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Establishment of Asia-Pacific Network for Enterovirus Surveillance

Chiu ML, Luo ST, Chen YY, Chung WY, Duong V, Dussart P, et al.

Vaccine, 2020 01 03;38(1):1-9.
PMID: 31679864 DOI: 10.1016/j.vaccine.2019.09.111

Enteroviruses (EV), the major pathogens of hand, foot, and mouth disease (HFMD) and herpangina, affect millions of children each year. Most human enteroviruses cause self-limited infections except polioviruses, enterovirus A71 (EV-A71), enterovirus D68 (EV-D68), and several echoviruses (Echo) and coxsackieviruses (CV). Especially, EV-A71 has repeatedly caused large-scale outbreaks in the Asia-Pacific region since 1997. Some Asian countries have experienced cyclical outbreaks of severe EV-A71 infections and initiated development of EV-A71 vaccines. Five EV-A71 vaccine candidates have been clinically evaluated and three of them were approved for marketing in China. However, none of the China-approved products seek marketing approval in other countries. This situation supports a role for collaboration among Asian countries to facilitate clinical trials and licensure of EV-A71 vaccines. Additionally, enterovirus D68 outbreaks have been reported in the US and Taiwan currently and caused severe complications and deaths. Hence, an Asia-Pacific Network for Enterovirus Surveillance (APNES) has been established to estimate disease burden, understand virus evolution, and facilitate vaccine development through harmonizing laboratory diagnosis and data collection. Founded in 2017, the APNES is comprised of internationally recognized experts in the field of enterovirus in Asian countries working to raise awareness of this potentially fatal and debilitating disease. This article demonstrated the summaries of the first expert meeting, 2017 International Workshop on Enterovirus Surveillance and Vaccine Development, held by APNES in Taipei, Taiwan, March 2017.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology*
Fulltext Epidemic dynamics, interactions and predictability of enteroviruses associated with hand, foot and mouth disease in Japan

Takahashi S, Metcalf CJE, Arima Y, Fujimoto T, Shimizu H, Rogier van Doorn H, et al.

J R Soc Interface, 2018 09 12;15(146).
PMID: 30209044 DOI: 10.1098/rsif.2018.0507

Outbreaks of hand, foot and mouth disease have been documented in Japan since 1963. This disease is primarily caused by the two closely related serotypes of Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16). Here, we analyse Japanese virologic and syndromic surveillance time-series data from 1982 to 2015. As in some other countries in the Asia Pacific region, EV-A71 in Japan has a 3 year cyclical component, whereas CV-A16 is predominantly annual. We observe empirical signatures of an inhibitory interaction between the serotypes; virologic lines of evidence suggest they may indeed interact immunologically. We fit the time series to mechanistic epidemiological models: as a first-order effect, we find the data consistent with single-serotype susceptible-infected-recovered dynamics. We then extend the modelling to incorporate an inhibitory interaction between serotypes. Our results suggest the existence of a transient cross-protection and possible asymmetry in its strength such that CV-A16 serves as a stronger forcing on EV-A71. Allowing for asymmetry yields accurate out-of-sample predictions and the directionality of this effect is consistent with the virologic literature. Confirmation of these hypothesized interactions would have important implications for understanding enterovirus epidemiology and informing vaccine development. Our results highlight the general implication that even subtle interactions could have qualitative impacts on epidemic dynamics and predictability.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology*
Fulltext Genetic characterization of Enterovirus 71 strains circulating in Vietnam in 2012

Donato C, Hoi le T, Hoa NT, Hoa TM, Van Duyet L, Dieu Ngan TT, et al.

