Clinical significance of inflammatory factors in severe EV71 hand-foot-and-mouth disease / 中国感染控制杂志

Objective To investigate the clinical significance of 5 kinds of inflammatory factors (MCP 1,IL 1β,IL-18,HMGB1,and IL-10) in severe EV71 hand-foot-and-mouth disease (HFMD).Methods Hospitalized children who were diagnosed with severe EV71 HFMD in a hospital in March August,2014 were as HFMD group,healthy children who underwent physical examination in outpatient department of the same hospital during the sameperiod were as control group,changes in expression levels of peripheral blood MCP-1,IL-1β,IL-18,HMGB1,and IL-10 of both groups were dynamically observed,clinical data of HFMD group were collected.Results There were 102 children in HFMD group,the average age was (2.18 ± 0.91) years old,80.39％ of whom were ≤3 years old;there were 77,16,and 9 cases in HFMD group at stage 2,3,and 4 respectively at admission.77,52,21,and 88 cases went through stage 2,3,4,and 5 respectively.Expression levels of 5 kinds of inflammatory factors at stage 2,3,and 4 in HFMD group were compared respectively with control group,differences were all statistically significant(all P＜0.05);expression levels of IL-10 at stage 3 and 4 in HFMD group were not significantly different (P＞0.05).In HFMD group,the expression levels of HMGB1 of stage 2,3 progression groups were both higher than recovery group(both P＜0.05).The expression levels of 5 kinds of inflammatory factors in the death group and survival group at admission were all significantly different (all P＜0.05).Conclusion The expression levels of MCP 1,HMGB1,IL-1β,IL-10,and IL-18 are closely related to the severity of HFMD,and has certain clinical significance for the prognosis of children.HMBG1 has certain predictive value in the prognosis of HFMD.

The association between toll-like receptor 7 single nucleotide polymorphisms and severity of hand, foot and mouth disease caused by enterovirus 71 infection / 中华传染病杂志

Objective To explore the association between toll-like receptor 7 (TLR7) single nucleotide polymorphisms (SNP) and susceptibility of hand, foot and mouth disease caused by enterovirus (EV)71 infection.Methods The genotype of SNP (rs179019 and rs3853839) was determined in 775 EV7l-infected cases (including 439 mild cases and 336 severe cases) and 748 healthy control cases with TaqMan assay.The difference of allele frequencies was compared.The difference of TLR7 mRNA expression in peripheral blood mononuclear cells (PBMCs) derived from different SNP genotype carriers was detected.PBMCs derived from different SNP genotype carriers were stimulated by imiquimod and the TLR7-specific interferon-α(IFN-α) and interleukin-6 (IL-6) secretions were detected.Logistic regression was used to analyze for genotype frequency.Results The frequencies of rs3853839 genotype CC and CG in female patients of severe group were significantly higher than mild group (rs3853839 GC: OR=0.36,95%CI:0.14-0.82, P=0.01;rs3853839 CC: OR=0.19,95%CI:0.11-0.69,P=0.01).In addition, the frequency of rs3853839 genotype C in severe male group was significantly higher compared with that in mild group (OR=0.35,95%CI:0.19-0.63, P=0.01).Female carriers with rs3853839 genotype CC had significantly lower TLR7 mRNA expression than genotype GC and GG (CC vs GG: P=0.005;CC vs GC: P=0.016).Male carriers with rs3853839 genotype C also had significantly lower TLR7 mRNA expression than genotype G (C vs G: P=0.004).After stimulation of imiquimod, the expression of IFN-α (CC vs GG, P=0.001;CC vs GC: P=0.026) and IL-6 productions (CC vs GG: P=0.001;CC vs GC: P=0.011) were significantly lower in female carriers with rs3853839 genotype CC.The same patterns were observed in male carriers with rs3853839 genotype CC (IFN-α: P=0.003;IL-6: P=0.018).Conclusions The rs3853839C allele is the risk factor of severe infection of EV71, which may be due to specific cytokine profiles in rs3853839C allele carriers in children.

Research progress of human enterovirus 71 vaccine / 中华实用儿科临床杂志

Human enterovirus 71 (HEV71) is a major causative agent of hand,foot and mouth disease.Children infection with HEV71 can lead to series of neurological complications including aseptic meningitis,cerebral ataxia and even fatal outcomes.During recent decades,epidemic of hand,foot and mouth disease have occurred in many countries and regions in the world,which has become a major public health problem for children's health.There are no specific antiviral drugs for HEV71 infection,so it is necessary to develop safe and effective vaccine.In recent years,the research on HEV71 vaccine has made a breakthrough,and this article reviews the research progress of the vaccine.

Enterovirus 71 infection and neurological complications / 소아과

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 Profile of Hand, Foot, and Mouth Disease and its Associated Complications among Children in Shimoga City, Southern Karnataka: A Hospital-Based Study.

