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 Table of Contents    
Year : 2013  |  Volume : 79  |  Issue : 2  |  Page : 165-175

Hand, foot, and mouth disease: Current scenario and Indian perspective

Department of Dermatology, NRS Medical College, Kolkata, West Bengal, India

Date of Web Publication22-Feb-2013

Correspondence Address:
Nilendu Sarma
Department of Dermatology, NRS Medical College, P. N. Colony, Sapuipara, Bally, Howrah, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0378-6323.107631

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Hand, foot, and mouth disease (HFMD), first reported in New Zealand in 1957 is caused by Coxsackievirus A16 (CVA16) and human enterovirus 71 (HEV71) and occasionally by Coxsackievirus A4-A7, A9, A10, B1-B3, and B5. This is characterized by erythematous papulo vesicular eruptions over hand, feet, perioral area, knees, buttocks and also intraorally mostly in the children. HFMD has been known for its self limiting course. Only small scale outbreaks have been reported from United States, Europe, Australia, Japan and Brazil for the first few decades. However, since 1997 the disease has conspicuously changed its behavior as noted in different Southeast Asian countries. There was sharp rise in incidence, severity, complications and even fatal outcomes that were almost unseen before that period. Following the near complete eradication of poliovirus, HEV71, the non-polio enterovirus, may become the greatest threat to cause significant neurological complications. This adds to the fact that effective therapy or vaccine is still a far reaching goal. There are reports of disease activity in different corners of India since 2004. Although of milder degree, continuous progress to affect larger parts of the country may indicate vulnerability of India from possible future fatal outbreaks. Low level of awareness among the health care providers may prove critical.

Keywords: Coxsackievirus A16, hand foot and mouth disease, human enterovirus 71, India, Southeast Asia

How to cite this article:
Sarma N. Hand, foot, and mouth disease: Current scenario and Indian perspective. Indian J Dermatol Venereol Leprol 2013;79:165-75

How to cite this URL:
Sarma N. Hand, foot, and mouth disease: Current scenario and Indian perspective. Indian J Dermatol Venereol Leprol [serial online] 2013 [cited 2021 Jan 15];79:165-75. Available from:

  Introduction Top

Hand, foot, and mouth disease (HFMD) was first reported in New Zealand in 1957. [1] Coxsackievirus A16 (CVA16) was first identified next year in 1958 in Canada. [1] HEV71 was discovered much later in 1969 in California [2] from the stool of an infant who was suffering from non-HFMD encephalitis. Etiological relation between HFMD and HEV71 was identified for the first time in 1973 in Sweden and Japan. [3]

In contrast to poliomyelitis, another enteroviral disease renowned for its significant neurological complications, HFMD has been considered to be a benign disease of self limiting nature. For this reason, this has got less attention from the medical fraternity, researchers, public health department and policy makers. This is evident from the non-availability of effective vaccines or stringent preventive policy. There is insufficient level of awareness among the practitioners. Now with reports of many fatal attacks in different Southeast Asian countries, it has become a cause of concern.

  Clinical Presentation Top

Children below 10 years of age are the prime target. [4] Generally, the manifestation is limited to the skin. Mild fever and constitutional symptoms may precede or accompany the skin eruptions. HFMD is characterized by sudden appearance of erythematous papulo vesicular eruptions. Vesicles are round or oval. Generally, they appear in crops and persist in groups over some specific areas like hand, feet, perioral area, knees, buttocks and also intraorally. Vesicle fluid is initially clear but rapidly becomes turbid mimicking pustules. There is characteristic perilesional erythema. Lesions in thick skin like palms and soles may not develop classical vesicle; they may instead persist as erythematous papules [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5] and [Figure 6]. Disease usually improves spontaneously after 7-10 days without any complication.
Figure 1: Perioral grouped vesicular eruptions in Hand, foot, and mouth disease

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Figure 2: Oral mucosal vesicular lesions in Hand, foot, and mouth disease

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Figure 3: Classical greyish vesicle with erythematous halo on finger

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Figure 4: Grouped vesicles on knees in a child

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Figure 5: Grouped vesicles on buttocks (Figure 2 and 5 have been reproduced from reference no. 109 with prior permission)

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Figure 6: Erythematous papules and ill-formed vesicular eruption on medial margin of foot. (Figure 3, 4 and 6 have been reproduced from reference no. 51 with prior permission)

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Skin lesion may resemble chicken pox, herpes simplex (of lip or other area), impetigo, pompholyx, papular urticaria, insect bite and some bullous disease like chronic bullous disease of childhood (CBDC).

Herpangina, another manifestation by the same organisms, is characterized by more limited involvement with ulcers over anterior tonsillar pillars, soft palate, buccal mucosa, or uvula without any skin lesions.

In severe disease, cardiorespiratory and neurological involvement may develop. Cardiopulmonary involvement indicates more severe disease and may herald fatality. Tachycardia, dyspnea, tachypnea, poor peripheral perfusion indicate involvement of cardiopulmonary system. Refractory cardiac dysfunction and fulminant pulmonary oedema may lead to abrupt death. It is said that the rapidity of event usually stuns the primary medical facility providers especially if they are not very much expectant and prepared to manage such situations. [5],[6],[7],[8],[8]

Neurological involvement ranges from aseptic meningitis, encephalitis, acute flaccid paralysis (AFP) and manifest with headache, irritability, stiff neck, lethargy, drowsiness, coma, seizures, myoclonus, and limb weakness to complete paralysis. Autonomic dysfunctions like neurogenic bladder, insomnia, profuse sweating, and unexplained transient hyperglycemia may also occur in HEV71 induced cases. [7]

Neurologic involvement, through development of 'neurogenic pulmonary edema' is often the reason behind the cardiac and pulmonary derangement that may ultimately lead to death.

An atypical phenotype of the disease was noted among fatal cases during the epidemic of Sarawak in 1997. These cases had predominant presentation of neurological disease. Similar clinical phenotype was observed in Taiwan in 1998 and Fuyang district, China in 2008. Even before the diagnosis was suspected as HFMD, large number of cases died. Surprisingly, all these three epidemics were primarily caused by HEV71.