Virology, 2016 08;495:1-9.
PMID: 27148893 DOI: 10.1016/j.virol.2016.04.026

BACKGROUND: Enterovirus 71 subgenogroup C4 caused the largest outbreak of Hand, Foot and Mouth Disease (HFMD) in Vietnam during 2011-2012, resulting in over 200,000 hospitalisations and 207 fatalities.
METHODS: A total of 1917 samples with adequate volume for RT-PCR analysis were collected from patients hospitalised with HFMD throughout Vietnam and 637 were positive for EV71. VP1 gene (n=87) and complete genome (n=9) sequencing was performed. Maximum-likelihood phylogenetic analysis was performed to characterise the B5, C4 and C5 strains detected.
RESULTS: Sequence analyses revealed that the dominant subgenogroup associated with the 2012 outbreak was C4, with B5 and C5 strains representing a small proportion of these cases.
CONCLUSIONS: Numerous countries in the region including Malaysia, Taiwan and China have a large influence on strain diversity in Vietnam and understanding the transmission of EV71 throughout Southeast Asia is vital to inform preventative public health measures and vaccine development efforts.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology
Fulltext Cyclical Patterns of Hand, Foot and Mouth Disease Caused by Enterovirus A71 in Malaysia

NikNadia N, Sam IC, Rampal S, WanNorAmalina W, NurAtifah G, Verasahib K, et al.

PLoS Negl Trop Dis, 2016 Mar;10(3):e0004562.
PMID: 27010319 DOI: 10.1371/journal.pntd.0004562

Enterovirus A71 (EV-A71) is an important emerging pathogen causing large epidemics of hand, foot and mouth disease (HFMD) in children. In Malaysia, since the first EV-A71 epidemic in 1997, recurrent cyclical epidemics have occurred every 2-3 years for reasons that remain unclear. We hypothesize that this cyclical pattern is due to changes in population immunity in children (measured as seroprevalence). Neutralizing antibody titers against EV-A71 were measured in 2,141 residual serum samples collected from children ≤12 years old between 1995 and 2012 to determine the seroprevalence of EV-A71. Reported national HFMD incidence was highest in children <2 years, and decreased with age; in support of this, EV-A71 seroprevalence was significantly associated with age, indicating greater susceptibility in younger children. EV-A71 epidemics are also characterized by peaks of increased genetic diversity, often with genotype changes. Cross-sectional time series analysis was used to model the association between EV-A71 epidemic periods and EV-A71 seroprevalence adjusting for age and climatic variables (temperature, rainfall, rain days and ultraviolet radiance). A 10% increase in absolute monthly EV-A71 seroprevalence was associated with a 45% higher odds of an epidemic (adjusted odds ratio, aOR1.45; 95% CI 1.24-1.69; P<0.001). Every 10% decrease in seroprevalence between preceding and current months was associated with a 16% higher odds of an epidemic (aOR = 1.16; CI 1.01-1.34 P<0.034). In summary, the 2-3 year cyclical pattern of EV-A71 epidemics in Malaysia is mainly due to the fall of population immunity accompanying the accumulation of susceptible children between epidemics. This study will impact the future planning, timing and target populations for vaccine programs.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology*
Fulltext Phylodynamics of Enterovirus A71-Associated Hand, Foot, and Mouth Disease in Viet Nam

Geoghegan JL, Tan le V, Kühnert D, Halpin RA, Lin X, Simenauer A, et al.

J Virol, 2015 Sep;89(17):8871-9.
PMID: 26085170 DOI: 10.1128/JVI.00706-15

Enterovirus A71 (EV-A71) is a major cause of hand, foot, and mouth disease (HFMD) and is particularly prevalent in parts of Southeast Asia, affecting thousands of children and infants each year. Revealing the evolutionary and epidemiological dynamics of EV-A71 through time and space is central to understanding its outbreak potential. We generated the full genome sequences of 200 EV-A71 strains sampled from various locations in Viet Nam between 2011 and 2013 and used these sequence data to determine the evolutionary history and phylodynamics of EV-A71 in Viet Nam, providing estimates of the effective reproduction number (Re) of the infection through time. In addition, we described the phylogeography of EV-A71 throughout Southeast Asia, documenting patterns of viral gene flow. Accordingly, our analysis reveals that a rapid genogroup switch from C4 to B5 likely took place during 2012 in Viet Nam. We show that the Re of subgenogroup C4 decreased during the time frame of sampling, whereas that of B5 increased and remained >1 at the end of 2013, corresponding to a rise in B5 prevalence. Our study reveals that the subgenogroup B5 virus that emerged into Viet Nam is closely related to variants that were responsible for large epidemics in Malaysia and Taiwan and therefore extends our knowledge regarding its associated area of endemicity. Subgenogroup B5 evidently has the potential to cause more widespread outbreaks across Southeast Asia.
IMPORTANCE: EV-A71 is one of many viruses that cause HFMD, a common syndrome that largely affects infants and children. HFMD usually causes only mild illness with no long-term consequences. Occasionally, however, severe infection may arise, especially in very young children, causing neurological complications and even death. EV-A71 is highly contagious and is associated with the most severe HFMD cases, with large and frequent epidemics of the virus recorded worldwide. Although major advances have been made in the development of a potential EV-A71 vaccine, there is no current prevention and little is known about the patterns and dynamics of EV-A71 spread. In this study, we utilize full-length genome sequence data obtained from HFMD patients in Viet Nam, a geographical region where the disease has been endemic since 2003, to characterize the phylodynamics of this important emerging virus.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology*
Temporal and spatial mapping of hand, foot and mouth disease in Sarawak, Malaysia

