Hand Foot and Mouth Disease Due to Enterovirus 71 in Malaysia

Hand foot and mouth disease is a febrile sickness complex characterized by cutaneous eruption (exanthem) on the palms and soles with simultaneous occurrence of muco-cutanous vesiculo-ulcerative lesions (enanthem) affecting the mouth. The illness is caused by a number of enteroviruses with coxsackievirus A16 and enterovirus 71 as the main causative agents. Human enterovirus 71 (EV71) belongs to the species Human enterovirus A under the genus Enterovirus within the family Picornaviridae. EV71 has been associated with an array of clinical diseases including hand foot and mouth disease (HFMD), aseptic meningitis, encephalitis and poliomyelitis-like acute flaccid paralysis. A large outbreak of HFMD due to highly neurovirulent EV71 emerged in Malaysia in 1997, and caused 41 deaths amongst young children. In late 2000, a recurrence of an outbreak of HFMD occurred in Malaysia with 8 fatalities in peninsular Malaysia. Outbreak of HFMD due to EV71 recurred in 2003 with an unknown number of cases and mortalities. A similar outbreak of HFMD with 2 recorded deaths in young children occurred in peninsular Malaysia in late 2005 and this was followed by a larger outbreak in Sarawak (Malaysian Borneo) with 6 reported fatalities in the early part of 2006. The current on-going outbreak of HFMD started in peninsular Malaysia in epidemiological week 12 of 2010. As with other HFMD outbreaks in Malaysia, both EV71 and CA16 were the main aetiological viruses isolated. In similarity with the HFMD outbreak in 2005, the isolation of CA16 preceded the appearance of EV71. Based on the VP1 gene nucleotide sequences, 4 sub-genogroups of EV71 (C1, C2, B3 and B4) co-circulated and caused the outbreak of hand, foot and mouth disease in peninsular Malaysia in 1997. Two sub-genogroups (C1 and B4) were noted to cause the outbreak in 2000 in both peninsular Malaysia and Sarawak. EV71 of sub-genogroup B5 with smaller contribution from sub-genogroup C1 caused the outbreak in 2003. In the 2005 outbreak, besides the EV71 strains of sub-genogroup C1, EV71 strains belonging to sub-genogroup B5 were isolated but formed a cluster which was distinct from the EV71 strains from the sub-genogroup B5 isolated in 2003. The four EV71 strains isolated from clinical specimens of patients with hand, foot and mouth disease in the Sarawak outbreak in early 2006 also belonged to sub-genogroup B5. Phylogenetic analysis of the VP1 gene suggests that the EV71 strains causing the outbreak in Sarawak could have originated from peninsular Malaysia. Epidemiological and molecular data since 1997 show the recurrence of HFMD due to EV71 in Malaysia every 2 to 4 years. In each of the past outbreaks, more than one sub-genogroup of the virus co-circulate.

Expression and clinical significance of pattern recognition receptor-associated genes in hand, foot and mouth disease

Objective:To explore which pattern recognition receptors(PRRs)play a key role in the development of hand,foot,and mouth disease(HFMD)by analyzing PRR-associated genes.Methods:We conducted a comparative analysis of PRR-associated gene expression in human peripheral blood mononuclear cells(PBMCs)infected with enterovirus 71(EV-A71)which were derived from patients with HFMD of different severities and at different stages.A total of 30 PRR-associated genes were identified as significantly upregulated both over time and across different EV-A71 isolates.Subsequently,ELISA was employed to quantify the expression of the six most prominent genes among these 30 identified genes,specifically,BST2,IRF7,IFI16,TRIM21,MX1,and DDX58.Results:Compared with those at the recovery stage,the expression levels of BST2(P=0.027),IFI16(P=0.016),MX1(P=0.046)and DDX58(P=0.008)in the acute stage of infection were significantly upregulated,while no significant difference in the expression levels of IRF7(P=0.495)and TRIM21(P=0.071)was found between different stages of the disease.The expression levels of BST2,IRF7,IFI16 and MX1 were significantly higher in children infected with single pathogen than those infected with mixed pathogens,and BST2,IRF7,IFI16 and MX1 expression levels were significantly lower in coxsackie B virus(COXB)positive patients than the negative patients.Expression levels of one or more of BST2,IRF7,IFI16,TRIM21,MX1 and DDX58 genes were correlated with PCT levels,various white blood cell counts,and serum antibody levels that reflect disease course of HFMD.Aspartate aminotransferase was correlated with BST2,MX1 and DDX58 expression levels.Conclusions:PRR-associated genes likely initiate the immune response in patients at the acute stage of HFMD.

