Phylogenetics and phylogeographic characteristics of coxsackievirus A16 in hand foot and mouth disease and herpangina cases collected in Beijing, China from 2019 to 2021.

Coxsackievirus A16 (CV-A16) is a significant pathogen responsible for causing hand foot and mouth disease (HFMD) and herpangina (HA). This study aimed to investigate the recent evolution and spread of CV-A16 by monitoring HFMD and HA cases in 29 hospitals across 16 districts in Beijing from 2019 to 2021. The first five cases of HFMD and the first five cases of HA each month in each hospital were included in the study. Real-time reverse transcription polymerase chain reaction was used to identify CV-A16, CV-A6, and EV-A71. From each district, two to four CV-A16 positive samples with a relatively long sampling time interval every month were selected for sequencing. A total of 3344 HFMD cases and 2704 HA cases were enrolled in this study, with 76.0% (2541/3344) of HFMD and 45.4% (1227/2704) of HA cases confirmed to be infected by enterovirus. Among the EV-positive samples, CV-A16 virus was detected in 33.61% (854/2541) of HFMD cases and 13.4% (165/1227) of HA cases, with the predominant cluster being B1a. Both B1a and B1b had a co-circulation of local and imported strains, with different origin time (1993 vs. 1995), different global distribution (14 countries vs. 10 countries), and different transmission centers but mainly distributed in the southern and eastern regions of Beijing. Strengthening surveillance of HFMD in southern and eastern regions will improve the prevention and control efficiency of enterovirus infections.

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.

Lack of effective home quarantine: The cause of the continuing prevalence of hand, foot, and mouth disease in China?

BACKGROUND: Home quarantine as a non-pharmaceutical measure is a key strategy for preventing the spread of hand, foot, and mouth disease (HFMD) and herpangina (HA). However, the status of home quarantine remains unclear. This study aimed to provide a theoretical basis for the prevention and control of the HFMD and HA by investigating the situation and determining the factors influencing home quarantine in children with HFMD or HA. METHODS: The convenience sampling method was used in this cross-sectional study involving parents whose children suffered from HFMD or HA in 2019. An online questionnaire tool was used to collect demographic information, socioeconomic status, clinical factors, sources of advice, and details of home quarantine. Logistic regression analysis was used to explore the factors influencing of home quarantine. RESULTS: A total of 3145 parents answered the electronic questionnaire; among them, 317 had children diagnosed with HFMD or HA in 2019. After quality control, 298 questionnaires were included in the analysis. The whole compliance rate of home quarantine for HFMD and HA was 59.1%. Results of multivariate logistic regression analysis indicated that having grandparents as the primary caregiver (OR=2.53, 95% CI: 1.20-5.43) was a risk factor of home-quarantine noncompliance, whereas doctor's notification (OR=0.35, 95% CI: 0.18-0.67) and advice from parents of other infected children (OR=0.53, 95% CI: 0.31-0.91) can increase the compliance with home quarantine. CONCLUSIONS: Home-quarantine measures for HFMD and HA were not well implemented. The caregivers, doctor's notification, and advice from parents of other infected children were associated with home-quarantine compliance. Corresponding measures should be taken to regulate home quarantine.

Mosaic genome of Human Coxsackievirus A4 associated with herpangina and HFMD in Yancheng, China, 2016 and 2018.

OBJECTIVES: To better understand the spectrums of pathogens causing herpangina and circulation of Coxsackievirus A4 in Yancheng, China. METHODS: Stool samples from herpangina and HFMD cases were collected. Real Time PCR Kits was used to identify Enterovirus 71, CV-A16 and CV-A6, and nested reverse transcription PCR (nRT-PCR) to detect the other enterovirus types. Complete VP1 and genome sequence of CV-A4 were amplified by using nRT-PCR. Genetic, phylogenetic and recombination analysis were performed. RESULTS: Co-circulation of three recombinant CV-A4 groups, including one novel (C2 lineage), was identified in Yancheng, China, 2016 and 2018. One was the major causative agent of herpangina, and another two were responsible for HFMD. Phylogenetic and recombination analysis indicated that the non-structural region of their genome originated from the same ancestry and subsequently adaptation. C2 lineage of CV-A4 group may be introduced from countries outside China and its genome occurred recombination in China. CONCLUSION: Novel recombinant CV-A4 was mainly associated with herpanginain in Yancheng, 2018, China. C2 lineage of CV-A4 group with recombinant non-structural region was also identified in HFMD patients.