Sham NM, Krishnarajah I, Ibrahim NA, Lye MS

Geospat Health, 2014 May;8(2):503-7.
PMID: 24893027

Hand, foot and mouth disease (HFMD) is endemic in Sarawak, Malaysia. In this study, a geographical information system (GIS) was used to investigate the relationship between the reported HFMD cases and the spatial patterns in 11 districts of Sarawak from 2006 to 2012. Within this 7-years period, the highest number of reported HFMD cases occurred in 2006, followed by 2012, 2008, 2009, 2007, 2010 and 2011, in descending order. However, while there was no significant distribution pattern or clustering in the first part of the study period (2006 to 2011) based on Moran's I statistic, spatial autocorrelation (P = 0.068) was observed in 2012.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology*
[Hand, foot and mouth disease--more than a harmless "childhood disease"]

Stock I

Med Monatsschr Pharm, 2014 Jan;37(1):4-10; quiz 11-2.
PMID: 24490433

Hand, foot and mouth disease (HFMD) is a highly contagious, world-wide distributed viral illness that affects predominantly children. It is caused by several enteroviruses, such as coxsackieviruses A6, A10, A16 and enterovirus 71. In most cases, HFMD follows a benign and self-limiting course. After an incubation period of 3 to 10 days, fever and sore throat, the first symptoms of the disease, appear. A few days later, maculopapular or vesicular eruptions form on the palms and soles as well as in the oral cavity. Since the year 2000, several large HFMD outbreaks have been reported in many Asian regions such as China, Malaysia and Vietnam. In some of these outbreaks, high incidences of severe progressive HFMD forms with some fatalities were observed. Such diseases have been caused primarily by enterovirus 71 strains and were characterized frequently by sudden onset of fever, encephalitis/meningitis and severe respiratory symptoms such as pulmonary edema. Further severe neurological and cardiac complications have also been observed during these outbreaks. Recently, some HFMD outbreaks caused by the coxsackievirus A6 have been reported in several parts of the world. These illnesses also affected adults and were characterized by more severe symptoms of "classical" HFMD. In addition, outbreaks of coxsackievirus-A6-associated HFMD in many countries were associated with onychomadesis, with the loss of nails occurring up to two months after initial symptoms. Treatment of "classical" HFMD is usually symptomatic, a generally recommended antiviral therapy does not exist. In severe HFMD cases, suitable treatment also encompasses mechanical ventilation, as well as the additional application of antiviral agents such as ribavirin. In the last years, several novel agents with good in vitro and in vivo activity against enteroviruses have been developed. A vaccine against HFMD is not yet available.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology
Fulltext Cell and tissue tropism of enterovirus 71 and other enteroviruses infections

