of initial diagnosis and subsequent re-diagnosis of HFMD in urban children 23 . Moreover, urban areas are characterised by high population density and greater levels of transience, both of which contribute to increased interpersonal proximity and thereby elevate the risk of viral exposure 34 , 35 . Diaspora children exhibit a higher risk of reinfection compared to those in childcare or other population groups, which may be attributable not only to lower immunisation coverage but also to comparatively poorer hygiene practices within this demographic. Limitations Our research comes with certain limitations that warrant consideration. Firstly, the pathogenicity laboratory test results for confirmed cases were obtained from the Infectious Disease Reporting Information System, where the detection reagents limited the scope of pathogen identification. The test results were predominantly for EV-A71, with fewer detections of Cox A16, and no further subtyping was performed for other enterovirus strains. This uneven rate of pathogen testing among confirmed cases may have introduced bias into the results. Secondly, we did not rigorously define or follow up on whether initial infections occurred prior to 2008. Consequently, the risk of reinfection may have been underestimated in this study. Conclusion In summary, the HFMD reinfection epidemic in Quzhou City between 2008 and 2024 appears to be relatively severe. It is therefore essential to strengthen health education for both parents and childcare institution staff, and to maintain heightened vigilance. Even among children with a history of HFMD infection, parents should remain attentive to the potential recurrence of symptoms. Attention should be focused on diaspora children who experienced their first HFMD episode before the age of three, reside in urban areas, and whose initial infection was caused by Cox A16. The risk of reinfection is heightened when Cox-A16 was the predominant circulating strain in the year of initial infection. Abbreviations HFMD Hand, foot and mouth disease EV-A71 Enterovirus 71 CV-A16 Coxsackievirus A16 IQR Interquartile ranges CISDCP Chinese Information System for Disease Control and Prevention HR Hazard ratios Declarations Acknowledgements We thank the Quzhou Centre for Disease Control and Prevention, the local community hospitals for their assistance in conducting the testing, and Mao Jilai and Wang Shuangqing for their valuable advice on data analysis Author contributions Conception and/or design: ZYY; Study management: QJF and JLM; Analysis of the data: SQW, XYG,CJZ; Interpretation of study results: all authors. Drafting of the manuscript for important intellectual content: ZYY and QJF. Review and editing of manuscript and approval of the final version to be published: all authors. Funding The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article. Data availability All information was sourced from the Chinese Center for Disease Prevention and Control Information System. However, restrictions apply to the availability of these data, as they were used under license for this study and are not publicly accessible. Data are available from the authors upon reasonable request and with permission from the Quzhou CDC. Ethics approval and consent to participate The study was approved by the Research Ethics Committee of the Centre for Disease Control and Prevention of Quzhou City (approval number: 2025-006-02) and was conducted in accordance with the principles of the Declaration of Helsinki. The Ethics Committee waived individual informed consent for the following reasons: (i) The study used anonymised surveillance data from the China Information System for Disease Control and Prevention (CISDCP), which are collected as part of mandatory public health reporting in accordance with the Law of the People's Republic of China on Prevention and Control of Infectious Diseases. (ii) All personally identifiable information (name, address, telephone number) was deleted before analysis. (iii) The National Health and Wellness Commission of China explicitly states that no ethical review is required for secondary analyses of anonymised statutory infectious disease data. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References Xing W, Liao Q, Viboud C, Zhang J, Sun J, Wu JT, Chang Z, Liu F, Fang VJ, Zheng Y, et al. Hand, foot, and mouth disease in China, 2008-12: an epidemiological study. Lancet Infect Dis. 2014;14(4):308-18. doi:10.1016/S1473-3099(13)70342-6. Tseng FC, Huang HC, Chi CY, Lin TL, Liu CC, Jian JW, Hsu LC, Wu HS, Yang JY, Chang YW, et al. Epidemiological survey of enterovirus infections occurring in Taiwan between 2000 and 2005: analysis of sentinel physician surveillance data. J Med Virol. 2007;79(12):1850-60. doi:10.1002/jmv.21006. Ooi MH, Wong SC, Lewthwaite P, Cardosa MJ, Solomon T. Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol. 2010;9(11):1097-105. doi:10.1016/S1474-4422(10)70209-X. Chan LG, Parashar UD, Lye MS, Ong FG, Zaki SR, Alexander JP, Ho KK, Han LL, Pallansch MA, Suleiman AB, et al. Deaths of children during an outbreak of hand, foot, and mouth disease in sarawak, malaysia: clinical and pathological characteristics of the disease. For the Outbreak Study Group. Clin Infect Dis. 2000;31(3):678-83. doi:10.1086/314032. Fujimoto T, Chikahira M, Yoshida S, Ebira H, Hasegawa A, Totsuka A, Nishio O. Outbreak of central nervous system disease associated with hand, foot, and mouth disease in Japan during the summer of 2000: detection and molecular epidemiology of enterovirus 71. Microbiol Immunol. 2002;46(9):621-7. doi:10.1111/j.1348-0421.2002.tb02743.x. Ho M, Chen ER, Hsu KH, Twu SJ, Chen KT, Tsai SF, Wang JR, Shih SR. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341(13):929-35. doi:10.1056/NEJM199909233411301. Chan KP, Goh KT, Chong CY, Teo ES, Lau G, Ling AE. Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore. Emerg Infect Dis. 2003;9(1):78-85. doi:10.3201/eid0901.020112. Zeng M, Li YF, Wang XH, Lu GP, Shen HG, Yu H, Zhu QR. Epidemiology of hand, foot, and mouth disease in children in Shanghai 2007-2010. Epidemiol Infect. 2012;140(6):1122-30. doi:10.1017/S0950268811001622. Zhang Y, Zhu Z, Yang W, Ren J, Tan X, Wang Y, Mao N, Xu S, Zhu S, Cui A, et al. An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of hand foot and mouth disease in Fuyang city of China. Virol J. 2010;7:94. doi:10.1186/1743-422X-7-94. Liu J, Wang H, Zhong S, Zhang X, Wu Q, Luo H, Luo L, Zhang Z. Spatiotemporal Changes and Influencing Factors of Hand, Foot, and Mouth Disease in Guangzhou, China, From 2013 to 2022: Retrospective Analysis. JMIR Public Health Surveill. 2024;10:e58821. doi:10.2196/58821. Han Y, Ji H, Shen W, Duan C, Cui T, Chen L, Hang H, Zhang Z, Sun H, Zhang X, et al. Disease burden in patients with severe hand, foot, and mouth disease in Jiangsu Province: a cross-sectional study. Hum Vaccin Immunother. 2022;18(5):2049168. doi:10.1080/21645515.2022.2049168. Li R, Liu L, Mo Z, Wang X, Xia J, Liang Z, Zhang Y, Li Y, Mao Q, Wang J, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med. 2014;370(9):829-37. doi:10.1056/NEJMoa1303224. Li JX, Song YF, Wang L, Zhang XF, Hu YS, Hu YM, Xia JL, Li J, Zhu FC. Two-year efficacy and immunogenicity of Sinovac Enterovirus 71 vaccine against hand, foot and mouth disease in children. Expert Rev Vaccines. 2016;15(1):129-37. doi:10.1586/14760584.2016.1096782. de Sousa IP Jr, Giamberardino HI, Raboni SM, Debur MC, de Lourdes Aguiar Oliveira M, Burlandy FM, da Silva EE. Simultaneous enterovirus EV-D68 and CVA6 infections causing acute respiratory distress syndrome and hand, foot and mouth disease. Virol J. 2021;18(1):88. doi:10.1186/s12985-021-01560-w. Li X, Chen S, Chen Y, Han S, Dai B, Li T, Yuan X, Su D, Li Z, Shen Y, et al. Epidemiological and genetic characterizations of hand, foot, and mouth disease and acute respiratory infections due to CV-A6 infection in Henan Province, China between 2021 and 2022. BMC Pediatr. 2025;25(1):264. doi:10.1186/s12887-025-05527-6. Wu H, Xue M, Wu C, Lu Q, Ding Z, Wang X, Fu T, Yang K, Lin J. Trend of hand, foot, and mouth disease from 2010 to 2021 and estimation of the reduction in enterovirus 71 infection after vaccine use in Zhejiang Province, China. PLoS One. 2022;17(9):e0274421. doi:10.1371/journal.pone.0274421. Alakrash L, Barakeh M, AlQahtani WI, AlKanaan RK. Recurrent Hand, Foot, and Mouth Disease in a Saudi Girl. Cureus. 