Molecular epidemiology of enterovirus from children with herpangina or hand, foot, and mouth disease in Hangzhou, 2016.

Enteroviruses (EVs) are the major cause of hand, foot, and mouth disease (HFMD) and herpangina in children. In this study, we conducted a molecular investigation of EVs in throat swab samples from children in Hangzhou, China with a diagnosis of HFMD or herpangina. EVs were detected using one-step real-time RT-PCR, and their serotypes were determined based on partial VP1 gene sequences. The molecular typing results revealed the presence of six different EV serotypes in HFMD cases, including coxsackievirus (CV) A16 (20/30, 66.7%), CVA4 (3/30, 10.0%), CVA6 (3/30, 10.0%), EVA71 (2/30, 6.7%), CVB4 (1/30, 3.3%), and CVB5 (1/30, 3.3%). Eleven different EV serotypes were detected in herpangina cases, among which CVA4 was the most frequently detected serotype (105/170, 61.8%), followed by CVA16 (30/170, 17.6%), CVB4 (9/170, 5.3%), CVA6 (6/170, 3.5%), CVB3 (5/170, 2.9%), CVA10 (3/170, 1.8%), EVA71 (4/170, 2.4%), Echo9 (3/170, 1.8%), CVA9 (2/170, 1.2%), CVB1 (3/170, 1.8%) and CVA5 (1/170, 0.6%). The nucleotide sequence identity of EV strains from the same subtype ranged from 80.7% to 100%, and most of the EVs were closely related to virus strains found in Australia and mainland China. In conclusion, CVA 16 and CVA 4 were the main serotypes causing HFMD and herpangina, respectively, in children in Hangzhou in 2016. Most of these EVs were closely related to virus strains from Australia and mainland China.

Recombinant CV-A6 strains related to hand-foot-mouth disease and herpangina at primary care centers (Barcelona, Spain).

Aim: To describe the genetic diversity of enteroviruses (EV) causing hand, foot and mouth disease (HFMD) and herpangina, especially of coxsackievirus (CV)-A6, from patients attended at pediatric primary care centers during the 2017-2018 season. Methods: Phylogenetic analysis of partial VP1 region was performed for genetic characterization. The complete VP1 and 3Dpol proteins were sequenced for lineage determination and detection of recombination events. Results: An 80% of samples were EV laboratory-confirmed. CV-A6 was the most detected (70%) and associated with atypical HFMD (78%). The comparison of VP1 and 3Dpol phylogenies showed evidence of recombination in three strains, in which two shifted to CV-A16 3Dpol. Conclusion: The study provides recent information regarding the nonrecombinant and recombinant EVs related to HFMD at primary care centers.

Comparison of Nonpolio Enteroviruses in Children With Herpangina and Hand, Foot and Mouth Disease in Taiwan.

BACKGROUND: Nonpolio enterovirus (NPEV) infections are often present with herpangina (HA) and hand, foot and mouth disease (HFMD). Most countries sample NPEVs in HFMD cases, targeting enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) that are associated with outbreaks and severe complications. HA is also monitored in Taiwan and several other countries, but its viral characteristics are underreported. METHODS: Through Taiwan's National Virologic Surveillance, information regarding ~100,000 child respiratory samples (2002-2015) was linked to concurrent (0-6 days before the sampling date) outpatient records from the National Health Insurance databases, including ~15,000 HA-related and ~7000 HFMD-related samples. We assessed sample representation and NPEV positive rates, and estimated total numbers of EV-A71 and CV-A16. RESULTS: There were more HA events (4.0 millions) than HFMD events (1.2 millions) in Taiwan. In every 1000 events with HFMD and HA, 6.0 and 4.1, respectively, respiratory samples were collected. The NPEV positive rate in HFMD-related samples was 48%, consistent across most sampling seasons, and predominantly EV-A71 or CV-A16 (74%). By comparison, the HA-related samples had a lower positive rate overall (43%), occasionally EV-A71 or CV-A16 (13%), and the positive rate depended strongly on HA incidence (P < 10). Compared with sampling HFMD alone, inclusion of HA-related information predicted an earlier onset of EV-A71 outbreak in 2011, and predicted 30% more EV-A71 cases. CONCLUSIONS: This is the first representative report on viral characteristics of HA. Our findings confirm that HFMD monitoring is a reliable strategy, but there is a measurable additional benefit when HA is also monitored.

