Mouse Scarb2 Modulates EV-A71 Pathogenicity in Neonatal Mice.

Enterovirus A71 (EV-A71) is a human pathogen that causes hand, foot, and mouth disease, which can progress to severe neurological disease. EV-A71 infects humans via the human scavenger receptor B2 (hSCARB2). It can also infect neonatal mice experimentally. Wild-type (WT) EV-A71 strains replicate primarily in the muscle of neonatal mice; however, susceptibility lasts only for a week after birth. Mouse-adapted (MA) strains, which can be obtained by serial passages in neonatal mice, are capable of infecting both muscle and neurons of the central nervous system. It is not clear how the host range and tropism of EV-A71 are regulated and why neonatal mice lose their susceptibility during development. We hypothesized that EV-A71 infection in neonatal mice is mediated by mouse Scarb2 (mScarb2) protein. Rhabdomyosarcoma (RD) cells expressing mScarb2 were prepared. Both WT and MA strains infected mScarb2-expressing cells, but the infection efficiency of the WT strain was much lower than that of the MA strain. Infection by WT and MA strains in vivo was abolished completely in Scarb2-/- mice. Scarb2+/- mice, in which Scarb2 expression was approximately half of that in Scarb2+/+ mice, showed a milder pathology than Scarb2+/+ mice after infection with the WT strain. The Scarb2 expression level in muscle decreased with aging, which was consistent with the reduced susceptibility of aged mice to infection. These results indicated that EV-A71 infection is mediated by mScarb2 and that the severity of the disease, the spread of virus, and the susceptibility period are modulated by mScarb2 expression. IMPORTANCE EV-A71 infects humans naturally but can also infect neonatal mice. The tissue tropism and severity of EV-A71 disease are determined by several factors, among which the virus receptor is thought to be important. We show that EV-A71 can infect neonatal mice using mScarb2. However, the infection efficiency of WT strains via mScarb2 is so low that an elevated virus-receptor interaction associated with mouse adaptation mutation and decrease in mScarb2 expression level during development modulate the severity of the disease, the spread of virus, and the susceptibility period in the artificial neonatal mice model.

Identifying pre-outbreak signals of hand, foot and mouth disease based on landscape dynamic network marker.

BACKGROUND: The high incidence, seasonal pattern and frequent outbreaks of hand, foot and mouth disease (HFMD) represent a threat for billions of children around the world. Detecting pre-outbreak signals of HFMD facilitates the timely implementation of appropriate control measures. However, real-time prediction of HFMD outbreaks is usually challenging because of its complexity intertwining both biological systems and social systems. RESULTS: By mining the dynamical information from city networks and horizontal high-dimensional data, we developed the landscape dynamic network marker (L-DNM) method to detect pre-outbreak signals prior to the catastrophic transition into HFMD outbreaks. In addition, we set up multi-level early warnings to achieve the purpose of distinguishing the outbreak scale. Specifically, we collected the historical information of clinic visits caused by HFMD infection between years 2009 and 2018 respectively from public records of Tokyo, Hokkaido, and Osaka, Japan. When applied to the city networks we modelled, our method successfully identified pre-outbreak signals in an average 5 weeks ahead of the HFMD outbreak. Moreover, from the performance comparisons with other methods, it is seen that the L-DNM based system performs better when given only the records of clinic visits. CONCLUSIONS: The study on the dynamical changes of clinic visits in local district networks reveals the dynamic or landscapes of HFMD spread at the network level. Moreover, the results of this study can be used as quantitative references for disease control during the HFMD outbreak seasons.

Estimation of the reproduction number and identification of periodicity for HFMD infections in northwest China.

