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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*; Hand, Foot and Mouth Disease/virology*
Molecular epidemiology of enterovirus 71 infection in the Western Pacific Region

Shimizu H, Utama A, Onnimala N, Li C, Li-Bi Z, Yu-Jie M, et al.

Pediatr Int, 2004 Apr;46(2):231-5.
PMID: 15056257

Recently, there have been large outbreaks of hand, foot and mouth disease (HFMD) mainly caused by enterovirus 71 (EV71) associated with severe neurological diseases in the Western Pacific Region (WPR). To monitor the realtime trend of EV71 transmission throughout the WPR, the authors conducted a molecular epidemiological analysis of EV71 infection.

Matched MeSH terms: Hand, Foot and Mouth Disease/epidemiology*; Hand, Foot and Mouth Disease/virology
Genetic and immunologic relationships between vaccine and field strains for vaccine selection of type A foot-and-mouth disease virus circulating in East Asia

Lee SY, Park ME, Kim RH, Ko MK, Lee KN, Kim SM, et al.

Vaccine, 2015 Jan 29;33(5):664-9.
PMID: 25528521 DOI: 10.1016/j.vaccine.2014.12.007

Of the seven known serotypes of foot-and-mouth disease virus (FMDV), type A has the most diverse variations. Genetic variations also occur frequently at VP1, VP2, VP3, and VP4 because these proteins constitute the viral capsid. The structural proteins of FMDV, which are closely related to immunologic correlations, are the most easily analyzed because they have highly accessible information. In this study we analyzed the type A vaccine viruses by alignment of available sequences in order to find appropriate vaccine strains. The matching rate of ASIA topotype-specific sites (20 amino acids) located on the viral surface, which are mainly VP1 and VP2, was highly related to immunologic reactivity. Among the available vaccines analyzed in this study, we suggest that A Malaysia 97 could be used as a vaccine virus as it has the highest genetic similarity and immunologic aspects to field strains originating in East Asia.

Matched MeSH terms: Foot-and-Mouth Disease/immunology*; Foot-and-Mouth Disease/virology*; Foot-and-Mouth Disease Virus/classification; Foot-and-Mouth Disease Virus/genetics*; Foot-and-Mouth Disease Virus/immunology*; Foot-and-Mouth Disease Virus/isolation & purification
Strategy for the control of foot-and-mouth disease in Southeast Asia (SEAFMD)

Edwards JR

Dev Biol (Basel), 2004;119:423-31.
PMID: 15742655

The OIE Southeast Asia Foot-and-Mouth Disease Campaign (SEAFMD) involves the coordinated control of foot-and-mouth disease by eight of the ASEAN countries. A long term vision for SEAFMD has been developed and the core element is a progressive zoning approach to the control and eradication of FMD in the region. This paper describes the current status of FMD in Southeast Asia and progress towards achievement of OIE free zone status for FMD in parts of the Philippines and Malaysia and the initiation of the Malaysia-Thailand-Myanmar (MTM) Peninsular Campaign for FMD Freedom. In mainland Southeast Asia, the progressive zoning approach involves several sub-regional groups working in parallel to oversee the epidemiological and economic studies required to determine the feasibility of the approach. Areas involved include the Lower Mekong Basin, Upper Mekong Basin, parts of Myanmar and the Red River Delta of Vietnam. The paper describes the current usage of vaccines for FMD in Southeast Asia and provides recommendations for their supply and use in the new regional initiatives.

Matched MeSH terms: Foot-and-Mouth Disease/economics; Foot-and-Mouth Disease/epidemiology; Foot-and-Mouth Disease/prevention & control*
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/blood; Hand, Foot and Mouth Disease/epidemiology*; Hand, Foot and Mouth Disease/virology*
Sequence analysis of recent Indian isolates of foot-and-mouth disease virus serotypes O, A and Asia 1 from clinical materials

