Surveillance for severe hand, foot, and mouth disease from 2009 to 2015 in Jiangsu province: epidemiology, etiology, and disease burden.
ABSTRACT: BACKGROUND:Severe hand, foot, and mouth disease (HFMD) is a common childhood illness caused by various enteroviruses. The disease has imposed increased burden on children younger than 5?years old. We aimed to determine the epidemiology, CNS complication, and etiology among severe HFMD patients, in Jiangsu, China. METHODS:Epidemiological, clinical, and laboratory data of severe HFMD cases were extracted from 2009 to 2015. The CNS complication, annually severe illness rates, mortality rates, severity-PICU admission rates, severity-hospitalization rates, and so on were analyzed to assess the disease burden of severe HFMD. All analyses were stratified by time, region, population, CNS involvement and serotypes. The VP1 gene from EV-A71, CV-A16, CV-A6, CV-A10 and other enteroviruses isolates was amplified. Phylogenetic analysis was performed using MEGA5.0. RESULTS:Seven thousand nine hundred ninety-four severe HFMD cases were reported, of them, 7224 cases were inpatients, 611 were PICU inpatients, and 68 were fatal. The average severe illness rate, mortality rate, severity-fatality rate, severity-PICU admission rate, and severity-hospitalization rate were 14.54, 0.12,8506, 76,430, and 903,700 per 1 million, respectively. The severe illness rate was the highest in the 12-23?months age group, and the greatest mortality rate was in the 6-11?months age group. Geographical difference in severe illness rate and mortality were found. Patients infected with EV-A71 were at a higher proportion in different CNS involvement even death. EV-A71, CV-A16 and other enteroviruses accounted for 79.14, 6.49, and 14.47%, respectively. A total of 14 non-EV-A71/ CV-A16 genotypes including CV-A2, CV-A4, CV-A 6, CV-A9, CV-A10, CV-B1, CV-B2, CV-B3, CV-B4, CV-B5, E-6, E-7, E-18, and EV-C96 were identified. Phylogentic analyses demonstrated that EV-A71 strains belonged to subgenotype C4a, while CV-A16 strains belonged to sub-genotype B1a and sub-genotype B1b of genotype B1. CV-A6 strains were assigned to genogroup F, and CV-A10 strains belonged to genogroup D. CONCLUSIONS:Future mitigation policies should take into account the age, region heterogeneities, CNS conditions and serotype of disease. Additional a more rigorous study between the mild and severe HFMD should be warranted to elucidate the difference epidemiology, pathogen spectrum and immunity patterns and to optimize interventions in the following study.
Project description:Large outbreaks of hand, foot, and mouth disease (HFMD) have repeatedly occurred in mainland of China since 2007. In this study, we investigated the epidemiological and aetiological characteristics of HFMD in Shijiazhuang City, one of the biggest northern cities of China. A total of 57,173 clinical HFMD cases, including 911 severe and 32 fatal cases, were reported in Shijiazhuang City during 2009-2012. The disease incidence peaked during March-July, with a small increase in the number of cases observed in November of each year. Seventeen potential HFMD-causing enterovirus serotypes were detected, with the most frequent serotypes being EV-A71 and CV-A16. CV-A10 was also a frequently detected causative serotype, and was associated with the second largest number of severe HFMD cases, following EV-A71. Phylogenetic analysis revealed that all EV-A71, CV-A16 and CV-A10 strains from Shijiazhuang City had co-evolved and co-circulated with those from other Chinese provinces. Our findings underscore the need for enhanced surveillance and molecular detection for HFMD, and suggest that EV-A71 vaccination may be an effective intervention strategy for HFMD prevention and vaccines against CV-A10 and CV-A16 are also urgently needed.
