• Clinical and Experimental Pediatrics
• /
• 제59권10호
• /
• pp.395-401
• /
• 2016

Since the outbreak of the enterovirus 71 (EV71) infection in Malaysia in 1997, large epidemics of EV71 have occurred in the Asia-Pacific region. Many children and infants have died from serious neurological complications during these epidemics, and EV71 infection has become a serious public health problem in these areas. EV71 infection causes hand, foot and mouth disease (HFMD) in children, and usually resolves spontaneously. However, EV71 occasionally involves the central nervous system (CNS), and induces diverse neurological complications such as brainstem encephalitis, aseptic meningitis, and acute flaccid paralysis. Among those complications, brainstem encephalitis is the most critical neurological manifestation because it can cause neurogenic pulmonary hemorrhage/edema leading to death. The characteristic clinical symptoms such as myoclonus and ataxia, cerebrospinal fluid (CSF) pleocytosis, and brainstem lesions on magnetic resonance imaging, in conjunction with the skin rash of HFMD and the isolation of EV71 from a stool, throat-swab, or CSF sample are typical findings indicating CNS involvement of EV71 infection. Treatment with intravenous immunoglobulin and milrinone are recommended in cases with severe neurological complications from EV71 infection, such as brainstem encephalitis. Despite the recent discovery of receptors for EV71 in human cells, such as the scavenger receptor B2 and P-selection glycoprotein ligand 1, it is not known why EV71 infection predominantly involves the brainstem. Recently, 3 companies in China have completed phase III clinical trials of EV71 vaccines. However, the promotion and approval of these vaccines in various countries are problems yet to be resolved.

• Clinical and Experimental Pediatrics
• /
• 제53권5호
• /
• pp.616-622
• /
• 2010

Enterovirus 71 (EV71) has been recognized as a frequent cause of epidemics of hand-foot-and-mouth disease (HFMD) associated with severe neurological symptoms. In the spring of 2009, HFMD was epidemic in Korea. Severe cases with complication, including death, have been reported and it has become a public health issue. Most symptomatic EV71 infections commonly result in HFMD or herpangina. These clinical manifestations can be associated with neurologic syndromes frequently. Neurologic syndromes observed in EV71 include meningitis, meningoencephalomyelitis, poliomyelitis-like paralytic disease, Guillain-Barr$\acute{e}$ syndrome, transverse myelitis, cerebellar ataxia, opsoclonus-myoclonus syndrome, benign intracranial hypertension, and brainstem encephalitis. Examinations for EV 71 were performed from the stools, respiratory secretion or CSF of the children by realtime PCR. Gene analysis showed that most of them were caused by EV71 subgenotype C4a which was prevalent in China, 2008. Public health measures including personal and environmental hygiene, must to target daycare centers, kindergartens, and schools where highly susceptible children congregate. To prevent the spread of infection, preschools where transmission persists for more than 2 incubation periods, have been recommended for closure, and trigger criteria for voluntary closure was instituted. During closure, operators are to thoroughly clean the centers before they are allowed to reopen. In addition, parents are advised to ensure that their children adopt a high standard of personal hygiene and to keep the infected child at home until full recovery. Because the outbreaks occur in a cyclical pattern, surveillance system to predict next outbreaks and adequate public health measures to control need to be planned for future. Control of EV71 epidemics through surveillance and public health intervention needs to be maintained in Korea. Future research should focus on understanding of EV71 virulence, identification of the receptor(s) for EV71, development of antiviral agents and development of vaccine.