Xiyanping injection therapy for children with mild hand foot and mouth disease:a randomized controlled trial

OBJECTIVE: To evaluate the clinical effects of Xiyan-ping injection intervention in pediatric patients with mild hand foot and mouth disease(HFMD).METHODS: A total of 329 patients were stratified and block-randomized for symptomatic treatment of HFMD and assigned to one of the following groups: Western Medicine(group A, n = 103), Xiyanping injection(group B, n = 109), or Xiyanping injection and symptomatic treatment using Western Medicine(group C, n = 117). During the trial, fever,rash, ulcers of the mouth were observed among participants in each group before and after treatment, and conversion rates from mild to severe HFMD were measured.RESULTS: After 3-7 days' treatment, no significant differences in the conversion rates from mild to severe HFMD were observed among the three groups(P > 0.05). There was a significantly low number of patients with the onset time of antifebrile effect,vanished time of hand and foot rashes and cumulative time for the ulcers in the mouth vanished,among the three groups(P < 0.05, P < 0.01). The onset time of antifebrile effect of patients in groups B and C were markedly shorter compared with those in group A(P < 0.05, P < 0.01); there was no statically significant difference observed between groups B and C(P > 0.05). No significant differences were observed in the time for body temperature recovery among the three groups(P > 0.05). There were no significant differences in adverse effects among the three groups(P > 0.05).CONCLUSION: Xiyanping injection together with use of Western Medicine is most effective for symptomatic treatment of mild HFMD. No severe adverse reactions were observed.

Characterization of Hand,Foot,and Mouth Disease in China between 2008 and 2009

Objective To investigate the epidemiological and cl （HFMD） since several outbreaks of HFMD caused between 2007 and 2008. inical features of hand, foot and mouth disease by enteroviruses were documented in China Methods HFMD cases reported to the National Infectious Disease Information Management System database between May 2008 and April 2009 were assessed. Clinical features in some of the severe and fatal cases were analyzed the etiology of the outbreaks was investigated. Results 89.1% of reported HFMD cases were found in children〈5 year-old with an age-specific incidence rate of 834.1/100 000 in the first year as the notifiable disease in China from May 2008 to April 2009. The incidence, mortality and percentage of severe cases were studied for three regions of China and found to be highest in the central region. The incidence of severe cases and mortality in rural population were significantly higher than those in urban population. Among the laboratory confirmed EV17 positive cases there were 52.6% mild, 83.5% severe, and 96.1% fatal cases. More myoclonic jerks were found in the severe case group than in group that died. Tachypnea, lip purpling, pink foaming and low limb temperature occurred more frequently in the fatal cases than in the severe cases. Conclusion The epidemic of HFMD in China was characterized predominantly by EV71 infections, had relatively high mortality rates especially in the central region, and was most prevalent in young, rural populations.