Project description:BACKGROUND:Hand, foot and mouth disease (HFMD) has been associated with large outbreaks among young children in the Asia-Pacific Region since 1997, including cases of severe illness and death. Severe illness is often associated with enterovirus A71 (EV-A71). Vietnam experienced a large sustained outbreak of 200000 hospitalized cases and over 200 deaths in 2011-12, the large majority occurring in southern Vietnam. METHODS:A prospective observational study was conducted in the outpatient clinics, infectious diseases wards, and paediatric intensive care units of the three main referral centres for the treatment of HFMD in southern Vietnam. Demographic data, basic laboratory parameters, and clinical data were recorded, and molecular diagnostic tests were performed. RESULTS:Between July 2013 and July 2015, a total of 1547 children were enrolled. Four serotypes of enterovirus A (EV-A71, Coxsackievirus (CV) A6, A10, and A16) were responsible for 1005 of 1327 diagnosed cases (75.7%). An unexpected dominance of EV-A71 was found among both inpatients and outpatients, as well as a strong association with severe illness. CV-A6 and CV-A10 emerged in Vietnam during the study period and replaced CV-A16. CV-A10 was associated with different clinical and laboratory characteristics. During admission, 119 children developed a more severe illness. It was found that children with a skin rash showed less progression of severity, but when a rash was present, a macular rash was significantly associated with an increased risk of progression. CONCLUSIONS:This study represents the most comprehensive descriptive HFMD study from Vietnam to date. Co-circulation and replacement of different serotypes has implications for vaccine development and implementation. These findings from a severely affected country add to our understanding of the presentation, progression, and aetiology of HFMD.
Project description: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.
Project description:BACKGROUND:Examining associations between viral genomic loads of enteroviruses and clinical severity is important for promoting and improving development of antiviral drugs related to hand, foot and mouth disease (HFMD). METHODS:Throat swabs were collected from HFMD cases at acute phase of illness using a standardized technique in a prospective study. The viral genomic load was categorized into low, medium, and high groups using parameters of real-time reverse transcription-polymerase chain reaction. The clinical severities were assessed with four indicators, respectively. FINDINGS:We analysed 1109 HFMD cases, including 538 children with CV-A6, 231 with CV-A16, 156 with EV-A71, 78 with CV-A10, 59 with CV-A4, and 47 with CV-A2. EV-A71 genomic load categories were associated with risks of diagnoses of CNS complications (p = 0.016), requiring systemic corticosteroids or IVIG (p = 0.011), intensive care unit admission (p = 0.002) and length of hospital stay over 5 days (p = 0.048). In the multivariate analyses, point estimates of adjusted odds ratio (OR) tended to increase with viral genomic loads for all four severe outcomes and ORs of highest viral genomic load were all significantly larger than one for EV-A71. INTERPRETATION:HFMD clinical severities positively associate with viral genomic loads of EV-A71 in throat swabs. Specific antiviral drugs should be developed to reduce enterovirus load and to alleviate the clinical severities for HFMD cases. FUNDING:National Science Fund for Distinguished Young Scholars.
Project description:Enteroviruses (EVs) are the most common viral agents in humans. Although most infections are mild or asymptomatic, there is a wide spectrum of clinical manifestations that may be caused by EV infections with varying degrees of severity. Among these viruses, EV-A71 and coxsackievirus (CV) CV-A16 from group A EVs attract the most attention because they are responsible for hand, foot and mouth disease (HFMD). Other EV-A viruses such as CV-A6 and CV-A10 were also reported to cause HFMD outbreaks in several countries or regions. Group B EVs such as CV-B3, CV-B5 and echovirus 30 were reported to be the main pathogens responsible for myocarditis and encephalitis epidemics and were also detected in HFMD patients. Vaccines are the best tools to control infectious diseases. In December 2015, China's Food and Drug Administration approved two inactivated EV-A71 vaccines for preventing severe HFMD.The CV-A16 vaccine and the EV-A71-CV-A16 bivalent vaccine showed substantial efficacy against HFMD in pre-clinical animal models. Previously, research on EV-B group vaccines was mainly focused on CV-B3 vaccine development. Because the HFMD pathogen spectrum has changed, and the threat from EV-B virus-associated severe diseases has gradually increased, it is necessary to develop multivalent HFMD vaccines. This study summarizes the clinical symptoms of diseases caused by EVs, such as HFMD, myocarditis and encephalitis, and the related EV vaccine development progress. In conclusion, developing multivalent EV vaccines should be strongly recommended to prevent HFMD, myocarditis, encephalitis and other severe diseases.
