Epidemiology of hand, foot, and mouth disease and the genetic characteristics of Coxsackievirus A16 in Taiyuan, Shanxi, China from 2010 to 2021.

Hand, foot, and mouth disease (HFMD) is a common childhood infectious disease caused by human enteroviruses (EV). This study aimed to describe the epidemiological features of HFMD and the genetic characteristics of Coxsackievirus A16 (CVA16) in Taiyuan, Shanxi, China, from 2010 to 2021. Descriptive epidemiological methods were used to analyze the time and population distribution of HFMD and the genetic characteristics of CVA16. Except being affected by the COVID-19 epidemic in 2020, HFMD epidemics were sporadic from January to March each year, and began to increase in April, with a major epidemic peak from May to August, which declined in September, followed by a secondary peak from October to December. The prevalence of EV infection was the highest in children aged one to five years (84.42%), whereas its incidence was very low in children under one year of age (5.48%). Enterovirus nucleic acid was detected by real-time reverse transcription polymerase chain reaction in 6641 clinical specimens collected from patients with HFMD from 2010 to 2021, and 4236 EV-positive specimens were detected, including 988 enterovirus A71 (EV-A71), 1488 CVA16, and 1760 other enteroviruses. CVA16 remains prevalent and has co-circulated with other EVs in Taiyuan from 2010 to 2021. A phylogenetic tree constructed based on the VP1 region showed that all CVA16 strains belonged to two different clades of the B1 genotype, B1a and B1b. They showed a nucleotide similarity of 86.5-100%, and an amino acid similarity of 96.9-100%. Overall, these findings add to the global genetic resources of CVA16, demonstrate the epidemiological characteristics of HFMD as well as the genetic features of CVA16 in Taiyuan City during 2010-2021, and provide supporting evidence for the prevention and control of HFMD.

Application of the double bounded dichotomous choice model to the estimation of parent's willingness to pay for the hand foot mouth disease vaccination: A survey in Selangor, Malaysia.

Hand foot and mouth disease (HFMD) is a notifiable viral disease in Malaysia, and is transmitted primarily among young children. Although vaccines for enteroviruses 71 (EV-71) were approved in China against HFMD, the availability and the acceptance of the vaccine in the Malaysia are unknown. This study investigated and ascertained the determinants of willingness-to-pay (WTP) for HFMD vaccination in Selangor Malaysia. This study adopted a cross-sectional, contingent valuation method involving 390 parents of young children aged six and below. The double bounded dichotomous choice (DBDC) approach was employed to assess the WTP for HFMD vaccine among respondents. A bivariate probit model was used to assess the key determinants of WTP for HFMD vaccine, while the mean WTP was measured using the Krinsky and Robb procedure. We found that 279 (71.5%) of parents were willing to pay for the HFMD vaccination. The estimated single bounded mean WTP was MYR460.23 (equivalent to US$ 102.17) for two doses of HFMD vaccination. The double bounded analysis revealed that the vaccine's price, poor education background and lower income were the key factors that significantly affected the WTP, with the estimated mean WTP being MYR394.00 (US$ 87.47). In conclusion, most Malaysian parents are willing to pay for the HFMD vaccination. The estimated WTP identifies the optimal price point for HFMD vaccination in Malaysia. Furthermore, the government should focus on an awareness programme for the HFMD vaccination among parents who have lower income or education level.

Hand Foot Mouth Disease During the SARS-CoV-2 Pandemic: A Multicentric Study.

OBJECTIVES: This prospective observational study aimed to identify the current trend of the circulating viral strains responsible for HFMD outbreak in four tertiary care centers in Rajasthan, amidst the COVID-19 pandemic (April-October 2022). METHODS: Cases with suspected HFMD, presenting to our skin outpatient department were assessed clinically and serologically (IgM antibodies against coxsackie virus (CV) A6, A16 and enterovirus 71) for evidence of the disease. RESULTS: We identified 718 new HFMD patients (161 adults) with peaks in May and August, 2022. Male:female ratio decreased with increasing age. Most children were asymptomatic. A total of 385/409 patients assessed serologically, were found positive, most commonly against CV-A6. CONCLUSION: Though HFMD typically affects young children, an unusually higher proportion of adults were affected during the current pandemic. There were some subtle differences between pediatric and adult presentation of HFMD.