Lin JY, Shih SR

J Biomed Sci, 2014;21:18.
PMID: 24602216 DOI: 10.1186/1423-0127-21-18

Enterovirus 71 (EV71) is a member of Picornaviridae that causes mild and self-limiting hand, foot, and mouth disease (HFMD). However, EV71 infections can progress to polio-like paralysis, neurogenic pulmonary edema, and fatal encephalitis in infants and young children. Large EV71 outbreaks have been reported in Taiwan, China, Japan, Malaysia, Singapore, and Australia. This virus is considered a critical emerging public health threat. EV71 is an important crucial neurotropic enterovirus for which there is currently no effective antiviral drug or vaccine. The mechanism by which EV71 causes severe central nervous system complications remains unclear. The interaction between the virus and the host is vital for viral replication, virulence, and pathogenicity. SCARB2 or PSGL-1 receptor binding is the first step in the development of viral infections, and viral factors (e.g., 5' UTR, VP1, 3C, 3D, 3' UTR), host factors and environments (e.g., ITAFs, type I IFN) are also involved in viral infections. The tissue tropism and pathogenesis of viruses are determined by a combination of several factors. This review article provides a summary of host and virus factors affecting cell and tissue tropism and the pathogenesis of enteroviruses.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology*
Outbreaks of foot-and-mouth disease in Peninsular Malaysia from 2001 to 2007

Ramanoon SZ, Robertson ID, Edwards J, Hassan L, Isa KM

Trop Anim Health Prod, 2013 Feb;45(2):373-7.
PMID: 22826115 DOI: 10.1007/s11250-012-0226-x

This is a retrospective study of the outbreaks of foot-and-mouth disease (FMD) in Peninsular Malaysia between 2001 and May 2007. In total, 270 outbreaks of FMD were recorded. Serotype O virus (89.95 %) and serotype A (7.7 %) had caused the outbreaks. Significant differences on the occurrence of FMD were found between the years (t = 5.73, P = 0.000, df = 11), months (t = 4.7, P = 0.000, df = 11), monsoon season (t = 2.63, P = 0.025, df = 10) and states (t = 4.84, P = 0.001, df = 10). A peak of outbreaks observed in 2003 could be due to increased animal movement and the other peak in 2006 could be due to a compromised FMD control activities due to activities on the eradication of highly pathogenic avian influenza. Cattle (86 % of outbreaks) suffered the most. However, no difference in disease occurrence between species was observed. The populations of cattle (r = 0.672, P = 0.023) and sheep (r = 0.678, P = 0.022) were significantly correlated with occurrence of FMD. Movement of animals (66 % of outbreaks) was the main source for outbreaks. A combination of control measures were implemented during outbreaks. In conclusion, the findings of this study show that FMD is endemic in Peninsular Malaysia, and information gained could be used to improve the existing control strategy.

Matched MeSH terms: Foot-and-Mouth Disease/epidemiology*
Fulltext Molecular epidemiology of coxsackievirus A16: intratype and prevalent intertype recombination identified

Chen X, Tan X, Li J, Jin Y, Gong L, Hong M, et al.

PLoS One, 2013;8(12):e82861.
PMID: 24340064 DOI: 10.1371/journal.pone.0082861

Coxsackievirus A16 (CVA16) is responsible for nearly 50% of all the conﬁrmed hand, foot, and mouth disease (HFMD) cases in mainland China, sometimes it could also cause severe complications, and even death. To clarify the genetic characteristics and the epidemic patterns of CVA16 in mainland China, comprehensive bioinfomatics analyses were performed by using 35 CVA16 whole genome sequences from 1998 to 2011, 593 complete CVA16 VP1 sequences from 1981 to 2011, and prototype strains of human enterovirus species A (EV-A). Analysis on complete VP1 sequences revealed that subgenotypes B1a and B1b were prevalent strains and have been co-circulating in many Asian countries since 2000, especially in mainland China for at least 13 years. While the prevalence of subgenotype B1c (totally 20 strains) was much limited, only found in Malaysia from 2005 to 2007 and in France in 2010. Genotype B2 only caused epidemic in Japan and Malaysia from 1981 to 2000. Both subgenotypes B1a and B1b were potential recombinant viruses containing sequences from other EV-A donors in the 5'-untranslated region and P2, P3 non-structural protein encoding regions.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology
Fulltext Molecular epidemiology of enterovirus 71 infection in the central region of Taiwan from 2002 to 2012

Wu WH, Kuo TC, Lin YT, Huang SW, Liu HF, Wang J, et al.