2024;16(1):e51813. doi:10.7759/cureus.51813. Duan FY, Du ZQ, Wang Y, Luo L, Du LJ, Jiang H, Ma Y, Yang YL. The effects of SCARB2 and SELPLG gene polymorphisms on EV71 infection in hand, foot and mouth disease. Biomol Biomed. 2023;23(5):815-24. doi:10.17305/bb.2023.8948. Xu Y, Ma J, Ouyang W, Yao R, Cao W, Li J, Zou R, Fang C, Zeng F, Yang F, et al. Suppression of innate and acquired immunity in severe hand foot and mouth disease caused by EV71 infections in children. Clin Immunol. 2023;248:109260. doi:10.1016/j.clim.2023.109260. Huang J, Liao Q, Ooi MH, Cowling BJ, Chang Z, Wu P, Liu F, Li Y, Luo L, Yu S, et al. Epidemiology of Recurrent Hand, Foot and Mouth Disease, China, 2008-2015. Emerg Infect Dis. 2018;24(3):432-42. doi:10.3201/eid2403.171303. Li P, Li T, Gu Q, Chen X, Li J, Chen X, Chen Y, Zhang D, Gao R, He Z, et al. Children's Caregivers and Public Playgrounds: Potential Reservoirs of Infection of Hand-foot-and-mouth Disease. Sci Rep. 2016;6:36375. doi:10.1038/srep36375. Ang LY, Too HK, Tan EL, Chow TK, Shek LP, Tham EH, Alonso S. Antiviral activity of Lactobacillus reuteri Protectis against Coxsackievirus A and Enterovirus 71 infection in human skeletal muscle and colon cell lines. Virol J. 2016;13:111. doi:10.1186/s12985-016-0567-6. Peng Y, Yu B, Kong DG, Zhao YY, Wang P, Pang BB, Gong J. Reinfection hazard of hand-foot-mouth disease in Wuhan, China, using Cox-proportional hazard model. Epidemiol Infect. 2018;146(10):1337-42. doi:10.1017/S0950268818001322. Shi C, Liu J, Shi P, Ji H, Shen Y, Qian YH. Epidemiological characteristics and influential factors of hand, foot, and mouth disease reinfection in Wuxi, China, 2008-2016. BMC Infect Dis. 2018;18(1):472. doi:10.1186/s12879-018-3385-1. Tian H, Zhang Y, Shi Y, Li X, Sun Q, Liu L, Zhao D, Xu B. Epidemiological and aetiological characteristics of hand, foot, and mouth disease in Shijiazhuang City, Hebei province, China, 2009-2012. PLoS One. 2017;12(5):e0176604. doi:10.1371/journal.pone.0176604. Xu M, Yu W, Tong S, Jia L, Liang F, Pan X. Non-Linear Association between Exposure to Ambient Temperature and Children's Hand-Foot-and-Mouth Disease in Beijing, China. PLoS One. 2015;10(5):e0126171. doi:10.1371/journal.pone.0126171. Zhonghang X, Yansheng Y, Rongtao H, et al. A cohort study on the characteristics of the recurrent epidemics on hand，foot and mouth disease，in Fujian province[J]. Chinese Journal of Epidemiology,2014,(10):1109-1114. (In Chinese) Qiu Q, Zhou J, Cheng Y, Zhou Y, Liang L, Cui P, Xue Y, Wang L, Wang K, Wang H, et al. Kinetics of the neutralising antibody response in patients with hand, foot, and mouth disease caused by EV-A71: A longitudinal cohort study in Zhengzhou during 2017-2019. EBioMedicine. 2021;68:103398. doi:10.1016/j.ebiom.2021.103398. Klein MH. EV71 vaccines: a first step towards multivalent hand, foot and mouth disease vaccines. Expert Rev Vaccines. 2015;14(3):337-40. doi:10.1586/14760584.2015.993385. Chen GP, Wu JB, Wang JJ, Pan HF, Zhang J, Shi YL, Cao C, Li FR, Fan YG, Meng FY, et al. Epidemiological characteristics and influential factors of hand, foot and mouth disease (HFMD) reinfection in children in Anhui province. Epidemiol Infect. 2016;144(1):153-60. doi:10.1017/S0950268815001107. Duan X, Chen Z, Li X, Yuan P, Long L. Virus Shedding in Patients With Hand, Foot and Mouth Disease Induced by EV71, CA16 or CA6: Systematic Review and Meta-analysis. Pediatr Infect Dis J. 2021;40(4):289-94. doi:10.1097/INF.0000000000002985. Luo L, Xing W, Liao Q, Yu H. [Research progress on seroepidemiological study of enterovirus 71 and coxsackievirus A16 infection among children]. Zhonghua Yu Fang Yi Xue Za Zhi. 2015;49(2):184-8 Zhang D, Chen Y, Chen X, He Z, Zhu X, Hao Y. Enterovirus 71 Neutralizing Antibodies Seroepidemiological Research among Children in Guangzhou, China between 2014 and 2015: A Cross-Sectional Study. Int J Environ Res Public Health. 2017;14(3):319. doi:10.3390/ijerph14030319. Huang R, Wei J, Li Z, Gao Z, Mahe M, Cao W. Spatial-temporal mapping and risk factors for hand foot and mouth disease in northwestern inland China. PLoS Negl Trop Dis. 2021;15(3):e0009210. doi:10.1371/journal.pntd.0009210. Gao Y, Wang H, Yi S, Wang D, Ma C, Tan B, Wei Y. Spatial and Temporal Characteristics of Hand-Foot-and-Mouth Disease and Their Influencing Factors in Urumqi, China. Int J Environ Res Public Health. 2021;18(9):4919. doi:10.3390/ijerph18094919. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6903689","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":491062855,"identity":"fb55cf3c-e55b-4652-bdf5-4d9fc3446450","order_by":0,"name":"Quanjun Fang","email":"","orcid":"","institution":"Quzhou Center for Disease Control and Prevention","correspondingAuthor":false,"prefix":"","firstName":"Quanjun","middleName":"","lastName":"Fang","suffix":""},{"id":491062857,"identity":"2cc9a5da-8d6a-415a-81c6-a46dd54ed05a","order_by":1,"name":"Jilai Mao","email":"","orcid":"","institution":"Jiangshan Center for Disease Control and Prevention","correspondingAuthor":false,"prefix":"","firstName":"Jilai","middleName":"","lastName":"Mao","suffix":""},{"id":491062859,"identity":"b387fcd6-2916-4378-b3a1-a5e49c3e15a9","order_by":2,"name":"Shuangqing Wang","email":"","orcid":"","institution":"Quzhou Center for Disease Control and Prevention","correspondingAuthor":false,"prefix":"","firstName":"Shuangqing","middleName":"","lastName":"Wang","suffix":""},{"id":491062861,"identity":"1ec07d6e-d11a-4097-943a-46c08198e59e","order_by":3,"name":"Xiaoying Gong","email":"","orcid":"","institution":"Quzhou Center for Disease Control and Prevention","correspondingAuthor":false,"prefix":"","firstName":"Xiaoying","middleName":"","lastName":"Gong","suffix":""},{"id":491062863,"identity":"7b1676c0-c13f-4ed4-ac19-f03bfbf58320","order_by":4,"name":"Canjie Zheng","email":"","orcid":"","institution":"Quzhou Center for Disease Control and Prevention","correspondingAuthor":false,"prefix":"","firstName":"Canjie","middleName":"","lastName":"Zheng","suffix":""},{"id":491062864,"identity":"13726822-a23b-498e-bd25-a9eca0bc69ff","order_by":5,"name":"Zhiying Yin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuklEQVRIiWNgGAWjYJCCAx8M/skxMPAQr4Px4IyCA8YkaWE+zPPhQGID0VoMzp8xODjD4E76/PbeYxIMNTbRhLUcOGMA9Muz3A1nzqVJMBxLy20gqOVgD8gW5twNEjlmEowNh4nQcpgHhJjT5WcQreUYWMvhBIYbxGqRPMNWAHRYmuGGM2eMLRKI8Qvf+cObP3z4YyMv395jeONDjQ1hLQoHOAwQvARCykFAvoH9ATHqRsEoGAWjYCQDAI5MRlVejCPmAAAAAElFTkSuQmCC","orcid":"","institution":"Quzhou Center for Disease Control and Prevention","correspondingAuthor":true,"prefix":"","firstName":"Zhiying","middleName":"","lastName":"Yin","suffix":""}],"badges":[],"createdAt":"2025-06-16 09:08:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6903689/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6903689/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87832570,"identity":"38928cac-02e9-4384-a0b1-e6e11b90161e","added_by":"auto","created_at":"2025-07-29 12:40:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":229424,"visible":true,"origin":"","legend":"\u003cp\u003eWorkflow for data cleaning and analysis of HFMD reinfection cases in Quzhou, 2008–2024\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6903689/v1/505077b932c13639450d02a0.png"},{"id":87832571,"identity":"98916ba6-ab0e-4a24-8b92-80a94b12f608","added_by":"auto","created_at":"2025-07-29 12:40:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":97325,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of time intervals between onset of HFMD reinfection episodes in Quzhou, 2008–2024\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6903689/v1/731c52cf7e72a26b16afa92d.png"},{"id":87832572,"identity":"850726a8-4e14-462d-9479-0db186f0a23e","added_by":"auto","created_at":"2025-07-29 12:40:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":233112,"visible":true,"origin":"","legend":"\u003cp\u003ePrevalence curve of reinfection cases of HFMD in Quzhou, 2008-2024\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6903689/v1/b1f83025ef0af64e1831ba28.png"},{"id":87832573,"identity":"50ba6e68-a3d6-4b03-8d3c-c2b2a73ba564","added_by":"auto","created_at":"2025-07-29 12:40:24","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":137185,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curve depicting the cumulative hazard of HFMD reinfection.