Nationwide Survey of Pediatric Inpatients With Hand, Foot, and Mouth Disease, Herpangina, and Associated Complications During an Epidemic Period in Japan: Estimated Number of Hospitalized Patients and Factors Associated With Severe Cases.

BACKGROUND: Severe pediatric cases of hand, foot, and mouth disease (HFMD), herpangina (HA), and associated complications caused by enterovirus 71 (EV71) infection have brought substantial public health impact in Asia. This study aimed to elucidate the epidemiology of these pediatric cases in Japan. METHODS: A nationwide survey was conducted using stratified random sampling of hospital pediatric departments. We estimated the number of inpatients with HFMD, HA, and associated complications between April 1 and September 30, 2010, during which EV71 was circulating predominantly. Factors associated with severe cases with ≥7 days of admission, sequelae, or outcome of death were analyzed using multivariate logistic regression. RESULTS: During the 6-month epidemic period, the number of pediatric inpatients aged <15 years was about 2,900 (estimated cumulative incidence of hospitalized cases: 17.0 per 100,000 population). Severe cases were significantly associated with younger age. Compared to patients ≥5 years of age, the odds ratios (ORs) for <1 year of age and 1 to <3 years of age were 5.74 (95% confidence interval [CI], 2.14-15.4) and 2.94 (95% CI, 1.02-8.51), respectively. Elevated ORs for hyperglycemia (plasma glucose level of ≥8.3 mmol/L) on admission (OR 3.60; 95% CI, 0.94-13.8) were also observed. CONCLUSIONS: Disease burden of pediatric inpatients with HFMD, HA, and associated complications in Japan was described for the first time. During an EV71 epidemic, younger age and, suggestively, hyperglycemia may have been critical factors requiring more careful treatment.

Hand, foot and mouth disease and herpangina caused by enterovirus A71 infections: a review of enterovirus A71 molecular epidemiology, pathogenesis, and current vaccine development.

Enterovirus A71 (EV-A71) infections are one of the main etiological agents of hand, foot and mouth disease (HFMD) and herpangina worldwide. EV-A71 infection is a life-threatening communicable disease and there is an urgent global need for the development of vaccines for its prevention and control. The morbidity rate of EV-A71 infection differs between countries. The pathogen's genetic lineages are undergoing rapid evolutionary changes. An association between the occurrence of EV-A71 infection and the circulation of different genetic strains of EV-A71 virus has been identified around the world. In this review, we present and discuss the molecular epidemiology and pathogenesis of the human disease caused by EV-A71 infection, as well as current prospects for the development of an EV-A71 vaccine.

Sex differences in common childhood infections in Taiwan.

Sex differences in childhood infections are commonly reported in case-only studies. In this population-based study of 278000 Taiwanese children followed from 3 months to 18 years of age during the period 2000-2012, age-trajectories of monthly numbers of all-cause healthcare visits and monthly rates of infection-specific healthcare visits were compared between boys and girls. For all-cause healthcare visits and for healthcare visits related to conjunctivitis, respiratory tract infections, enteritis, hand, foot, and mouth disease, and herpangina, there was good resemblance of age trajectories between boys and girls. Despite this resemblance, there was evidence of a slightly higher rate in boys than in girls under age 6 years (i.e., a male tendency, or male-to-female ratio >1.0) across all diagnoses except herpangina. For urinary tract infection, where an age-specific sex difference is well reported in case-only studies, this population-based study confirmed that there was a much higher rate of kidney infection among boys than among girls during infancy, and a higher rate of kidney and bladder infection among girls than among boys after this period. The age-specific sex difference in urinary tract infections was so strong that the age trajectories in boys and girls were qualitatively different. This report confirms previously reported sex differences in other countries, whilst placing this in the context of age dynamics in childhood infection.