PLoS One, 2013;8(12):e83711.
PMID: 24391812 DOI: 10.1371/journal.pone.0083711

Enterovirus 71 (EV71), a causative agent of hand, foot, and mouth disease can be classified into three genotypes and many subtypes. The objectives of this study were to conduct a molecular epidemiological study of EV71 in the central region of Taiwan from 2002-2012 and to test the hypothesis that whether the alternative appearance of different EV71 subtypes in Taiwan is due to transmission from neighboring countries or from re-emergence of pre-existing local strains. We selected 174 EV71 isolates and used reverse transcription-polymerase chain reaction to amplify their VP1 region for DNA sequencing. Phylogenetic analyses were conducted using Neighbor-Joining, Maximum Likelihood and Bayesian methods. We found that the major subtypes of EV71 in Taiwan were B4 for 2002 epidemic, C4 for 2004-2005 epidemic, B5 for 2008-2009 epidemic, C4 for 2010 epidemic and B5 for 2011-2012 epidemic. Phylogenetic analysis demonstrated that the 2002 and 2008 epidemics were associated with EV71 from Malaysia and Singapore; while both 2010 and 2011-2012 epidemics originated from different regions of mainland China including Shanghai, Henan, Xiamen and Gong-Dong. Furthermore, minor strains have been identified in each epidemic and some of them were correlated with the subsequent outbreaks. Therefore, the EV71 infection in Taiwan may originate from pre-existing minor strains or from other regions in Asia including mainland China. In addition, 101 EV71 isolates were selected for the detection of new recombinant strains using the nucleotide sequences spanning the VP1-2A-2B region. No new recombinant strain was found. Analysis of clinical manifestations showed that patients infected with C4 had significantly higher rates of pharyngeal vesicles or ulcers than patients infected with B5. This is the first study demonstrating that different EV 71 genotypes may have different clinical manifestations and the association of EV71 infections between Taiwan and mainland China.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology*
In enterovirus 71 encephalitis with cardio-respiratory compromise, elevated interleukin 1β, interleukin 1 receptor antagonist, and granulocyte colony-stimulating factor levels are markers of poor prognosis

Griffiths MJ, Ooi MH, Wong SC, Mohan A, Podin Y, Perera D, et al.

J Infect Dis, 2012 Sep 15;206(6):881-92.
PMID: 22829643 DOI: 10.1093/infdis/jis446

BACKGROUND: Enterovirus 71 (EV71) causes large outbreaks of hand, foot, and mouth disease (HFMD), with severe neurological complications and cardio-respiratory compromise, but the pathogenesis is poorly understood.
METHODS: We measured levels of 30 chemokines and cytokines in serum and cerebrospinal fluid (CSF) samples from Malaysian children hospitalized with EV71 infection (n = 88), comprising uncomplicated HFMD (n = 47), meningitis (n = 8), acute flaccid paralysis (n = 1), encephalitis (n = 21), and encephalitis with cardiorespiratory compromise (n = 11). Four of the latter patients died.
RESULTS: Both pro-inflammatory and anti-inflammatory mediator levels were elevated, with different patterns of mediator abundance in the CSF and vascular compartments. Serum concentrations of interleukin 1β (IL-1β), interleukin 1 receptor antagonist (IL-1Ra), and granulocyte colony-stimulating factor (G-CSF) were raised significantly in patients who developed cardio-respiratory compromise (P = .013, P = .004, and P < .001, respectively). Serum IL-1Ra and G-CSF levels were also significantly elevated in patients who died, with a serum G-CSF to interleukin 5 ratio of >100 at admission being the most accurate prognostic marker for death (P < .001; accuracy, 85.5%; sensitivity, 100%; specificity, 84.7%).
CONCLUSIONS: Given that IL-1β has a negative inotropic action on the heart, and that both its natural antagonist, IL-1Ra, and G-CSF are being assessed as treatments for acute cardiac impairment, the findings suggest we have identified functional markers of EV71-related cardiac dysfunction and potential treatment options.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology
Fulltext Comparative genetic analysis of VP4, VP1 and 3D gene regions of enterovirus 71 and coxsackievirus A16 circulating in Malaysia between 1997-2008

Chan YF, Wee KL, Chiam CW, Khor CS, Chan SY, Amalina W MZ, et al.