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6903689/v1/bf13e501ca0d24ede8168e82.png"},{"id":105564970,"identity":"9d2e8ad5-9d90-482b-8150-489226898163","added_by":"auto","created_at":"2026-03-27 12:51:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1435403,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6903689/v1/67e6e6ab-6bf9-4cfa-9bae-ee936ca3d2ff.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Epidemiological Characteristics and Risk Factor Analysis of Hand, Foot and Mouth Disease Reinfection Cases in Quzhou, China, 2008-2024","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHand, foot and mouth disease (HFMD) is a notifiable Class C infectious disease primarily affecting children under the age of five\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. It is caused by a range of enteroviruses, with enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16) representing the most prevalent aetiological agents. The majority of patients with HFMD exhibit a mild, self-limiting illness, typically characterised by a vesicular rash on the hands, feet or buttocks, accompanied by oral ulcers or blisters, with or without fever\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. However, a subset of patients may progress to severe disease, and in extreme cases, the condition can be fatal\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSince the 1990s, numerous outbreaks of HFMD have been documented in countries across the Western Pacific region\u0026mdash;including Malaysia, Japan, Taiwan and Singapore\u0026mdash;and the disease has become an increasingly serious public health issue\u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. In China, HFMD has occurred annually across much of the country since it was first identified in Shanghai in 1981\u003csup\u003e8\u003c/sup\u003e. In 2008, a major outbreak in Fuyang City, Anhui Province, resulted in 22 fatalities\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. That same year, the Chinese Ministry of Health classified HFMD as a Category C notifiable infectious disease. In recent years, the average annual number of reported HFMD cases in mainland China has exceeded one million\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, ranking first among all notifiable infectious diseases\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. As such, HFMD has emerged as a major public health concern.\u003c/p\u003e\u003cp\u003eVaccination remains the most cost-effective strategy for the prevention of infectious diseases. In 2016, an EV-A71 vaccine was introduced in mainland China, with clinical trials demonstrating an efficacy of 97.4%\u003csup\u003e12\u003c/sup\u003e. However, the vaccine offers protection solely against EV-A71 and does not confer cross-protection against other enteroviruses. Moreover, the antibody response elicited by the EV-A71 vaccine is not lifelong, and reinfection remains possible\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Consequently, recurrent cases of HFMD are relatively common. Reinfection with HFMD may result not only in more complex clinical presentations, such as atypical rashes and bacterial co-infections, but may also increase the overall disease burden due to variations in the immune response\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Epidemiological data indicate a rising trend in HFMD reinfection rates, potentially attributable to pathogen diversity and the transient nature of host immune memory\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. For instance, reinfection cases reported in Saudi Arabia suggest that insufficient cross-immunoprotection against different viral serotypes, or antigenic drift, may be key factors driving reinfection\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Additionally, host genetic factors and immunosuppressive conditions may affect the risk of reinfection by modulating the efficiency of viral receptor binding or the antibody response\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003ePrevious studies have predominantly focused on primary infections, with limited systematic analyses of the temporal patterns of reinfection and the interplay of multidimensional risk factors. Conventional analytical approaches, such as logistic regression, struggle to effectively capture risks associated with temporal dynamics. There is an urgent need for more robust statistical modelling techniques; however, few survival analysis models capable of handling time-dependent variables have been employed to date. In this study, a Cox proportional hazards regression model was employed, with reinfection as the event of interest and the interval from initial infection to reinfection as the survival time. The effects of multiple factors on survival time were analysed to elucidate the prevalence characteristics of HFMD and identify risk factors for reinfection in Quzhou City between 2008 and 2024. These findings aim to inform strategies for the prevention and control of HFMD.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eData collection\u003c/h2\u003e\u003cp\u003eHFMD cases were obtained from the Chinese Information System for Disease Control and Prevention (CISDCP), with data extracted based on current address and date of onset, and only cases with verified information were included. The study period was defined by onset dates ranging from 1 January 2008 to 31 December 2024. Data on age, sex, population classification, region, disease severity, and pathogenicity test results were collected for each case. Additionally, pathogenetic findings from previous HFMD sentinel surveillance in Quzhou City were incorporated.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eCase definitions\u003c/h3\u003e\n\u003cp\u003eThe diagnostic criteria for HFMD were based on the Clinical Guidelines for Hand, Foot and Mouth Disease (2018 edition), issued by the Chinese Ministry of Health. A clinically diagnosed case was defined by the presence of a vesicular rash on the hands, feet, mouth or buttocks, with or without fever. A laboratory-confirmed case was defined as a clinically diagnosed case accompanied by laboratory evidence of enterovirus infection (EV-A71, CV-A16, or other enteroviruses), confirmed through reverse transcription-polymerase chain reaction or viral isolation. Cases were classified as severe if clinical or laboratory diagnosis revealed the development of neurological complications, cardiopulmonary complications, or both. Cases not meeting these criteria were classified as mild. HFMD reinfection cases were defined as individuals infected with HFMD two or more times during the period from 2008 to 2024.\u003c/p\u003e\n\u003ch3\u003eData Cleaning\u003c/h3\u003e\n\u003cp\u003eA total of 80,050 HFMD case records were exported from the system, with 79,841 cases remaining after excluding suspected and duplicate reports. We established criteria for the inclusion and exclusion of HFMD reinfection cases. Inclusion criteria were as follows: (i) identical identity card number; (ii) matching parent\u0026rsquo;s name and date of birth; (iii) identical telephone number and date of birth. Applying these criteria yielded 5,712, 5,462, and 5,648 case records, respectively. Exclusion criteria were as follows: (i) dissimilar names; (ii) an interval of less than 14 days between onset dates of two mild infections, or less than 23 days between the onset of a severe infection and a subsequent infection\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e; (iii) differing home addresses across counties (cities or districts). Applying the exclusion criteria resulted in 5,416, 4,952 and 5,286 case records remaining in the three groups, respectively. Duplicate entries across the groups were then consolidated, yielding 4,026 unique cases and a total of 8,198 case records (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eMethods\u003c/h3\u003e\n\u003cp\u003eDescriptive epidemiological methods were employed to analyse the timing of reinfection onset, population distribution, regional distribution, and aetiological characteristics. Cox proportional hazards regression, a widely used method in medical survival analysis, was employed in this study to investigate the risk factors associated with HFMD reinfection. Cumulative risk probabilities were estimated and plotted, and subgroup differences in survival curves were assessed using the log-rank test. In this study, survival time was defined as the interval between the first infection and subsequent reinfection; for individuals with three or four episodes, only the interval between the first and second infections was considered. To assess the impact of the predominant strain during the year of initial HFMD infection on the risk of reinfection, data from previous pathogen surveillance in Quzhou City were utilised. EV-A71 was identified as the predominant strain in 2009, 2019, 2022, and 2024; CV-A16 in 2010, 2011, and 2018; while other enterovirus types predominated in the remaining years. The dominant strain in the year of first infection was incorporated into the model analysis as the epidemic strain variable. The six counties (cities and districts) of Quzhou were categorised into urban and rural areas based on geographic distribution, with Kecheng District and Qujiang District classified as urban, and the remaining areas as rural. Cox proportional hazards regression was used to calculate hazard ratios (HR), where an HR greater than 1 indicates that the exposure is a risk factor for the event of interest, while an HR less than 1 suggests a protective effect.