Repeated outbreaks of Hand, foot and mouth disease (HFMD) infections have been observed in recent decades and dominated by various enteroviral serotypes. In particular, enterovirus 71 (EV-A71), coxsackievirus A16 (CV-A16) and coxsackievirus A6 (CV-A6) dominated the prevalence of HFMD infections alternatively in recent years with various outbreak sizes in Baoji, a city of Shaanxi Province in Northwest China. Estimating the reproduction number for various enteroviruses serotypes in northwest China (north temperate zone) and identification of cyclicity of HFMD infections are therefore an issue of great importance for future epidemics prediction and control. The basic/effective reproduction numbers for EV-A71, CV-A16 and CV-A6 were estimated based on daily new cases in 2010, 2011 and 2018, respectively, in which the corresponding pathogen dominated the epidemic. Two different methods based on serial interval were adopted and the basic reproduction number were estimated to be in the range of (1.33, 1.46) for CV-A16, (1.20, 1.29) for EV-A71, and (1.38, 1.59) for CV-A6, respectively. The estimated daily effective reproduction numbers significantly fluctuated before June or after July but varied mildly in (0.5,2) in around June to July for three serotypes. The weekly effective reproduction number for HFMD was estimated based on weekly new cases from year 2010 to 2018, and in most years it peaked in the range of (1.6,2.0) in February to March as well as in the range of (1.0,1.2) in September to October. The wavelet analysis based on the time series of HFMD cases from 2008 to 2018 showed obvious annual and semi-annual cyclicity, while the inter-annual cycles are infeasible. In this study we found that CV-A6 shows the greatest transmission ability among these three pathogens while EV-A71 exhibits the weakest ability of transmission, and moreover, the estimated values of basic reproduction number in northwest China are lower than those in Singapore, Hongkong and Guangdong, which may be due to different climatic circumstances.

Integration of a Kalman filter in the geographically weighted regression for modeling the transmission of hand, foot and mouth disease.

BACKGROUND: Hand, foot and mouth disease (HFMD) is a common infectious disease whose mechanism of transmission continues to remain a puzzle for researchers. The measurement and prediction of the HFMD incidence can be combined to improve the estimation accuracy, and provide a novel perspective to explore the spatiotemporal patterns and determinant factors of an HFMD epidemic. METHODS: In this study, we collected weekly HFMD incidence reports for a total of 138 districts in Shandong province, China, from May 2008 to March 2009. A Kalman filter was integrated with geographically weighted regression (GWR) to estimate the HFMD incidence. Spatiotemporal variation characteristics were explored and potential risk regions were identified, along with quantitatively evaluating the influence of meteorological and socioeconomic factors on the HFMD incidence. RESULTS: The results showed that the average error covariance of the estimated HFMD incidence by district was reduced from 0.3841 to 0.1846 compared to the measured incidence, indicating an overall improvement of over 50% in error reduction. Furthermore, three specific categories of potential risk regions of HFMD epidemics in Shandong were identified by the filter processing, with manifest filtering oscillations in the initial, local and long-term periods, respectively. Amongst meteorological and socioeconomic factors, the temperature and number of hospital beds per capita, respectively, were recognized as the dominant determinants that influence HFMD incidence variation. CONCLUSIONS: The estimation accuracy of the HFMD incidence can be significantly improved by integrating a Kalman filter with GWR and the integration is effective for exploring spatiotemporal patterns and determinants of an HFMD epidemic. Our findings could help establish more accurate HFMD prevention and control strategies in Shandong. The present study demonstrates a novel approach to exploring spatiotemporal patterns and determinant factors of HFMD epidemics, and it can be easily extended to other regions and other infectious diseases similar to HFMD.

Relative transmissibility of hand, foot and mouth disease from male to female individuals.

Hand, foot and mouth disease (HFMD) has spread widely and leads to high disease burden in many countries. However, relative transmissibility from male to female individuals remains unclear. HFMD surveillance database was built in Shenzhen City from 2013 to 2017. An intersex transmission susceptible-infectious-recovered model was developed to calculate the transmission relative rate among male individuals, among female individuals, from male to female and from female to male. Two indicators, ratio of transmission relative rate (Rß) and relative transmissibility index (RTI), were developed to assess the relative transmissibility of male vs. female. During the study period, 270 347 HFMD cases were reported in the city, among which 16 were death cases with a fatality of 0.0059%. Reported incidence of total cases, male cases and female cases was 0.0057 (range: 0.0036-0.0058), 0.0052 (range: 0.0032-0.0053) and 0.0044 (range: 0.0026-0.0047), respectively. The difference was statistically significant between male and female (t = 3.046, P = 0.002). Rß of male vs. female, female vs. female, from female to male vs. female and from male to female vs. female was 7.69, 1.00, 1.74 and 7.13, respectively. RTI of male vs. female, female vs. female, from female to male vs. female and from male to female vs. female was 3.08, 1.00, 1.88 and 1.43, respectively. Transmissibility of HFMD is different between male and female individuals. Male cases seem to be more transmissible than female.