Using Interrupted Time Series Design to Analyze Changes in Hand, Foot, and Mouth Disease Incidence during the Declining Incidence Periods of 2008-2010 in China

Objective To identify patterns of hand, foot and mouth disease （HFMD） incidence in China during declining incidence periods of 2008, 2009, and 2010. Methods Reported HFMD cases over a period of 25 months were extracted from the National Disease Reporting System （NDRS） and analyzed. An interrupted time series （ITS） technique was used to detect changes in HFMD incidence rates in terms of level and slope between declining incidence periods of the three years. Results Over 3.58 million HFMD cases younger than 5 years were reported to the NDRS between May 1, 2008, and May 31, 2011. Males comprised 63.4% of the cases. ITS analyses demonstrated a significant increase in incidence rate level （P〈0.0001） when comparing the current period with the previous period. There were significant changes in declining slopes when comparing 2010 to 2009, and 2010 to 2008 （all P〈O.O05）, but not 2009 to 2008. Conclusion Incremental changes in incidence rate level during the declining incidence periods of 2009 and 2010 can potentially be attributed to a few factors. The more steeply declining slope in 2010 compared with previous years could be ascribed to the implementation of more effective interventions and preventive strategies in 2010. Further investigation is required to examine this possibility.

Molecular Epidemiological Analysis of Echovirus 19 Isolated From an Outbreak Associated With Hand, Foot, and Mouth Disease (HFMD) in Shandong Province of China

To elucidate the genetic characterization and molecular epidemiological features of Echovirus 19 （El9） isolates collected from an outbreak associated with hand, foot and mouth disease （HFMD） in Tai＇an city of Shandong Province of China from July to September, 2003. Methods Thirty seven Echovirus 19 isolates were isolated from stool specimens and throat swabs collected during the outbreak, then major capsid （VP1） genomic sequence was determined, and phylogenetic tree was done based on the VP1 sequences among these 37 and other El9 viruses deposited in the Genbank. Also a representative strain named CHN-SD03-TN12 was selected for sequencing of 5′-untranslated regions （5′-UTR）. Results The identity rate was about 98.9%-100% among all these 37 El9 viruses. The genetic relationships between these 37 El9 isolates and other strains reported were also depicted. The identity rate was about 78.4%-78.9% compared with El9 reference strain Burke. The substitutions in the sequence of 5′-UTR resulted in changes in the conjectural properties of 5′-UTR of El9 viruses. Condusion The genetic features of El9 viruses isolated during the outbreak in Shandong Province in 2003 may be associated with a genetic and antigenic drift that changes the virulence of the Shandong isolates, but the molecular changes in Shandong El9 viruses contributing to their phenotype remain to be further illuminated. However, the sequences described in this paper substantiate the changes taken place in capsid VPI and 5′UTR regions. These substitutions may contribute to their tropism and virulence, and play a significant role in pathogenesis and clinical manifestations of the disease.

Coxsackievirus A6 was the most common enterovirus serotype causing hand,foot,and mouth disease in Shiyan City,central China

BACKGROUND Hand,foot,and mouth disease(HFMD)has become one of the most common infectious diseases in China.Before 2016,the primary causal serotypes were enterovirus A71(EV-A71)and coxsackievirus A16(CV-A16).Following the introduction of EV-A71 vaccines in China since 2016,the situation could change.CV-A6 has recently replaced EV-A71 and CV-A16 in some areas of China.However,the epidemiological characteristics of central China remain unknown.AIM To investigate the clinical symptoms and pathogen spectrum of HFMD in Shiyan City,central China,in recent years.METHODS The epidemiological,clinical,and laboratory data from HFMD cases reported to the Shiyan Center for Disease Control and Prevention between January 2016 and December 2020 were analyzed.196 throat swab specimens were collected from hospitalized HFMD patients between January 2018 and December 2020.To detect and genotype enteroviruses,real-time reverse transcription-polymerase chain reaction and sequencing of the 5'-untranslated region were used.In Shiyan,168 laboratory-confirmed HFMD cases were studied using a logistic regression model to determine the effect of predominant enterovirus serotypes.Based on the logistic regression model,the least absolute shrinkage and selection operator model was used to analyze the correlation between CV-A6 infection and various clinical characteristics in HFMD patients in Shiyan.RESULTS From 2016 to 2020,35840 HFMD cases were reported in Shiyan.The number of cases decreased by 48.4%from 2016 to 2017.Approximately 1.58-fold increases were found in 2018 and 2019 when compared to the previous year,respectively.In 2020,a decrease of about 85.5%was reported when compared to 2019.The most common serotypes shifted from EV-A71 and CV-A16(about 60%-80%in 2016 and 2018)to others(more than 80.0%in 2017,2019,and 2020).EV-A71 lost its dominance in 2017 in Shiyan.Among 196 confirmed HFMD cases,85.7%tested positive for enterovirus,with CV-A6 being the most common serotype(121/168,72.0%).The positive rates for CV-A16 and CVA10 were 4.8%and 3.0%,respectively.There was no EV-A71 discovered.Infection with CV-A6 was linked to fever,myocardial damage,increased creatine kinase MB isoenzyme,and lactate dehydrogenase levels.CONCLUSION CV-A6 was the most common enterovirus serotype in Shiyan City,replacing EV-A71 and CV-A16 as the HFMD pathogen.Developing vaccines against CV-A6 or multiple pathogens,as well as rising CV-A6 surveillance,will help prevent HFMD in central China.