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eData were compiled using Microsoft Excel 2010, and statistical analyses were performed using SPSS version 27.0. The HFMD reinfection rate was calculated as follows: reinfection rate = (number of HFMD reinfection cases / total number of HFMD cases) \u0026times; 100%. Continuous variables were described using medians and interquartile ranges (IQR), while categorical variables were summarised using proportions and rates. The Kaplan\u0026ndash;Meier method was applied to stratify and estimate the cumulative risk probability of first HFMD reinfection by sex, age, population type, region, symptom severity, and the predominant strain in the year of initial infection. Differences were assessed using the log-rank test. Cox proportional hazards regression models were utilised for univariate and multivariate analyses of potential risk factors influencing reinfection. A significance level of α\u0026thinsp;=\u0026thinsp;0.05 was adopted.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eEpidemiological characteristics of reinfection cases\u003c/h2\u003e\u003cp\u003eBetween January 2008 and December 2024, a total of 4,026 cases of HFMD reinfection were reported in Quzhou, representing a reinfection rate of 5.04% (4,026/79,841). Among them, 2,519 were male, with a reinfection rate of 5.41% (2,519/46,552), and 1,507 were female, with a reinfection rate of 4.53% (1,507/33,289). The difference in reinfection rates between sexes was statistically significant (χ\u0026sup2; = 31.686, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Most individuals (3,883 cases; 96.45%) experienced two infections, while 140 cases (3.48%) experienced three infections and three cases (0.07%) experienced four infections. By region, the number of reinfection cases was highest in Kecheng District (1,388; 34.48%), followed by Qujiang District (761; 18.90%), Kaihua County (637; 15.82%), Longyou County (494; 12.27%), Changshan County (432; 10.73%), and Jiangshan City (314; 7.80%). The corresponding reinfection rates were 5.68% (1,388/24,451) in Kecheng District, 5.80% (761/13,120) in Qujiang District, 5.31% (637/11,996) in Kaihua County, 4.74% (432/9,113) in Changshan County, 4.12% (494/11,993) in Longyou County, and 3.42% (314/9,168) in Jiangshan City. Severe cases accounted for 0.10% (4/4,026) during the first infection and 0.07% (3/4,026) during the second, with no severe cases reported in the third or fourth infections. All seven severe cases occurred in children.\u003c/p\u003e\u003cp\u003eComparison of the characteristics of cases with first, second, and third to fourth HFMD infections revealed that the median age at infection was 1.72 years (IQR: 1.21\u0026ndash;2.64), 3.43 years (IQR: 2.57\u0026ndash;4.51), and 3.83 years (IQR: 3.08\u0026ndash;5.34), respectively. The intervals between successive infections exhibited a skewed distribution, with median values of 1.35 years (IQR: 0.82\u0026ndash;2.10), 1.10 years (IQR: 0.75\u0026ndash;1.81), and 0.82 years, respectively. The population classifications were predominantly migrant children (78.07%) for first infections, and children in early childhood care for both second (53.43%) and third to fourth infections (63.51%). The number of severe cases reported was four, three, and zero for first, second, and subsequent infections, respectively. Aetiological test results were dominated by EV-A71 across all episodes, accounting for 65.48%, 47.56%, and 84.62%, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eEpidemiological characteristics of HFMD reinfection cases in Quzhou, 2008\u0026ndash;2024\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eFirst infection (n\u0026thinsp;=\u0026thinsp;4026)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eSecond infection (n\u0026thinsp;=\u0026thinsp;4026)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eThe 3rd to 4th infection (n\u0026thinsp;=\u0026thinsp;146)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e%\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e%\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e%\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eAge(years)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0.5-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e555\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1769\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e477\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e11.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1603\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2833\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e70.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e66.89\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e677\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e29.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003ePopulation classification\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScattered children\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3143\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e78.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1688\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e41.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e28.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKindergarten children\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e875\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2151\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e53.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e63.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e187\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eClinical type\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSevere\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e99.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e146\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e100.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eLaboratory results\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEV-A71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e110\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e65.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e47.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e84.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCox A16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e21.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther EV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e31.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e15.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eNote: a The number of cases with pathogen detection during the 1st, 2nd, and 3rd to 6th infections was 168, 164, and 13, respectively.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTemporal distribution of reinfection cases\u003c/h3\u003e\n\u003cp\u003eThere was a clear seasonal pattern in the onset of all first to third infections, displaying a bimodal distribution. The first peak of incidence occurred between April and June, accounting for 38.28%, 50.17%, and 49.32% of cases, respectively; the second peak occurred between November and December, comprising 19.92%, 14.90%, and 12.33% of cases, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The fourth infection was reported in three cases, with onset occurring in April, June, and July, respectively.