Trop Biomed, 2012 Sep;29(3):451-66.
PMID: 23018509 MyJurnal

Three genomic regions, VP4 capsid, VP1 capsid and 3D RNA polymerase of human enterovirus 71 (EV-71) and coxsackievirus A16 (CV-A16) were sequenced to understand the evolution of these viruses in Malaysia. A total of 42 EV-71 and 36 CV-A16 isolates from 1997- 2008 were sequenced. Despite the presence of many EV-71 subgenotypes worldwide, only subgenotypes B3, B4, B5, C1 and C2 were present in Malaysia. Importation of other subgenotypes such as C3, C4/D and C5 from other countries was infrequent. For CV-A16, the earlier subgenotype B1 was replaced by subgenotypes B2a and the recent B2c. Subgenotype B2a was present throughout the study while B2c only emerged in 2005. No genetic signatures could be attributed to viral virulence suggesting that host factors have a major role in determining the outcome of infection. Only three EV-71 B3 isolates showed non-consistent phylogeny in the 3D RNA polymerase region which indicated occurrence of recombination in EV-71. High genetic diversity was observed in the Malaysian EV-71 but Malaysian CV-A16 showed low genetic diversity in the three genomic regions sequenced. EV-71 showed strong purifying selection, but that occurred to a lesser extent in CV-A16.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology
Hand foot and mouth disease due to enterovirus 71 in Malaysia

Chua KB, Kasri AR

Virol Sin, 2011 Aug;26(4):221-8.
PMID: 21847753 DOI: 10.1007/s12250-011-3195-8

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.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology*
Phylogeography of foot-and-mouth disease virus types O and A in Malaysia and surrounding countries

Abdul-Hamid NF, Hussein NM, Wadsworth J, Radford AD, Knowles NJ, King DP

Infect Genet Evol, 2011 Mar;11(2):320-8.
PMID: 21093614 DOI: 10.1016/j.meegid.2010.11.003

Foot-and-mouth disease (FMD) is endemic in the countries of mainland Southeast Asia where it represents a major obstacle to the development of productive animal industries. The aim of this study was to use genetic data to determine the distribution of FMD virus (FMDV) lineages in the Southeast Asia region, and in particular identify possible sources of FMDV causing outbreaks in Malaysia. Complete VP1 sequences, obtained from 214 samples collected between 2000 and 2009, from FMD outbreaks in six Southeast Asian countries, were compared with sequences previously reported. Phylogenetic analysis of these sequences showed that there were two patterns of FMDV distribution in Malaysia. Firstly, for some lineages (O/SEA/Mya98 and serotype A), outbreaks occurred every year in the country and did not appear to persist, suggesting that these incursions were quickly eradicated. Furthermore, for these lineages FMD viruses in Malaysia were closely related to those from neighbouring countries, demonstrating the close epidemiological links between countries in the region. In contrast, for O/ME-SA/PanAsia lineage, viruses were introduced and remained to cause outbreaks in subsequent years. In particular, the recent incursion and maintenance of the PanAsia-2 sublineage into Malaysia appears to be unique and independent from other outbreaks in the region. This study is the first characterisation of FMDV in Malaysia and provides evidence for different epidemiological sources of virus introduction into the country.

Matched MeSH terms: Foot-and-Mouth Disease/epidemiology*
Molecular characterization of serotype A foot-and-mouth disease viruses circulating in Vietnam in 2009

Le VP, Nguyen T, Lee KN, Ko YJ, Lee HS, Nguyen VC, et al.

Vet Microbiol, 2010 Jul 29;144(1-2):58-66.
PMID: 20097490 DOI: 10.1016/j.vetmic.2009.12.033

