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  • Serious Hand Foot and Mouth - Enterovirus 71

    Enterovirus 71 Infection

    Causative agent
    Enterovirus 71 (EV71) is a single stranded, RNA virus and one of the causative agents for hand, foot and mouth disease (HFMD). The disease occurs commonly in Southeast Asian areas, especially in summer and early autumn. Large outbreaks have been reported in Taiwan and Malaysia in 1990s.

    Clinical features
    EV71 infection is usually found among young children. It most commonly presents with symptoms of HFMD, characterised by fever, sores in the mouth, and a rash with blisters. Usually it begins with fever, poor appetite, malaise and sore throat. One to two days later, painful sores develop in the mouth. The sores are characterised by small red spots with blisters which then often become ulcers. They are usually located on the tongue, gums, and inside of the cheeks. The non-itchy skin rash manifests as flat or raised red spots. The rash is usually found on the palms of the hands and soles of the feet. Asymptomatic infections can occur. Rarely, EV71 may cause more serious diseases, such as viral (aseptic) meningitis, encephalitis, poliomyelitis-like paralysis and myocarditis.

    Mode of transmission
    EV71 infection is transmitted from person to person by direct contact with nose and throat discharges, saliva, fluid from blisters, or the stool of infected persons. The illness is contagious during the acute stage and perhaps longer, as faecal shedding of virus can be detected for several weeks.

    Incubation period
    The incubation period ranges from 3 to 7 days.

    Currently, no specific treatment is available for EV71 infection. Some symptomatic treatments can relief fever and pain from the ulcers. In most cases, the illness is self-limiting. Symptoms including fever, rash and ulcers subside spontaneously in one week. Parents should pay attention to the health of their children and seek medical advice if their children having HFMD developing the following symptoms:
    • Persistent and high fever;
    • Repeated vomiting;
    • Persistent sleepiness or drowsiness;
    • Myoclonic jerks or sudden limb weakness.
    Infected children should refrain from schools or group activities such as parties, interest classes, swimming until two weeks after fever has subsided and all the vesicular lesions have dried and crusted to prevent the spread of disease. Protect other family members, especially children, from getting the infection through strict personal and environmental hygiene (see advice on prevention below).

    Vaccine is not available at the moment. Good personal and environmental hygienic are the most important measures to prevent EV71 infection. While in Hong Kong or during travel, members of the public are advised to:--
    • Wash hands before eating and after going to toilet, managing vomitus or changing diapers;
    • Cover nose and mouth while sneezing or coughing, and proper disposal of nasal and mouth discharge;
    • Never share personal items such as towels and eating utensils;
    • Maintain good ventilation;
    • Clean and disinfect frequently touched surface, furniture and toilets regularly with diluted bleach of 1:99 concentration (mixing 1 part of 5.25% household bleach with 99 parts of water);
    • Disinfect toys/places which are contaminated by secretions or excreta with diluted household bleach of 1:49 concentration;
    • Avoid close contact with HFMD patients.

  • #2
    Re: Serious Hand Foot and Mouth - Enterovirus 71


    Viral outbreak in China tests government efforts
    Researchers call for greater focus on surveillance and genomics.
    Jane Qiu

    An outbreak of hand, foot and mouth disease in China, which since January has killed 19 children and made nearly 42,000 ill, has researchers calling for a better surveillance system to detect the disease and for action to speed up vaccine development.

    "The situation of preventing and containing hand, foot and mouth disease is very serious at the moment,"
    Deng Haihua, spokesman for China's health ministry, said last week. More cases are expected, as the disease normally peaks between May and July. In the absence of a drug treatment, the ministry is focusing on prevention and containment.

    The outbreak is the latest in a series to have hit China in recent years, caused by a fast-spreading virus called enterovirus 71. "The persistence of enterovirus 71 outbreaks in China is a wake-up call," says Jane Cardosa, a virologist at the University Malaysia Sarawak in Kota Samarahan. In 1997, Sarawak saw the first outbreak of hand, foot and mouth disease in the Asia-Pacific region.

    The disease causes flu-like symptoms, along with rashes on the hands and feet, and mouth ulcers. It can be caused by many types of human enterovirus belonging to the Picornaviridae family, which are mainly transmitted through faecal or oral routes. Although normally mild, the disease can be life-threatening: some viruses, particularly enterovirus 71, can cause inflammation of the brain stem, resulting in heart failure and fluid accumulation in the lungs.

    In 1997 in Sarawak, more than 2,600 cases of the disease were reported and 29 people died. The next year in Taiwan, there were 129,000 reported cases and 78 deaths. In mainland China, the first reported case was in Shenzhen, Guangdong province, in 1999. At first, outbreaks were local and there were no reported fatalities (L. Li et al. J. Clin. Microbiol. 43, 3835?3839; 2005).
    But since 2004, the outbreaks have become more severe and widespread, says Xu Wenbo, an infectious-disease expert at the Beijing-based China Center for Disease Control and Prevention.

    In May 2008, the country's health ministry added hand, foot and mouth to its category 'C' of notifiable diseases, meaning that all diagnosed cases must be reported through a national web-based system for disease surveillance, and took measures to streamline reporting requirements. The ministry also vowed to take a tough stance against cover-ups and last month sacked four health officials in Henan province for concealing the number of infections and deaths.