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003ePathogenetic features of reinfection cases\u003c/h2\u003e\u003cp\u003eAmong the reinfection cases, 54 had laboratory confirmation for both the first and second infections. EV-A71, CV-A16, and other enterovirus types were all capable of causing recurrent infections. The highest proportion of cases involved EV-A71 on both occasions (66.67%), followed by reinfection with CV-A16 after an initial EV-A71 infection (12.96%) and other enterovirus types following EV-A71 infection (11.11%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There were 13 confirmed cases of third infection, among which 11 were caused by EV-A71 (with both first and second infections confirmed, comprising 5 cases of EV-A71, 5 cases of CV-A16, and 1 case of other enterovirus types), and 1 case was caused by other enterovirus types (with both first and second infections clinically diagnosed). All fourth infections were clinically diagnosed cases.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAetiology of First and Second Infections in Reinfected HFMD Cases in Quzhou, 2008\u0026ndash;2024\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVirus of First Infection\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVirus of Second Infection\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e%\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEV-A71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEV-A71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e66.67\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEV-A71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCV-A16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e12.96\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEV-A71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOther EV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e11.11\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCV-A16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCV-A16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCV-A16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOther EV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.85\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther EV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEV-A71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.85\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther EV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCV-A16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.85\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eNote: EV-A71, enterovirus A71; CV- A16, coxsackievirus A 16. Among the reinfection cases, 54 had laboratory confirmation for both the first and second infections\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eThe hazard of HFMD reinfection\u003c/h2\u003e\u003cp\u003eThe risk of reinfection was significantly elevated within 20 months following the initial HFMD infection, with 25.41% (1,023/4,026) of cases reinfected within 10 months and 62.47% (2,515/4,026) reinfected within 20 months. The cumulative hazard probability curves for HFMD reinfection, stratified by six factors\u0026mdash;sex, population category, symptom severity, age group, place of residence, and the predominant strain in the year of first infection\u0026mdash;indicated a higher risk of reinfection among children under 3 years of age, scattered children, those living in urban areas, and individuals whose first infection occurred during a year when CV-A16 was the predominant circulating strain (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eCox proportional hazards regression analyses, adjusted for relevant covariates, indicated that age group, population classification, region of residence, and the predominant enterovirus strain during the year of primary infection were all significantly associated with the risk of HFMD reinfection, even after accounting for potential confounding variables. Notably, children aged\u0026thinsp;\u0026ge;\u0026thinsp;3 years exhibited a substantially lower risk of reinfection compared with those aged\u0026thinsp;\u0026lt;\u0026thinsp;3 years (HR\u0026thinsp;=\u0026thinsp;0.312, 95% CI: 0.286\u0026ndash;0.339). Compared with scattered children, those in kindergarten care and school students had a significantly lower risk of reinfection (HR\u0026thinsp;=\u0026thinsp;0.124, 95% CI: 0.101\u0026ndash;0.151; and HR\u0026thinsp;=\u0026thinsp;0.743, 95% CI: 0.689\u0026ndash;0.801, respectively) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCox proportional hazards regression analysis of factors influencing HFMD reinfection in Quzhou, 2008\u0026ndash;2024\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003eSingle-variable analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u003cp\u003eMultivariable analysis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eHR\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003e95%CI\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eHR\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003e95%CI\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.038\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.974\u0026ndash;1.106\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.253\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.957\u0026ndash;1.087\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.539\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eAge(Years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.237\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.219\u0026ndash;0.256\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.312\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.286\u0026ndash;0.339\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003ePopulation classification\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScattered children\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eKindergarten children\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.485\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.454\u0026ndash;0.518\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.743\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.689\u0026ndash;0.801\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStudent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.081\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.067\u0026ndash;0.098\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.124\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.101\u0026ndash;0.151\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eRegion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRural\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUrban\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.265\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.188\u0026ndash;1.346\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.051\u0026ndash;1.191\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eClinical type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSevere\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.201\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.387\u0026ndash;3.727\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.751\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.106\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.245\u0026ndash;3.339\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.658\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003ePrevalent strain in year of first infection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEV-A71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCV-A16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.183\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.701\u0026ndash;3.751\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.391\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.025\u0026ndash;2.822\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOther EV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.590\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.484\u0026ndash;1.704\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.367\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.274\u0026ndash;1.467\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eLaboratory results\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEV-A71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCV-A16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.517\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.323\u0026ndash;5.412\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOther EV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.504\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.342\u0026ndash;1.256\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.283\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eNote:\u003csup\u003ea\u003c/sup\u003e Among the 4,026 reinfection cases, only 168 were confirmed by laboratory testing. Consequently, the \u0026lsquo;pathogen\u0026rsquo; variable contains numerous missing values and was excluded from the multivariate analysis.