The 2022 outbreak and the pathobiology of the coxsackie virus [hand foot and mouth disease] in India.

Outbreaks of HFMD in children aged <5 years have been reported worldwide and the major causative agents are Coxsackievirus (CV) A16, enterovirus (EV)-A71 and recently CVA6. In India, HFMD is a disease that is not commonly reported. The purpose of the study was to identify the enterovirus type(s) associated with large outbreak of Hand, foot, and mouth disease during COVID-19 pandemic in 2022. Four hundred and twenty five clinical samples from 196-suspected cases were collected from different parts of the country. This finding indicated the emergence of CVA6 in HFMD along with CVA16, soon after the gradual easing of non-pharmaceutical interventions during-pandemic COVID-19 and the relevance of continued surveillance of circulating enterovirus types in the post-COVID pandemic era.

Current status of hand-foot-and-mouth disease.

Hand-foot-and-mouth disease (HFMD) is a viral illness commonly seen in young children under 5 years of age, characterized by typical manifestations such as oral herpes and rashes on the hands and feet. These symptoms typically resolve spontaneously within a few days without complications. Over the past two decades, our understanding of HFMD has greatly improved and it has received significant attention. A variety of research studies, including epidemiological, animal, and in vitro studies, suggest that the disease may be associated with potentially fatal neurological complications. These findings reveal clinical, epidemiological, pathological, and etiological characteristics that are quite different from initial understandings of the illness. It is important to note that HFMD has been linked to severe cardiopulmonary complications, as well as severe neurological sequelae that can be observed during follow-up. At present, there is no specific pharmaceutical intervention for HFMD. An inactivated Enterovirus A71 (EV-A71) vaccine that has been approved by the China Food and Drug Administration (CFDA) has been shown to provide a high level of protection against EV-A71-related HFMD. However, the simultaneous circulation of multiple pathogens and the evolution of the molecular epidemiology of infectious agents make interventions based solely on a single agent comparatively inadequate. Enteroviruses are highly contagious and have a predilection for the nervous system, particularly in child populations, which contributes to the ongoing outbreak. Given the substantial impact of HFMD around the world, this Review synthesizes the current knowledge of the virology, epidemiology, pathogenesis, therapy, sequelae, and vaccine development of HFMD to improve clinical practices and public health efforts.

Hand Foot Mouth Disease During the SARS-CoV-2 Pandemic: A Multicentric Study.

OBJECTIVES: This prospective observational study aimed to identify the current trend of the circulating viral strains responsible for HFMD outbreak in four tertiary care centers in Rajasthan, amidst the COVID-19 pandemic (April-October 2022). METHODS: Cases with suspected HFMD, presenting to our skin outpatient department were assessed clinically and serologically (IgM antibodies against coxsackie virus (CV) A6, A16 and enterovirus 71) for evidence of the disease. RESULTS: We identified 718 new HFMD patients (161 adults) with peaks in May and August, 2022. Male:female ratio decreased with increasing age. Most children were asymptomatic. A total of 385/409 patients assessed serologically, were found positive, most commonly against CV-A6. CONCLUSION: Though HFMD typically affects young children, an unusually higher proportion of adults were affected during the current pandemic. There were some subtle differences between pediatric and adult presentation of HFMD.

Influence of anti-coronavirus disease 2019 policies on 10 pediatric infectious diseases.