Evaluation on Common Hand, Foot and Mouth Disease Treated by Integrative Traditional Chinese Medicine and Western Medicine

Objective To evaluate the efifcacy and safety of traditional Chinese medicine (TCM) combined with Western medicine in the treatment of patients with common hand, foot and mouth disease (HFMD) by conducting a prospective, controlled, and randomized trial. Methods A total of 452 patients with common HFMD were randomly assigned to receive Western medicine alone (n=220) or combined with TCM (Reduning or Xiyanping injections) (n=232). The primary outcome was the incidence rate of rash/herpes disappearance within 5 days, while secondary outcomes included the incidence rate for fever, cough, lethargy, agitation, and vomiting clearance within 5 days. Results The rash/herpes disappearance rate was 45.5% (100/220) in Western medicine therapy group, and 67.2% (156/232) in TCM and Western medicine combined therapy group, with significant difference (P<0.001). Moreover, TCM remarkably increased the incidence rate of secondary disappearance, which was 56.4%in Western medicine therapy group and 71.4%in TCM and Western medicine combined therapy group (P=0.001). No drug-related adverse events were observed. Conclusions It’s suggested that the integrative TCM and Western medicine therapy achieved a better therapeutic efficacy. TCM may become an important complementary therapy on relieving the symptoms of HFMD.

Investigation on Factors Associated with Severe Hand, Foot and Mouth Disease

Objective To analyze the clinical and laboratory features of patients with mild and severe HFMD to identify early predictive or diagnostic markers for severe cases. Methods Samples of feces, nasopharyngeal-swab specimens, peripheral blood, serum and cerebral spinal fluid were collected. Postmortem pathological examination was conducted on 2 dead patients with complication due to neurogenic pulmonary edema. Reverse transcription-polymerase chain-reaction(RT-PCR), culture and isolation of enterovirus 71(EV71) were performed to detect EV71 infection. Both univariate and multivariate logistic analysis were used to identify factors associated with severe cases. Results EV71 was mainly responsible for HFMD. In this study, 5 isolated EV71 strains belonged to C4 gene subtype. Compared with mild patients, EV71-RNA detection rate was higher and Cox A16 detection rate was lower among severe patients(P < 0.01). Inflammatory cell infiltration in the lung, cardiac and liver tissues were mild by postmortem pathological examination. It was found that body temperature, vomitting, limb tremor, neutrophil, blood glucose and EV71 infection were significantly related to the severe cases by univariate logistic analysis. However, after multivariate logistic regression analysis, only vomiting(OR 16.1, CI 2.3-110.5, P < 0.01) and limb tremor(OR 117.6, CI 13.8-1004.5, P < 0.01) were significantly and independently correlated with the severe cases.Conclusions EV71 was mainly responsible for HFMD, particularly for severe cases. Vomiting and limb tremor were predictive markers for severe cases.