Association between enterovirus infection and speech and language impairments: A nationwide population-based study.

BACKGROUND AND AIMS: Delay and impairment in Speech and language are common developmental problems in younger populations. Hitherto, there has been minimal study of the association between common childhood infections (e.g. enterovirus [EV]) and speech and language. The impetus for evaluating this association is provided by evidence linking inflammation to neurodevelopmental disorders. Herein we sought to determine whether an association exists between EV infection and subsequent diagnoses of speech and language impairments in a nationwide population-based sample in Taiwan. METHODS: Our study acquired data from the Taiwan National Health Insurance Research Database. The sample was comprised of individuals under 18 years of age with newly diagnosed EV infection during the period from January 1998 to December 2011. 39669 eligible cases were compared to matched controls and assessed during the study period for incident cases of speech and language impairments. Cox regression analyses were applied, adjusting for sex, age and other physical and mental problems. RESULTS: In the fully adjusted Cox regression model for hazard ratios, EV infection as positively associated with speech and language impairments (HR = 1.14, 95% CI: 1.06-1.22) after adjusting for age, sex and other confounds. Compared to the control group, the hazard ratio for speech and language impairments was 1.12 (95% CI: 1.03-1.21) amongst the group of EV infection without hospitalization, and 1.26 (95% CI: 1.10-1.45) amongst the group of EV infection with hospitalization. CONCLUSIONS: EV infection is temporally associated with incident speech and language impairments. Our findings herein provide rationale for educating families that EV infection may be associated with subsequent speech and language problems in susceptible individuals and that monitoring for such a presentation would be warranted. WHAT THIS PAPER ADDS?: Speech and language impairments associated with central nervous system infections have been reported in the literature. EV are medically important human pathogens and associated with select neuropsychiatric diseases. Notwithstanding, relatively few reports have mentioned the effects of EV infection on speech and language problems. Our study used a nationwide longitudinal dataset and identified that children with EV infection have a greater risk for speech and language impairments as compared with control group. Infected children combined other comorbidities or risk factors might have greater possibility to develop speech problems. Clinicians should be vigilant for the onset of language developmental abnormalities of preschool children with EV infection.

Epidemiological and etiological characteristics of herpangina and hand foot mouth diseases in Jiangsu, China, 2013-2014.

Herpangina (HA) and hand, foot, and mouth disease (HFMD) are common infectious diseases caused by human enteroviruses and frequently occurr in young children. Previous published studies have mainly focused on HFMD, while the HA epidemiological and etiological characteristics in mainland China have not been described. From June, 2013 to March, 2014, HA and HFMD patients were monitored in participants from clinical trial of EV-A71 vaccine conducted during 2012-2013. A total of 95 HA patients and 161 HFMD patients were defined. Enteroviruses of HA samples were differentiated into 17 serotypes (EV-A71, CV-A16, CV-A24, E6, CV-B5, CV-A22, CV-A6, CV-A10, CV-B3, E9, CV-A9, CV-B4, CV-B2, E1, E7, E21 and CV-A20), the most common serotypes were EV-A71(10/95,10.5%), CV-A16(4/95,4.2%) and CV-A24(4/95,4.2%); while enteroviruses detected from HFMD samples were classfied into 21 serotypes ( EV-A71, CV-A16, CV-A10, CV-A6, E6, CV-B3, CV-B5, CV-A9, E9, CV-B2, CV-B4, E3, E11, E15, E16, CV-A1, EV-A69, E5, CA22, CA24 and EV99), the most common serotypes were EV-A71(28/161,17.4%), CV-A16(7/161,4.4%) and CV-A10(5/161,3.1%). The first HA epidemic peak occurred in summer and a second smaller peak occurred in January. In HA patients, the body temperature (P < 0.0001) and the incidence of fever (P < 0.05) were significant higher than those in HFMD patients. Between HA and HFMD patients infected with EV-A71, no significant differences were found in age, sex, circulating season, and the viral genome diversity. In summary, we firstly reported the epidemiological and etiological characteristics of HA in mainland China. Developing a multivalent vaccine will be helpful for the control of the HA/HFMD epidemic.