Muthuchelvan D, Venkataramanan R, Hemadri D, Sanyal A, Tosh C

Acta Virol., 2001 Jun;45(3):159-67.
PMID: 11774894

Partial nucleotide sequences of 1D gene of 38 isolates of foot-and-mouth disease virus (FMDV) of serotypes O, A and Asia 1 originating from various parts of India were determined. Field materials were subjected straight to RNA extraction, reverse transcription - PCR (RT-PCR) and sequencing. Also 3 FMDV vaccine strains, IND R2/75 (serotype O), IND 63/72 (serotype Asia 1) and IND 17/77 (serotype A) were included in the analysis. The seqences were compared mutually as well as with available corresponding sequences of other FMDV isolates, and their phylogenetic relationships were calculated. The deduced amino acid sequences showed that the serotype O isolates were relatively conserved as compared to serotype Asia 1 or A isolates from India. In phylogenetic analysis, the serotype O viruses clustered in two genotypes, one including the European vaccine strain (O1/K) and the other represented by the isolates from Bangladesh, India, Nepal and Turkey. The serotype Asia 1 viruses clustered in two groups of single genotype where the prototype strain from Pakistan (PAK 1/54) formed one group and the other was formed by the isolates from Bangladesh, Bhutan, India, Israel and Nepal. In serotype A viruses three well-differentiated genotypes were observed. The isolates from Azerbaijan, Bangladesh, Malaysia and India formed the first genotype. The second genotype was formed by isolates from Iran, Saudi Arabia and Turkey, while two recent Iranian isolates represented the third genotype. In India, the prevalence of at least one genotype could be identified in each serotype. This evolutionary clustering of isolates from the neighbor countries is not surprising, since these countries share border with India. The genetic relatedness between sequences of isolates from India and those from distant places is indicative of spread of the virus between the countries. Of importance is the fact that clinical materials proved useful for rapid generation of sequences and subsequent studying of molecular epidemiology of the disease.

Matched MeSH terms: Foot-and-Mouth Disease Virus/classification; Foot-and-Mouth Disease Virus/genetics*; Foot-and-Mouth Disease Virus/isolation & purification
A 12-residue epitope displayed on phage T7 reacts strongly with antibodies against foot-and-mouth disease virus

Wong CL, Yong CY, Muhamad A, Syahir A, Omar AR, Sieo CC, et al.

Appl Microbiol Biotechnol, 2018 May;102(9):4131-4142.
PMID: 29564523 DOI: 10.1007/s00253-018-8921-9

Foot-and-mouth disease (FMD) is a major threat to the livestock industry worldwide. Despite constant surveillance and effective vaccination, the perpetual mutations of the foot-and-mouth disease virus (FMDV) pose a huge challenge to FMD diagnosis. The immunodominant region of the FMDV VP1 protein (residues 131-170) displayed on phage T7 has been used to detect anti-FMDV in bovine sera. In the present study, the functional epitope was further delineated using amino acid sequence alignment, homology modelling and phage display. Two highly conserved regions (VP1145-152 and VP1159-170) were identified among different FMDV serotypes. The coding regions of these two epitopes were fused separately to the T7 genome and displayed on the phage particles. Interestingly, chimeric phage displaying the VP1159-170 epitope demonstrated a higher antigenicity than that displaying the VP1131-170 epitope. By contrast, phage T7 displaying the VP1145-152 epitope did not react significantly with the anti-FMDV antibodies in vaccinated bovine sera. This study has successfully identified a smaller functional epitope, VP1159-170, located at the C-terminal end of the structural VP1 protein. The phage T7 displaying this shorter epitope is a promising diagnostic reagent to detect anti-FMDV antibodies in vaccinated animals.

Matched MeSH terms: Foot-and-Mouth Disease/diagnosis; Foot-and-Mouth Disease Virus/metabolism*
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/genetics; Foot-and-Mouth Disease/epidemiology*; Foot-and-Mouth Disease/virology; Foot-and-Mouth Disease Virus/classification*; Foot-and-Mouth Disease Virus/genetics*
Implementation in Australia of molecular diagnostic techniques for the rapid detection of foot and mouth disease virus