The Comparative Study on Two Models of Syndrome Differentiation of the Hand, Foot and Mouth Disease: An Investigation Analysis of the Signs and Symptoms on 2325 Cases

Objective To realize the characteristics of "zheng" differentiation-treatment for hand, foot and mouth disease(HFMD), a new methodology of syndrome differentiation for different stages of HFMD has been explored. Methods Total of 2 325 cases with HFMD were recorded by distributing them into exterior syndrome stage, interior syndrome stage, severe syndrome stage and recovered syndrome stage, respectively, and the main symptoms and subsidiary symptoms of different stages of HFMD have been observed. The major and minor pathogenesis of HFMD in different stages were obtained, and compared with the "2010 Guideline for the Diagnosis and Treatment of HFMD". Results It was found that the major pathogenesis of exterior stage was defined as "the invation of the wenevil to the defender of the body with the collaterals got involved ", and the minor as "qi deficiency"; in interior stage, "the fury of Gan-Yang" was the main pathogenesis, and "qi in chaos and qi deficiency" was the minor; in severe syndrome stage, "the damage of heart, liver and lung" was the main pathogenesis, and "qi in chaos" was the minor; and the pathogenesis of recovered stage was "qi-yin deficiency". Compared with the "2010 Guideline for the Diagnosis and Treatment of HFMD", it showed that "the obstruction of the fei-pi qi by the mixture of shi-re evil" and "the mixture of shi-re" in vivo was quite difficult to be explained in completely different context in the general situation; in the severe stage, the TCM clinical characteristics of syndrome differentiation might lose; in the early acute severe cases, the phenomenon that xin-yang and fei-qi almost ran out was difficult to be observed, then, the line between the severe and the acute severe became vague.Conclusions The theory of syndrome differentiation by stages of HFMD was reasonable in the actual situation of clinical description on HFMD which was expected to be further tested and widely applied in the "zheng" differentiation-treatment of HFMD in the future.

The key mechanisms of multi-system responses triggered by central nervous system damage in hand,foot,and mouth disease severity

Hand,foot,and mouth disease(HFMD)is a prevalent infectious affliction primarily affecting children,with a small portion of cases progressing to neurological complications.Notably,in a subset of severe HFMD cases,neurological manifestations may result in significant sequelae and pose a risk of mortality.We systematically conducted literature retrieval from the databases PubMed(1957–2023),Embase(1957–2023),and Web of Science(1957–2023),in addition to consulting authoritative guidelines.Subsequently,we rigorously selected the most relevant articles within the scope of this review for comprehensive analysis.It is widely recognized that the severity of HFMD is attributed to a multifaceted array of pathophysiological mechanisms.The implication of multi-system dysfunction appears to be perturbances of the human defense system;therefore,it contributes to the severity of HFMD.In this review,we provide an overview and analysis of recent insights into the molecular mechanisms contributing to the severity of HFMD,with a particular focus on cytokine release syndrome,the involvement of the renin-angiotensin system,regional immunity,endothelial dysfunction,catecholamine storm,viral invasion,and the molecular mechanisms of neurological damage.We speculate that the domino effect of diverse physiological systems,initiated by damage to the central nervous system,serve as the primary mechanisms governing the severity of HFMD.Simultaneously,we emphasize the knowledge gaps and research urgently required to delineate a quick roadmap for ongoing and essential studies on HFMD.

The impact of EV71 vaccination program on hand,foot and mouth disease in Zhejiang Province,China:A negative control study

Objective:To estimate the potential causal impact of Enterovirus A71(EV71)vaccination program on the reduction of EV71-infected hand,foot,and mouth disease(HFMD)in Zhejiang Province.Methods:We utilized the longitudinal surveillance dataset of HFMD and EV71 vaccination in Zhejiang Province during 2010-2019.We estimated vaccine efficacy using a Bayesian structured time series(BSTS)model,and employed a negative control outcome(NCO)model to detect unmeasured confounding and reveal potential causal association.Results:We estimated that 20,132 EV71 cases(95%CI:16,733,23,532)were prevented by vaccination program during 2017-2019,corresponding to a reduction of 29%(95%CI:24%,34%).The effectiveness of vaccination increased annually,with reductions of 11%(95%CI:6%,16%)in 2017 and 66%(95%CI:61%,71%)in 2019.Children under 5 years old obtained greater benefits compared to those over 5 years.Cities with higher vaccination coverage experienced a sharper EV71 reduction compared to those with lower coverage.The NCO model detected no confounding factors in the association between vaccination and EV71 cases reduction.