Project description:Hand, foot, and mouth disease (HFMD) commonly produces herpangina, but fatal neurological complications have been observed in children. Enterovirus 71 (EV-A71) and Coxsackievirus 16 (CV-A16) are the predominant viruses causing HFMD worldwide. With rising concern about HFMD outbreaks, there is a need for an effective vaccine against EV-A71 and CV-A16. Although an inactivated vaccine has been developed against EV-A71 in China, the inability of the inactivated vaccine to confer protection against CV-A16 infection and other HFMD etiological agents, such as CV-A6 and CV-A10, necessitates the exploration of other vaccine platforms. Thus, the antigenic peptide-based vaccines are promising platforms to develop safe and efficacious multivalent vaccines, while the monoclonal antibodies are viable therapeutic and prophylactic agents against HFMD etiological agents. This article reviews the available information related to the antigenic peptides of the etiological agents of HFMD and their neutralizing antibodies that can provide a basis for the design of future therapies against HFMD etiological agents.
Project description:Using China's national surveillance data on hand, foot and mouth disease (HFMD) for 2008-2015, we described the epidemiologic and virologic features of recurrent HFMD. A total of 398,010 patients had HFMD recurrence; 1,767 patients had 1,814 cases of recurrent laboratory-confirmed HFMD: 99 reinfections of enterovirus A71 (EV-A71) with EV-A71, 45 of coxsackievirus A16 (CV-A16) with CV-A16, 364 of other enteroviruses with other enteroviruses, 383 of EV-A71 with CV-A16 and CV-A16 with EV-A71, and 923 of EV-A71 or CV-A16 with other enteroviruses and other enteroviruses with EV-A71 or CV-A16. The probability of HFMD recurrence was 1.9% at 12 months, 3.3% at 24 months, 3.9% at 36 months, and 4.0% at 38.8 months after the primary episode. HFMD severity was not associated with recurrent episodes or time interval between episodes. Elucidation of the mechanism underlying HFMD recurrence with the same enterovirus serotype and confirmation that HFMD recurrence is not associated with disease severity is needed.
Project description:Hand, foot, and mouth disease (HFMD) is a common childhood illness caused by serotypes of the Enterovirus A species in the genus Enterovirus of the Picornaviridae family. The disease has had a substantial burden throughout East and Southeast Asia over the past 15 y. China reported 9 million cases of HFMD between 2008 and 2013, with the two serotypes Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16) being responsible for the majority of these cases. Three recent phase 3 clinical trials showed that inactivated monovalent EV-A71 vaccines manufactured in China were highly efficacious against HFMD associated with EV-A71, but offered no protection against HFMD caused by CV-A16. To better inform vaccination policy, we used mathematical models to evaluate the effect of prospective vaccination against EV-A71-associated HFMD and the potential risk of serotype replacement by CV-A16. We also extended the model to address the co-circulation, and implications for vaccination, of additional non-EV-A71, non-CV-A16 serotypes of enterovirus.Weekly reports of HFMD incidence from 31 provinces in Mainland China from 1 January 2009 to 31 December 2013 were used to fit multi-serotype time series susceptible-infected-recovered (TSIR) epidemic models. We obtained good model fit for the two-serotype TSIR with cross-protection, capturing the seasonality and geographic heterogeneity of province-level transmission, with strong correlation between the observed and simulated epidemic series. The national estimate of the basic reproduction number, R0, weighted by provincial population size, was 26.63 for EV-A71 (interquartile range [IQR]: 23.14, 30.40) and 27.13 for CV-A16 (IQR: 23.15, 31.34), with considerable variation between provinces (however, predictions about the overall impact of vaccination were robust to this variation). EV-A71 incidence was projected to decrease monotonically with higher coverage rates of EV-A71 vaccination. Across provinces, CV-A16 incidence in the post-EV-A71-vaccination period remained either comparable to or only slightly increased from levels prior to vaccination. The duration and strength of cross-protection following infection with EV-A71 or CV-A16 was estimated to be 9.95 wk (95% confidence interval [CI]: 3.31, 23.40) in 68% of the population (95% CI: 37%, 96%). Our predictions are limited by the necessarily short and under-sampled time series and the possible circulation of unidentified serotypes, but, nonetheless, sensitivity analyses indicate that our results are robust in predicting that the vaccine should drastically reduce incidence of EV-A71 without a substantial competitive release of CV-A16.The ability of our models to capture the observed epidemic cycles suggests that herd immunity is driving the epidemic dynamics caused by the multiple serotypes of enterovirus. Our results predict that the EV-A71 and CV-A16 serotypes provide a temporary immunizing effect against each other. Achieving high coverage rates of EV-A71 vaccination would be necessary to eliminate the ongoing transmission of EV-A71, but serotype replacement by CV-A16 following EV-A71 vaccination is likely to be transient and minor compared to the corresponding reduction in the burden of EV-A71-associated HFMD. Therefore, a mass EV-A71 vaccination program of infants and young children should provide significant benefits in terms of a reduction in overall HFMD burden.