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eHFMD is a common infectious illness in children, responsible for numerous clinical cases annually and posing a risk of mortality in severe instances\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. In recent years, parental awareness and preventative measures against HFMD have steadily improved; however, reinfection continues to pose a significant threat to children\u0026rsquo;s health\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. The reinfection rate of HFMD in Quzhou was 5.04%, exceeding the 1.93% reported in Wuhan between 2008 and 2015\u003csup\u003e23\u003c/sup\u003e and the 3.25% nationwide during the same period\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, yet remaining lower than the 6.01% observed in Wuxi from 2008 to 2016\u003csup\u003e24\u003c/sup\u003e. The observed differences may be attributed to variations in the temporal scope of the analysis, the criteria used to define reinfection, and regional factors such as geographic location, economic status, and population density. These findings also indicate that the reinfection rate of HFMD in Quzhou remains high, emphasising the urgent need for further research into the risk of reinfection.\u003c/p\u003e\u003cp\u003eThe HFMD reinfection rate varied across counties, cities and districts within Quzhou City, ranging from 3.42\u0026ndash;5.80%. This suggests potential spatial heterogeneity in reinfection rates, the underlying causes of which require further investigation. HFMD reinfections predominantly involved two episodes, with cases of three or more infections being less common, consistent with previous studies\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Multiple HFMD infections predominantly occurred in children aged under four years, with median ages of 3.43 and 3.83 years for the second and third infections, respectively. Correspondingly, the population categories for the first to third infections were primarily composed of children living in scattered settings for the initial infection, followed by those in early childhood care for the second and third infections. A marked seasonality was evident in the onset of HFMD reinfection cases, with the seasonal patterns of the first, second and third infections being largely consistent. The primary peak in incidence occurred between April and June, consistent with the findings of Tian et al\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. However, this study also identified a secondary peak during November\u0026ndash;December. Xu et al\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e reported that the incidence of HFMD was positively associated with ambient temperature, with the strongest correlation observed within the 25.0\u0026ndash;27.5 ℃ range. From the perspective of the temporal interval between reinfections, the median duration between successive HFMD episodes exceeded one year, consistent with findings from Fujian Province\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. This underscores the importance of disseminating relevant health education to parents and emphasising the need for vigilance in preventing reinfection within two years of the initial episode.\u003c/p\u003e\u003cp\u003eHFMD reinfection can be attributed to a diverse range of enteroviruses. Reinfection with EV-A71, Cox A16, or other enterovirus types may occur following an initial EV-A71 infection, and in some instances, homologous reinfection has been observed. The underlying reasons may be attributed, firstly, to the failure of some patients to develop effective humoral immunity following HFMD virus infection\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e; and secondly, to the limited or absent cross-immunity between different enterovirus types\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. However, the high proportion of recurrent EV-A71 infections following initial EV-A71 infection may be attributable to the fact that EV-A71 testing is primarily conducted in Quzhou City, and therefore, the results may not be generalisable. Furthermore, the incidence of reinfection was higher when the initial infection was caused by Cox A16 or when Cox A16 was the predominant strain in the year of first infection. This finding aligns with studies conducted nationwide\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, as well as in Wuhan City\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e and Anhui Province\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e, and may be related to differences in the shedding rates of various subtypes. A review indicated that EV-A71 exhibits slower viral shedding and requires a longer period for complete clearance by the host compared with Cox A16. This prolonged clearance may contribute to the development of more durable immunity against EV-A71 and consequently a reduced risk of reinfection\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. In this study, it was observed that while reinfection could occur following a severe initial infection, subsequent episodes did not progress to severe disease. Conversely, cases where the first infection was mild could still result in reinfection with progression to severe disease. This phenomenon may be related to the viral subtype and warrants further investigation.\u003c/p\u003e\u003cp\u003eBoth univariate and multivariate analyses indicated that the risk of hand, HFMD reinfection was significantly associated with demographic factors, including age, area of residence and population classification. Notably, being under three years of age, residing in urban settings, and belonging to the Scattered children emerged as independent risk factors for reinfection. In a systematic study, Luo et al\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e reported that neonatal antibody levels against EV-A71 and CV-A16 declined to their lowest point by one year of age, followed by a gradual increase, peaking at approximately four years of age. Zhang et al\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e observed that organismal immunity to enteroviruses in children increases progressively with age. Consequently, reinfection with HFMD is more likely to be observed in children under three years of age. This study identified a relatively higher risk of reinfection among children residing in urban areas compared to their rural counterparts. This finding contrasts with the commonly held assumption that superior urban sanitation correlates with a reduced risk of reinfection. It may be attributable to enhanced access to and utilisation of healthcare services among urban populations, greater parental awareness regarding the importance of seeking medical care, and consequently, a higher likelihood of initial diagnosis and subsequent re-diagnosis of HFMD in urban children\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Moreover, urban areas are characterised by high population density and greater levels of transience, both of which contribute to increased interpersonal proximity and thereby elevate the risk of viral exposure\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Diaspora children exhibit a higher risk of reinfection compared to those in childcare or other population groups, which may be attributable not only to lower immunisation coverage but also to comparatively poorer hygiene practices within this demographic.