During the fatal epidemic of Taiwan in 1998, many cases developed brainstem encephalitis that was classified into three grades (I to III). [9] Most advanced stage (grade III) severely damaged the medulla oblongata, pons and midbrain structures leading to a condition described as 'neurogenic pulmonary edema'. [7],[9],[10] Neurogenic pulmonary edema is now known as the most dreaded complication that has caused large number of fatalities in Southeast Asian countries in last two decades. Even all the fatalities in Bulgarian epidemic were also supposed to be caused by this. Clinical diagnosis of this condition may be difficult as it may clinically mimic acute myocarditis. [9],[10]

It has been shown that pleocytosis in CSF may be a helpful guide to predict sudden death due to cardiorespiratory failure, [6],[11] even without obvious neurological symptoms. Presence of intense inflammation in the midbrain has been repeatedly detected in post-mortem histology of the midbrain structures among cases who died of neurogenic pulmonary edema. [12] This is in fact a condition with extremely poor prognosis where mortality may reach up to 80% [7] and may result in high morbidity among the survivors. [13]

Prognosis may not be predicted correctly, especially early in the course. Presence of some atypical physical findings like tachycardia, tachypnea, hypotension, hypertension, bleeding in GIT and neurological deficits, elevated leukocyte count, vomiting and absence of mouth ulcers are reported to have some predictive value. [14]

  The Organisms and its Interplay with the Host Top

Coxsackievirus A16 (CVA16) and human enterovirus 71 (HEV71), the most common organisms of HFMD are members of Enterovirus genus, [1] family Picornaviridae. HEV71 is a small, non-enveloped, positive-stranded RNA virus. Simultaneous presence of both has also been reported. [2],[15],[16] Other than these two organisms, Coxsackievirus A4-A7, A9, A10, B1-B3, and B5 have also been reported as relatively rare etiologic agents. [17],[18]

HEV71 has four capsid proteins VP1, VP2, VP3 and VP4. These play role in adsorption and uncoating of the virus in the infected human cells. Among these, VP1 is the most pathogenic and crucial one. [19] Thus this has been a good target antigen for preparing an effective subunit vaccine. [20] Based on the highly variable genetic sequences of the VP1 capsid antigen gene, HEV71 has been classified into different genogroups (A, B, C and D). [21],[22] Each genogroup has many lineages like B0-5, C1-5. [21],[23],[24],[25] As per the latest report, genogroup D consist of only single strain. [22] Within the same genogroup, there is more than 92% nucleotide sequence identity that is much higher than the rate (78-83%) in other groups. [26]

So far, only two types of receptor for viral entry into the cell is identified. These are human P-selectin glycoprotein ligand (PSGL)-1 and scavenger receptor (SCAR) B2. [27],[28] Identification of receptors are useful in understanding the disease pathogenesis because the distribution of the receptors signifies the susceptible cells of the human body.

Neurological involvement is frequently noted in HFMD associated with HEV71 but this is very unusual in CA16 associated cases. [29] This fact is unexplained and may be due to possible existence of a specific HEV71 receptor on neuronal cells. However, such receptors remain unidentified.

  The Growing Concern Top

For about 3 decades following its discovery, only small scale outbreaks have been reported from United States, Europe, Australia, Japan and Brazil. [2],[30],[31],[32],[33],[34],[35] Larger outbreaks with high mortality were almost unseen except the outbreak that occurred in Bulgaria in 1975 [36] and Hungary in 1978 [37] and caused high mortality. However, shift in the behavior of the disease since its entry into Southeast Asian countries was quite conspicuous. There have been many hypotheses to explain this as discussed later.

  Disease in Southeast Asia Top

The first report of occurrence of HFMD in mainland China dates back to 1981. [1] The etiologic agent was identified as CVA16 in the stool specimens in Xiamen City in 1983. The disease subsequently affected other areas of China. Outbreak HEV71 occurred in Wuhan City in 1987. [38] In ensuing years, the disease became a regular visitor in many parts of China with larger capacity. It showed a tendency to affect mostly the children less than 5 years of age. [3]

Disease started to show its presence in different Southeast Asian countries like Singapore, [14] Vietnam, [17] Taiwan, [39] China, [40] Japan, [41] Malaysia, [42],[43],[44] South Korea, [43] and recently in India. [44]

During the last two decades, there was a sharp rise in incidence, severity, complications and fatalities in the Southeast Asian countries. [45] Mortality has been reported to be increased to a whopping 156% over the last years as reported from China. [46] Fatal outbreak occurred in Malaysia (Sarawak) in 1997, [42] Taiwan in 1998 [39],[47] and Singapore in 2000. [14] There are recent reports of large epidemics with significantly fatal outcome from the World Health Organization's Western Pacific Region. [48],[49],[50] Most severe disease outbreak, so far the highest in the world, occurred in China in 2008 that resulted in largest number of complication and fatality. [1] WHO has published reports regarding the growing threat of HFMD. [51] The disease that kept a low profile for long became a cause for concern.

The Chinese outbreak of 2008 was reported to be an ongoing epidemic that has already caused 1200 cases of brainstem encephalitis and 193 deaths. [1]

An unexplained tendency of gradual shift towards HEV71 was noted. This was correlated with progression of severity as well. Coxsackievirus was detected in the non-fatal outbreaks in 1996 and 1997 but HEV71 in fatal outbreak in 1998 in Taiwan. [11] Similar things happened in China also.

  Indian Perspective Top

India having a population of more than 1.2 billion, being the 2 nd largest country in south East Asia and a close neighbour of China, the worst affected country in the world, had no evidence of the disease till recently. The first report of disease outbreak in India came in 2004 from Calicut. [52] After 3 years, the first large scale outbreak occurred in 2007 from Kolkata and surrounding areas of the eastern state, West Bengal. [44] Since then, many small scale outbreaks have been repeatedly reported from different places. [53],[54],[55],[56],[57]

All previous cases of severe outbreaks followed many years of milder attacks, intermittent periods of quiescence and progressively larger areas of involvement. The disease was present in Taiwan since 1980 with only sporadic attacks of mild nature before culminating in a fatal outbreak in 1998. [39],[47] Showing the first appearance in 1981, disease caused many progressively larger attacks in China before culminating in the worst ever outbreak in 2008. [1]

Although, no cases of neurological or pulmonary manifestations were detected so far and all the cases improved spontaneously without any requirement for hospitalization, continuous spread of the disease over larger parts of the country reminds the pre-epidemic periods of China and Taiwan [Table 1]. This is complicated with the extremely low level of awareness among the health care professionals especially the primary level staffs who generally take the most significant step in curbing a severe outbreak.
Table 1: Some comparative details on the fatal south east Asian HFMD epidemics and the Indian epidemic

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  Various Factors Regulating Severity Top

Factors that may play an important role in inducing severity are virological factors, host factor and environmental factors.