BACKGROUND: To combat the coronavirus disease 2019 pandemic, many countries, including Japan, implemented policies limiting social activities and encouraging preventive behaviors. This study examines the influence of such policies on the trends of 10 infectious pediatric diseases: pharyngoconjunctival fever; group A streptococcal pharyngitis; infectious gastroenteritis; chickenpox; erythema infectiosum; hand, foot, and mouth disease; herpangina; respiratory syncytial virus; exanthem subitum; and mumps. METHODS: The research adopted a retrospective cohort study design. We collected data from Japan's National Epidemiological Surveillance Program detailing the incidences of the 10 diseases per pediatric sentinel site for a period beginning at 9 weeks before government-ordered school closures and ending at 9 weeks after the end of the state of emergency. We obtained corresponding data for the equivalent weeks in 2015-2019. We estimated the influence of the policies using a difference-in-differences regression model. RESULTS: For seven diseases (pharyngoconjunctival fever; group A streptococcal pharyngitis; infectious gastroenteritis; chickenpox; erythema infectiosum; hand, foot, and mouth disease; and herpangina), the incidence in 2020 decreased significantly during and after the school closures. Sensitivity analysis, in which the focus area was limited to the policy-implementation period or existing trend patterns, replicated these significant decreases for one of the above mentioned seven diseases - infectious gastroenteritis. CONCLUSIONS: Policies such as school closures and encouragement of preventive behaviors were associated with significant decreases in the incidences of most of the 10 diseases, which sensitivity analysis replicated in infectious gastroenteritis. To determine the long-term effects of these policies, prospective cohort studies are needed.

Virtual flavonoids screening identifies potent compounds against enterovirus A71 and coxsackievirus A16 (preprint)

Worldwide outbreaks of hand, foot, and mouth disease (HFMD) are caused by enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16). Since no anti-HFMD drugs are currently available, it is interesting to study potential viral inhibitors. Rupintrivir is a rhinovirus 3C protease (3Cpro) inhibitor with apparent inhibitory activity against HFMD. This study constructs pharmacophore models of the EV-A71 and CV-A16 3Cpro complexed with rupintrivir using molecular dynamics (MD) simulations. Both models had similar pharmacophore features, including hydrogen bond donors and acceptors and hydrophobic interactions. These pharmacophore models were then used as a template to screen 39 flavonoid compounds as potential novel inhibitors. Diosmin, epigallocatechin gallate (EGCG), and RTH-011 showed high binding affinities for EV-A71 and CV-A16 3Cpro. They formed hydrogen bonds with important surrounding residues in both proteins, including H40, L127, T142, A144, T145, H161, I162, G163, and G164. In addition, their effective concentrations against rhabdomyosarcoma (RD) cell infection by EV-A71 and CV-A16 were determined. EGCG had the highest half maximal effective concentration (EC50) of 12.86 ± 1.30 µM for EV-A71 and 15.54 ± 1.50 µM for CV-A16, while diosmin had EC50 of 21.01 ± 1.57 µM for EV-A71 and 30.68 ± 3.25 µM for CV-A16. Both compounds were non-toxic in RD cells, with 50% cytotoxic concentrations of > 100 µM for EGCG and > 500 µM for diosmin. In addition, MD simulation analysis showed that EGCG had a higher binding affinity than diosmin, supported by its significantly lower solvated binding free energies and greater numbers of contact atoms and key binding residues. Moreover, previous studies reported EGCG’s inhibitory effect on other viruses, such as severe acute respiratory syndrome coronavirus 2. Therefore, our findings suggest that EGCG can effectively inhibit the EV-A71 and CV-A16 3Cpro.

Human exposure risk assessment for infectious diseases due to temperature and air pollution: an overview of reviews (preprint)