Boyle DB, Taylor T, Cardoso M

Aust Vet J, 2004 Jul;82(7):421-5.
PMID: 15354851

OBJECTIVE: To evaluate and implement rapid molecular diagnostic techniques for the detection of foot and mouth disease virus (FMDV) suitable for use in Australia.
DESIGN: Two PCR TaqMan assays targeted to the FMDV internal ribosome entry site or the 3D polymerase coding region for the rapid detection of FMDV were evaluated using non-infectious materials to determine the test most appropriate for implementation as part of Australia's national preparedness for the rapid detection and diagnosis of FMD outbreaks.
RESULTS: Two published tests (PCR TaqMan assays targeted to the FMDV IRES region or the FMDV 3D polymerase coding region) were evaluated for their ability to detect FMDV genetic material in non-infectious FMDV ELISA antigen stocks held at Australian Animal Health Laboratory. Both tests were able to detect FMDV genetic material from strains O1 Manisa, O-3039, A22, A24, A Malaysia, C, Asia 1 and SAT 1, 2 and 3. With the exception of Asia 1, the TaqMan assay targeted to the FMD 3D polymerase coding region had Ct values equal to or lower than for the TaqMan assay targeted to the IRES region suggesting that this test may provide broader serotype detection and sensitivity. However, the TaqMan assay directed to the FMDV IRES is the only one to date to have undergone substantial evaluation using clinical samples collected during an outbreak. The greatest differences observed were for O-3039, SAT 1, and 3.
CONCLUSION: Given the ease of setting up both tests, AAHL currently runs both tests on highly suspect FMD investigations to provide independent confirmation of the absence of FMDV because the tests are focused on two independent regions of the FMDV genome. These tests add substantially to Australia's preparedness for FMD diagnosis complementing the already well-established virus isolation and antigen capture ELISA tests for index case diagnosis of FMD in Australia.

Matched MeSH terms: Foot-and-Mouth Disease/diagnosis*; Foot-and-Mouth Disease/epidemiology; Foot-and-Mouth Disease/prevention & control; Foot-and-Mouth Disease Virus/genetics; Foot-and-Mouth Disease Virus/isolation & purification*
A review of the status of foot and mouth disease in South-East Asia and approaches to control and eradication

Gleeson LJ

Rev. - Off. Int. Epizoot., 2002 Dec;21(3):465-75.
PMID: 12530354

The author presents reports of foot and mouth disease (FMD) submitted between 1996 and 2001 to the Office International des Epizooties (OIE: World organisation for animal health) Sub-Commission for FMD in South-East Asia. Of the ten countries in South-East Asia, FMD is endemic in seven (Cambodia, Laos, Malaysia, Myanmar, the Philippines, Thailand and Vietnam) and three are free of the disease (Brunei, Indonesia and Singapore). Part of the Philippines is also recognised internationally as being free of FMD. From 1996 to 2001, serotype O viruses caused outbreaks in all seven of the endemically infected countries. On the mainland, three different type O lineages have been recorded, namely: the South-East Asian (SEA) topotype, the pig-adapted or Cathay topotype and the pan-Asian topotype. Prior to 1999, one group of SEA topotype viruses occurred in the eastern part of the region and another group in the western part. However, in 1999, the pan-Asian lineage was introduced to the region and has become widespread. The Cathay topotype was reported from Vietnam in 1997 and is the only FMD virus currently endemic in the Philippines. Type Asia 1 has never been reported from the Philippines but was reported from all countries on the mainland except Vietnam between 1996 and 2001. Type A virus has not been reported from east of the Mekong River in the past six years and seems to be mainly confined to Thailand with occasional spillover into Malaysia. The distribution and movement of FMD viruses in the region is a reflection of the trade-driven movement of livestock. There is great disparity across the region in the strength and resources of the animal health services and this has a direct impact on FMD control. Regulatory environments are not well developed and enforcement of regulations can be ineffectual. The management of animal movement is quite variable across the region and much market-driven transboundary movement of livestock is unregulated. Formal quarantine approaches are generally not supported by traders or are not available. Vaccination is not used widely as a control tool because of the expense. However, it is applied by the Veterinary Services in Malaysia to control incursions of the disease and there is a mass vaccination programme for large ruminants in Thailand where the Government produces and distributes vaccine. Vaccination is also used by the commercial pig sector, particularly in the Philippines and Thailand.