• Journal of Microbiology and Biotechnology
• /
• 제30권1호
• /
• pp.38-43
• /
• 2020

Hand, foot, and mouth disease (HFMD) is caused by enterovirus 71 (EV71) in infants and children under six years of age. HFMD is characterized by fever, mouth ulcers, and vesicular rashes on the palms and feet. EV71 also causes severe neurological manifestations, such as brainstem encephalitis and aseptic meningitis. Recently, frequent outbreaks of EV71 have occurred in the Asia-Pacific region, but currently, no effective antiviral drugs have been developed to treat the disease. In this study, we investigated the antiviral effect of salvianolic acid B (SalB) on EV71. SalB is a major component of the Salvia miltiorrhiza root and has been shown to be an effective treatment for subarachnoid hemorrhages and myocardial infarctions. HeLa cells were cultured in 12-well plates and treated with SalB (100 or 10 ㎍/ml) and 10⁶ PFU/ml of EV71. SalB treatment (100 ㎍/ml) significantly decreased the cleavage of the eukaryotic eIF4G1 protein and reduced the expression of the EV71 capsid protein VP1. In addition, SalB treatment showed a dramatic decrease in viral infection, measured by immunofluorescence staining. The Akt signaling pathway, a key component of cell survival and proliferation, was significantly increased in EV71-infected HeLa cells treated with 100 ㎍/ml SalB. RT-PCR results showed that the mRNA for anti-apoptotic protein Bcl-2 and the cell cycle regulator Cyclin-D1 were significantly increased by SalB treatment. These results indicate that SalB activates Akt/PKB signaling and inhibits apoptosis in infected HeLa cells. Taken together, these results suggest that SalB could be used to develop a new therapeutic drug for EV71-induced HFMD.

• Pediatric Infection and Vaccine
• /
• 제30권2호
• /
• pp.91-96
• /
• 2023

Enterovirus (EV) 71은 무균성 뇌수막염 환자로부터 처음 분리된 이후로 주로 수족구병으로 나타났으며 소아에서 전형적인 피부 발진, 구강 병변 및 발열을 동반한다. 피부 발진은 수포성으로 손과 발에 영향을 미치고 수포가 없는 반구진 양상일 수도 있으며 특히 어린 소아 및 유아에서는 팔꿈치, 무릎 그리고 엉덩이를 침범할 수도 있다. EV 71 감염으로 인한 신경학적 합병증은 매우 드물지만 주로 뇌간 뇌염으로 나타난다. 대근육 운동 발달 지연 이외에 건강했던 30개월 된 남아가 발열, 혼수 증상으로 내원하였고 입원 후 무호흡 및 호흡 정지 증상이 동반되어 뇌척수액 검사 및 뇌 MRI, 뇌파검사를 하였다. 검사 결과 뇌간 뇌염 및 미만성 대뇌 기능 장애가 확인되었고 비인두도말 및 대변 검체에서 EV 71이 검출되었으며 유전자 검사에서 myoclonic epilepsy with ragged red fiber syndrome이 확인되었다. 저자들은 기저미토콘드리아 질환으로 인해 인후 및 피부 발진의 증상 없이 발열 하루 만에 빠르게 진행되는 EV 71 감염으로 인한 뇌간 뇌염 1예를 보고하는 바이다.

• Journal of Applied Biological Chemistry
• /
• 제51권3호
• /
• pp.123-127
• /
• 2008

Anti-enterovirus 71 (EV 71) activities of fifteen herb plant species extracts were examined by SRB assay, among which Origanum vulgare and Rosmarinus officinalis (Anna Rosemary) extracts exhibited the activities with $IC_{50}$ of 8.28 and $8.17\;{\mu}g/mL$, respectively. Their 50% cytotoxicity concentrations ($CC_{50}$) were 691.89 and $1104.19\;{\mu}g/mL$, and the therapeutic indices were 83.56 and 135.15, respectively. Amantadine (positive control) showed anti-EV 71 activity with 50% inhibitory concentration and $CC_{50}$ of 4.46 and $145.22\;{\mu}g/mL$, respectively. Addition of the methanol extracts of O. vulgare and R. officinalis (Anna Rosemary) in EV 71-infected Vero cells strongly inhibited the formation of visible cytopathic effects without changing the normal morphology of the cells. These results indicate that methanol extracts of O. vulgare and R. officinalis (Anna Rosemary) may contain antiviral compound inhibiting the EV 71 replication.