    This year, enterovirus 71 has caused nearly all of the laboratory-confirmed cases in two hot-spots, the provinces of Henan and Shandong. Xu suspects that the disease's increasing virulence may be due to a genetic change in the circulating virus strain. Before 2004, the predominant strain was called C4b; since then, a different strain, C4a, has been most common (Y. Zhang et al. J. Clin. Virol. 44, 262?267; 2009).

    What caused this switch isn't clear, says Xu, as little is known about the genetics and transmission trends of the fast-mutating virus. Most studies have been clinical, aimed at, for example, identifying the strains behind a given outbreak and the disease's clinical features, especially when there are neurological complications. Many researchers say it is time to step up efforts to understand the basic biology of enterovirus 71 to speed vaccine development.

    In a major push financed by the Chinese health ministry and the Center for Disease Control and Prevention, Xu and his colleagues measured the infection rate in adults and children during last year's outbreak and analysed stool samples and throat swabs taken from more than 18,000 patients. Preliminary results suggest that the infection rate is alarmingly high, meaning that there are large populations of virus carriers who do not show any symptoms of the disease.

    Experts are divided as to how worried the world should be about the virus. Tom Solomon, a neurologist at the University of Liverpool, UK, argues that enterovirus 71 infection is underappreciated on a global scale and may pose a bigger risk to public health than is currently thought. But Hans Troedsson, the World Health Organization's representative in China, says "there is no cause for alarm". The public-health impact of hand, foot and mouth disease, including cases caused by enterovirus 71, is no more serious than other common childhood diseases, he says.

    Troedsson thinks that the recent apparent increase in enterovirus 71 infection might be due to higher reporting rates rather than an increase in disease prevalence. "We will closely monitor the situation and decide polices accordingly," he says.


    • #3
      Re: Serious Hand Foot and Mouth - Enterovirus 71


      Google translation:

      Study shows that: hand, foot and mouth disease is not pathogenic virus mutates EV71
      2009-04-20 19:30:05
      Source: Xinhuanet

      Xinhua Beijing April 20 (Xinhua) China's CDC researcher virus XU Wen-bo on the 20th during the online interview, said that from 1998 to 2009, China carried out pathogen detection and analysis showed that the hand, foot and mouth EV71 virus disease the main cause of variation is not significant, did not increase virulence.

      According to him, in 2008, China's 31 provinces in the country established a network of hand, foot and mouth disease laboratories, carrying out pathogen monitoring, virus isolation and gene sequencing analysis. The results showed that my hand, foot and mouth disease to the major pathogen and the EV71 intestinal virus CoxA16 mainly caused by severe and mortality for EV71, laboratory confirmed cases accounted for 90%.

      It is understood that the hand, foot and mouth disease vaccine EV71 has not now successfully developed the world, China and the international community has already begun in some countries EV71 vaccine development. However, vaccine development needs of 3-5 year cycle is applied to people, and now also without the approval of the international community to prevent the vaccine.

      Hand, foot and mouth disease mainly mainly fecal-oral route of transmission, but also through direct contact and respiratory droplets spread, therefore, XU Wen-bo pointed out that strengthening personal hygiene, sanitation, food hygiene, especially hand-foot-mouth disease to prevent contact with children and their excreta secretions and respiratory secretions is the main preventive measure.

      XU Wen-bo pointed out that hand, foot and mouth disease is caused by a variety of intestinal virus diseases of children, is not a new emerging infectious diseases, people are unfamiliar with it mainly due to Hand, Foot and Mouth 2008 non-statutory reporting of infectious disease, the lack of the disease laboratory testing data and data integrity of the epidemic. May 2008, my hand, foot and mouth has been incorporated into the statutory reporting of infectious disease.

      Prevention from the national level, XU Wen-bo suggested that the state should be gradually incorporated into the normal hand, foot and mouth disease management, increase training for medical personnel on the grass-roots efforts, particularly in children with severe to raise the point where treated the capacity of hospitals. At the same time, the speedy setting up of hand, foot and mouth disease in China pathogenic biological information base and strengthen scientific and technological, as soon as possible to provide effective prevention and treatment products.

      Beijing Ditan Hospital Dr Lu said the joint, hand, foot and mouth disease for more than 50% of the early symptoms, parents should pay attention to the spirit of good kids, good to eat, sleep any jitter, and whether there will be such a headache. In addition, if the child appeared cold extremities, skin color green, and so on to speed up breathing than usual, we must go to hospital.

      According to statistics, the main hand, foot and mouth disease to the incidence under 5 years of age-based groups (91% -95%), incidence of very few young people and adults. Severe hand-foot-mouth disease mortality is about 3 thousandths, most to the success of the rescue. (This article Source: Xinhua) netease


      • #4
        Re: Serious Hand Foot and Mouth - Enterovirus 71


        The cross-reactivity of the enterovirus 71 to human brain tissue and identification of the cross-reactivity related fragments

        EV71 occasionally cause a series of severe neurological symptoms, including aseptic meningitis, encephalitis, and poliomyelitis-like paralysis. However, the neurological destruction mechanism was remained to be clarified.

        This study described the cross reaction between EV71 induced IgG and human brain tissue.

        Results: Cross reaction of the IgG from 30 EV71 infected patients'sera to human tissues of cerebra was observed, which suggested that some EV71 antigens could induce IgG cross-reactivity to human cerebra. To identify the regions of EV71 virus that containing above antigens, the polypeptide of virus was divided into 19 peptides by expression in prokaryotes cell.