\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eOur research comes with certain limitations that warrant consideration. Firstly, the pathogenicity laboratory test results for confirmed cases were obtained from the Infectious Disease Reporting Information System, where the detection reagents limited the scope of pathogen identification. The test results were predominantly for EV-A71, with fewer detections of Cox A16, and no further subtyping was performed for other enterovirus strains. This uneven rate of pathogen testing among confirmed cases may have introduced bias into the results. Secondly, we did not rigorously define or follow up on whether initial infections occurred prior to 2008. Consequently, the risk of reinfection may have been underestimated in this study.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, the HFMD reinfection epidemic in Quzhou City between 2008 and 2024 appears to be relatively severe. It is therefore essential to strengthen health education for both parents and childcare institution staff, and to maintain heightened vigilance. Even among children with a history of HFMD infection, parents should remain attentive to the potential recurrence of symptoms. Attention should be focused on diaspora children who experienced their first HFMD episode before the age of three, reside in urban areas, and whose initial infection was caused by Cox A16. The risk of reinfection is heightened when Cox-A16 was the predominant circulating strain in the year of initial infection.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHFMD Hand, foot and mouth disease\u003c/p\u003e\n\u003cp\u003eEV-A71 Enterovirus 71\u003c/p\u003e\n\u003cp\u003eCV-A16 Coxsackievirus A16\u003c/p\u003e\n\u003cp\u003eIQR Interquartile ranges\u003c/p\u003e\n\u003cp\u003eCISDCP Chinese Information System for Disease Control and Prevention\u003c/p\u003e\n\u003cp\u003eHR Hazard ratios\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the Quzhou Centre for Disease Control and Prevention, the local community hospitals for their assistance in conducting the testing, and Mao Jilai and Wang Shuangqing for their valuable advice on data analysis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and/or design: ZYY; Study management: QJF and JLM; Analysis of the data: SQW, XYG,CJZ; Interpretation of study results: all authors. Drafting of the manuscript for important intellectual content: ZYY and QJF. Review and editing of manuscript and approval of the final version to be published: all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll information was sourced from the Chinese Center for Disease Prevention and Control Information System. However, restrictions apply to the availability of these data, as they were used under license for this study and are not publicly accessible. Data are available from the authors upon reasonable request and with permission from the Quzhou CDC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Research Ethics Committee of the Centre for Disease Control and Prevention of Quzhou City (approval number: 2025-006-02) and was conducted in accordance with the principles of the Declaration of Helsinki. The Ethics Committee waived individual informed consent for the following reasons:\u003c/p\u003e\n\u003cp\u003e(i) The study used anonymised surveillance data from the China Information System for Disease Control and Prevention (CISDCP), which are collected as part of mandatory public health reporting in accordance with the Law of the People\u0026apos;s Republic of China on Prevention and Control of Infectious Diseases.\u003c/p\u003e\n\u003cp\u003e(ii) All personally identifiable information (name, address, telephone number) was deleted before analysis.\u003c/p\u003e\n\u003cp\u003e(iii) The National Health and Wellness Commission of China explicitly states that no ethical review is required for secondary analyses of anonymised statutory infectious disease data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eXing W, Liao Q, Viboud C, Zhang J, Sun J, Wu JT, Chang Z, Liu F, Fang VJ, Zheng Y, et al. Hand, foot, and mouth disease in China, 2008-12: an epidemiological study. Lancet Infect Dis. 2014;14(4):308-18. doi:10.1016/S1473-3099(13)70342-6.\u003c/li\u003e\n\u003cli\u003eTseng FC, Huang HC, Chi CY, Lin TL, Liu CC, Jian JW, Hsu LC, Wu HS, Yang JY, Chang YW, et al. Epidemiological survey of enterovirus infections occurring in Taiwan between 2000 and 2005: analysis of sentinel physician surveillance data. J Med Virol. 2007;79(12):1850-60. doi:10.1002/jmv.21006.\u003c/li\u003e\n\u003cli\u003eOoi MH, Wong SC, Lewthwaite P, Cardosa MJ, Solomon T. Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol. 2010;9(11):1097-105. doi:10.1016/S1474-4422(10)70209-X.\u003c/li\u003e\n\u003cli\u003eChan LG, Parashar UD, Lye MS, Ong FG, Zaki SR, Alexander JP, Ho KK, Han LL, Pallansch MA, Suleiman AB, et al. Deaths of children during an outbreak of hand, foot, and mouth disease in sarawak, malaysia: clinical and pathological characteristics of the disease. For the Outbreak Study Group. Clin Infect Dis. 2000;31(3):678-83. doi:10.1086/314032.\u003c/li\u003e\n\u003cli\u003eFujimoto T, Chikahira M, Yoshida S, Ebira H, Hasegawa A, Totsuka A, Nishio O. Outbreak of central nervous system disease associated with hand, foot, and mouth disease in Japan during the summer of 2000: detection and molecular epidemiology of enterovirus 71. Microbiol Immunol. 2002;46(9):621-7. doi:10.1111/j.1348-0421.2002.tb02743.x.\u003c/li\u003e\n\u003cli\u003eHo M, Chen ER, Hsu KH, Twu SJ, Chen KT, Tsai SF, Wang JR, Shih SR. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341(13):929-35. doi:10.1056/NEJM199909233411301.\u003c/li\u003e\n\u003cli\u003eChan KP, Goh KT, Chong CY, Teo ES, Lau G, Ling AE. Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore. Emerg Infect Dis. 2003;9(1):78-85. doi:10.3201/eid0901.020112.\u003c/li\u003e\n\u003cli\u003eZeng M, Li YF, Wang XH, Lu GP, Shen HG, Yu H, Zhu QR. Epidemiology of hand, foot, and mouth disease in children in Shanghai 2007-2010. Epidemiol Infect. 2012;140(6):1122-30. doi:10.1017/S0950268811001622.\u003c/li\u003e\n\u003cli\u003eZhang Y, Zhu Z, Yang W, Ren J, Tan X, Wang Y, Mao N, Xu S, Zhu S, Cui A, et al. An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of hand foot and mouth disease in Fuyang city of China. Virol J. 2010;7:94. doi:10.1186/1743-422X-7-94.\u003c/li\u003e\n\u003cli\u003eLiu J, Wang H, Zhong S, Zhang X, Wu Q, Luo H, Luo L, Zhang Z. Spatiotemporal Changes and Influencing Factors of Hand, Foot, and Mouth Disease in Guangzhou, China, From 2013 to 2022: Retrospective Analysis. JMIR Public Health Surveill. 2024;10:e58821. doi:10.2196/58821.\u003c/li\u003e\n\u003cli\u003eHan Y, Ji H, Shen W, Duan C, Cui T, Chen L, Hang H, Zhang Z, Sun H, Zhang X, et al. Disease burden in patients with severe hand, foot, and mouth disease in Jiangsu Province: a cross-sectional study. Hum Vaccin Immunother. 2022;18(5):2049168. doi:10.1080/21645515.2022.2049168.\u003c/li\u003e\n\u003cli\u003eLi R, Liu L, Mo Z, Wang X, Xia J, Liang Z, Zhang Y, Li Y, Mao Q, Wang J, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med. 2014;370(9):829-37. doi:10.1056/NEJMoa1303224.\u003c/li\u003e\n\u003cli\u003eLi JX, Song YF, Wang L, Zhang XF, Hu YS, Hu YM, Xia JL, Li J, Zhu FC. Two-year efficacy and immunogenicity of Sinovac Enterovirus 71 vaccine against hand, foot and mouth disease in children. Expert Rev Vaccines. 2016;15(1):129-37. doi:10.1586/14760584.2016.1096782.\u003c/li\u003e\n\u003cli\u003ede Sousa IP Jr, Giamberardino HI, Raboni SM, Debur MC, de Lourdes Aguiar Oliveira M, Burlandy FM, da Silva EE. Simultaneous enterovirus EV-D68 and CVA6 infections causing acute respiratory distress syndrome and hand, foot and mouth disease. Virol J. 2021;18(1):88. doi:10.1186/s12985-021-01560-w.\u003c/li\u003e\n\u003cli\u003eLi X, Chen S, Chen Y, Han S, Dai B, Li T, Yuan X, Su D, Li Z, Shen Y, et al. Epidemiological and genetic characterizations of hand, foot, and mouth disease and acute respiratory infections due to CV-A6 infection in Henan Province, China between 2021 and 2022. BMC Pediatr. 2025;25(1):264. doi:10.1186/s12887-025-05527-6.\u003c/li\u003e\n\u003cli\u003eWu H, Xue M, Wu C, Lu Q, Ding Z, Wang X, Fu T, Yang K, Lin J. Trend of hand, foot, and mouth disease from 2010 to 2021 and estimation of the reduction in enterovirus 71 infection after vaccine use in Zhejiang Province, China. PLoS One. 2022;17(9):e0274421. doi:10.1371/journal.pone.0274421.\u003c/li\u003e\n\u003cli\u003eAlakrash L, Barakeh M, AlQahtani WI, AlKanaan RK. Recurrent Hand, Foot, and Mouth Disease in a Saudi Girl. Cureus. 2024;16(1):e51813. doi:10.7759/cureus.51813.