Diagnostic performance of different specimens in detecting enterovirus A71 in children with hand,foot and mouth disease

Hand,foot and mouth disease(HFMD)is a major public health problem among children in the Asia-Pacific region.The optimal specimen for HFMD virological diagnosis remains unclear.Enterovirus A71(EV-A71)neutralizing antibody titres detected in paired sera were considered the reference standard for calculating the sensitivity,specificity,positive and negative predictive value of throat swabs,rectal swabs,stool,blood samples and cerebrospinal fluid(CSF)by RT-PCR or ELISA assay.In this study,clinical samples from 276 HFMD patients were collected for analysing the sensitivity of different kind of specimens.Our results showed that stool had the highest sensitivity(88%,95%CI:74%–96%)and agreement with the reference standard(91%).The order of diagnostic yield for EV-A71 infection was stool samplerectal swab>throat swab>blood sample>CSF sample,and using a combination of clinical samples improved sensitivity for enterovirus detection.The sensitivity of ELISA for IgM antibody detection in sterile-site specimens was significantly higher than that of RT-PCR(serum/plasma:62%vs.2%,CSF:47%vs.0%)(P<0.002).In conclusion,our results suggest that stool has the highest diagnostic yield for EV-A71-infected HFMD.If stool is unavailable,rectal swabs can be collected to achieve a similar diagnostic yield.Otherwise,throat swabs may be useful in detecting positive samples.Although IgM in blood or CSF is diagnostically accurate,it lacks sensitivity,missing 40%–50%of cases.The higher proportion of severe cases and shorter interval between onset and sampling contributed to the increase in congruency between clinical testing and the serological reference standard.

Pattern Classification of Enterovirus 71-Associated Hand, Foot, and Mouth Disease in Chinese Medicine: A Retrospective Study in 433 Cases

Objective： To determine whether patterns of enterovirus 71（EV71）-associated hand, foot, and mouth disease（HFMD） were classified based on symptoms and signs, and explore whether individual characteristics were correlated with membership in particular pattern. Methods： Symptom-based latent class analysis（LCA） was used to determine whether patterns of EV71-HFMD existed in a sample of 433 cases from a clinical data warehouse system. Logistic regression was then performed to explore whether demographic, and laboratory data were associated with pattern membership. Results： LCA demonstrated a two-subgroup solution with an optimal fit, deduced according to the Bayesian Information Criterion minima. Hot pattern（59.1% of all patients） was characterized by a very high fever and high endorsement rates for classical HFMD symptoms（i.e., rash on the extremities, blisters, and oral mucosa lesions）. Non-hot pattern（40.9% of all patients） was characterized by classical HFMD symptoms. The multiple logistic regression results suggest that white blood cell counts and aspartate transaminase were positively correlated with the hot pattern（adjust odds ratio=1.07, 95% confidence interval： 1.006–1.115; adjust odds ratio=1.051, 95% confidence interval： 1.019–1.084; respectively）. Conclusions： LCA on reported symptoms and signs in a retrospective study allowed different subgroups with meaningful clinical correlates to be defined. These findings provide evidence for targeted prevention and treatment interventions.