Virological factors

HFMD caused by CA16 is relatively milder. [59] In contrast, the disease caused by EV71 is generally more severe [17],[39],[60] with higher chances of serious complications like myocarditis, neurological involvement like aseptic meningitis, encephalitis, and poliomyelitis-like paralysis. [10],[14],[61],[62] Pulmonary edema is frequently reported from HEV71 associated HFMD. [43],[62] For unknown reason, HEV71 associated HFMD has a propensity to infect mostly the children, especially in the 0-24 months age range. [17],[50]

Difference in the viral strain may be crucial in determining the disease severity. The strain involved in the outbreaks in China was detected to be only of C4 genotype [58]

These viruses are known to induce mutation to form newer genetic strains following genetic recombination to escape the existing immunity. This may result in re-emergence of the virus. [26] Genotype replacement may occur even during a large epidemic and even between HEV71 and CA16. [63],[64],[65]

Since 1997, the most frequently detected strains in south-east Asia are B3-5 and C3-5. [26],[66] , The single strain in genogroup D was isolated from India in 2002. [22]

Host factors

As mentioned, the striking difference in the disease severity of the disease in many Asian countries hinted at strong possibilities of susceptibility of this population incurred upon by their genetic make-up. HLA-A33 haplotype, glucose-6-phophate dehydrogenase deficiency, [67] a specific cytotoxic T lymphocyte antigen haplotype (CTLA-4) and some inflammatory cytokines have been proposed as important susceptibility inducing factors. Prevalence of HLA-A33 haplotype is significantly higher in the Asian populations (17-35%) in comparison to the Caucasian populations. [43] HLA-A 33 (class I) and HLA-DR17 (class II) may also contribute to the severity of the disease caused by HEV71 infection.

Severity of the disease may correlate with the degree of response of some of the indices of cellular immunity like antigen-specific Th1 cytokines and lymphocyte proliferation against HEV71 antigen. [68]

As reported, severe HEV71 encephalitis may have intimate relation with a specific cytotoxic T lymphocyte antigen haplotype (CTLA4). [69] A direct correlation has also been reported with certain inflammatory cytokines in serum and cerebrospinal fluid [10-12]. [70],[71],[72],[73] Neutralizing antibody levels was not found to have any direct correlation with the severity of the disease caused by HEV71. [46]

  Diagnosis Top

HFMD is generally easily diagnosed on clinical grounds. Although, this shares some clinical resemblance with other diseases like varicella zoster, papular urticaria, impetigo and pompholyx, the constellation of features are unique enough to aid instant clinical diagnosis with certainty in almost all cases. Presence of the disease is usually noted in the surrounding neighbourhoods or schools. Laboratory confirmation is mostly necessary for research purpose, strain analysis or occasionally in cases with atypical manifestations.

Laboratory confirmation can be done directly through the identification of the virus in culture or indirectly through detection of neutralizing antibody in the serum. The last one is particularly helpful in retrospective evaluation of seroprevalence of the disease in the community.


Stool, throat swab, vesicle fluid can be used for culture. Stool is considered the most appropriate sample owing to its capacity to keep the virus alive for longer duration. [74] It is necessary to keep the transport time as short as possible.

Culture of the organism allows identification of the specific virus through observation of the cytopathic effect in cell culture or formation of plaques in a cell monolayer (plaque assay). [75],[76],[77]

HEV71 is known to infect a wide range of cell lines like human RD cells, vero cells, simian virus 40-transformed African green monkey kidney cells (Cos-7), human colorectal carcinoma cells (Caco-2), human pulmonary adenocarcinoma cells (A549), human rhabdomyosarcoma and human embryonic kidney cells, HeLa cells, MRC-5 cells, human immature dendritic cells, human glioblastoma cells (SF268) and human neuroblastoma cells. [1] RD cells is a better cell line for culture than the standard cell line like GMK and L20B cells. [74] Any single cell line cannot grow all the human enteroviruses. [78] Apart from identification of the virus, functional aspects of the virus like replicative fitness and fidelity can also be assessed in culture. [79],[80],[81] Its neurotropic effects can be analyzed through its cytopathic effect and neurotoxic mediator release (Cox-2 and PG 2) in human neuroblastoma (SK-N-SH) cell line culture. [82] Nucleotide sequencing of VP1 and VP4 genes can be done for identification of involved strain. [45],[83] Another method of identification is fluorescence resonance energy transfer system for HEV71 detection in HeLa cells. [84]

Neutralizing antibody detection

Neutralization with serotype-specific antisera is done to identify the involved serotypes. Plaque reduction neutralization test is generally followed for detection of neutralizing antibody of HEV71. [85]

Heated serum at 56°C for 30 min is serially diluted with 50% tissue culture infective doses of HEV71. It is incubated for 2 h at 37°C in specific cells for 2-7 days. The dilution of plasma that induces cytopathic effect in ≥50% of the tissue culture wells is called the neutralization titre (the reciprocal value). [86],[87]

The most important role of detection of neutralizing antibody is evaluation of seroprevalence of the organism in the community. It indirectly reflects the susceptibility of the individual to the organism.

Enzyme-linked immunosorbent assay

In contrast to the culture, RT-PCR or neutralization assay, that are expensive, time consuming and not suitable for use in large mass and in developing country, IgM ELISA has been utilised for rapid diagnosis. It has been shown to be useful with high degree of sensitivity from 1 st week till many weeks after infection. [88],[89],[90],[91]

Reverse transcriptase-polymerase chain reaction

A recent addition to the diagnostic tests is reverse transcriptase-polymerase chain reaction (RT-PCR) amplification and nucleotide sequencing of the VP1 gene. Reverse transcription polymerase chain reaction (RT-PCR), a variant of polymerase chain reaction (PCR) is a sophisticated and highly sensitive technique where very low copy levels of RNA is reverse transcribed into its DNA complement (cDNA) with reverse transcriptase. PCR then amplifies the cDNA. Among many other uses, this technique is commonly used in diagnosis of viral infections that are caused by RNA viruses like enteroviruses.