Large outbreak of herpangina in children caused by enterovirus in summer of 2015 in Hangzhou, China.

Herpangina, usually caused by coxsackie virus A, is prevalent in children spreading through the fecal-oral transmission and the respiratory droplets dissemination. Also, it is mostly asymptomatic and self-limiting. In our study, we found that large outbreak of herpangina in children occurred in the summer of 2015 in Hangzhou, China. From May 1th to August 31th, a total of 10 210 children were diagnosed with herpangina in Children's Hospital of Zhejiang University School of Medicine. 2 310 throat swabs were collected and tested for enterovirus detection by real-time RT-PCR, while 1 651 cases were positive with the rate of 71.5%. Based on VP1 gene or 5'UTR region sequences, Coxsackievirus A2, A4, A6, A10, B2, B4 and echovirus 30 were detected in these cases. More importantly, Coxsackievirus A2 may be the major subtype of enterovirus resulting in children with herpangina in hangzhou, China.

Molecular epidemiology of the enteroviruses associated with hand, foot and mouth disease/herpangina in Dongguan, China, 2015.

Enteroviruses (EVs) are the etiological agents involved in most cases of hand, foot and mouth disease (HFMD) and herpangina (HA). Information on the epidemiology profiles of EVs in China is very limited, as the present surveillance system of China focuses on CAV16 and EV71, and no published data are available in Dongguan. The aim of this study is to determine the prevalence of EVs among patients with HFMD and HA in Dongguan, China, during 2015. A total of 271 clinical stool specimens that were clinically determined to be positive for enteroviruses were genotyped by semi-nested polymerase chain reaction (PCR) for the VP1 genes of EVs. The results showed that a total of 14 enterovirus genotypes were identified among HFMD and HA patients in this study. CVA6 was the most common genotype for HFMD, and CVA2 accounted for the majority of HA cases in this study. Sequence and phylogenetic analysis showed that all of the CVA6 and CVA2 strains identified in our study displayed a close genetic relationship to strains identified in other cities in China. This study also demonstrates that there are associations between particular causative enterovirus genotypes and some clinical symptoms, which may provide useful information for improving case prevention, diagnosis and treatment of HFMD and HA.

Changes in enterovirus serotype constituent ratios altered the clinical features of infected children in Guangdong Province, China, from 2010 to 2013.

BACKGROUND: Enterovirus (EV)-related hand, foot, and mouth disease/herpangina (HFMD/HA) has been prevalent in Guangdong Province, China, since 2010. METHODS: Clinical data for EV-related HFMD/HA inpatients admitted to the Department of Paediatrics of Zhujiang Hospital from 2010 to 2013 were retrospectively reviewed. The corresponding EV serotypes were also determined by reverse transcription-polymerase chain reaction or BLAST analysis of the sequenced partial lengths of the viral protein1/5'-untranslated region. RESULTS: A total of 867 eligible inpatients admitted during 2010-2013 were included in the study. Of these, the serotype of the responsible EV was successfully identified in 824 cases. The incidence of enterovirus 71 (EV71) infection amongst pediatric HFMD/HA inpatients decreased dramatically from 55.5 % in 2010 to 8.1 % in 2013, with a similar decrease recorded for coxsackievirus A16 (CVA16). However, the incidence of non-EV71/CVA16 infection increased from 30.0 % in 2010 to 83.8 % in 2013. We noted that the types of infection caused by different EV serotypes varied: EV71 was responsible for 100 % of the paralysis cases (26/26), 84.6 % of the deaths (11/13), and 84.1 % of cases with severe central nervous system involvement (SCNSI) (74/88); echovirus contributed to 16.4 % of the deaths (2/13) and 4.4 % of the SCNSI cases; and coxsackievirus accounted for only 2.2 % of the SCNSI cases (2/90). The clinical features of HFMD/HA cases varied greatly during the time period examined, with drastic changes in the hospitalization rates (45.1, 63.7, 36.4, and 19.1 % for 2010, 2011, 2012, and 21013, respectively), mortality rates (2.3, 0.9, 2.5, and 0.0 %, respectively), paralysis (5.1, 1.2, 5.4, and 0.0 %, respectively), SCNSI (16.8, 7.1, 12.7, and 2.2 %, respectively), and acute respiratory infection (21.1, 22.0, 45.9, and 59.0 %, respectively). CONCLUSIONS: The incidences of infection caused by different EV serotypes, along with the clinical features of HFMD/HA cases, changed drastically in Guangdong Province, China, from 2010 to 2013, with the biggest changes observed in 2013. The changed constituent ratios of the different EV serotypes might therefore be responsible for the differences in the observed clinical features of HFMD/HA during this period.