        Mouse anti-sera of these peptides was prepared and applied in immunohistochemical staining with human adult and fetus brain tissue, respectively. The result indicated the 19 peptides can be classified into three groups: strong cross-reactivity, weak cross-reactivity and no cross-reactivity with human brain tissue according the cross reaction activity.

        Then, the increased Blood Brain Barrier (BBB) permeability and permits IgG entry in neonatal mice after EV71 infection was determined.

        Conclusion: EV71 induced IgG could enter BBB andcross-reacted with brain tissue in EV71 infected neonatal mice, and then the peptides of EV71 that could induce cross-reactivity with brain tissue were identified, which should be avoided in future vaccine designing.

        Author: Chun Shi JiaJiang Ning LiuWan Bo LiChun Mei MaShu Zhu LinYi HaoXue Zhong GaoXiao Lin LiuYan Feng XuLian Feng ZhangChuan Qin
        Credits/Source: Virology Journal 2010, 7:47


        • #5
          Re: Serious Hand Foot and Mouth - Enterovirus 71

          Macao children infected with EV71 virus

 2010-05-25 07:22:33 FeedbackPrintRSS

          MACAO, May 24 (Xinhua) -- Macao's Health Bureau Monday reported one newly confirmed enterovirus 71 (EV71) case at a local creche, bringing the total number of such cases to 15 so far.

          According to the Bureau, the 15 infected children were all from the same local creche, and the young patients have received treatments at medical institutions, none of whom needed to be admitted into the hospital.

          The collective outbreak of such cases were firstly recorded at the creche on May 20.

          EV71 are the common cause of Hand, foot and mouth disease, and it typically occurs in small epidemics in nursery schools or kindergartens, usually during the summer and autumn months.

          Aside from the EV71 infection, the Bureau also said that a patient infected with the A/H1N1 flu was admitted into local hospital between May 17 and 24, and has since recovered and been discharged.

          Editor: An

          Twitter: @RonanKelly13
          The views expressed are mine alone and do not represent the views of my employer or any other person or organization.


          • #6
            Re: Serious Hand Foot and Mouth - Enterovirus 71


            Retrospective seroepidemiology indicated that human enterovirus 71 and coxsackievirus A16 circulated wildly in central and southern China before large-scale outbreaks from 2008

            Large nationwide outbreaks of hand, foot, and mouth disease (HFMD) occurred in China from 2008; most of the cases were in children under 5 years. This study aims to identify the situation of natural human enterovirus 71 (HEV71) and coxsackievirus A16 (CVA16) infections in children before 2008 in China...

            ...Conclusions: This report confirmed that HEV71 and CVA16 had wildly circulated in a couple provinces in China before the large-scale outbreaks from 2008...

            Author: Zhen ZhuShuangli ZhuXuebin GuoJitao WangDongyan WangDongmei YanXiaojuan TanLiuying TangHui ZhuZhaohui YangXiaohong JiangYixin JiYong ZhangWenbo Xu
            Credits/Source: Virology Journal 2010, 7:300


            • #7
              Re: Serious Hand Foot and Mouth - Enterovirus 71


              Evaluation of human enterovirus 71 and coxsackievirus A16 specific immunoglobulin M antibodies for diagnosis of hand-foot-and-mouth disease

              Hand-foot-and-mouth disease (HFMD) is caused mainly by the human enterovirus type 71 (HEV71) and the Coxsackievirus A group type 16 (CVA16). Large outbreaks of disease have occurred frequently in the Asia-Pacific region.

              Reliable methods are needed for diagnosis of HFMD in childen. IgM-capture ELISA, with its notable advantages of convenience and low cost, provides a potentially frontline assay.

              We aimed to evaluate the newly developed IgM-capture ELISAs for HEV71 and CVA16 in the diagnosis of HFMD, and to measure the kinetics of IgM over the course of HEV71 or CVA16 infections...

              ...Conclusions: HEV71- and CVA16-IgM ELISAs can be deployed successfully as a convenient and cost-effective diagnostic tool for HFMD in clinical laboratories.

              Author: Nan YuMin GuoSi-Jie HeYu-Xian PanXin-Xin ChenXi-Xia DingWei HaoYa-Di WangSheng-Xiang GeNing-Shao XiaXiao-Yan Che
              Credits/Source: Virology Journal 2012, 9:12

              Published on: 2012-01-11


              • #8
                Re: Serious Hand Foot and Mouth - Enterovirus 71


                Excretion of enterovirus 71 in persons infected with hand, foot and mouth disease

                Hand, foot and mouth disease (HFMD) is a common illness in young children. It also can be seen in adults occasionally.

                Enterovirus 71 (EV71), a pathogen that causes not only HFMD but also neurological complications and even death, has caused many HFMD outbreaks in China. However, till now the data about the duration of EV71 shedding is very limited. ..

                ...Conclusions: HFMD is characterized by extended excretion of EV71. Our results suggest that the duration of EV71 shedding is correlated with the severity of the disease.

                EV71 shedding through feces can persist more than 54 days. Prolonged virus shedding is a potential risk factor of proliferating HFMD epidemic.

                Author: Jie LiChangying LinMei QuXinyu LiZhiyong GaoXin ZhangYuan LiuYing HuangXiaoli WangLei JiaXitai LiGuirong LiuHanqiu YanLijuan ChenQuanyi Wang
                Credits/Source: Virology Journal 2013, 10:31

                Published on: 2013-01-23


                • #9
                  Re: Serious Hand Foot and Mouth - Enterovirus 71


                  January 29, 2014
                  Findings point to potential treatment for virus causing childhood illnesses
                  Rossmann EV71

                  WEST LAFAYETTE, Ind. - Researchers have discovered a potential treatment for a viral infection that causes potentially fatal brain swelling and paralysis in children. The findings also point to possible treatments for related viruses including those that cause "common cold" symptoms.