RT-PCR is now considered as the primary modality for enterovirus "serotype" identification [16],[92],[93],[94] replacing the neutralization technique in this regard. [95] This was further improvised to introduce multiplex RT-PCR assay to allow amplification of several RNA viral targets in a single reaction. This can screen multiple pathogens in a single reaction, thus can be a cost effective, as well as rapid screening method [95],[96],[97] [Figure 7].
Figure 7: Results of multiplex RT-PCR from a representative sample of throat swab specimens obtained from the HFMD cases:. Lane 1 -enterovirus (unknown serotype); Lanes 2 and 3 -CVA16; Lanes 4 and 5 -HEV71; Lane 6 - negative control; Lane 7 - positive control (a mixture of infected HEV71- and CVA16-infected cell RNA templates). Pan-enterovirus RT-PCR amplicon size - 440 bp; HEV71-specific RT-PCR amplicon size - 264 bp; CVA16-specific RT-PCR amplicon - 550 bp. Molecular weight markers are the 100 bp DNA ladder (Promega). (Figure 7 and legend reproduced from reference no. 95 with prior permission)

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In resource poor set up as in India, laboratory confirmation is generally difficult. Among the seven reports, laboratory confirmation was performed in only two. In one of them, diagnosis of all 4 cases was done clinically and laboratory confirmation through RT-PCR was done in only one case. [57] It detected presence of CA16. In one series, although all those cases improved spontaneously without any fatality, all the 19 cases (100%) were confirmed through microneutralization test in cell culture to be infected with EV71. [52] Phylogenetic analysis was not done so far in any of these Indian cases.

  Management Top

There is neither an effective antiviral therapy nor an effective vaccine available against the disease. This is a contagious disease and has the potentiality to spread very fast over a large population in the community. Prevention of further spread of the disease is the only way to control a disease from becoming a large outbreak. As the organisms are enterovirus, they spread through faeco-oral route. Strict implementation of basic protocols like monitoring cleanliness of the hands, utensils and drinking water and avoiding direct contact with affected people can be rewarding. Restriction of the children from attending schools or other outdoor activities is a very simple but effective strategy.

To prevent disease outbreak, disease surveillance, both clinical and laboratory, is useful as found previously in other countries. [17],[98],[99] Utilizing the information thus obtained can assist the health care authorities to implement early control measure and reduce neurological complication.

Vaccination, currently at research level can be an excellent option for protection of the community. The vaccination has been proposed to be best given at 9 months of age because the maternal protective antibody (Neut-Ab to EV71) wanes off by 6 months of age. [86] As both humoral and cell mediated immunity play definite role in the disease, ideally both should be targeted. Large number of research works are underway, especially against HEV71, the more fatal one.

Inactivated vaccines have been shown to confer satisfactory protection. Formaldehyde inactivation is the most commonly used method for inactivation. Formaldehyde-inactivated whole virus vaccine from a mouse-adapted strain of a genotype B3 clinical isolate was reported to confer significant cross protection against different genotypes. However, there are chances that the inactivated whole virus may regain its virulence if the mutations that are induced by the attenuation process are reversed in the human body. Other ways to induce attenuation have also been tried like inclusion of mRNA homology sequences. [100]

Candidate live-attenuated enterovirus vaccines have largely solved the problem of regaining the virulence. Subunit vaccines [101],[102],[103] have also been evaluated but the protective efficacy of these vaccines is yet to be confirmed. [63],[65],[89],[103],[104],[105],[106] Monoclonal antibody belonging to isotype IgM reported to have strong neutralizing activity in mice targeting epitope on VP1 capsid protein has raised some hope. [20]

  Conclusion Top

Considering the impact of the severe form of disease, HFMD deserves special attention. Following the near complete eradication of poliovirus, HEV71, the non-polio enterovirus, may become the greatest threat to cause significant neurological complications. This adds to the worry that effective therapy or vaccine is still a far reaching goal.

Monitoring of the disease is required to predict the disease behavior so that control measures can be effectively planned to abort or halt a prospective fatal outbreak. HFMD is classified as category C notifiable infectious disease by the Ministry of Health of China on May 2, 2008. [1] This has also been declared as notifiable diseases in Croatia [74] and Singapore [107] as well. Unfortunately, awareness level in many South-East Asian countries including India is far from the expected level. Research work from Indian subcontinent appears scant. [108] Institution of strict preventive policies, training of health care professionals, initiation of mass awareness programs and encouraging basic and molecular level research activities on this disease seems urgently necessary. [109]