The complex transmission seasonality of hand, foot, and mouth disease and its driving factors.

BACKGROUND: The transmission rate seasonality is an important index for transmission dynamics in many childhood infections, and has been widely studied in industrialized countries. However, it has been neglected in the study of pathogens in China. METHODS: To understand the transmission dynamics of hand, foot and mouth disease (HFMD), we examined the transmission rate seasonality of HFMD in three provinces, Henan, Anhui and Chongqing, in China, using a dynamical stochastic SIR model. We investigated potential driving factors, including school terms, the Chinese Spring Festival period, meteorological factors and population flux for their effects on the HFMD transmission seasonality using multiple regression models. RESULTS: The transmission rate of HFMD had complex seasonality with one large major peak in March and one small peak in autumn. School terms, the Chinese Spring Festival period, population flux and meteorological factors had combined effects on the HFMD transmission seasonality in mainland China. The school terms reflects the seasonal contact rate in Children, while the population flux and the Chinese Spring Festival period reflect the seasonal contact rate in population. They drove HFMD transmission rate seasonality in different time periods of the year in China. Contact rate seasonality in population dominated effects on HFMD transmission in February and March. The dramatic increase in transmission rate during February coincides with the Chinese Spring Festival period and high population flux in this month. The contact rate seasonality in children dominated effects on the transmission in the other months of the year in Chongqing. Meteorological factors can not solely explain the seasonality in HFMD transmission in mainland China; however, they may have combined effects with school terms and the highway passenger traffic on the transmission rate in Anhui during the fall semester. CONCLUSION: The transmission rate of HFMD in three provinces in China had complex seasonality. The Chinese Spring Festival period, population flux and (or) school terms explained the majority of the transmission rate seasonality of HFMD, and they drove HFMD transmission rate seasonality in different time periods of the year. The Chinese Spring Festival period dominantly caused the dramatic increase of the HFMD transmission rate during February.

Seasonality of the transmissibility of hand, foot and mouth disease: a modelling study in Xiamen City, China.

This study attempts to figure out the seasonality of the transmissibility of hand, foot and mouth disease (HFMD). A mathematical model was established to calculate the transmissibility based on the reported data for HFMD in Xiamen City, China from 2014 to 2018. The transmissibility was measured by effective reproduction number (Reff) in order to evaluate the seasonal characteristics of HFMD. A total of 43 659 HFMD cases were reported in Xiamen, for the period 2014 to 2018. The median of annual incidence was 221.87 per 100 000 persons (range: 167.98/100,000-283.34/100 000). The reported data had a great fitting effect with the model (R2 = 0.9212, P < 0.0001), it has been shown that there are two epidemic peaks of HFMD in Xiamen every year. Both incidence and effective reproduction number had seasonal characteristics. The peak of incidence, 1-2 months later than the effective reproduction number, occurred in Summer and Autumn, that is, June and October each year. Both the incidence and transmissibility of HFMD have obvious seasonal characteristics, and two annual epidemic peaks as well. The peak of incidence is 1-2 months later than Reff.

Transmission and serotype features of hand foot mouth disease in household contacts in Dong Thap, Vietnam.