                  The virus, called enterovirus 71 (EV71), causes yearly outbreaks of hand, foot, and mouth disease in Southeast Asian countries including China and Malaysia. Some of the infected children develop encephalitis that can be fatal or result in permanent brain damage. There are no anti-EV71therapeutic agents available.

                  The researchers prepared antibodies by immunizing mice with immature EV71 particles. Antibodies generated by this immunization induced a change in the mature EV71 virus, rendering it non-infectious by causing the virus particles to lose their genome.

                  The findings reveal a potential treatment mechanism, demonstrating that the antibody, called E18, has potential as an anti-EV71 therapy, said Michael G. Rossmann, Purdue's Hanley Distinguished Professor of Biological Sciences...



                  PNA Neutralizing antibodies can initiate genome release from human enterovirus 71

                  Pavel Plevka1, Pei-YinLim2, RushikaPerera1, JaneCardosa2,3, AmpaSuksatu1, Richard J. Kuhn1, and Michael G. Rossmann1

                  1 Department of Biological Sciences, Purdue University, West Lafayette, IN47907; 2 Sentinext Therapeutics, 10050Penang, Malaysia; and 3 MAB Explorations, 10050Penang, Malaysia

                  Antibodies were prepared by immunizing mice with empty, immature particles of human enterovirus71 (EV71), a picornavirus that causes severe neurological disease in young children. The capsid structure of these empty particles is different from that of the mature virus and is similar to "A" particles encountered when picornaviruses recognize a potential host cell before genome release. The monoclonal antibody E18, generated by this immunization, induced a conformational change when incubated at temperatures between 4?C and 37?C with mature virus, transforming infectious virions into A particles. The resultant loss of genome that was observed by cryo-EM and a fluorescent SYBR Green dye assay inactivated the virus, establishing the mechanism by which the virus is inactivated and demonstrating that the E18 antibody has potential as an anti-EV71 therapy. The antibody-mediated virus neutralization by the induction of genome release has not been previously demonstrated. Furthermore, the present results indicate that antibodies with genome-release activity could also be produced for other picornaviruses by immunization with immature particles.


                  • #10
                    Re: Serious Hand Foot and Mouth - Enterovirus 71


                    An atypical winter outbreak of hand, foot, and mouth disease associated with human enterovirus 71, 2010

                    To analyze the epidemiological characteristics and pathogenic molecular characteristics of an hand, foot, and mouth disease (HFMD) outbreak caused by enterovirus 71 in Linyi City, Shandong Province, China during November 30 to December 28, 2010.

                    Methods: One hundred and seventy three stool specimens and 40 throat samples were collected from 173 hospitalized cases. Epidemiologic and clinical investigations, laboratory testing, and genetic analyses were performed to identify the causal pathogen of the outbreak...

                    ...Conclusion: This outbreak of HMFD was caused by EV71 in an atypical winter. EV71 strains associated with this outbreak represented three separate chains of transmission.

                    Substitution at amino acid position 145 of the VP1 region of EV71 might be an important virulence marker for severe cases. These findings suggest that continued surveillance for EV71 variants has the potential to greatly impact HFMD prevention and control.

                    Author: Nan LiuJing XieXiaoli QiuLeili JiaZhihao WuYuhua MaZhongqiang WangPeng LiXingbin RenRongzhang HaoLigui WangYong WangShaofu QiuHongbin Song
                    Credits/Source: BMC Infectious Diseases 2014, 14:123

                    Published on: 2014-03-04


                    • #11

                      Enterovirus 71 infection in children with hand, foot, and mouth disease in Shanghai, China: epidemiology, clinical feature and diagnosis

                      In 2012 a large outbreak of hand, foot, and mouth disease (HFMD) widely spread over China, causing more than 2 million cases and 567 deaths. Our purpose was to characterize the major pathogens responsible for the 2012 HFMD outbreak and analyze the genetic characterization of the enterovirus 71 (EV71) strains in Shanghai; also, to analyze the dynamic patterns of neutralizing antibody (NAb) against EV71 and evaluate the diagnostic value of several methods for clinical detection of EV71...

                      ...Conclusions: EV71 C4a remained the predominant subgenotype circulating in Shanghai.

                      The severity of the EV71 infection is not associated with the virulence determinants in VP1. RT-PCR together with IgM detection can enhance the early diagnosis of severe EV71-associated HFMD.