Project description:Hand, foot and mouth disease (HFMD) continues to challenge Asia with pandemic potential. In Vietnam, there have been two major outbreaks occurring during 2011-2012 (>200,000 hospitalizations and >200 deaths) and more recently in 2018 (>130,000 hospitalizations and 17 deaths). Given the high burden and the complex epidemic dynamics of HFMD, synthesizing its clinical and epidemiological data remains essential to inform the development of appropriate interventions and design public health measures. We report the results of a hospital-based study conducted during 2015-2018, covering the severe HFMD outbreak recently documented in Vietnam in 2018. The study was conducted at three major hospitals responsible for receiving HFMD patients from southern Vietnam with a population of over 40 million. A total of 19 enterovirus serotypes were detected in 1196 HFMD patients enrolled in the clinical study during 2015-2018, with enterovirus A71 (EV-A71), coxsackievirus A6 (CV-A6), CV-A10 and CV-A16 being the major causes. Despite the emergence of coxsackieviruses, EV-A71 remains the leading cause of severe HFMD in Vietnam. EV-A71 was consistently detected at a higher frequency during the second half of the years. The emergence of EV-A71 subgenogroup C4 in late 2018 was preceded by its low activity during 2017-early 2018. Compared with EV-A71 subgenogroup B5, C4 was more likely to be associated with severe HFMD, representing the first report demonstrating the difference in clinical severity between subgenogroup C4 and B5, the two predominant EV-A71 subgenogroups causing HFMD worldwide. Our data have provided significant insights into important aspects of HFMD over four years (2015-2018) in Vietnam, and emphasize active surveillance for pathogen circulation remains essential to inform the local public health authorities in the development of appropriate intervention strategies to reduce the burden of this emerging infections. Multivalent vaccines are urgently needed to control HFMD.
Project description:Hand, foot and mouth disease (HFMD) has become a major public health problem across the Asia-Pacific region, and is commonly caused by enterovirus A71 (EV-A71) and coxsackievirus A6 (CV-A6), CV-A10 and CV-A16. Generating pathogen whole-genome sequences is essential for understanding their evolutionary biology. The frequent replacements among EV serotypes and a limited numbers of available whole-genome sequences hinder the development of overlapping PCRs for whole-genome sequencing. We developed and evaluated a non-ribosomal random PCR (rPCR) and next-generation sequencing based assay for sequence-independent whole-genome amplification and sequencing of HFMD pathogens. A total of 16 EV-A71/CV-A6/CV-A10/CV-A16 PCR positive rectal/throat swabs (Cp values: 20.9-33.3) were used for assay evaluation.Our assay evidently outperformed the conventional rPCR in terms of the total number of EV-A71 reads and the percentage of EV-A71 reads: 2.6 % (1275/50,000 reads) vs. 0.1 % (31/50,000) and 6 % (3008/50,000) vs. 0.9 % (433/50,000) for two samples with Cp values of 30 and 26, respectively. Additionally the assay could generate genome sequences with the percentages of coverage of 94-100 % of 4 different enterovirus serotypes in 73 % of the tested samples, representing the first whole-genome sequences of CV-A6/10/16 from Vietnam, and could assign correctly serotyping results in 100 % of 24 tested specimens. In all but three the obtained consensuses of two replicates from the same sample were 100 % identical, suggesting that our assay is highly reproducible.In conclusion, we have successfully developed a non-ribosomal rPCR and next-generation sequencing based assay for sensitive detection and direct whole-genome sequencing of HFMD pathogens from clinical samples.