BACKGROUND: Hand, foot and mouth disease (HFMD) has emerged as a major public health issue in Vietnam since 2003. We aimed to investigate the household transmission of HFMD and its causative viruses from 150 households in a high incidence province in Vietnam. METHODS: A longitudinal study was conducted in patients presenting to the provincial hospital with a HFMD-like syndrome, along with their household members between April and August 2014 in Dong Thap Province. Each participant was followed up for 2 weeks. We enrolled 150 patients aged under 15 who were clinically diagnosed with HFMD in Dong Thap Hospital, 600 household members, and 581/600 household members completed the study. All participants were interviewed using a standard questionnaire. Throat swabs and blood samples were taken for molecular detection of viruses and assessment of neutralizing antibodies, respectively. Index cases were defined using a clinical case definition, household contact cases were defined using a similar definition applied to the 2 weeks before admission and 2 weeks after discharge of the index case. Characteristics of index cases, household contacts, the attack rate, serotype features and related factors of HFMD were reported. RESULT: Among 150 index cases, 113 were laboratory confirmed: 90/150 were RT-PCR-positive, 101/142 had a ≥ 4-fold increase of neutralizing antibody against Enterovirus A71 (EV-A71), Coxsackievirus (CV) A6 or CV-A16 across the two samples collected. 80/150 (53%) were males, and 45/150 (30%) were under the age of 1. The predominant serotype was CV-A6, identified in 57/87 (65.5%) of the specimens. No deaths were reported. Among 581 household contacts, 148 were laboratory confirmed: 12/581 were RT-PCR-positive, 142/545 had a ≥ 4-fold increase of neutralizing antibodies against EV-A71, CV-A6 or CV-A16; 4 cases experienced HFMD in the past 4 weeks. Attack rate among household contacts was 148/581 (25.5%). In 7/12 (58%) instances, the index and secondary cases were infected with the same serotype. Having a relationship to index case was significantly associated with EV infection. CONCLUSION: The attack rate among household contacts was relatively high (25.5%) in this study and it seems justified to also consider the household setting as an additional target for intervention programs.

Estimating the transmissibility of hand, foot, and mouth disease by a dynamic model.

OBJECTIVE: Hand, foot, and mouth disease (HFMD) is a serious public health issue in many countries; however, its transmissibility in county-level outbreaks remains unclear. The aim of this study is to estimate the transmissibility of HFMD epidemics on both city level and county level, for a better understanding of the transmission dynamics of HFMD epidemics. STUDY DESIGN: Simulation based on data obtained from the China Information System for Disease Control and Prevention. METHODS: The weekly number of reported HFMD cases from April 2009 to December 2017 in nine regions of Changsha City was collected. A susceptible-infectious-recovered model was used to estimate the transmissibility of HFMD. The reproduction number of reported cases during the ascending (denoted as Rasc) and descending (denoted as Rdes) period was used to describe the transmissibility of HFMD. RESULTS: The Rasc and Rdes for HFMD in Changsha was 1.44 (95% confidence interval [CI]: 1.41-1.48) and 0.71 (95% CI: 0.69-0.73), respectively. There was no statistical significance of Rasc values among nine regions (F = 1.056, P = 0.396), nor of Rdes values among nine regions (F = 1.676, P = 0.106). The average Rasc (1.53, 95% CI: 1.46-1.61) from 2009 to 2012 was higher than the one (1.37, 95% CI: 1.34-1.40) from 2013 to 2017 (t = 3.974, P < 0.001), but the average Rdes (0.67, 95% CI: 0.63-0.70) from 2009 to 2012 was lower than the one (0.74, 95% CI: 0.73-0.76) from 2013 to 2017 (t = -3.751, P < 0.001). CONCLUSIONS: The epidemic of HFMD in Changsha City is still grim, and integrated strategies should be taken for controlling and preventing HFMD.

Phylogeography of Coxsackievirus A16 Reveals Global Transmission Pathways and Recent Emergence and Spread of a Recombinant Genogroup.