                      Author: Ying WangGang ZouAimei XiaXiangshi WangJiehao CaiQianqian GaoShilin YuanGuimei HeShuyi ZhangMei ZengRalf Altmeyer
                      Credits/Source: Virology Journal 2015, 12:83


                      • #12
                        Volume 22, Number 1?January 2016


                        Seroepidemiology of Human Enterovirus 71 Infection among Children, Cambodia

                        On This Page



                        Technical Appendicies


                        Paul F. Horwood, Alessio Andronico, Arnaud Tarantola, Henrik Salje, Veasna Duong, Channa Mey, Sovann Ly, Philippe Dussart, Simon Cauchemez, and Philippe Buchy
                        Author affiliations: Institut Pasteur in Cambodia, Phnom Penh, Cambodia (P.F. Horwood, A. Tarantola, V. Duong, C. Mey, P. Dussart, P. Buchy); Institut Pasteur, Paris, France (A. Andronico, H. Salje, S. Cauchemez); Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA (H. Salje); Ministry of Health, Phnom Penh (S. Ly); GlaxoSmithKline Vaccines, Singapore (P. Buchy)
                        Suggested citation for this article

                        Enterovirus 71 is reported to have emerged in Cambodia in 2012; at least 54 children with severe encephalitis died during that outbreak. We used serum samples collected during 2000?2011 to show that the virus had been widespread in the country for at least a decade before the 2012 outbreak.

                        In the Asia-Pacific region, human enterovirus 71 (EV71) is a widespread pathogen that causes hand, foot and mouth disease among children. Potentially fatal neurologic and systemic manifestations develop in a small proportion of patients (1).
                        In Cambodia during 2012, a disease outbreak characterized by severe encephalitis with cardiovascular collapse and pulmonary edema seized international headlines and resulted in the death of at least 54 children; EV71 subgenogroup C4 was identified as the cause (2). The large number of deaths during a short period was a concern for health authorities. To investigate whether EV71 had circulated in Cambodia before the 2012 outbreak, we retrospectively screened blood samples collected from children during 2000?2011.
                        The Study

                        We screened serum samples collected from inpatient children in Cambodia through routine national dengue surveillance. The study set was extracted from the Institut Pasteur in Cambodia biobank of strictly anonymized samples collected from 9,408 febrile inpatients during 2000?2011. Ethics clearance was obtained from the Cambodian National Ethics Committee for Human Research before testing commenced.
                        After exclusion of data entry errors, outliers in terms of year of participation, and insufficient data or samples, the database included 7,823 children 2?15 years of age for whom age, sex, and province of residence were documented. To avoid any influence from maternal antibodies, we excluded children <2 years of age from the study. Provinces were allocated to geographic quadrants and mapped by using ArcGIS 10 (Esri Co., Redlands, CA, USA) (Technical Appendix[PDF - 790 KB - 4 pages] Figure 1). Random sampling was applied by using Stata 11 (StataCorp LP, College Station, TX, USA) with a representation of samples for each year. A total of 1,707 anonymized samples (1 sample/child) were selected and tested. All available samples from the sparsely populated northeastern quadrant (4% of the dataset) were included. Because the southeastern quadrant (bordering Vietnam) is the most populated quadrant, samples were selected in approximate proportion to population (46% of the dataset). Samples from the southwestern (18% of dataset) and northwestern (31% of the dataset) quadrants, each of which borders Thailand, were selected proportionally to represent a total of 48% from the quadrants bordering Thailand (Table).

                        The 1,707 serum samples were screened by use of a microneutralization assay to detect neutralizing antibodies against an EV71 strain (genotype C4a) isolated from an infected child during the 2012 outbreak in Cambodia. The assay was conducted on Vero E6 cells by mixing 2-fold serial dilutions (1:8 to 1:8,192) of heat-inactivated human serum samples with 100 μL (2,000 50% tissue culture infective doses/mL) of the EV71 strain. Cytopathic effect was determined visually before and after staining with 2.5% crystal violet solution. All serum samples were tested in duplicate, and positive control serum was added to each reaction plate for quality control purposes. The lowest dilution at which cytopathic effect was observed in >50% of wells was considered the antibody titer of the serum sample. A titer of >1:16 was considered the cutoff for a positive antibody response and was a more stringent cutoff than that used in previously published EV71 seroprevalence studies, in which the cutoff was usually >1:8 (3?6).
                        To reconstruct the historical annual probability of infection, we used information about the serostatus and age of the children. This reconstruction assumed that after infection, detectable antibody titers are long lasting; this method has been used to estimate the historical force of infection for other diseases, such as dengue (7). We estimated a separate annual probability of infection for each year from 1994 through 2011. Because no patients in our dataset had been born before 1994, we could not estimate the force of infection before this time (online Technical Appendix). Because samples included in this study were from children with a denguelike illness, rates of EV71 infection among study participants might not accurately reflect rates among all children in Cambodia. However, because an average of 87.8% of patients recruited by the National Dengue Surveillance Program had a laboratory-confirmed dengue infection (8), the febrile episode that triggered the hospitalization could be only slightly associated with EV71 infection and thus would have negligible influence on the EV71 neutralizing titers of the patient population.

                        Figure 1. Age-associated seroprevalence of enterovirus 71 (EV71) infection in Cambodia, estimated by detection of EV71 seroneutralizing antibodies in inpatient children 2?15 years of age, 2000?2011. Error bars indicate 95% CIs. Serum samples...

                        Among children in this study, the overall seroprevalence of EV71 neutralizing antibodies was 88.8%: 1,300 (94.8%) of 1,371 (95% CI 93.5%?95.9%) among children 2?15 years of age sampled during 2006?2011 and 216 (64.3%) of 336 (95% CI 58.9%?69.4%) among those 2?7 years of age sampled during 2000?2005 (Figure 1). Seroprevalence did not vary substantially by age group. This profile across age groups remained unchanged in more stringent analyses with higher cutoff values (Technical Appendix[PDF - 790 KB - 4 pages] Figure 2) in which, despite levels of seropositivity decreasing with higher cutoff titers, the reduction was consistent across all age groups. Seroprevalence of EV71 relative to sex did not differ significantly (89.8% among girls vs. 87.7% among boys; p = 0.18).