\u003c/li\u003e\n\u003cli\u003eDuan FY, Du ZQ, Wang Y, Luo L, Du LJ, Jiang H, Ma Y, Yang YL. The effects of SCARB2 and SELPLG gene polymorphisms on EV71 infection in hand, foot and mouth disease. Biomol Biomed. 2023;23(5):815-24. doi:10.17305/bb.2023.8948.\u003c/li\u003e\n\u003cli\u003eXu Y, Ma J, Ouyang W, Yao R, Cao W, Li J, Zou R, Fang C, Zeng F, Yang F, et al. Suppression of innate and acquired immunity in severe hand foot and mouth disease caused by EV71 infections in children. Clin Immunol. 2023;248:109260. doi:10.1016/j.clim.2023.109260.\u003c/li\u003e\n\u003cli\u003eHuang J, Liao Q, Ooi MH, Cowling BJ, Chang Z, Wu P, Liu F, Li Y, Luo L, Yu S, et al. Epidemiology of Recurrent Hand, Foot and Mouth Disease, China, 2008-2015. Emerg Infect Dis. 2018;24(3):432-42. doi:10.3201/eid2403.171303.\u003c/li\u003e\n\u003cli\u003eLi P, Li T, Gu Q, Chen X, Li J, Chen X, Chen Y, Zhang D, Gao R, He Z, et al. Children\u0026apos;s Caregivers and Public Playgrounds: Potential Reservoirs of Infection of Hand-foot-and-mouth Disease. Sci Rep. 2016;6:36375. doi:10.1038/srep36375.\u003c/li\u003e\n\u003cli\u003eAng LY, Too HK, Tan EL, Chow TK, Shek LP, Tham EH, Alonso S. Antiviral activity of Lactobacillus reuteri Protectis against Coxsackievirus A and Enterovirus 71 infection in human skeletal muscle and colon cell lines. Virol J. 2016;13:111. doi:10.1186/s12985-016-0567-6.\u003c/li\u003e\n\u003cli\u003ePeng Y, Yu B, Kong DG, Zhao YY, Wang P, Pang BB, Gong J. Reinfection hazard of hand-foot-mouth disease in Wuhan, China, using Cox-proportional hazard model. Epidemiol Infect. 2018;146(10):1337-42. doi:10.1017/S0950268818001322.\u003c/li\u003e\n\u003cli\u003eShi C, Liu J, Shi P, Ji H, Shen Y, Qian YH. Epidemiological characteristics and influential factors of hand, foot, and mouth disease reinfection in Wuxi, China, 2008-2016. BMC Infect Dis. 2018;18(1):472. doi:10.1186/s12879-018-3385-1.\u003c/li\u003e\n\u003cli\u003eTian H, Zhang Y, Shi Y, Li X, Sun Q, Liu L, Zhao D, Xu B. Epidemiological and aetiological characteristics of hand, foot, and mouth disease in Shijiazhuang City, Hebei province, China, 2009-2012. PLoS One. 2017;12(5):e0176604. doi:10.1371/journal.pone.0176604.\u003c/li\u003e\n\u003cli\u003eXu M, Yu W, Tong S, Jia L, Liang F, Pan X. Non-Linear Association between Exposure to Ambient Temperature and Children\u0026apos;s Hand-Foot-and-Mouth Disease in Beijing, China. PLoS One. 2015;10(5):e0126171. doi:10.1371/journal.pone.0126171.\u003c/li\u003e\n\u003cli\u003eZhonghang X, Yansheng Y, Rongtao H, et al. A cohort study on the characteristics of the recurrent epidemics on hand，foot and mouth disease，in Fujian province[J]. Chinese Journal of Epidemiology,2014,(10):1109-1114. (In Chinese)\u003c/li\u003e\n\u003cli\u003eQiu Q, Zhou J, Cheng Y, Zhou Y, Liang L, Cui P, Xue Y, Wang L, Wang K, Wang H, et al. Kinetics of the neutralising antibody response in patients with hand, foot, and mouth disease caused by EV-A71: A longitudinal cohort study in Zhengzhou during 2017-2019. EBioMedicine. 2021;68:103398. doi:10.1016/j.ebiom.2021.103398.\u003c/li\u003e\n\u003cli\u003eKlein MH. EV71 vaccines: a first step towards multivalent hand, foot and mouth disease vaccines. Expert Rev Vaccines. 2015;14(3):337-40. doi:10.1586/14760584.2015.993385.\u003c/li\u003e\n\u003cli\u003eChen GP, Wu JB, Wang JJ, Pan HF, Zhang J, Shi YL, Cao C, Li FR, Fan YG, Meng FY, et al. Epidemiological characteristics and influential factors of hand, foot and mouth disease (HFMD) reinfection in children in Anhui province. Epidemiol Infect. 2016;144(1):153-60. doi:10.1017/S0950268815001107.\u003c/li\u003e\n\u003cli\u003eDuan X, Chen Z, Li X, Yuan P, Long L. Virus Shedding in Patients With Hand, Foot and Mouth Disease Induced by EV71, CA16 or CA6: Systematic Review and Meta-analysis. Pediatr Infect Dis J. 2021;40(4):289-94. doi:10.1097/INF.0000000000002985.\u003c/li\u003e\n\u003cli\u003eLuo L, Xing W, Liao Q, Yu H. [Research progress on seroepidemiological study of enterovirus 71 and coxsackievirus A16 infection among children]. Zhonghua Yu Fang Yi Xue Za Zhi. 2015;49(2):184-8\u003c/li\u003e\n\u003cli\u003eZhang D, Chen Y, Chen X, He Z, Zhu X, Hao Y. Enterovirus 71 Neutralizing Antibodies Seroepidemiological Research among Children in Guangzhou, China between 2014 and 2015: A Cross-Sectional Study. Int J Environ Res Public Health. 2017;14(3):319. doi:10.3390/ijerph14030319.\u003c/li\u003e\n\u003cli\u003eHuang R, Wei J, Li Z, Gao Z, Mahe M, Cao W. Spatial-temporal mapping and risk factors for hand foot and mouth disease in northwestern inland China. PLoS Negl Trop Dis. 2021;15(3):e0009210. doi:10.1371/journal.pntd.0009210.\u003c/li\u003e\n\u003cli\u003eGao Y, Wang H, Yi S, Wang D, Ma C, Tan B, Wei Y. Spatial and Temporal Characteristics of Hand-Foot-and-Mouth Disease and Their Influencing Factors in Urumqi, China. Int J Environ Res Public Health. 2021;18(9):4919. doi:10.3390/ijerph18094919.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"hand foot and mouth disease, reinfection, epidemiological characteristic, risk factors, cox regression analysis","lastPublishedDoi":"10.21203/rs.3.rs-6903689/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6903689/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Previous studies on Hand, foot and mouth disease (HFMD) have predominantly focused on primary infections, with limited systematic analysis of the temporal distribution of reinfection and the interplay of multidimensional risk factors. Moreover, conventional analytical approaches, such as logistic regression, have been insufficient in effectively capturing the temporal dynamics of reinfection risk.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In this study, a Cox proportional hazards regression model was employed to analyse the epidemiological characteristics and risk factors associated with HFMD reinfection in Quzhou City from 2008 to 2024, with the aim of informing targeted prevention and control strategies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Between 2008 and 2024, a total of 4,026 cases of HFMD reinfection were reported in Quzhou, corresponding to a reinfection rate of 5.04% (4,026/79,841). Among these, 3,883 cases (96.45%) involved two episodes of infection, 140 cases (3.48%) involved three episodes, and 3 cases (0.07%) experienced four episodes. The timing of onset for the first to third HFMD infections exhibited a bimodal distribution, with peaks occurring in April–June and November–December. The median intervals between successive infections were 1.35 years (interquartile range: 0.82–2.10) between the first and second infections, 1.10 years (0.75–1.81) between the second and third, and 0.82 years between the third and fourth. Cox proportional hazards regression modelling identified age under three years, Scattered children, urban residence, initial infection with Cox A16, and Cox-A16 being the predominant circulating strain in the year of initial infection as significant risk factors for HFMD reinfection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThe HFMD reinfection epidemic in Quzhou City between 2008 and 2024 appears to be relatively severe. It is therefore essential to strengthen health education for both parents and childcare institution staff, and to maintain heightened vigilance. Even among children with a history of HFMD infection, parents should remain attentive to the potential recurrence of symptoms. Attention should be focused on diaspora children who experienced their first HFMD episode before the age of three, reside in urban areas, and whose initial infection was caused by Cox A16. The risk of reinfection is heightened when Cox-A16 was the predominant circulating strain in the year of initial infection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e Not applicable.\u003c/p\u003e","manuscriptTitle":"Epidemiological Characteristics and Risk Factor Analysis of Hand, Foot and Mouth Disease Reinfection Cases in Quzhou, China, 2008-2024","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-29 12:40:19","doi":"10.21203/rs.3.rs-6903689/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2545023f-dcd5-46f8-8250-2ddfd81b2e56","owner":[],"postedDate":"July 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-25T08:28:58+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-29 12:40:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6903689","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6903689","identity":"rs-6903689","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}