Coxsackievirus A16 (CV-A16; Picornaviridae) is an enterovirus (EV) type associated with hand, foot, and mouth disease (HFMD) in children. To investigate the spatial spread of CV-A16, we used viral sequence data sampled during a prospective sentinel surveillance of HFMD in France (2010 to 2014) and phylogenetic reconstruction. A data set of 168 VP1 sequences was assembled with 416 publicly available sequences of various geographic origins. The CV-A16 sequences reported were assigned to two clades, genogroup B and a previously uncharacterized clade D. The time origins of clades B and D were assessed in 1978 (1973 to 1981) and 2004 (2001 to 2007), respectively. The shape of the global CV-A16 phylogeny indicated worldwide cocirculation of genetically distinct virus lineages over time and across geographic regions. Phylogenetic tree topologies and Bayes factor analysis indicated virus migration. Virus transportation events in clade B within Europe and Asia and between countries of the two geographic regions were assessed. The sustained transmission of clade D viruses over 4 years was analyzed at the township level in France and traced back to Peru in South America. Comparative genomics provided evidence of recombination between CV-A16 clades B and D and suggested an intertype recombinant origin for clade D. Time-resolved phylogenies and HFMD surveillance data indicated that CV-A16 persistence is sustained by continuing virus migration at different geographic scales, from community transmission to virus transportation between distant countries. The results showed a significant impact of virus movements on the epidemiological dynamics of HFMD that could have implications for disease prevention.IMPORTANCE Coxsackievirus A16 is one of the most prevalent enterovirus types in hand, foot, and mouth disease outbreaks reported in Southeast Asia. This study is based on epidemiological and viral data on HFMD caused by CV-A16 in a European country. The phylogeographic data complemented the syndromic surveillance with virus migration patterns between geographic regions in France. The results show how viral evolutionary dynamics and global virus spread interact to shape the worldwide pattern of an EV disease. CV-A16 transmission is driven by movements of infected individuals at different geographic levels: within a country (local dynamics), between neighboring countries (regional dynamics), and between distant countries (transcontinental dynamics). The results are consistent with our earlier data on EV-A71 and confirm the epidemiological interconnection of Asia and Europe with regard to EV infections.

Atypical Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6 in Denmark: A Diagnostic Mimicker.

Since 2008, outbreaks of atypical hand, foot, and mouth disease (HFMD) in children and adults have been reported worldwide. The majority of these outbreaks are caused by a new lineage of Coxsackie virus A6 (CV-A6) presenting a more severe clinical phenotype than the classical childhood HFMD caused by CV-A16. Between June 2014 and January 2016, 23 cases of atypical HFMD disease presented at a Dermatology Department at a regional University Hospital in Denmark. Patients were referred by general practitioners and dermatologists with a variety of clinical diagnoses, including eczema herpeticum, vasculitis, syphilis, dermatophytid, erythema multiforme and Stevens-Johnson syndrome. Three adults and 3 children required hospitalization due to extensive skin involvement and fever. All reported patients had laboratory-confirmed enterovirus infection. This study demonstrated an upsurge in atypical HFMD caused by CV-A6 in the Region of Southern Denmark and that atypical HFMD can be difficult to diagnose clinically as it may mimic other severe skin diseases.

An outbreak of Coxsackievirus A6-associated hand, foot, and mouth disease in a kindergarten in Beijing in 2015.

BACKGROUND: Coxsackievirus A6 (CVA6) is one of the major agents to cause hand, foot and mouth disease (HFMD) outbreaks globally. The objective of this study is to investigate the epidemiologic and clinical manifestations of CVA6 outbreak, and thus guide the diagnosis and treatment of the disease, as well as disease prevention. METHODS: An HFMD outbreak in a kindergarten was reported to Shijingshan District Center for Disease Control and Prevention (SCDC) on November 2, 2015 in Beijing, China. Epidemiological investigation was conducted. We performed a nine-week follow-up study to collect and analyze the clinical manifestations of HFMD cases. RESULTS: The outbreak yield 56 (15.7%) clinical diagnosed HFMD cases out of 357 registered children in the kindergarten with the mean age of 3.5 years old. This outbreak lasted for three days and ceased after initiating infectious disease controlling procedures, including periodical suspension of the kindergarten activities, environmental disinfection, and family health education. Fifty-one cases were followed for nine weeks. The positive rate of clinical manifestations of rash, fever, desquamation, pigmentation and onychomadesis were 100.0%, 84.3%, 68.6%, 17.6% and 43.1%, respectively. Children developed desquamation within the first 4 weeks after disease onset and developed onychomadesis between the 3th and 8th week after disease onset. Children with desquamation had 9.3 (95%CI: 1.836-47.437) times higher odds of developing onychomadesis compared to those without this manifestation. Ten out of 14 collected samples were CVA6 positive, and five positive samples shared a high degree of similarity in the VP1 nucleotide and amino acid sequences (99.9-100.0% and 100%). CONCLUSION: This HFMD outbreak was caused by CVA6, featured with delayed symptoms. Emerging CVA6-associated HFMD and its delayed symptoms should be paid more attention to reduce outbreaks and provide more information to doctors and parents.

Epidemiology and etiology of hand, foot, and mouth disease in Fujian province, 2008-2014.