• Biomolecules & Therapeutics
• /
• 제24권5호
• /
• pp.552-558
• /
• 2016

Severe complications associated with EV71 infections are a common cause of neonatal death. Lack of effective therapeutic agents for these infections underlines the importance of research for the development of new antiviral compounds. In the present study, the anti-EV71 activity of norwogonin, oroxylin A, and mosloflavone from Scutellaria baicalensis Georgi was evaluated using a cytopathic effect (CPE) reduction method, which demonstrated that all three compounds possessed strong anti-EV71 activity and decreased the formation of visible CPEs. Norwogonin, oroxylin A, and mosloflavone also inhibited virus replication during the initial stage of virus infection, and they inhibited viral VP2 protein expression, thereby inhibiting viral capsid protein synthesis. However, ribavirin has a relatively weaker efficacy compared to the other drugs. Therefore, these findings provide important information that will aid in the utilization of norwogonin, oroxylin A, and mosloflavone for EV71 treatment.

• Biomolecules & Therapeutics
• /
• 제22권1호
• /
• pp.41-46
• /
• 2014

Enterovirus 71 (EV71) is the predominant cause of hand, foot and mouth disease (HFMD). The antiviral activity of hederasaponin B from Hedera helix against EV71 subgenotypes C3 and C4a was evaluated in vero cells. In the current study, the antiviral activity of hederasaponin B against EV71 C3 and C4a was determined by cytopathic effect (CPE) reduction method and western blot assay. Our results demonstrated that hederasaponin B and 30% ethanol extract of Hedera helix containing hederasaponin B showed significant antiviral activity against EV71 subgenotypes C3 and C4a by reducing the formation of a visible CPE. Hederasaponin B also inhibited the viral VP2 protein expression, suggesting the inhibition of viral capsid protein synthesis.These results suggest that hederasaponin B and Hedera helix extract containing hederasaponin B can be novel drug candidates with broad-spectrum antiviral activity against various subgenotypes of EV71.

• Pediatric Infection and Vaccine
• /
• 제16권1호
• /
• pp.73-79
• /
• 2009

목 적: 장 바이러스 감염은 소아에서 중요한 바이러스 감염중 하나이며 우리 나라에서도 최근 장 바이러스 71형의 감염이 산발적으로 보고되고 있기에 장 바이러스 감염 환아들의 임상양상을 분석하고, 또한 그 중 장 바이러스 71감염으로 확인된 환아들의 임상양상과 장 바이러스 71형이 아닌 장 바이러스 감염 환아들의 임상양상을 비교 분석하고자 하였다. 방 법: 2000년 4월 1일부터 6월 30일까지 제주의료원 소아과 외래를 방문하거나 입원한 소아 239명을 대상으로, 바이러스를 확인하기 위하여 바이러스 배양검사와 RT-PCR 방법을 사용하였고 EV71 확인을 위해서 VP1 유전자의 유전자 분석을 시행하였다. 환자들의 의무기록 분석을 통하여 성별, 연령, 발병 시기 및 임상 양상을 조사하였고 환자들을 주된 진단명에 따라 A군(피부 발진이나 구협염 등의 장 바이러스 감염 증세를 보이면서 식욕부진, 복통, 구토와 설사등 급성 위장관염 증세가 주된 환자들), B군(피부 발진이나 구협염 등의 장 바이러스 감염 증세를 보이면서 하기도 감염 증세가 주된 환자들), C군(상기도 감염증세와 함께 구내 궤양이나 피부 발진 등을 보이는 환자들), D군(주로 두통, 마비, 수막염 증세 등 신경학적 증상을 보이는 환자들)으로 나누어 임상양상을 분석하였다. 결 과: 전체 87명 중 A군은 16명(18%), B군은 21명(24 %), C군은 42명(48%), D군은 8명(9%)이었으며 전체(87명)적으로 포진성 구협염은 63명(71%), 발진은 40명(46%), 발열 증상은 50명(57%)에서 있었고 평균 발열 기간은 3.3일이었다. 장 바이러스 71형 양성 반응 환자 11명에서 A군이 1명, B군이 2명, C군 7명, D군이 1명이었으며 피부 발진 8명(73%), 포진성 구협염 9명(82%), 발열 증상이 8명(73%)로 나타났고 평균 발열기간은 2.71일이었다. 위장관 증상은 8명(73%)에서 나타났고 신경학적 증상을 보인 환자는 2명 있었다. 결 론: 2000년 4월부터 6월까지 3개월 동안 제주도 소아에서 발생한 장 바이러스 감염은 특징적인 장바이러스 감염의 임상 소견을 보인 수족구병이나 구협염 및 무균성 수막염 외에도 하기도 감염, 급성 위장관염, 등과 함께 많은 경우에 동반되었다. 장바이러스 중 심한 중추신경계 감염으로 치명적인 결과를 자주 초래하는 EV71 감염도 드물지 않게 관찰되었으나 다른 장바이러스 감염과의 임상양상의 중증도에는 차이를 보이지 않는 특징을 보였다.