Clinical characteristics of hand, foot and mouth disease in Harbin and the prediction of severe cases

Background Hand, foot and mouth disease （HFMD） is an emerging public health problem in China, not only threatening the health of children, but also causing tremendous loss and burden to both families and society. The aim of this study was to characterize the epidemiology and clinical features of HFMD, and to understand the key factors affecting HFMD in the Harbin region to provide scientific evidence for effective prevention and control strategies. Methods Epidemiological and clinical information from 2379 randomly chosen cases of HFMD treated at the Harbin Center for Disease Control and Prevention from May 2008 to November 2011 were analyzed. All cases were separated into common and severe HFMD, with key factors for severe HFMD analyzed using multivariable Logistic regression. Results Among the 2379 patients, 1798 were common cases and 581 severe cases, 14 of which resulted in death. Most cases were in children younger than 5 years. Morbidity peaked in July and was higher in the surrounding country and cities than in Harbin proper. Medical expenses were significantly higher for severe than for common cases （P 〈0.001）. The primary clinical symptoms were fever and erythema; laboratory examination showed leucocytosis together with pneumonia, carditis, and abnormal electrocardiogram and electroencephalogram in severe cases. Multivariabie Logistic regression analysis showed that the key factors for severe HFMD were age, morbidity location, morbidity area, fever duration, mouth mucosal symptoms, and abnormal serum levels of neutrophils （NEUT）, hemoglobin and glucose （P 〈0.05）. Conclusions To improve prognosis, reduce medical expense and prevent the development of severe cases, we should improve the epidemiological detection of HFMD to treat patients quickly. We should also closely monitor children with the EV71 virus, who present with continuous fever as well as abnormal laboratory results, from areas highly susceptible to

From Monovalent to Multivalent Vaccines, the Exploration for Potential Preventive Strategies Against Hand, Foot, and Mouth Disease(HFMD)

Hand,foot,and mouth disease(HFMD)recently emerged as a global public threat.The licensure of inactivated enterovirus A71(EV-A71)vaccine was the first step in using a vaccine to control HFMD.New challenges arise from changes in the pathogen spectrum while vaccines directed against other common serotypes are in the preclinical stage.The mission of a broad-spectrum prevention strategy clearly favors multivalent vaccines.The development of multivalent vaccines was attempted via the simple combination of potent monovalent vaccines or the construction of chimeric vaccines comprised of epitopes derived from different virus serotypes.The present review summarizes recent advances in HFMD vaccine development and discusses the next steps toward a safe and effective HFMD vaccine that is capable of establishing a crossprotective antibody response.

Reduning injection for fever, rash, and ulcers in children with mild hand, foot, and mouth disease: a randomized controlled clinical study

OBJECTIVE： To assess the efficacy and safety of Re- duning injection for fever, rash, and ulcers in chil- dren with mild hand, foot, and mouth disease （HFMD）. METHODS： A stratified-block randomized, dou- ble-blind, parallel-controlled, and multicenter clini- cal trial was conducted with 360 patients in five hospitals across China： Quanzhou Children＇s Hospi- tal, Shijiazhuang No. 5 Hospital, Shanghai Public Health Centre, Hunan Provincial Children＇s Hospi- tal, and Kaifeng Children＇s Hospital. Patients were randomized into three groups with 120 in each. Group A was treated with Western Medicine, group B with Reduning injection, a Chinese herbal medi- cine, and group C with both Reduning injection and Western Medicine. Results were compared for treatment efficacy and safety on HFMD. The clinical outcomes were observed as follows： fever and on- set time of antifebrile effect （time to bring the body temperature down 〉0.5~C after medication）; cumu- lative time for fever recovery （body temperature re- covering to normal and lasting more than 24 h without medication）; cumulative time for rash dis- appearance （without new rashes or ulcers appear- ing and the original ones fading away）; and cumula- tive time for mouth ulcer disappearance. RESULTS： For the onset time of the antifebrile ef- fect, there was no statistical difference between groups A and B （P〉O.05） and groups B and C （P〉 0.05）. However, there was a statistical difference be- tween groups A and C （P〈0.05）, and the effect ingroup C was the best. For the cumulative time for rash disappearance, there was no statistical differ- ence between groups A and B （P〉0.05）. There were statistical differences between groups A and C, and groups B and C （P〈0.05）, and the effect in group C was the best. For the cumulative time for mouth ul- cers disappearance, there were no statistical differ- ences among the three groups （P〉0.05）. CONCLUSION： Reduning injection with Western Medicine for symptomatic treatment is most effec- tive for mild HFMD. No adverse reactions were ob- served.