Matched MeSH terms: Foot-and-Mouth Disease/epidemiology*; Foot-and-Mouth Disease/prevention & control*; Foot-and-Mouth Disease Virus/classification
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*; Foot-and-Mouth Disease/virology; Foot-and-Mouth Disease Virus/classification*; Foot-and-Mouth Disease Virus/isolation & purification
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*
Fulltext T Cell Immunity To Enterovirus 71 Infection In Humans And Implications For Vaccine Development

Yee PTI, Poh CL

Int J Med Sci, 2018;15(11):1143-1152.
PMID: 30123051 DOI: 10.7150/ijms.26450

Enterovirus 71 (EV-A71) is one of the major pathogens causing hand, foot and mouth disease (HFMD). Some strains can lead to neurological disease and fatality in children. Up to date, there is no FDA-approved vaccine to prevent severe HFMD and mortality. Although the inactivated vaccine has advanced to production in China, lack of long-term protection and the requirement of multiple boosters have necessitated the development of other types of vaccines. Recent studies indicate that cellular and not humoral immunity determines the clinical outcome of EV-A71 infections. High levels of cytokines such as IL-1β, IL-6, IL-10 and IFN-γ tend to correlate with clinical severity in patients with pulmonary edema and encephalitis. The live attenuated vaccine may serve as the preferred choice as it can induce excellent humoral and cellular immunity as well as live-long immunity. Expression of certain HLA alleles such as TNF-α promoter type II (-308 allele), HLA-A33 and HLA-DR17 responses have been linked to severe HFMD. However, the high variability of MHC genes could restrict T cell recognition and be a major obstacle in the design of peptide vaccines. Hence, the development of a T cell universal vaccine (incorporating both CD4+ and CD8+ T cell epitopes) that induces broad, multifunctional and cross-reactive CD8+ T cell responses maybe desirable.

Matched MeSH terms: Hand, Foot and Mouth Disease/immunology
Global situation of foot-and-mouth disease (FMD)--a short review

Kesy A

Pol J Vet Sci, 2002;5(4):283-7.
PMID: 12512564

This article reviews the actual world FMD situation. In 2000, fifty nine countries officially reported outbreaks of FMD. The disease occurred in Europe (Greece), Asia (Russia, Mongolia, Bangladesh, Cambodia, China, Japan, Laos, Nepal, Pakistan, Philippines, Republic of Korea, Taiwan, Thailand, Vietnam, Iran, Iraq, Turkey, in Caucasian region--Georgia, Azerbaijan and Armenia as well as in Kazakhstan, Kyrgyzstan, Turkmenistan and Tajikistan), Africa (Egypt, Kenya, Mauritania, South Africa, Tanzania, Uganda, Malawi, Namibia, Zambia and Zimbabwe) and in South America (Brazil, Colombia, Uruguay, Bolivia, Peru, Ecuador and Venezuela). In 2001, FMD was still spreading throughout the endemic regions and appeared in some of the west European countries--Great Britain, The Netherlands, France and Ireland. In South America, FMD occurred in Argentina, Uruguay, Brazil and Colombia. In Asia the FMD spread in Turkey, Iran, Afghanistan, Georgia, Azerbaijan, Mongolia, Kuwait, Bahrain, Yemen, Qatar, United Arab Emirates, Oman, Iran, Bhutan, Nepal, Malaysia, Philippines, Thailand and Taiwan. The FMD situation in Africa was unclear, but probably most countries in West, East and South Africa were affected. The most recent data of the OIE from May 2002 confirmed FMD outbreaks in population of pigs in Republic of Korea.