  References Top

1.Zhu Z, Zhu S, Guo X, Wang J, Wang D, Yan D, et al. Retrospective seroepidemiology indicated that human enterovirus 71 and coxsackievirus A16 circulated wildly in central and southern China before large-scale outbreaks from 2008. Virol J 2010;7:300.  Back to cited text no. 1
2.Schmidt NJ, Lennette EH, Ho HH. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis 1974;129:304-9.  Back to cited text no. 2
3.Hagiwara A, Tagaya I, Yoneyama T. Epidemic of hand, foot and mouth disease associated with enterovirus 71 infection. Intervirology 1978;9:60-3.  Back to cited text no. 3
4.Chatproedprai S, Theanboonlers A, Korkong S, Thongmee C, Wananukul S, Poovorawan Y. Clinical and molecular characterization of hand-foot-and-mouth disease in Thailand, 2008-2009. JpnJ Infect Dis 2010;63:229-33.  Back to cited text no. 4
5.Ooi MH, Wong SC, Mohan A, Podin Y, Perera D, Clear D, et al. Identification and validation of clinical predictors for the risk of neurological involvement in children with hand, foot, and mouth disease in Sarawak. BMC Infect Dis2009;9:3.  Back to cited text no. 5
6.Cardosa MJ, Krishnan S, Tio PH, Perera D, Wong SC. Isolation of subgenus B adenovirus during a fatal outbreak of enterovirus 71-associated hand, foot, and mouth disease in Sibu, Sarawak. Lancet 1999;354:987-91.  Back to cited text no. 6
7.Chang LY, Lin TY, Hsu KH, Huang YC, Lin KL, Hsueh C, et al. Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth disease. Lancet 1999;354:1682-6.  Back to cited text no. 7
8.Huang FL, Jan SL, Chen PY, Chi CS, Wang TM, Fu YC, et al. Left ventricular dysfunction in children with fulminant enterovirus 71 infection: an evaluation of the clinical course. Clin Infect Dis 2002;34:1020-4.  Back to cited text no. 8
9.Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF. Neurologic complications in children with enterovirus 71 infection. N Engl J Med 1999;341:936-42.  Back to cited text no. 9
10.McMinn P, Stratov I, Nagarajan L, Davis S. Neurological manifestations of enterovirus 71 infection in children during an outbreak of hand, foot, and mouth disease in Western Australia. Clin Infect Dis2001;32:236-42.  Back to cited text no. 10
11.Wang SM, Liu CC, Tseng HW, Wang JR, Huang CC, Chen YJ, et al. Clinical spectrum of enterovirus 71 infection in children in southern Taiwan, with an emphasis on neurological complications. Clin Infect Dis 1999;29:184-90.  Back to cited text no. 11
12.Hsueh C, Jung SM, Shih SR, Kuo TT, Shieh WJ, Zaki S, et al. Acute encephalomyelitis during an outbreak of enterovirus type 71 infection in Taiwan: report of an autopsy case with pathologic, immunofluorescence, and molecular studies. Mod Pathol 2000;13:1200-5.  Back to cited text no. 12
13.Prager P, Nolan M, Andrews IP, Williams GD. Neurogenic pulmonary edema in enterovirus 71 encephalitis is not uniformly fatal but causes severe morbidity in survivors. Pediatr Crit Care Med 2003;4:377-81.  Back to cited text no. 13
14.Chong CY, Chan KP, Shah VA, Ng WY, Lau G, Teo TE, et al. Hand foot and mouth disease in Singapore: a comparison of fatal and non-fatal cases. Acta Paediatr 2003;92:1163-9.  Back to cited text no. 14
15.Li L, He Y, Yang H, Zhu J, Xu X, Dong J, et al. Genetic characteristics of human enterovirus 71 and coxsackievirus A16 circulating from 1999 to 2004 in Shenzhen, People′s Republic of China. J Clin Microbiol 2005;43:3835-9.  Back to cited text no. 15
16.Perera D, Podin Y, Akin W, Tan CS, Cardosa MJ. Incorrect identification of recent Asian strains of coxsackievirus A16 as human enterovirus 71: Improved primers for the specific detection of human enterovirus 71 by RT PCR. BMC Infect Dis 2004;4:11.  Back to cited text no. 16
17.Tu PV, Thao NT, Perera D, Huu TK, Tien NT, Thuong TC, et al. Epidemiologic and virologic investigation of hand, foot, and mouth disease, southern Vietnam, 2005. Emerg Infect Dis 2007;13:1733-41.  Back to cited text no. 17
18.Chan YF, Sam IC, AbuBakar S. Phylogenetic designation of enterovirus 71 genotypes and subgenotypes using complete genome sequences. Infect Genet Evol 2010;10:404-12.  Back to cited text no. 18
19.Li C, Wang H, Shih SR, Chen TC, Li ML. The efficacy of viral capsid inhibitors in human enterovirus infection and associated diseases. Curr Med Chem 2007;14:847-56.  Back to cited text no. 19
20.Lim XF, Jia Q, Khong WX, Yans B, Premanand B, Alonso S, et al. Characterization of an Isotype-Dependent Monoclonal Antibody against Linear Neutralizing Epitope Effective for Prophylaxis of Enterovirus 71 Infection. PLoS One 2012;7:e29751.  Back to cited text no. 20
21.Tee KK, Lam TT, Chan YF, Bible JM, Kamarulzaman A, Tong CY, et al. Evolutionary genetics of human enterovirus 71: origin, population dynamics, natural selection, and seasonal periodicity of the VP1 gene. J Virol 2010;84:3339-50.  Back to cited text no. 21
22.Deshpande JM, Nadkarni SS, Francis PP. Enterovirus 71 isolated from a case of acute flaccid paralysis in India represents a new genotype. Curr Sci 2003;84:1350-3.  Back to cited text no. 22
23.Shimizu H, Utama A, Onnimala N, Li C, Li-Bi Z, Yu-Jie M, et al. Molecular epidemiology of enterovirus 71 in the Western Pacific region. Pediatr Int 2004;46:231-5.  Back to cited text no. 23
24.Bible JM, Iturriza-Gomara M, Megson B, Brown D, Pantelidis P, Earl P, et al. Molecular epidemiology of human enterovirus 71 in the United Kingdom from 1998 to 2006. J Clin Microbiol 2008;46:3192-200.  Back to cited text no. 24
25.van der Sanden S, Koopmans M, Uslu G, van der Avoort H. Dutch Working Group for Clinical Virology. Epidemiology of enterovirus 71 in the Netherlands, 1963 to 2008. J Clin Microbiol 2009;47:2826-33.  Back to cited text no. 25
26.Bek EJ, McMinn PC. Recent advances in research on human enterovirus 71. Future Virol2010;5:453-68.  Back to cited text no. 26
27.Nishimura Y, Shimojima M, Tano Y, Miyamura T, Wakita T, Shimizu H. Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med 2009;15:794-7.  Back to cited text no. 27