Surveillance, epidemiology, and pathogen spectrum of hand, foot, and mouth disease in mainland of China from 2008 to 2017

Hand,foot and mouth disease(HFMD)was reported in May 2,2008 to be the 38th legally notifiable disease in China's National Notifiable Disease Reporting and Surveillance System.In order to solve the infection,an extensive three-level HFMD surveillance laboratory network was established.In this study,the framework of that network is assessed and the incidence of HFMD in China from 2008 to 2017 is reported using a descriptive epidemiologic method.During these 10 years,a series of techniques have been widely applied in all the network laboratories.Using information and material obtained from the network,a virus bank and database containing 18,238 viruses were established.Nationally,18,184,834 HFMD cases,including 152,436 severe cases and 3633 fatal cases,were reported in mainland of China.The average annual incidence in the population was 133.99/100,000 people,with a maximum incidence of 205.06/100,000 people in 2014.The incidence and mortality rates of HFMD were the highest in children aged 1–2 years.The numbers of reported cases fluctuated,with a high incidence observed every 2 years.An overall increase in the number of reported cases was also observed throughout the study period.Despite this,the incidence of severe cases and the mortality rate have been decreasing.High-risk regions are located in southern,eastern,and central China.Two peaks of HFMD infection cases were observed annually except for Northeast China.Different proportions of enterovirus serotypes were observed during the studied years.The predominant enterovirus varies from year to year,but the disease severity is always closely related to the specific serotype.EV-A71 is the dominant serotype associated with severe and fatal cases,with constituent ratios of 70.03%and 92.23%,respectively.The studied highly sensitive and efficient surveillance network provides information that is critical for prevention and control of the disease.It is extremely necessary and important to continuously conduct extensive virological surveillance for HFMD.

Review of hand, foot and mouth disease

Hand,foot and mouth disease(HFMD)is an acute viral illness that primarily affects infants and young children,and often occurs in clusters or outbreaks.The major causative agents of HFMD are coxsackievirus A16(CVA16),human enterovirus 71(HEV71)and coxsack-ievirus A10(CVA10),of the genus Enterovirus in the family Picornaviridae.HFMD caused by EV71 is associated with severe neurological complications and death.Since the late 1990s,several major epidemics of EV71 HFMD have swept through the Asia-Pacific region,associated with a rapid fulminant course,severe neurolo-gical complications,and a large number of fatalities.Until now,little has been known about the genetics and transmission trends of the fast-mutation virus,and there is no effective and specific antiviral therapy or vaccine for HFMD.It is time to step up efforts to understand the molecular epidemics and pathogenesis so that we can develop effective management strategies and surveillance programs.

Analysis of a hand-foot-mouth disease model

In this paper, we have introduced a six-compartmental epidemic model with hand, foot and mouth disease （HFMD） infection. The total population is divided into six subclasses, namely susceptible, exposed, infective in asymptomatic phase, infective in symptomatic phase, quarantined and recovered class. Some basic properties such as boundedness and non-negativity of solutions are discussed. The basic reproduction number （R0） of the system is obtained using next generation matrix method. Then the deterministic dynamical behaviors of the system are studied. Our study includes the existence and stability analysis of equilibrium points of the system. The sensitivity analysis of our system helps us to find out the parameters of greater interest. Next, we deal with the epidemic model with three controls （two treatment controls with quarantine control）. We show that there exists an optimal control, which is effective in controlling the disease outbreak in a cost effective way. Numerical simulation is presented with the help of MATLAB, which shows tile reliability of our model from the practical point of view.