Foot-and-mouth disease (FMD) is a major cause of endemic outbreaks in Vietnam in recent years. In this work, six serotype A foot-and-mouth disease viruses (FMDV), collected from endemic outbreaks during January and February of 2009 in four different provinces in Vietnam, were genetically characterized for their complete genome sequences. Genetic analysis based on the complete viral genome sequence indicated that they were closely related to each other and shared 99.0-99.8% amino acid (aa) identity. Genetic and deduced aa analysis of the capsid coding gene VP1 showed that the six Vietnamese strains were all classified into the genotype IX from a total of 10 major genotypes worldwide, sharing 98.1-100% aa identity each other. They were most closely related to the type A strains recently isolated in Laos (A/LAO/36/2003, A/LAO/1/2006, A/LAO/6/2006, A/LAO/7/2006, and A/LAO/8/2006), Thailand (A/TAI/2/1997 and A/TAI/118/1987), and Malaysia (A/MAY/2/2002), sharing 88.3-95.5% nucleotide (nt) identities. In contrast, Vietnamese type A strains showed low nt identities with the two old type A FMDVs, isolated in 1960 in Thailand (a15thailand iso43) and in 1975 in the Philippines (aphilippines iso50), ranging from 77.3 to 80.9% nt identity. A multiple alignment based on the deduced amino acid sequences of the capsid VP1 coding gene of type A FMDV revealed three amino acid substitutions between Vietnamese strains and the strains of other Southeast Asian countries (Laos, Thailand, Malaysia, and the Philippines). Alanine was replaced by valine at residue 24, asparagine by arginine at residue 85, and serine by threonine at residue 196. Furthermore, type A FMDV strains recently isolated in Vietnam, Laos, Thailand, and Malaysia all have one amino acid deletion at residue 140 of the capsid VP1 protein compared with the two old type A FMDV strains from Thailand and the Philippines as well as most other type A representatives worldwide. This article is the first to report on the comprehensive genetic characterization of type A FMDV circulating in Vietnam.

Matched MeSH terms: Foot-and-Mouth Disease/epidemiology
Fulltext Identification and validation of clinical predictors for the risk of neurological involvement in children with hand, foot, and mouth disease in Sarawak

Ooi MH, Wong SC, Mohan A, Podin Y, Perera D, Clear D, et al.

BMC Infect Dis, 2009 Jan 19;9:3.
PMID: 19152683 DOI: 10.1186/1471-2334-9-3

BACKGROUND: Human enterovirus 71 (HEV71) can cause Hand, foot, and mouth disease (HFMD) with neurological complications, which may rapidly progress to fulminant cardiorespiratory failure, and death. Early recognition of children at risk is the key to reduce acute mortality and morbidity.
METHODS: We examined data collected through a prospective clinical study of HFMD conducted between 2000 and 2006 that included 3 distinct outbreaks of HEV71 to identify risk factors associated with neurological involvement in children with HFMD.
RESULTS: Total duration of fever >or= 3 days, peak temperature >or= 38.5 degrees C and history of lethargy were identified as independent risk factors for neurological involvement (evident by CSF pleocytosis) in the analysis of 725 children admitted during the first phase of the study. When they were validated in the second phase of the study, two or more (>or= 2) risk factors were present in 162 (65%) of 250 children with CSF pleocytosis compared with 56 (30%) of 186 children with no CSF pleocytosis (OR 4.27, 95% CI2.79-6.56, p < 0.0001). The usefulness of the three risk factors in identifying children with CSF pleocytosis on hospital admission during the second phase of the study was also tested. Peak temperature >or= 38.5 degrees C and history of lethargy had the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 28%(48/174), 89%(125/140), 76%(48/63) and 50%(125/251), respectively in predicting CSF pleocytosis in children that were seen within the first 2 days of febrile illness. For those presented on the 3rd or later day of febrile illness, the sensitivity, specificity, PPV and NPV of >or= 2 risk factors predictive of CSF pleocytosis were 75%(57/76), 59%(27/46), 75%(57/76) and 59%(27/46), respectively.
CONCLUSION: Three readily elicited clinical risk factors were identified to help detect children at risk of neurological involvement. These risk factors may serve as a guide to clinicians to decide the need for hospitalization and further investigation, including cerebrospinal fluid examination, and close monitoring for disease progression in children with HFMD.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology
Genetic diversity of enterovirus 71 isolated from cases of hand, foot and mouth disease in the 1997, 2000 and 2005 outbreaks, Peninsular Malaysia

Chua KB, Chua BH, Lee CS, Chem YK, Ismail N, Kiyu A, et al.