• Biomolecules & Therapeutics
• /
• 제31권3호
• /
• pp.350-358
• /
• 2023

Hand-foot-and-mouth disease (HFMD) is a viral infectious disease that occurs in children under 5 years of age. Its main causes are coxsackievirus (CV) and enterovirus (EV). Since there are no efficient therapeutics for HFMD, vaccines are effective in preventing the disease. To develop broad coverage against CV and EV, the development of a bivalent vaccine form is needed. The Mongolian gerbil is an efficient and suitable animal model of EV71 C4a and CVA16 infection used to investigate vaccine efficacy following direct immunization. In this study, Mongolian gerbils were immunized with a bivalent inactivated EV71 C4a and inactivated CVA16 vaccine to test their effectiveness against viral infection. Bivalent vaccine immunization resulted in increased Ag-specific IgG antibody production; specifically, EV71 C4a-specific IgG was increased with medium and high doses and CVA16-specific IgG was increased with all doses of immunization. When gene expression of T cell-biased cytokines was analysed, Th1, Th2, and Th17 responses were found to be highly activated in the high-dose immunization group. Moreover, bivalent vaccine immunization mitigated paralytic signs and increased the survival rate following lethal viral challenges. When the viral RNA content was determined from various organs, all three doses of bivalent vaccine immunization were found to significantly decrease viral amplification. Upon histologic examination, EV71 C4a and CVA16 induced tissue damage to the heart and muscle. However, bivalent vaccine immunization alleviated this in a dose-dependent manner. These results suggest that the bivalent inactivated EV71 C4a/CVA16 vaccine could be a safe and effective candidate HFMD vaccine.

• Clinical and Experimental Pediatrics
• /
• 제53권5호
• /
• pp.639-643
• /
• 2010

Purpose: Hand-foot-mouth disease (HFMD) is a common viral illness in children, which is usually mild and self-limiting. However, in recent epidemics of HFMD in Asia, enterovirus 71 (EV71) has been recognized as a causative agent with severe neurological symptoms with or without cardiopulmonary involvement. HFMD was epidemic in Korea in the spring of 2009. Severe cases with complications including death have been reported. The clinical characteristics in children with neurologic manifestations of EV71 were studied in Ewha Womans University Mokdong Hospital. Methods: Examinations for EV71 were performed from the stools, respiratory secretion or CSF of children who presented neurologic symptoms associated with HFMD by realtime PCR. Clinical and radiologic data of the patients were collected and analyzed. Results: EV71 was isolated from the stool of 16 patients but not from respiratory secretion or CSF. Among the 16 patients, meningitis (n=10) was the most common manifestation, followed by Guillain-Barre syndrome (n=3), meningoencephalitis (n=2), poliomyelitis-like paralytic disease (n=1), and myoclonus (n=1). Gene analysis showed that most of them were caused by EV71 subgenotype C4a, which was prevalent in China in 2008. Conclusion: Because EV71 causes severe complications and death in children, a surveillance system to predict upcoming outbreaks should be established and maintained and adequate public health measures are needed to control disease.