Matched MeSH terms: Foot-and-Mouth Disease/epidemiology*
Fulltext A sudden paediatric death due to hand, foot and mouth disease: the importance of vigilance

Rahimi R, Omar E, Tuan Soh TS, Mohd Nawi SFA, Md Noor S

Malays J Pathol, 2017 Aug;39(2):167-170.
PMID: 28866699 MyJurnal

BACKGROUND: Hand, foot and mouth disease (HFMD) is caused by enteroviruses such as Coxsackie virus A16 (CVA16) and Enterovirus 71 (EV71). The diagnostic hallmarks are oral ulcers and maculo-papular or vesicular rash on the hands and feet. Severe form of this disease can lead to death due to neurological and cardiopulmonary complications. This case report aims to describe a fatal case of HFMD with minimal oral and skin manifestations.
CASE REPORT: A four-year-old girl was brought to a hospital after suddenly becoming unresponsive at home. She had a history of fever and lethargy for three days prior to her demise. The patient, and f ive other children in her neighbourhood had been diagnosed to have HFMD at a local health clinic; the other children had recovered without complications.
RESULTS: Autopsy revealed a few punctate, sub-epidermal vesicles measuring 1 to 2 mm on the palm of her right hand and sole of the right foot, visible only with a magnifying glass. Internal examination revealed prominent nodularity at the oro- and hypopharynxes. The lungs were markedly congested and oedematous. Histopathology of the lung showed marked oedema and haemorrhage with mild pneumonic changes. Oedema with increase in macroglia and astrocytic proliferation were seen in the cerebral tissue, but no lymphocytic infiltration was evident. Enterovirus EV71 was detected by polymerase chain reaction in samples from the lung, cerebrospinal fluid and serum. The cause of death was given as HFMD complicated by pneumonia.
CONCLUSION: Fatal HFMD may have minimal signs. A complete history, careful physical examination and relevant investigations lead to a diagnosis at post mortem examination. Awareness of the subtle signs and rapid deterioration associated with a fatal case of HFMD is a challenge to clinicians who encounter these cases.

Matched MeSH terms: Hand, Foot and Mouth Disease/pathology*
Antiviral activity of SP81 peptide against Enterovirus A71 (EV-A71)

Abd-Aziz N, Lee MF, Ong SK, Poh CL

Virology, 2024 Jan;589:109941.
PMID: 37984152 DOI: 10.1016/j.virol.2023.109941

The hand, food, and mouth disease (HFMD) is primarily caused by Enterovirus A71 (EV-A71). EV-A71 outbreaks in the Asia Pacific have been associated with severe neurological disease and high fatalities. Currently, there are no FDA-approved antivirals for the treatment of EV-A71 infections. In this study, the SP81 peptide, derived from the VP1 capsid protein of EV-A71 was shown to be a promising antiviral candidate for the treatment of EV-A71 infections. SP81 peptide was non-toxic to RD cells up to 45 μM, with a half-maximal cytotoxic concentration (CC50) of 90.32 μM. SP81 peptide exerted antiviral effects during the pre- and post-infection stages with 50% inhibitory concentrations (IC50) of 4.529 μM and 1.192 μM, respectively. Direct virus inactivation of EV-A71 by the SP81 peptide was also observed with an IC50 of 8.076 μM. Additionally, the SP81 peptide exhibited direct virus inactivation of EV-A71 at 95% upon the addition of the SP81 peptide within 5 min. This study showed that the SP81 peptide exhibited significant inhibition of EV-A71 and could serve as a promising antiviral agent for further clinical development against EV-A71 infections.

Matched MeSH terms: Hand, Foot and Mouth Disease*
Genetic characteristics of human enterovirus 71 and coxsackievirus A16 circulating from 1999 to 2004 in Shenzhen, People's Republic of China

Li L, He Y, Yang H, Zhu J, Xu X, Dong J, et al.

J Clin Microbiol, 2005 Aug;43(8):3835-9.
PMID: 16081920

The genetic and phylogenetic characteristics of human enterovirus 71 (EV71) and coxsackievirus A16 (CA16) sampled from children with hand, foot, and mouth disease in Shenzhen, People's Republic of China, over a 6-year period (1999 to 2004) were examined with reverse transcription-PCR and DNA sequencing. Out of 147 stool specimens, 60 showed positive signals when screened with EV71- and CA16-specific primers. EV71 was identified in 19 specimens, and CA16 was identified in 41 specimens; coinfection by EV71 and CA16 was not observed. Phylogenetic analysis of all EV71 strains isolated from the mainland Chinese samples established C4 as the predominant genotype. Only one other known strain (3254-TAI-98; AF286531), isolated in Taiwan in 1998, was identified as belonging to genotype C4. Phylogenetic analysis of CA16 strains allowed us to identify three new genetic lineages (A, B, and C), with lineage C recently predominating in Asian countries, such as the People's Republic of China, Malaysia, and Japan. These new observations indicate that CA16 circulating in the People's Republic of China is genetically diverse, and additional surveillance is warranted.