Enterovirus-related diarrhoea in Guangdong, China: clinical features and implications in hand, foot and mouth disease and herpangina.

BACKGROUND: A series of complications caused by enteroviruses, including meningitis, encephalitis, acute flaccid paralysis, acute cardiopulmonary failure, respiratory infection, and myocardial injury have been reported in hand, foot and mouth disease/herpangina (HFMD/HA). However, the complication of diarrhoea caused by enteroviruses has been neglected, and a summary of its clinical features and impact on HFMD/HA is unavailable. METHODS: We included inpatients with HFMD/HA admitted to the Paediatric Department of Zhujiang Hospital during 2009-2012. We summarised and compared clinical data for cases with and without diarrhoea, and determined enterovirus serotypes by reverse transcriptase polymerase chain reaction and genotyping based on a partial-length fragment of viral protein 1 or the 5'-untranslated region. RESULTS: There were 804 inpatients with HFMD/HA and 28 (3.5%) presented with diarrhoea. Gastrointestinal symptoms were mild in most cases of diarrhoea (82.1%), with high prevalence of no dehydration (82.1%), short duration of diarrhoea (78.6%) and watery stools (75.0%). The prevalence of multi-organ dysfunction syndrome (10.7 vs 0.40%) (p = 0.001), hepatic injury (14.3 vs 3.4%) (p = 0.019), myocardial injury (21.4 vs 6.1%) (p = 0.002) and convulsion (21.4 vs 7.2%) (p = 0.016) was significantly higher in the diarrhoea than no diarrhoea group. There was no significant difference between the two groups regarding prevalence of death, altered consciousness, paralysis, central nervous system involvement, or acute respiratory infection. CONCLUSIONS: Most patients with diarrhoea caused by enteroviruses circulating in Guangdong Province in 2009-2012 had mild or moderate gastrointestinal symptoms. Although enterovirus-related diarrhoea caused additional multi-organ dysfunction syndrome, hepatic injury and myocardial injury in children with HFMD/HA, timely intervention efficiently reduced disease severity and improved outcome.

Diagnostic uncertainty of herpangina and hand-foot-and-mouth disease and its impact on national enterovirus syndromic monitoring.

The community burden of enterovirus is often monitored through syndromic monitoring systems based on reported cases of enterovirus-related infection (EVI) diagnoses. The extent to which this is affected by under- and over-diagnosis has not been reported. In Taiwan, children often make more than one healthcare visit during an episode of infection. We used change of diagnosis within an episode of infection as a guide of diagnostic uncertainty in a nationally representative cohort of Taiwanese children (n = 13 284) followed from birth to the 9th birthday through electronic health records. We conducted a nested case-control analysis and estimated cross-diagnosis ratios (CDRs) as the observed proportion of acute respiratory infection (ARI) diagnoses following an EVI diagnosis in excess of background ARI burdens. With 19 357 EVI diagnoses in this cohort, the CDR within 7 days was 1·51 (95% confidence interval 1·45-1·57), confirming a significant excess of ARI diagnoses within the week following an EVI diagnosis. We used age-specific CDRs to calibrate the weekly EVI burden in children aged 3-5 years in 2008, and the difference between observed and calibrated weekly EVI burdens was small. Therefore, there was evidence suggesting a small uncertainty in EVI diagnosis, but the observed EVI burdens through syndromic monitoring were not substantially affected by the small uncertainty.

Predicting the characteristics of the aetiological agent for Kawasaki disease from other paediatric infectious diseases in Japan.