                        Figure 2. Annual probability of enterovirus 71 infection (EV71) in Cambodia during 1994?2011, estimated by detection of EV71 seroneutralizing antibodies in inpatient children 2?15 years of age. Serum samples were collected from routine...

                        Epidemic curves derived from the seroprevalence data show the dynamics of infection for the whole country (Figure 2) and across the 4 quadrants (Technical Appendix[PDF - 790 KB - 4 pages] Figure 3). The reconstructed curves were coherent, showing large-scale, countrywide circulation of the virus since 2002. Seroprevalence peaks every 2?3 years indicate a cyclical pattern of EV71 outbreaks. This pattern has been reported from other Asia-Pacific countries (9?11) and probably represents the time needed for establishment of a new cohort of immunologically naive patients. In countries with a larger population, such as China, infection might peak annually (12).
                        Despite our use of a more stringent cutoff value, the seroprevalence detected in our study was considerably higher than that reported from previous studies in the region, during which a cutoff of 1:8 was invariably used (3?6). If we had used a neutralization titer of 1:8, seroprevalence would have been 93.1% (n = 1,590 positive samples). Intense circulation of EV71 was therefore occurring in Cambodia long before the 2012 outbreak.
                        In Cambodia and other Asia-Pacific countries, other enteroviruses commonly cocirculate with EV71. Some of these strains, such as coxsackieviruses A6 and A16, have also been associated with severe neurologic illnesses in children. Previous studies have established that cross-neutralization occurs among different EV71 strains and genogroups (13,14). However, there is no evidence of cross-neutralization between EV71 and other enteroviruses (15). Cross-neutralization at high dilutions would probably not have generated a consistent profile of seropositivity across children of different ages (Technical Appendix[PDF - 790 KB - 4 pages] Figure 2). Thus, the high level of seropositivity observed in this study is probably specific for EV71.


                        Our data support the widespread circulation of EV71 at least a decade before its reported emergence in 2012. Furthermore, reconstructed epidemic curves suggest that EV71 outbreaks occurred in a cyclical pattern in Cambodia and that the virus infected large proportions of immunologically naive children every 2?3 years. Before 2012, this circulation remained undetected, highlighting the need to further reinforce the surveillance systems in developing countries. Also needed is enhanced medical education for better identification of infectious diseases such as hand, foot and mouth disease, which, despite its association with relatively specific clinical signs, requires careful physical examination of patients.
                        It is still unknown why so many severe cases were detected during the 2012 EV71 outbreak in Cambodia. However, seroepidemiologic studies in other settings have also confirmed widespread circulation before outbreaks (5,9). For combatting this pathogen, developments in vaccines and antiviral drugs are urgently needed.

                        Dr. Horwood is the deputy-head of the Virology Unit at the Institut Pasteur in Cambodia. His research interests include molecular characterization and epidemiology of emerging tropical infectious diseases.


                        This study was supported by the Second Health Sector Support Program, Ministry of Health of the Kingdom of Cambodia, and the Asian Development Bank.


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                        • Iwai M, Masaki A, Hasegawa S, Obara M, Horimoto E, Nakamura K, Genetic changes of coxsackievirus A16 and enterovirus 71 isolated from hand, foot, and mouth disease patients in Toyama, Japan between 1981 and 2007. Jpn J Infect Dis. 2009;62:254?9 .PubMed
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                        • Mizuta K, Aoki Y, Suto A, Ootani K, Katsushima N, Itagaki T, Cross-antigenicity among EV71 strains from different genogroups isolated in Yamagata, Japan, between 1990 and 2007. Vaccine. 2009;27:3153?8. DOIPubMed
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                        • Huang WC, Huang LM, Kao CL, Lu CY, Shao PL, Cheng AL, Seroprevalence of enterovirus 71 and no evidence of crossprotection of enterovirus 71 antibody against the other enteroviruses in kindergarten children in Taipei city. J Microbiol Immunol Infect. 2012;45:96?101. DOIPubMed



                        Technical Appendix

                        Suggested citation for this article: Horwood PF, Andronico A, Tarantola A, Salje H, Duong V, Mey C, et al. Seroepidemiology of human enterovirus 71 infection among children, Cambodia. Emerg Infect Dis. 2016 Jan [date cited].
                        DOI: 10.3201/eid2201.151323
                        Table of Contents ? Volume 22, Number 1?January 2016


                        • #13

                          Prohibitin plays a critical role in Enterovirus 71 neuropathogenesis

                          Issac Horng Khit Too,
                          Isabelle Bonne,
                          Eng Lee Tan,
                          Justin Jang Hann Chu,
                          Sylvie Alonso


                          Published: January 11, 2018
                          Author summary A close relative of poliovirus, Enterovirus 71 (EV71) causes Hand, Foot and Mouth Disease and has been associated with neurological complications in young children. The lack of effective therapeutics is largely due to our limited understanding of the mechanisms involved in EV71 neuropathogenesis. Here, using a proteomics approach, we have identified a unique panel of host proteins that were modulated during EV71 infection of motor-neuron cells, which are found at the neuromuscular junctions where EV71 enters the central nervous system. Among the candidate proteins, we focused our attention on prohibitin (PHB), a protein that is involved in multiple cellular pathways and the target of anti-cancer drug Rocaglamide (Roc-A). We demonstrated that cell surface-expressed PHB is involved in EV71 entry into neuronal cells specifically, while mitochondria-associated PHB is required for viral replication. Furthermore, Roc-A treatment of EV71-infected neuronal cells led to significantly lower virus yields. In vivo, EV71-infected mice treated with Roc-A survived longer than the vehicle-treated animals and had significantly lower virus titers in their spinal cord and brain. Together, our work uncovers PHB as the first host factor that is specifically involved in EV71 neuropathogenesis and a possible drug target to limit neurological complications.