Matched MeSH terms: Hand, Foot and Mouth Disease/virology*
Fulltext Epidemiology of foot-and-mouth disease outbreaks in Thailand from 2011 to 2018

Chanchaidechachai T, Saatkamp H, de Jong M, Inchaisri C, Hogeveen H, Premashthira S, et al.

Transbound Emerg Dis, 2022 Nov;69(6):3823-3836.
PMID: 36321258 DOI: 10.1111/tbed.14754

Foot-and-mouth disease (FMD) is one of the most important animal diseases hindering livestock production in Thailand. In this study, a temporal and spatial analysis at the subdistrict level was performed on FMD outbreak reports in Thailand from 2011 to 2018. Risk factors associated with FMD outbreaks were furthermore investigated using generalized estimating equations. The results showed that the incidence of FMD outbreaks was the highest in 2016 and was affected by season, with a peak in FMD outbreaks occurring in the rainy-winter season, during October to December. FMD outbreaks were mostly distributed in small clusters within a few subdistricts. Some high-risk areas with repeated outbreaks were detected in the central regions. Risk factors, including the increase of subdistrict's size of the dairy population, beef population or pig population, the low percentage of forest area, subdistricts in the provinces adjacent to Malaysia, the presence of a livestock market and the occurrence of an FMD outbreak in a neighbouring subdistrict in the previous month significantly increased the odds of having an FMD outbreak. The increase in proximity to the nearest subdistrict with an FMD outbreak in the previous month decreased the odds of having FMD outbreaks. This study helped to identify high-risk areas and periods of FMD outbreaks in Thailand. Together with the identified risk factors, its results can be used to optimize the FMD control programme in Thailand and in other countries having a similar livestock industry and FMD situation.

Matched MeSH terms: Foot-and-Mouth Disease Virus*
Fulltext Application of the double bounded dichotomous choice model to the estimation of parent's willingness to pay for the hand foot mouth disease vaccination: A survey in Selangor, Malaysia

Rajamoorthy Y, Taib NM, Harapan H, Wagner AL, Munusamy S

PLoS One, 2023;18(6):e0286924.
PMID: 37307254 DOI: 10.1371/journal.pone.0286924

Hand foot and mouth disease (HFMD) is a notifiable viral disease in Malaysia, and is transmitted primarily among young children. Although vaccines for enteroviruses 71 (EV-71) were approved in China against HFMD, the availability and the acceptance of the vaccine in the Malaysia are unknown. This study investigated and ascertained the determinants of willingness-to-pay (WTP) for HFMD vaccination in Selangor Malaysia. This study adopted a cross-sectional, contingent valuation method involving 390 parents of young children aged six and below. The double bounded dichotomous choice (DBDC) approach was employed to assess the WTP for HFMD vaccine among respondents. A bivariate probit model was used to assess the key determinants of WTP for HFMD vaccine, while the mean WTP was measured using the Krinsky and Robb procedure. We found that 279 (71.5%) of parents were willing to pay for the HFMD vaccination. The estimated single bounded mean WTP was MYR460.23 (equivalent to US$ 102.17) for two doses of HFMD vaccination. The double bounded analysis revealed that the vaccine's price, poor education background and lower income were the key factors that significantly affected the WTP, with the estimated mean WTP being MYR394.00 (US$ 87.47). In conclusion, most Malaysian parents are willing to pay for the HFMD vaccination. The estimated WTP identifies the optimal price point for HFMD vaccination in Malaysia. Furthermore, the government should focus on an awareness programme for the HFMD vaccination among parents who have lower income or education level.

Matched MeSH terms: Hand, Foot and Mouth Disease*
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/genetics; Hand, Foot and Mouth Disease/epidemiology*; Hand, Foot and Mouth Disease/virology

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