Malays J Pathol, 2007 Dec;29(2):69-78.
PMID: 19108398

All known field isolates of enterovirus 71 (EV71) can be divided into three distinct genogroups (A, B, C) and 10 subgenogroups (A, B1-5, C1-4) based on VP1 gene sequences. We examined VP1 gene sequences of 10, 12 and 11 EV71 strains isolated in peninsular Malaysia during the outbreaks of hand, foot and mouth disease in 1997, 2000 and 2005 respectively. Four EV71 strains isolated in the hand, foot and mouth disease outbreak of 2006 in Sarawak (Malaysian Borneo) were included to describe their genetic relationship. Four subgenogroups (C1, C2, B3 and B4) of EV71 co-circulated and caused the outbreak of hand, foot and mouth disease in peninsular Malaysia in 1997. Two subgenogroups (C1 and B4) were noted to cause the outbreak in 2000. In the 2005 outbreak, besides EV71 strains of subgenogroup C1, EV71 strains belonged to subgenogroup B5 were isolated but formed a cluster which was distinct from EV71 strains of the subgenogroup 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 subgenogroup B5. Phylogenetic analysis of the VP1 gene sequences showed that the four Sarawak EV71 isolates belonged to the same cluster as the EV71 strains that were isolated in peninsular Malaysia as early as May 2005. The data suggested that the EV71 strains causing the outbreak in Sarawak could have originated from peninsular Malaysia.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology
Fulltext Epidemiologic and virologic investigation of hand, foot, and mouth disease, southern Vietnam, 2005

Van Tu P, Thao NTT, Perera D, Truong KH, Tien NTK, Thuong TC, et al.

Emerg Infect Dis, 2007 Nov;13(11):1733-41.
PMID: 18217559 DOI: 10.3201/eid1311.070632

During 2005, 764 children were brought to a large children's hospital in Ho Chi Minh City, Vietnam, with a diagnosis of hand, foot, and mouth disease. All enrolled children had specimens (vesicle fluid, stool, throat swab) collected for enterovirus isolation by cell culture. An enterovirus was isolated from 411 (53.8%) of the specimens: 173 (42.1%) isolates were identified as human enterovirus 71 (HEV71) and 214 (52.1%) as coxsackievirus A16. Of the identified HEV71 infections, 51 (29.5%) were complicated by acute neurologic disease and 3 (1.7%) were fatal. HEV71 was isolated throughout the year, with a period of higher prevalence in October-November. Phylogenetic analysis of 23 HEV71 isolates showed that during the first half of 2005, viruses belonging to 3 subgenogroups, C1, C4, and a previously undescribed subgenogroup, C5, cocirculated in southern Vietnam. In the second half of the year, viruses belonging to subgenogroup C5 predominated during a period of higher HEV71 activity.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology*
Evaluation of different clinical sample types in diagnosis of human enterovirus 71-associated hand-foot-and-mouth disease

Ooi MH, Solomon T, Podin Y, Mohan A, Akin W, Yusuf MA, et al.

J Clin Microbiol, 2007 Jun;45(6):1858-66.
PMID: 17446325

Human enterovirus 71 and coxsackievirus A16 are important causes of hand-foot-and-mouth disease (HFMD). Like other enteroviruses, they can be isolated from a range of sterile and nonsterile sites, but which clinical sample, or combination of samples, is the most useful for laboratory diagnosis of HFMD is not clear. We attempted virus culture for 2,916 samples from 628 of 725 children with HFMD studied over a 3 1/2-year period, which included two large outbreaks. Overall, throat swabs were the single most useful specimen, being positive for any enterovirus for 288 (49%) of 592 patients with a full set of samples. Vesicle swabs were positive for 169 (48%) of 333 patients with vesicles, the yield being greater if two or more vesicles were swabbed. The combination of throat plus vesicle swabs enabled the identification of virus for 224 (67%) of the 333 patients with vesicles; for this patient group, just 27 (8%) extra patients were diagnosed when rectal and ulcer swabs were added. Of 259 patients without vesicles, use of the combination of throat plus rectal swab identified virus for 138 (53%). For 60 patients, virus was isolated from both vesicle and rectal swabs, but for 12 (20%) of these, the isolates differed. Such discordance occurred for just 11 (10%) of 112 patients with virus isolated from vesicle and throat swabs. During large HFMD outbreaks, we suggest collecting swabs from the throat plus one other site: vesicles, if these are present (at least two should be swabbed), or the rectum if there are no vesicles. Vesicle swabs give a high diagnostic yield, with the added advantage of being from a sterile site.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology

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