                          A close relative of poliovirus, enterovirus 71 (EV71) is regarded as an important neurotropic virus of serious public health concern. EV71 causes Hand, Foot and Mouth Disease and has been associated with neurological complications in young children. Our limited understanding of the mechanisms involved in its neuropathogenesis has hampered the development of effective therapeutic options. Here, using a two-dimensional proteomics approach combined with mass spectrometry, we have identified a unique panel of host proteins that were differentially and dynamically modulated during EV71 infection of motor-neuron NSC-34 cells, which are found at the neuromuscular junctions where EV71 is believed to enter the central nervous system. Meta-analysis with previously published proteomics studies in neuroblastoma or muscle cell lines revealed minimal overlapping which suggests unique host-pathogen interactions in NSC-34 cells. Among the candidate proteins, we focused our attention on prohibitin (PHB), a protein that is involved in multiple cellular functions and the target of anti-cancer drug Rocaglamide (Roc-A). We demonstrated that cell surface-expressed PHB is involved in EV71 entry into neuronal cells specifically, while membrane-bound mitochondrial PHB associates with the virus replication complex and facilitates viral replication. Furthermore, Roc-A treatment of EV71-infected neuronal cells reduced significantly virus yields. However, the inhibitory effect of Roc-A on PHB in NSC-34 cells was not through blocking the CRAF/MEK/ERK pathway as previously reported. Instead, Roc-A treated NSC-34 cells had lower mitochondria-associated PHB and lower ATP levels that correlated with impaired mitochondria integrity. In vivo, EV71-infected mice treated with Roc-A survived longer than the vehicle-treated animals and had significantly lower virus loads in their spinal cord and brain, whereas virus titers in their limb muscles were comparable to controls. Together, this study uncovers PHB as the first host factor that is specifically involved in EV71 neuropathogenesis and a potential drug target to limit neurological complications...


                          • #14
                            Notes from the Field: Enterovirus A71 Neurologic Disease in Children ? Colorado, 2018

                            Weekly / September 14, 2018 / 67(36);1017?1018

                            Kevin Messacar, MD1,2,3; Alexis Burakoff, MD4,5; W. Allan Nix6; Shannon Rogers, MS6; M. Steven Oberste, PhD6; Susan I. Gerber, MD6; Emily Spence-Davizon, MPH5; Rachel Herlihy, MD5; Samuel R. Dominguez, MD, PhD1,3 (View author affiliations)View suggested citation

                            On May 10, 2018, the Colorado Department of Public Health and Environment (CDPHE) was notified by Children?s Hospital Colorado (CHCO) of an increase in pediatric cases of meningitis and encephalitis in which patients tested positive for enterovirus (EV). CDPHE surveillance data for May 2018 showed a 2.75-fold increase in encephalitis of unknown etiology compared with the 5-year (May 2013?2017) average; this coincided with a threefold rise in enterovirus/rhinovirus (EV/RV) detections from clinical testing at CHCO during the same period. Specimens from children with neurologic disease were tested by EV reverse transcription?polymerase chain reaction (RT-PCR) at CHCO and VP1 sequencing at CDC (1). As of August 26, 2018, EV-A71 was identified in 34 children with neurologic disease. This report describes the clinical, laboratory, and radiologic findings for the first 13 children identified with EV-A71 neurologic disease for whom complete information is available.
                            Patients with EV-A71 central nervous system (CNS) infection had symptom onset during March 10?June 5, 2018; median age was 13 months (range = 10 days?35 months); 11 were male. Twelve had meningitis, nine had encephalitis, and three had acute flaccid myelitis (AFM). All 13 children had fever and irritability; three developed lesions typical of hand, foot, and mouth disease. Neurologic signs included encephalopathy (seven), ataxia (seven), myoclonus (six), limb weakness (four), cranial nerve deficits (two), and seizures (one). Nine of 10 children with a cerebrospinal fluid (CSF) specimen analyzed had a pleocytosis (median white blood cell count = 106 cells/μL, range = 17?698 [normal = 0?5]). Six of eight children who had brain imaging results had abnormalities; five were in the brainstem, three in the cerebellum, and three in the spinal cord. All 13 children had EV-A71 identified in nasopharyngeal, pharyngeal, or rectal specimens. However, only two of 11 children whose CSF was tested had a specimen positive for enterovirus by pan-EV RT-PCR; one of two was available for typing and was identified as EV-A71. All 13 children were hospitalized (median = 5 days; range = 1?23 days), and four required intensive care. The three children who received an AFM diagnosis had residual limb weakness at discharge. All children survived.
                            EV-A71 can cause hand, foot, and mouth disease and neurologic disease, primarily among children aged <5 years (2,3). Common manifestations include a febrile illness with lesions on the palms, soles, oral mucous membranes, or perineum; and aseptic meningitis. Severe CNS EV-A71 infection can cause brainstem encephalitis leading to cardiopulmonary collapse and polio-like AFM (4). EV-A71 epidemics have occurred in the Asian-Pacific region since the late 1990s (5). Since the 1980s, the National Enterovirus Surveillance System has detected seasonal endemic EV-A71 activity in the United States; EV-A71 accounts for <1% of typed EVs (3). Limited, regional U.S. outbreaks have occurred sporadically in an unpredictable pattern; factors causing year-to-year circulation have not been identified (3,6). Peak U.S. circulation of EVs, including EV-A71, usually occurs during June?October (3,6). Although associated with neurologic disease, EV-A71 is uncommonly detected in CSF and is more frequently identified in respiratory and fecal specimens (7). In similar EV-A71 outbreaks in Colorado during 2003 and 2005, EV-A71 CNS infection was identified in 16 children (eight in each cluster); 11 children recovered fully, four had residual limb paralysis, and one child died (7). At this time, no other clusters of EV-A71 neurologic disease have been reported to CDC in 2018.
                            This investigation highlights the importance of testing nonsterile sites when CNS disease associated with EV is suspected and CSF is negative. Furthermore, health care providers should consider EV-A71 as an etiology when febrile patients display myoclonus, ataxia, or limb weakness. CDPHE has alerted Colorado health care providers to the EV-A71 outbreak and requested reports of EV meningitis and encephalitis, in addition to routine AFM surveillance.