28.Yamayoshi S, Yamashita Y, Li J, Hanagata N, Minowa T, Takemura T, et al. Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat Med 2009;15:798-801.  Back to cited text no. 28
29.Patel KP, Bergelson JM. Receptors identified for hand, foot and mouth virus. Nat Med 2009;15:728-9.  Back to cited text no. 29
30.Blomberg J, Lycke E, Ahlfors K, Johnsson T, Wolontis S, von Zeipel G. New enterovirus type associated with epidemic of aseptic meningitis and-or hand, foot, and mouth disease. Lancet 1974;2:112.  Back to cited text no. 30
31.Ishimaru Y, Nakano S, Yamaoka K, Takami S. Outbreaks of hand, foot,and mouth disease by enterovirus 71: high incidence of complication disorders of central nervous system. Arch Dis Child 1980;55:583-8.  Back to cited text no. 31
32.Melnick JL. Enterovirus type 71 infections: a varied clinical pattern sometimes mimicking paralytic poliomyelitis. Rev Infect Dis 1984;6(Suppl 2):S387-90.  Back to cited text no. 32
33.Gilbert GL, Dickson KE, Waters MJ, Kennett ML, Land SA, Sneddon M. Outbreak of enterovirus 71 infection in Victoria, Australia, with a high incidence of neurologic involvement. Pediatr Infect Dis J 1988;7:484-8.  Back to cited text no. 33
34.Alexander JP, Baden L, Pallansch MA, Anderson LJ. Enterovirus 71infections and neurologic disease: United States, 1977-1991. J Infect Dis 1994;169:905-8.  Back to cited text no. 34
35.da Silva EE, Winkler MT, Pallansch MA. Role of enterovirus 71 in acute flaccid paralysis after the eradication of poliovirus in Brazil. Emerg Infect Dis 1996;2:231-3.  Back to cited text no. 35
36.Shindarov LM, Chumakov MP, Voroshilova MK, Bojinov S, Vasilenko SM, Iordanov I, et al. Epidemiological, clinical and pathomorphological characteristics of epidemic poliomyelitis-like disease caused by enterovirus 71. J Hyg Epidemiol Microbiol Immunol 1979;23:284-95.  Back to cited text no. 36
37.Nagy G, Takatsy S, Kukan E, Mihaly I, Domok I. Virological diagnosis of enterovirus type 71 infections: experiences gained during an epidemic of acute CNS diseases in Hungary in 1978. Arch Virol 1982;71:217-27.  Back to cited text no. 37
38.Ang LW, Koh BK, Chan KP, Chua LT, James L, Goh KT. Epidemiology and control of hand, foot and mouth disease in Singapore, 2001-2007. Ann Acad Med Singapore 2009;38:106-12.  Back to cited text no. 38
39.WPRO. WHO warns of growing threat from severe form of hand, foot and mouth disease. Available at:   Back to cited text no. 39
40.Centers for Disease Control and Prevention (CDC). Deaths among children during an outbreak of hand, foot and mouth disease-Taiwan, Republic of China, April-July 1998. MMWR Morb Mortal Wkly Rep 1998;47:629-32.  Back to cited text no. 40
41.Yang C, Deng C, Wan J, Zhu L, Leng Q. Neutralizing antibody response in the patients with hand, foot and mouth disease to enterovirus 71 and its clinical implications. Virol J 2011;8:306.  Back to cited text no. 41
42.Zheng ZM, He PJ, Caueffield D, Neumann M, Specter S, Baker CC, et al. Enterovirus 71 isolated from China is serologically similar to the prototype E71 BrCr strain but differs in the 5′-noncoding region. J Med Virol 1995;47:161-7.  Back to cited text no. 42
43.Zhang Y, Zhu Z, Yang WZ, Ren J, Tan XJ, Wang Y, et al. An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of hand foot and mouth disease in Fuyang city of China. Virol J 2010;7:94.  Back to cited text no. 43
44.Fujimoto T, Chikahira M, Yoshida S, Ebira H, Hasegawa A, Totsuka A, et al. Outbreak of central nervous system disease associated with hand, foot, and mouth disease in Japan during the summer of 2000: detection and molecular epidemiology of enterovirus 71. Microbiol Immunol 2002;46:621-7.  Back to cited text no. 44
45.Jee YM, Cheon DS, Kim K, Cho JH, Chung YS, Lee J, et al. Genetic analysis of the VP1 region of human enterovirus 71 strains isolated in Korea during 2000. Arch Virol 2003;148:1735-46.  Back to cited text no. 45
46.Sarma N, Sarkar A, Mukherjee A, Ghosh A, Dhar S, Malakar R. Epidemic of hand, foot and mouth disease in West Bengal, India in August, 2007: A multicentric study. Indian J Dermatol 2009;54:26-30.  Back to cited text no. 46
[PUBMED]  Medknow Journal  
47.Cardosa MJ, Perera D, Brown BA, Cheon D, Chan HM, Chan KP, et al. Molecular epidemiology of human enterovirus 71 strains and recent outbreaks in the Asia-Pacific region: comparative analysis of the VP1 and VP4 genes . Emerg Infect Dis 2003;9:461-8.  Back to cited text no. 47
48.Chan LG, Parashar UD, Lye MS, Ong FG, Zaki SR, Alexander JP, et al. Deaths of Children during an Outbreak of Hand, Foot, and Mouth Disease in Sarawak, Malaysia: Clinical and Pathological Characteristics of the Disease. Clin Infect Dis 2000;31:678-83.  Back to cited text no. 48
49.Ho M, Chen ER, Hsu KH, Twu SJ, Chen KT, Tsai SF, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med 1999;341:929-35.  Back to cited text no. 49
50.Chen SC, Chang HL, Yan TR, Cheng YT, Chen KT. An eight-year study of epidemiologic features of enterovirus 71 infection in Taiwan. Am J Trop Med Hyg 2007;77:188-91.  Back to cited text no. 50
51.Lee TC, Guo HR, Su HJ, Yang YC, Chang HL, Chen KT. Diseases caused by enterovirus 71 infection. Pediatr Infect Dis J 2009;28:904-10.  Back to cited text no. 51
52.Sasidhran CK, Sugathan P, Agarwal R, Khare S, Lal S, Jayaram Paniker CK. Hand-Foot and Mouth disease in Calicut. Indian J Pediatr 2005;72:17-21.  Back to cited text no. 52
53.Dwibedi B, Kar BR, Kar SK. Hand, foot and mouth disease (HFMD): a newly emerging infection in Orissa, India. Natl Med J India 2010;23:313.  Back to cited text no. 53
54.Ghosh SK, Bandyopadhyay D, Ghosh A, Dutta A, Biswas S, Mandal RK, et al. Mucocutaneous features of hand, foot, and mouth disease: a reappraisal from an outbreak in the city of Kolkata. Indian J Dermatol Venereol Leprol 2010;76:564-6.  Back to cited text no. 54