Although Kawasaki disease (KD), which was first reported in the 1960s, is assumed to be infectious, its aetiological agent(s) remains unknown. We compared the geographical distribution of the force of infection and the super-annual periodicity of KD and seven other paediatric infectious diseases in Japan. The geographical distribution of the force of infection, which was estimated as the inverse of the mean patient age, was similar in KD and other paediatric viral infections. This similarity was due to the fact that the force of infection was determined largely by the total fertility rate. This finding suggests that KD shares a transmission route, i.e. sibling-to-sibling infection, with other paediatric infections. The super-annual periodicity, which is positively associated with the sum of an infectious disease's incubation period and infectious period, was much longer for KD and exanthema subitum than other paediatric infectious diseases. The virus for exanthema subitum is known to persist across the host's lifespan, which suggests that the aetiological agent for KD may also be capable of persistent infection. Taken together, these findings suggest that the aetiological agent for KD is transmitted through close contact and persists asymptomatically in most hosts.

Risk of leukaemia in children infected with enterovirus: a nationwide, retrospective, population-based, Taiwanese-registry, cohort study.

BACKGROUND: The association between enterovirus infections in children and risk of leukaemia is unclear. We aimed to assess the risk of leukaemia after enterovirus infection in children. METHODS: We did a nationwide retrospective cohort study by analysing data from the National Health Insurance Research Database (NHIRD) in Taiwan. Children with enterovirus infections aged younger than 18 years were identified. With use of computer-generated random numbers, children not infected with enterovirus were randomly selected and frequency matched (1:1) with children infected with enterovirus by sex, age, urbanisation level, parental occupation, and index year of enterovirus infection. We only included children with complete baseline data for age and sex and who had at least three clinic visits with the diagnosis of enterovirus infection. The diagnosis date of the first clinic visit for the enterovirus infection was defined as the index date for initiation of follow-up person-year measurement and participants. All study patients were followed up until they developed leukaemia, were lost to follow-up, withdrew from the NHI programme, or until the end of the study without leukaemia (censored). Our primary endpoint was a diagnosis of leukaemia during follow-up. FINDINGS: Insurance claims data for 3 054 336 children younger than 18 years were randomly selected from all insured children in the NHIRD. We identified 282 360 children infected with enterovirus and 282 355 children not infected with enterovirus between Jan 1, 2000, and Dec 31, 2007. The incidence density rates of leukaemia were 3·26 per 100 000 person-years for the enterovirus-infected and 5·84 per 100 000 person-years for the non-enterovirus-infected cohorts. The risk of leukaemia was significantly lower in the enterovirus-infected cohort than in the non-enterovirus-infected cohort (adjusted subhazard ratio [SHR] 0·44, 95% CI 0·31-0·60; p<0·0001). Children infected with enterovirus have a reduced risk of both lymphocytic leukaemia (adjusted SHR 0·44, 0·30-0·65; p<0·0001) and acute myeloid leukaemia (adjusted SHR 0·40, 0·17-0·97; p=0·04). Herpangina and hand-foot-and-mouth disease were the main diseases associated with the reduced risk of leukaemia. INTERPRETATION: The association between enterovirus infection and the reduced risk of developing leukaemia supports Greaves' delayed infection hypothesis for the cause of childhood leukaemia.

PREVALENCE OF HUMAN ENTEROVIRUS AMONG PATIENTS WITH HAND, FOOT, AND MOUTH DISEASE AND HERPANGINA IN THAILAND, 2013.

Human enterovirus (EV) infection causes hand, foot, and mouth disease (HFMD) and herpangina (HA). We studied the prevalence of enterovirus (EV) among patients with HFMD and HA in Thailand during 2013. We conducted a study in archived specimens of patients sent for screening for enterovirus. A total of 203 clinical specimens from 184 individuals with painful blister in the oropharynx and on the palms, soles, knees, elbows or buttock were examined by semi-nested polymerase chain reaction (PCR) for the 5'UTR and VP1 genes of EV. Eighty-six samples were positive: EV71 was detected in 14 (30%), CV-A8 in 12 (26%) and CV-A16 in 10 (21%). Classification of EV species detected revealed that 46 specimens were EV-A, 14 specimens were EV-B, 1 specimen was EV-D, and 16 specimens were positive for unclassified enterovirus. The majority of individuals with EV infection were aged 2-6 years. Multiple EV-A serotypes were detected among HFMD and HA patients in our study.