Millions of cases of hand, foot, and mouth disease (HFMD) have been reported annually in mainland China since 2008. In this study, we investigated the epidemiology and etiology of an HFMD epidemic in Fujian province, which is located in subtropical southeastern China. Our study found similar epidemiological features of HFMD in southern areas of China, including seasonality and demographic distribution, as well as correlation between severity of illness and serotype. At least 22 serotypes of other enterovirus co-circulating with enterovirus 71 were found to belong to clade C4a, and those circulating with coxsackievirus A16 were associated with clades B1a and B1b.

Age patterns and transmission characteristics of hand, foot and mouth disease in China.

BACKGROUND: Hand, foot and mouth disease (HFMD) has circulated in China and caused yearly outbreak. To understand the transmission of the disease and to assess the spatial variation in cases reported, we examined age-specific transmission characteristics and reporting rates of HFMD for 31 provinces in mainland China. METHODS: We first analyzed incidence spatial patterns and age-specific incidence patterns using dataset from 2008 to 2012. Transmission characteristics were estimated based on catalytic model. Reporting rates were estimated using a simple mass action model from "Time Series Susceptible Infectious Recovered" (TSIR) modeling. RESULTS: We found age-specific spatial incidence patterns: age-specific proportions of HFMD cases varied geographically in China; larger case percentage was among children of 3-5 years old in the northern part of China and was among children of 0-2 years old in the southern part of China. Our analysis results revealed that: 1) reporting rates and transmission characteristics including the average age at infection, the force of infection and the basic reproduction number varied geographically in China; 2) patterns of the age-specific force of infection for 30 provinces were similar to that of childhood infections in developed countries; the age group that had the highest infection risk was 3-5 years old in 30 provinces, and 10-14 years old in Tibet; 3) a large difference in HFMD transmission existed between northwest region and southeast region; 4) transmission characteristics determined incidence patterns: the higher the disease transmission in a province, the earlier the annual seasonality started and the more case percentage was among children 0-2 years old and less among 3-5 years old. CONCLUSION: Because HFMD has higher transmission than most childhood infections reported, high effective vaccine coverage is needed to substantially reduce HFMD incidence. Control measures before the vaccine implementation should focus on 2-6 years old children in 30 provinces and 10-14 years old children in Tibet.

Important roles of public playgrounds in the transmission of hand, foot, and mouth disease.

Intra-home and kindergarten transmissions were the reported major modes of hand, foot, and mouth disease (HFMD) transmission in preschool children. However, infection at home is not common and 65-80% of cases do not attend preschool. We conducted a matched case-control study to explore the role of public playgrounds in the transmission of HFMD in addition to direct and indirect exposure to HFMD patients. We used 156 hospital source cases and 156 community source controls. Univariate analysis was followed by conditional logistic regression with attributable fraction computed. Adjusted odds ratios were 11·70 [95% confidence interval (CI) 1·26-109·40] for having HFMD cases in the same class, 14·19 (95% CI 3·55-56·74) for having HFMD cases within the 20 nearest neighbourhoods, 6·03 (95% CI 2·84-12·80) for exposure to public playgrounds, 2·13 (95% CI 1·05-4·32) for finger sucking and 0·29 (95% CI 0·11-0·78) for hand washing with soap before meals. The attributable fractions for the first four risk factors were 6·4%, 20·9%, 57·2% and 27·5%, respectively, while the population prevented fraction for hand washing with soap before meals was 18·7%. Based on our findings, hand washing with soap should be advocated. Health education could include topics which underline the precautions which need to be taken and the advice given regarding avoiding the use of public playgrounds during epidemic periods, especially when children have been getting sick.

Short-term effects of meteorological factors on children hand, foot and mouth disease in Guangzhou, China.