[PUBMED]  Medknow Journal  
55.Mehta KI, Mahajan VK. Hand foot and mouth disease. Indian Pediatr 2010;47:345-6.  Back to cited text no. 55
56.Arora S, Arora G, Tewari V. Hand foot and mouth disease: emerging epidemics. Indian J Dermatol Venereol Leprol 2008;74:503-5.  Back to cited text no. 56
[PUBMED]  Medknow Journal  
57.Saoji VA. Hand, foot and mouth disease in Nagpur. Indian J Dermatol Venereol Leprol 2008;74:133-5.  Back to cited text no. 57
[PUBMED]  Medknow Journal  
58.Chen KT, Chang HL, Wang ST, Cheng YT, Yang JY. Epidemiologic features of hand-foot-mouth disease and herpangina caused by enterovirus 71 in Taiwan, 1998-2005. Pediatrics 2007;120:e244-52.  Back to cited text no. 58
59.McMinn PC. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev 2002;26:91-107.  Back to cited text no. 59
60.Shimizu H, Utama A, Yoshii K, Yoshida H, Yoneyama T, Sinniah M, et al. Enterovirus 71 from fatal and nonfatal cases of hand, foot and mouth disease epidemics in Malaysia, Japan and Taiwan in 1997-1998. Jpn J Infect Dis 1999;52:12-15.  Back to cited text no. 60
61.Wang LC, Tang SQ, Li YM, Zhao HL, Dong CH, Cui PF, et al. A comparison of the biological characteristics of EV71 C4 subtypes from different epidemic strains. Virol Sin 2010;25:98-106.  Back to cited text no. 61
62.Chang LY, Lin TY, Huang YC, Tsao KC, Shih SR, Kuo ML, et al. Comparison of enterovirus 71 and coxsackie-virus A16 clinical illnesses during the Taiwan enterovirus epidemic, 1998. Pediatr Infect Dis J 1999;18:1092-6.  Back to cited text no. 62
63.Ong KC, Devi S, Cardosa MJ, Wong KT. Formaldehyde-inactivated whole-virus vaccine protects a murine model of enterovirus 71 encephalomyelitis against disease. J Virol 2010;84:661-5.  Back to cited text no. 63
64.Xu J, Qian Y, Wang S, Serrano JM, Li W, Huang Z, et al. EV71: an emerging infectious disease vaccine target in the Far East? Vaccine 2010;28:3516-21.  Back to cited text no. 64
65.Zhang D, Lu J, Lu J. Enterovirus 71 vaccine: Close but still far. Int J Infect Dis 2010;14:e739-43.  Back to cited text no. 65
66.Huang SW, Hsu YW, Smith DJ, Kiang D, Tsai HP, Lin KH, et al. Reemergence of enterovirus 71 in 2008 in Taiwan: Dynamics of genetic and antigenic evolution from 1998 to 2008 . J Clin Microbiol 2009;47:3653-62.  Back to cited text no. 66
67.Ho HY, Cheng ML, Weng SF, Chang L, Yeh TT, Shih SR, et al. Glucose-6-phosphate dehydrogenase deficiency enhances enterovirus 71 infection . J Gen Virol 2008;89:2080-9.  Back to cited text no. 67
68.Chang LY, Hsiung CA, Lu CY, Lin TY, Huang FY, Lai YH, et al. Status of cellular rather than humoral immunity is correlated with clinical outcome of enterovirus 71. Pediatr Res 2006;60:466-71.  Back to cited text no. 68
69.Yang KD, Yang MY, Li CC, Lin SF, Chong MC, Wang CL, et al. Altered cellular but not humoral reactions in children with complicated enterovirus 71 infections in Taiwan . J Infect Dis 2001;183:850-6.  Back to cited text no. 69
70.Wang SM, Lei HY, Huang KJ, Wu JM, Wang JR, Yu CK, et al. Pathogenesis of Enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema. J Infect Dis 2003;188:564-70.  Back to cited text no. 70
71.Lin TY, Chang LY, Huang YC, Hsu KH, Chiu CH, Yang KD. Different proinflammatory reactions in fatal and non-fatal enterovirus 71 infections: Implications for early recognition and therapy. Acta Paediatr 2002;91:632-5.  Back to cited text no. 71
72.Lin TY, Hsia SH, Huang YC, Wu CT, Chang LY. Proinflammatory cytokine reactions in enterovirus 71 infections of the central nervous system. Clin Infect Dis 2003;36:269-74.  Back to cited text no. 72
73.Chang GH, Lin L, Luo YJ, Cai LJ, Wu XY, Xu HM, et al. Sequence analysis of six enterovirus 71 strains with different virulences in humans. Virus Res 2010;151:66-73.  Back to cited text no. 73
74.Ljubin-Sternak S, Slavic-Vrzic V, Vilibiæ-Èavlek T, Aleraj B, Gjenero-Margan I. Outbreak of hand, foot and mouth disease caused by Coxsackie A16 virus in a childcare centre in Croatia, February to March 2011. Euro Surveill 2011;16:pii=19875. Available online:   Back to cited text no. 74
75.Wang YF, Chou CT, Lei HY, Liu CC, Wang SM, Yan JJ, et al. A mouse-adapted enterovirus 71 strain causes neurological disease in mice after oral infection. J Virol 2004;78:7916-24.  Back to cited text no. 75
76.Diamond SE, Kirkegaard K. Clustered charged-to-alanine mutagenesis of poliovirus RNA-dependent RNA polymerase yields multiple temperature-sensitive mutants defective in RNA synthesis. J Virol 1994;68:863-76.  Back to cited text no. 76
77.Gromeier M, Alexander L, Wimmer E. Internal ribosomal entry site substitution eliminates neurovirulence in intergeneric poliovirus recombinants. Proc Natl Acad Sci USA 1996;93:2370-5.  Back to cited text no. 77
78.Pallansch M, Roos R. Enteroviruses: Polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses. In: Knipe DM, Howley PM, editors. Fields virology. 5 th ed. Philadelphia: Lippincot WandW-Wolters Kluwer; 2007. p. 839-93.  Back to cited text no. 78
79.Kirkegaard K, Baltimore D. The mechanism of RNA recombination in poliovirus. Cell 1986;47:433-43.  Back to cited text no. 79
80.Liu Y, Franco D, Paul AV, Wimmer E. Tyrosine 3 of poliovirus terminal peptide VPg(3B) has an essential function in RNA replication in the context of its precursor protein, 3AB. J Virol 2007;81:5669-84.  Back to cited text no. 80
81.Mueller S, Papamichail D, Coleman JR, Skiena S, Wimmer E. Reduction of the rate of poliovirus protein synthesis through large-scale codon deoptimisation causes attenuation of viral virulence by lowering specific infectivity. J Virol 2006;80:9687-96.  Back to cited text no. 81
82.Tung WH, Hsieh HL, Yang CM. Enterovirus 71 induces COX-2 expression via MAPKs, NF-kB, and AP-1 in SK-N-SH cells: Role of PGE2 in viral replication. Cell Signal 2010;22:234-46.  Back to cited text no. 82