Air pollution and global temperature change are expected to affect infectious diseases. Yet to date overview of systematic reviews assessing the exposure risk of air pollutants and temperature on infectious diseases is unavailable. PubMed, Embase, the Cochrane Library, Web of Science, and the Cumulative Index to Nursing and Allied Health Literature were searched. Systematic reviews and meta-analyses investigated the exposure risk of pollutants or temperature on infectious diseases were included. Two investigators screened literature, extracted data and performed the risk of bias assessments independently. A total of 23 articles met the inclusion criteria, which 3 (13%) were "low" quality and 20 (87%) were "critically low" quality. COVID-19 morbidity was associated with long-term exposure PM2.5 (RR = 1.056 per 1μg/m  3, 95% CI: 1.039-1.072) and NO2 (RR = 1.042 per 1 μg/m 3, 95% CI: 1.017-1.068). In addition, for each 1°C increase in temperature, the risk of dengue fever morbidity increased 13% (RR = 1.130 per 1°C, 95% CI: 1.120-1.150), infectious diarrhea morbidity increased 8% (RR =1.080 per 1°C, 95% CI: 1.050-1.200), and hand, foot and mouth disease (HFMD) morbidity increased 5% (RR = 1.050 per 1 °C, 95% CI: 1.020-1.080). In conclusion, PM2.5 and NO2 increased the risk of COVID-19 and temperatures were associated with dengue, infectious diarrhoea and HFMD morbidity. Moreover, the exposure risk of temperature on COVID-19 need to be further explored. 

Drug Repositioning for Hand, Foot, and Mouth Disease.

Hand, foot, and mouth disease (HFMD) is a highly contagious disease in children caused by a group of enteroviruses. HFMD currently presents a major threat to infants and young children because of a lack of antiviral drugs in clinical practice. Drug repositioning is an attractive drug discovery strategy aimed at identifying and developing new drugs for diseases. Notably, repositioning of well-characterized therapeutics, including either approved or investigational drugs, is becoming a potential strategy to identify new treatments for virus infections. Various types of drugs, including antibacterial, cardiovascular, and anticancer agents, have been studied in relation to their therapeutic potential to treat HFMD. In this review, we summarize the major outbreaks of HFMD and the progress in drug repositioning to treat this disease. We also discuss the structural features and mode of action of these repositioned drugs and highlight the opportunities and challenges of drug repositioning for HFMD.

Effects of different levels of non-pharmaceutical interventions on hand, foot and mouth disease in Guangzhou, China.

BACKGROUND: Non-pharmaceutical interventions (NPIs) against coronavirus disease 2019 (COVID-19) may have suppressed the transmission of other infectious diseases. This study aimed to evaluate the impact of different degrees of NPIs during the COVID-19 pandemic on hand, foot and mouth disease (HFMD) in Guangzhou, China. METHODS: Weekly reported HFMD cases and pathogens information during 2015-2021 in Guangzhou were collected from the China National Notifiable Disease Reporting System. The observed number of HFMD cases in 2020 and 2021 was compared to the average level in the same period during 2015-2019. Then, an interrupted time-series segmented regression analysis was applied to estimate the impact of NPIs on HFMD, such as social distancing, suspension of schools, community management and mask wearing. The effects across different subgroups stratified by gender, children groups and enterovirus subtype of HFMD were also examined. RESULTS: A total of 13,224 and 36,353 HFMD cases were reported in 2020 and 2021, which decreased by 80.80% and 15.06% respectively compared with the average number of cases in the same period during 2015-2019. A significant drop in the number of HFMD cases during time when strict NPIs were applied (relative change: 69.07% [95% confidence interval (CI): 68.84%-69.30%]). The HFMD incidence rebounded to historical levels in 2021 as the lockdown eased. The slightest reduction of HFMD cases was found among children at kindergartens or childcare centres among the three children groups (children at kindergartens or childcare centres: 55.50% [95% CI: 54.96%-56.03%]; children living at home: 72.64% [95% CI: 72.38%-72.89%]; others: 74.06% [95% CI: 73.19%-74.91%]). CONCLUSIONS: The strong NPIs during the COVID-19 epidemic may have a significant beneficial effect on mitigating HFMD. However, the incidence of HFMD rebounded as the NPIs became less stringent. Authorities should consider applying these NPIs during HFMD outbreaks and strengthening personal hygiene in routine prevention.