Hand, foot and mouth disease (HFMD) is a contagious viral illness that commonly affects infants and children. The underlying risk factors have not yet been systematically examined. This study analyzed the short-term effects of meteorological factors on children HFMD in Guangzhou, China. Daily count of HFMD among children younger than 15 years and meteorological variables from 2009 to 2011 were collected to construct the time series. A generalized additive model was applied to estimate the effects of meteorological factors on HFMD occurrence, after adjusting for long-term trend, seasonal trend, day of week, and public holidays. A negative association between temperature and children HFMD occurrence was observed at lag days 1-3, with the relative risk (RR) for a 1 °C increase on lag day 2 being 0.983 (95% confidence intervals (CI) 0.977 to 0.989); positive effect was found for temperature at lag days 5-9, with the highest effect at lag day 6 (RR = 1.014, 95% CI 1.006 to 1.023). Higher humidity was associated with increased HFMD at lag days 3-10, with the highest effect at lag day 8 (RR = 1.009 for 1% increase in relative humidity, 95% CI 1.007 to 1.010). And we also observed significant positive effect for rainfall at lag days 4 and 8 (RR = 1.001, 95% CI 1.000 to 1.002) for 1-mm increase. Subgroup analyses showed that the positive effects of temperature were more pronounced among younger children. This study suggests that meteorological factors might be important predictors of children HFMD occurrence in Guangzhou.

[The possibility of outbreak control by real-time surveillance with PCR method perfomed immediately--a case study of hand foot and mouth disease outbreak in a day care facility for children].

OBJECT: We examined the relationship between syndromic surveillance and laboratory confirmation, at an early stage of an outbreak of hand foot and mouth disease and RS virus infection. METHOD: We observed the epidemiological situation from a surveillance system at a day care facility for young children in Tokyo from one week before onset of the indicator until one month thereafter. For laboratory diagnosis, we collected a rectal swab or a nasal swab from one patient in the early stage of the outbreak. RESULT: A total of 20 patients, comprising 12 1-year-old, 5 2-year-old and 3 3-year-old children, were found to have hand foot and mouth disease on August 1st, 2011. From a rectal swab from one HFMD patient, enterovirus genome was detected and identified as coxsackievirus type A6 (CA6) with PCR sequencing. The CA6 had 99% identity to CA6 (Genbank No AB663318) in the VP4 coding region. RS virus also was detected from a nasal swab. DISCUSSION: The establishment of a surveillance system at day care facilities for children can monitor infectious diseases among young children promptly. Laboratory confirmation, even though from only one patient as shown in this study, can provide critical information regarding the causative agent of the outbreak. This method is easy to conduct and could be used for activating appropriate countermeasures. CONCLUSION: We believe that the combination of the timeliness of a surveillance system at day care facility for children and the convenience of laboratory diagnosis of even one patient can detect the causative pathogen, and thus enable the activation of countermeasures before an outbreak become widespread.

Hand, foot, and mouth disease in China: patterns of spread and transmissibility.

BACKGROUND: There were large outbreaks of hand, foot, and mouth disease in both 2008 and 2009 in China. METHODS: Using the national surveillance data since 2 May 2008, we summarized the epidemiologic characteristics of the recent outbreaks. Using a susceptible-infectious-recovered transmission model, we evaluated the transmissibility of the disease and potential risk factors. RESULTS: Children ages 1.0 to 2.9 years were the most susceptible to hand, foot, and mouth disease (odds ratios [OR] >2.3 as compared with other age-groups). Infant cases had the highest incidences of severe disease (ORs >1.4) and death (ORs >2.4), as well as the longest delay from symptom onset to diagnosis (2.3 days). Boys were more susceptible than girls (OR = 1.56 [95% confidence interval = 1.56-1.57]). A 1-day delay in diagnosis was associated with increases in the odds of severe disease by 40% (39%-42%) and in the odds of death by 54% (44%-65%). Compared with Coxsackie A16, enterovirus 71 is more strongly associated with severe disease (OR = 16 [13-18]) and death (OR = 40 [13-127]). The estimated local effective reproductive numbers among prefectures ranged from 1.4 to 1.6 (median = 1.4) in spring and stayed below 1.2 in other seasons. A higher risk of transmission was associated with temperatures in the range of 70° F to 80°F, higher relative humidity, higher [corrected] wind speed, more precipitation, greater population density, and [corrected] periods during which schools were open. CONCLUSION: Hand, foot, and mouth disease is a moderately transmittable infectious disease, mainly among preschool children. Enterovirus 71 was responsible for most severe cases and fatalities. Mixing of asymptomatically infected children in schools might have contributed to spread the of infection. Timely diagnosis may be [corrected] key to reducing the high mortality rate in infants.