83.McMinn P, Lindsay K, Perera D, Chan HM, Chan KP, Cardosa MJ. Phylogenetic analysis of enterovirus 71 strains isolated during linked epidemics in Malaysia, Singapore, and Western Australia. J Virol 2001;75:7732-8.  Back to cited text no. 83
84.Ghukasyan V, Hsu YY, Kung SH, Kao FJ. Application of fluorescence resonance energy transfer resolved by fluorescence lifetime imaging microscopy for the detection of enterovirus 71 infection in cells. J Biomed Opt 2007;12:024016  Back to cited text no. 84
85.Grandien M, Fosgren M, Ehrnst A. Enterovirus. In: Lennette EH, Lennette DA, Lennette ET, editors. Diagnostic Procedures for Viral, Rickettsial and Chlamydial Infections. 7 th ed. Washington, DC: American Public Health Association; 1995. p. 279-98.  Back to cited text no. 85
86.Tran CB, Nguyen HT, Phan HT, Tran NV, Wills B, Farrar J, et al. The Seroprevalence and Seroincidence of Enterovirus71 Infection in Infants and Children in Ho Chi Minh City, Viet Nam. PLoS One 2011;6:e21116.  Back to cited text no. 86
87.Chang LY, King CC, Hsu KH, Ning HC, Tsao KC, Li CC, et al. Risk Factors of Enterovirus 71 Infection and Associated Hand, Foot, and Mouth Disease/Herpangina in Children During an Epidemic in Taiwan. Pediatrics 2002;109:e88.  Back to cited text no. 87
88.Yu N, Guo M, He SJ, Pan YX, Chen XX, Ding XX. Evaluation of human enterovirus 71 and coxsackievirus A16 specific immunoglobulin M antibodies for diagnosis of hand-foot-and-mouth disease. Virol J 2012;9:12.  Back to cited text no. 88
89.Xu F, Yan Q, Wang H, Niu J, Li L, Zhu F, et al. Performance of detecting IgM antibodies against enterovirus 71 for early diagnosis. PLoS One 2010;5:e11388.  Back to cited text no. 89
90.Wang SY, Lin TL, Chen HY, Lin TS. Early and rapid detection of enterovirus 71 infection by an IgM-capture ELISA. J Virol Methods 2004;119:37-43.  Back to cited text no. 90
91.Xu F, He D, He S, Wu B, Guan L, Niu J, et al. Development of an IgM-capture ELISA for Coxsackievirus A16 infection. J Virol Methods 2011;171:107-10.  Back to cited text no. 91
92.Brown BA, Kilpatrick DR, Oberste MS, Pallansch MA. Serotype-specific identification of enterovirus 71 by PCR. J Clin Virol 2000;16:107-12.  Back to cited text no. 92
93.Leitch EC, Harvala H, Robertson I, Ubillos I, Templeton K, Simmonds P. Direct identification of human enterovirus serotypes in cerebrospinal fluid by amplification and sequencing of the VP1 region. J Clin Virol 2009;44:119-24.  Back to cited text no. 93
94.Oberste MS, Nix WA, Maher K, Pallansch MA. Improved molecular identification of enteroviruses by RT-PCR and amplicon sequencing. J Clin Virol 2003;26:375-7.  Back to cited text no. 94
95.Thao NT, Ngoc NT, Tú PV, Thúy TT, Cardosa MJ, McMinn PC, et al. Development of a multiplex polymerase chain reaction assay for simultaneous identification of human enterovirus 71 and coxsackievirus A16. J Virol Methods 2010;170:134-9.  Back to cited text no. 95
96.Naze F, Le Roux K, Schuffenecker I, Zeller H, Staikowsky F, Grivard P, et al. Laurent P. Simultaneous detection and quantitation of Chikungunya, dengue and West Nile viruses by multiplex RT-PCR assays and dengue virus typing using high resolution melting. J Virol Methods 2009;162:1-7.   Back to cited text no. 96
97.Wang W, Ren P, Sheng J, Mardy S, Yan H, Zhang J, et al. Simultaneous detection of respiratory viruses in children with acute respiratory infection using two different multiplex reverse transcription-PCR assays. J Virol Methods 2009;162:40-5.  Back to cited text no. 97
98.Ministry of Health, Singapore: Surveillance of hand, foot and mouth disease in Singapore.Epidemiol Bull 2000;26:3-5.  Back to cited text no. 98
99.Wu TN, Tsai SF, Li SF, Lee TF, Huang TM, Wang ML, et al. Sentinel surveillance for enterovirus 71, Taiwan, 1998. Emerg Infect Dis 1999;5:458-60.  Back to cited text no. 99
100.Barnes D, Kunitomi M, Vignuzzi M, Saksela K, Andino R. Harnessing endogenous miRNAs to control virus tissue tropism as a strategy for developing attenuated virus vaccines. Cell Host Microbe 2008;4:239-48.  Back to cited text no. 100
101.Chen HF, Chang MH, Chiang BL, Jeng ST. Oral immunization of mice using transgenic tomato fruit expressing VP1 protein from enterovirus 71. Vaccine 2006;24:2944-51.  Back to cited text no. 101
102.Wu CN, Lin YC, Fann C, Liao NS, Shih SR, Ho MS. Protection against lethal enterovirus 71 infection in newborn mice by passive immunization with subunit VP1vaccines and inactivated virus. Vaccine 2001;20:895-904.  Back to cited text no. 102
103.Tung WS, Bakar SA, Sekawi Z, Rosli R. DNA vaccine constructs against enterovirus 71 elicit immune response in mice. Genet Vaccines Ther 2007;5:6.  Back to cited text no. 103
104.Chen HL, Huang JY, Chu TW, Tsai TC, Hung CM, Lin CC, et al. Expression of VP1 protein in the milk of transgenic mice: a potential oral vaccine protects against enterovirus 71 infection. Vaccine 2008;26:2882-9.  Back to cited text no. 104
105.Chung CY, Chen CY, Lin SY, Chung YC, Chiu HY, Chi WK, et al. Enterovirus 71 virus-like particle vaccine: Improvedproduction conditions for enhanced yield. Vaccine 2010;28:6951-7.  Back to cited text no. 105
106.Arita M, Shimizu H, Nagata N, Ami Y, Suzaki Y, Sata T, et al. Temperature-sensitive mutants of enterovirus 71 show attenuation in cynomolgus monkeys. J Gen Virol 2005;86:(Pt 5):1391-401.  Back to cited text no. 106
107.Chan KP, Goh KT, Chong CY, Teo ES, Lau G, Ling AE. Epidemic Hand, Foot and Mouth Disease Caused by Human Enterovirus 71, Singapore. Emerg Infect Dis 2003;9:78-85.  Back to cited text no. 107
108.Lal SK, Kumar P, Yeo WM, Kar-Roy A, Chow VT. The VP1 protein of human enterovirus 71 selfassociates via an interaction domain spanning amino acids 66-297. J Med Virol 2006;78:582-90.  Back to cited text no. 108
109.Sarma N. Pediatric Dermatology. In: Dermatology Jewels- An Approach to Diagnosis. Gurgaon: MacMilan Medical Com; 2011. p. 12-41.  Back to cited text no. 109


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