Explanation of hand, foot, and mouth disease cases in Japan using Google Trends before and during the COVID-19: infodemiology study.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) pandemic affects common diseases, but its impact on hand, foot, and mouth disease (HFMD) is unclear. Google Trends data is beneficial for approximate real-time statistics and because of ease in access, is expected to be used for infection explanation from an information-seeking behavior perspective. We aimed to explain HFMD cases before and during COVID-19 using Google Trends. METHODS: HFMD cases were obtained from the National Institute of Infectious Diseases, and Google search data from 2009 to 2021 in Japan were downloaded from Google Trends. Pearson correlation coefficients were calculated between HFMD cases and the search topic "HFMD" from 2009 to 2021. Japanese tweets containing "HFMD" were retrieved to select search terms for further analysis. Search terms with counts larger than 1000 and belonging to ranges of infection sources, susceptible sites, susceptible populations, symptoms, treatment, preventive measures, and identified diseases were retained. Cross-correlation analyses were conducted to detect lag changes between HFMD cases and search terms before and during the COVID-19 pandemic. Multiple linear regressions with backward elimination processing were used to identify the most significant terms for HFMD explanation. RESULTS: HFMD cases and Google search volume peaked around July in most years, excluding 2020 and 2021. The search topic "HFMD" presented strong correlations with HFMD cases, except in 2020 when the COVID-19 outbreak occurred. In addition, the differences in lags for 73 (72.3%) search terms were negative, which might indicate increasing public awareness of HFMD infections during the COVID-19 pandemic. The results of multiple linear regression demonstrated that significant search terms contained the same meanings but expanded informative search content during the COVID-19 pandemic. CONCLUSIONS: The significant terms for the explanation of HFMD cases before and during COVID-19 were different. Awareness of HFMD infections in Japan may have improved during the COVID-19 pandemic. Continuous monitoring is important to promote public health and prevent resurgence. The public interest reflected in information-seeking behavior can be helpful for public health surveillance.

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.

BACKGROUND: Zhejiang, ranked in the top three in HFMD (hand, foot, and mouth disease) incidence, is located in the Yangtze River Delta region of southeast China. Since 2016, the EV71 vaccine has been promoted in Zhejiang Province. This study aimed to investigate the trend and seasonal variation characteristics of HFMD from 2010 to 2021 and estimate the reduction in enterovirus 71 infection after vaccine use. METHODS: The data on HFMD cases in Zhejiang Province from January 2010 to December 2021 were obtained from this network system. Individual information on cases and deaths was imported, and surveillance information, including demographic characteristics and temporal distributions, was computed by the system. The Joinpoint regression model was used to describe continuous changes in the incidence trend. The BSTS (Bayesian structural time-series models) model was used to estimate the monthly number of cases from 2017 to 2021 based on the observed monthly incidence during 2010-2016 by accounting for seasonality and long-term trends. The seasonal variation characteristics of HFMD pathogens were detected by wavelet analysis. RESULTS: From 2010 to 2021, the annual incidence rate fluctuated between 98.81 cases per 100,000 in 2020 and 435.63 cases per 100,000 in 2018, and 1711 severe HFMD cases and 106 fatal cases were reported in Zhejiang Province, China. The annual percent change (APC) in EV71 cases was -30.72% (95% CI: -45.10 to -12.50) from 2016 to 2021. The wavelet transform of total incidence and number of cases of the three pathogens all showed significant periodicity on the 1-year scale. The average 2-year scale periodicity was significant for the total incidence, EV71 cases and Cox A16 cases, but the other enterovirus cases showed significant periodicity on the 30-month scale. The 6-month scale periodicity was significant for the total incidence, EV71 case and Cox A16 case but not for the other enteroviruses case. The relative error percentage of the performance of the BSTS model was 0.3%. The estimated number of cases from 2017 to 2021 after the EV-A71 vaccines were used was 9422, and the reduction in the number of cases infected with the EV71 virus was 73.43% compared to 70.80% when the impact of the COVID-19 epidemic in 2020 was excluded. CONCLUSIONS: Since 2010, the incidence of EV71 infections has shown an obvious downward trend. All types of viruses showed significant periodicity on the 1-year scale. The periodicity of the biennial peak is mainly related to EV71 and Cox A16 before 2017 and other enteroviruses since 2018. The half-year peak cycle of HFMD was mainly caused by EV71 and Cox A6 infection. The expected incidence will be 2.76 times(include the cases of 2020) and 2.43 times(exclude the cases of 2020) higher than the actual value assuming that the measures of vaccination are not taken. EV71 vaccines are very effective and should be administered in the age window between 5 months and 5 years.