                            Corresponding author: Samuel R. Dominguez,, 720-777-8883.


                            1Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado; 2Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado; 3Children?s Hospital Colorado, Aurora, Colorado; 4Epidemic Intelligence Service, CDC; 5Colorado Department of Public Health and the Environment, 6Division of Viral Diseases, CDC.


                            All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. M.S. Oberste has been issued the following patents: U.S. patent no. 7,435,539 for typing of human enteroviruses and U.S. patent no. 6,846,621 for typing of human enteroviruses. W.A. Nix and M.S. Oberste have been issued the following US patents: U.S. patent no. 7,714,122 for kits including VP1 and VP3 nucleic acid molecules for detecting and identifying enteroviruses; U.S. patent no. 7,247,457 for detection and identification of enteroviruses by seminested amplification of the enterovirus VP1 protein; U.S. patent no. 8,048,630; and U.S. patent no. 2,651,123 for methods and agents for detecting parechovirus. K. Messacar reports grants from National Institutes of Health NIAID grant 1K23AI128069-01, during the conduct of the study. No other potential conflicts of interest were disclosed.



                            1. Nix WA, Oberste MS, Pallansch MA. Sensitive, seminested PCR amplification of VP1 sequences for direct identification of all enterovirus serotypes from original clinical specimens. J Clin Microbiol 2006;44:2698?704. CrossRef PubMed
                            2. Ooi MH, Wong SC, Lewthwaite P, Cardosa MJ, Solomon T. Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol 2010;9:1097?105. CrossRef PubMed
                            3. Khetsuriani N, Lamonte-Fowlkes A, Oberst S, Pallansch MA. Enterovirus surveillance?United States, 1970?2005. MMWR Surveill Summ 2006;55(No. SS-8). PubMed
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                            Suggested citation for this article: Messacar K, Burakoff A, Nix WA, et al. Notes from the Field: Enterovirus A71 Neurologic Disease in Children ? Colorado, 2018. MMWR Morb Mortal Wkly Rep 2018;67:1017?1018. DOI:


                            • #15

                              Experts concern over virus Enterovirus 71 (Vietnam)
                              VNA Sunday, October 07, 2018 - 16:05:00

                              The reoccurence of virus Enterovirus 71 (EV71), a common cause of life-threatening illnesses for hand-foot-mouth (HFMD) patients, has made the disease dangerous and could easily spread into an outbreak. (Photo: VNA)

                              Hanoi (VNS/VNA) - The reoccurrence of virus Enterovirus 71 (EV71), a common cause of life-threatening illnesses for hand-foot-mouth (HFMD) patients, has made the disease dangerous and could easily spread into an outbreak, health experts have said.

                              Speaking at the recent online seminar on the abnormal development of the HFMD hosted by online newspaper Vietnamplus, health experts said all six deaths had tested positive for EV71.

                              HFMD caused by virus EV71 is likely to cause illnesses ranging from mild to serious with severe neurological and pulmonary complications, respiratory and heart failure that can lead to death. EV71 was the virus that caused HFMD outbreak in 2011 with 70,000 cases of infection and 150 deaths, they said.

                              Phan Trong Lan, Director of HCM City?s Pasteur Institute said the HFMD was at its peak with more than 53,000 infected patients in the first nine months of this year.

                              Although the number of infection decreased compared to the same period of last year, the amount of deaths rose.

                              In HCM City?s Children No1 Hospital, the number of patients hospitalised for the disease has increased five times in the past three weeks leaving the hospital overcrowded.

                              Hanoi-based Vietnam-Cuba Hospital has received eight to ten HFDM patients each day recently.

                              The number of patients with serious illness stayed high in HCM City, posing the risk of outbreaks if preventive measures were not taken.

                              Lan said most of the six dead children were due to the disease were treated at home rather than going to the hospitals when showing symptoms of infection.

                              He said HFMD was commonly caused by the Coxsackie virus (A16) and Enterovirus (EV17). A16 was mild while EV71 could cause neurological complications, which was five times higher than other types of virus caused by the disease.

                              In the outbreak in 2011, 85 percent of deaths were positive with the virus...