Comprehensive profiling and characterization of cellular microRNAs in response to coxsackievirus A10 infection in bronchial epithelial cells.

Coxsackievirus A10 (CV-A10), the causative agent of hand, foot, and mouth disease (HFMD), caused a series of outbreaks in recent years and often leads to neurological impairment, but a clear understanding of the disease pathogenesis and host response remains elusive. Cellular microRNAs (miRNAs), a large family of non-coding RNA molecules, have been reported to be key regulators in viral pathogenesis and virus-host interactions. However, the role of host cellular miRNAs defensing against CV-A10 infection is still obscure. To address this issue, we systematically analyzed miRNA expression profiles in CV-A10-infected 16HBE cells by high-throughput sequencing methods in this study. It allowed us to successfully identify 312 and 278 miRNAs with differential expression at 12 h and 24 h post-CV-A10 infection, respectively. Among these, 4 miRNAs and their target genes were analyzed by RT-qPCR, which confirmed the sequencing data. Gene target prediction and enrichment analysis revealed that the predicted targets of these miRNAs were significantly enriched in numerous cellular processes, especially in regulation of basic physical process, host immune response and neurological impairment. And the integrated network was built to further indicate the regulatory roles of miRNAs in host-CV-A10 interactions. Consequently, our findings could provide a beneficial basis for further studies on the regulatory roles of miRNAs relevant to the host immune responses and neuropathogenesis caused by CV-A10 infection.

Comparison of Neutralizing Antibody Response Kinetics in Patients with Hand, Foot, and Mouth Disease Caused by Coxsackievirus A16 or Enterovirus A71: A Longitudinal Cohort Study of Chinese Children, 2017-2019.

Hand, foot, and mouth disease (HFMD), which is mainly caused by coxsackievirus A16 (CVA16) or enterovirus A71 (EV-A71), poses a serious threat to children's health. However, the long-term dynamics of the neutralizing Ab (NAb) response and ideal paired-serum sampling time for serological diagnosis of CVA16-infected HFMD patients were unclear. In this study, 336 CVA16 and 253 EV-A71 PCR-positive HFMD inpatients were enrolled and provided 452 and 495 sera, respectively, for NAb detection. Random-intercept modeling with B-spline was conducted to characterize NAb response kinetics. The NAb titer of CVA16 infection patients was estimated to increase from negative (2.1, 95% confidence interval [CI]: 1.4-3.3) on the day of onset to a peak of 304.8 (95% CI: 233.4-398.3) on day 21 and then remained >64 until 26 mo after onset. However, the NAb response level of EV-A71-infected HFMD patients was much higher than that of CVA16-infected HFMD patients throughout. The geometric mean titer was significantly higher in severe EV-A71-infected patients than in mild patients, with a 2.0-fold (95% CI: 1.4-3.2) increase. When a 4-fold rise in titer was used as the criterion for serological diagnosis of CVA16 and EV-A71 infection, acute-phase serum needs to be collected at 0-5 d, and the corresponding convalescent serum should be respectively collected at 17.4 (95% CI: 9.6-27.4) and 24.4 d (95% CI: 15.3-38.3) after onset, respectively. In conclusion, both CVA16 and EV-A71 infection induce a persistent humoral immune response but have different NAb response levels and paired-serum sampling times for serological diagnosis. Clinical severity can affect the anti-EV-A71 NAb response.

Hand, foot, and mouth disease outbreak by Coxsackievirus A6 during COVID-19 pandemic in 2021, São Paulo, Brazil.

INTRODUCTION: Hand, foot, and mouth disease (HFMD) is an acute febrile illness characterized by fever; sore throat; and vesicular eruptions on the hands, feet, and oral mucosa. Outbreaks of HFMD in children aged <5 years have been reported worldwide and the major causative agents are Coxsackievirus (CV)A16, enterovirus (EV)-A71 and recently CVA6. AIM AND METHODS: The aim of this study was to investigated a large outbreak of Hand, foot, and mouth disease during COVID-19 pandemic in 2021 from clinical samples of 315 suspected cases, in São Paulo State, Brazil. Diagnostic evaluation was performed by RT-qPCR, culture cell isolation and serological neutralization assay. EV-positive were genotyped by partial VP1 genome sequencing. RESULTS: One hundred and forty-nine cases analyzed were positive for enterovirus (47.3%; n = 149/315) by neutralizing test (n = 10 patients) and RT-qPCR (n = 139 patients), and identified as CVA6 sub-lineage D3 by analysis of VP1 partial sequences. CONCLUSIONS: This finding indicated the reemergence of CVA6 in HFMD, soon after the gradual easing of non-pharmaceutical interventions during-pandemic COVID-19 and the relevance of continued surveillance of circulating enterovirus types in the post-COVID pandemic era.

Effectiveness of case isolation and class suspension in mitigation of enterovirus transmission in children.

BACKGROUND: Appropriate mitigation strategy to minimize enterovirus (EV) transmission among children is essential to control severe EV epidemics. Scientific evidence for the effectiveness of case isolation and class suspension is lacking. METHODS: EV-infected children ≤ eight years are asked to stay at home for seven days. Classes were suspended for seven days if there are more than two classmates having an onset of herpangina or hand, foot, and mouth disease in one classroom within one week. Study subjects are divided into two groups, group A with class suspension for one week and group B without class suspension. RESULTS: Among 4153 reported EV-infected children from 1085 classes in May and June, 2015 were enrolled. Median incidence of EV infection in a class was 7% (range 3% -60%). The incidence was higher in group A (median 14%, range 3-60%) than that in group B (median 6%, range 3-80%) (P < 0.01). The median incidence is highest in day care center (20%), followed by kindergarten (8%), and primary school (4%) (P < 0.01). Most secondary cases in group A appeared within seven days after the disease onset of index case in the same class. The incidence of EV infection remained low and was similar between the two groups eight days and beyond after the disease onset of index cases. CONCLUSIONS: Targeted class suspension for seven days with case isolation for seven days is an effective measure to mitigate transmission of EV infection in children.

Predicting Hand, Foot, and Mouth Disease in Japan Using Google Trends: Infodemiology Study (preprint)

Objectives: We aimed to predict the number of hand, foot, and mouth disease (HFMD) infections before and during the COVID-19 pandemic using Internet search data. Methods: We obtained actual HFMD cases from the National Institute of Infectious Disease and Internet search data using Google Trends between 2004 and 2021 in Japan. We calculated the Pearson correlation coefficients between actual HFMD cases and the search topic "HFMD" from 2004 to 2021. We conducted a cross-correlation analysis between the actual HFMD cases and 43 HFMD-related search terms before and during the pandemic. We identified the most significant predictors of HFMD infection using stepwise multiple linear regression. Results: We found that actual HFMD cases and Internet search volume peaked around July in most years, except for 2020 and 2021. The search topic "HFMD" presented a strong correlation with actual HFMD cases, but the correlation was weaker in 2004, 2008, and 2020. Results from stepwise multiple linear regression exhibited that the search terms "infect," "daycare," "vomit," "HFMD," "eczema," "pain," and "high fever were the most significant predictors before the pandemic, while "infect," "enterovirus," "herpangina," "kindergarten," "myocarditis," "HFMD," "contact infection," "blister," "high fever" "dermatology," and "plantar" were the most significant predictors during the pandemic. Conclusions: The predictors for HFMD infections before and during the COVID-19 pandemic were different. The awareness of HFMD infection in Japan may improved during the COVID-19 pandemic. Continuous monitoring is important to promote public health and prevent resurgence. Public interest reflected in information-seeking behavior can be helpful for public health surveillance.