Hand, foot, and mouth disease (HFMD) is one of the important public health problems. It has become a common childhood illness in our part of the country. In most instances, this is a mild self-limiting illness. The affected children are often given outpatient care. However, over the last decade, HFMD has emerged as a growing health problem in Asian countries following frequent outbreaks of deaths associated with HFMD caused by a more virulent member of human enterovirus (HEV), namely, HEV71. A hospital-based descriptive study about the clinical presentations and complications of HFMD at the hospitals of Shimoga city between March 2013 and August 2013 is documented and presented here. HFMD was more common in the 1-3-year old age group, with aseptic meningitis being the most common complication. Surveillance of HFMD must be maintained as there is no effective chemoprophylaxis or vaccine available.

Systemic antibody response to nano-size calcium phospate biocompatible adjuvant adsorbed HEV-71 killed vaccine

PURPOSE: Since 1980s, human enterovirus-71 virus (HEV-71) is one of the common infectious disease in Asian Pacific region since late 1970s without effective commercial antiviral or protective vaccine is unavailable yet. The work examines the role of vaccine adjuvant particle size and the route of administration on postvaccination antibody response towards HEV-71 vaccine adsorbed to calcium phosphate (CaP) adjuvant. MATERIALS AND METHODS: First, CaP nano-particles were compared to a commercial micro-size and vaccine alone. Secondly, intradermal reduced dosage was compared to the conventional intramuscular immunization. Killed HEV-71 vaccines adsorbed to CaP nano-size (73 nm) and commercial one of micro-size (1.7 microm) were administered through intradermal, intramuscular, rabbits received vaccine alone and unvaccinated animals. RESULTS: CaP nano-particles adsorbed HEV-71 vaccine displayed higher antibody than the micro-size or unadsorbed vaccine alone, through both parenteral immunization routes. Moreover, the intradermal route (0.5 microg/mL) of 0.1-mL volume per vaccine dose induced equal IgG antibody level to 1.0-mL intramuscular route (0.5 microg/mL). CONCLUSION: The intradermal vaccine adsorbed CaP nano-adjuvant showed safer and significant antibody response after one-tenth reduced dose quantity (0.5 microg/mL) of only 0.1-mL volume as the most suitable protective, cost effective and affordable formulation not only for HEV-71; but also for developing further effective vaccines toward other human pathogens.

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

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.

Etiologic and epidemiologic analysis of hand, foot, and mouth disease in Guangzhou city: a review of 4,753 cases

OBJECTIVES: This study aimed to review etiological and epidemiological data for hand, foot, and mouth disease (HFMD) cases that occurred between 2008 and 2010 in Guangzhou City, to help develop and implement precautionary measures applicable for future outbreaks. METHODS: The characteristics of 4,753 HFMD episodes were retrospectively reviewed in 4,636 patients reported between 2008 and 2010 by the Guangdong Women and Children's Hospital, which is the national enterovirus monitoring agent and the designated hospital in China for treating severe HFMD. RESULTS: Out of 4,753 incident episodes reviewed, 525 patients were hospitalized; 60% were males. Most patients (93.8%) were children under 5 years old, with a median age at onset of 2.4 years. HFMD incidence peaked in April/May and September/October. From the total, 1,067 (22.4%) infections were positive for human enterovirus 71 (HEV71), 1,094 (23.0%) were positive for coxsackievirus A16 (CA16), and 941 (19.8%) were positive for other common enteroviruses. In contrast, 1,666 (35.0%) cases were negative to HEV71, CA16, and other common enteroviruses. Cross-correlation coefficients demonstrated associations between the number of cases, seasonal temperatures, and humidity. Among hospitalized cases, HEV71 was positive in 261 (24.5%), and 42 (3.9%) critical cases were positive for HEV71. CONCLUSION: Seasonal fluctuations and HEV71 and CA16 were the two key factors influencing the Guangzhou HFMD epidemic. The infection predominantly affected children younger than 5 years old.

A case of Enterovirus 71 Infection Presented with Acute Flaccid Paralysis in Jeju Island / 대한소아신경학회지

Most human enterovirus 71 (EV71) infections present with mild conditions such as hand-foot-mouth disease or herpangina. However, EV71 can invade the central nervous system, causing neurologic diseases such as brainstem encephalitis, meningitis and acute flaccid paralysis despite the near complete eradication of polioviruses. Neurological complications from EV71 infection occur within a few days and can lead to death even though rare. There is no report for EV71 infection with severe neurological manifestation in Jeju Island so far. We therefore report a case of EV 71 infection with bilateral acute flaccid paralysis for the first time in Jeju Island with review of related articles.

A Case of Enterovirus 71 Infection Presented with Acute Flaccid Paralysis / 대한소아신경학회지

Hand-foot-mouth disease (HFMD) is characterized by distinctive skin lesions on the hand, foot, and mouth and in general, recovery occurs within one week. However, in cases of HFMD by enterovirus 71 (EV71) infection, the development of neurologic complications such as brainstem encephalitis, acute flaccid paralysis, and aseptic meningitis has been common. Moreover, it has been reported that some patients with neuologic complications have expired in severe cases. Here, we report a case of EV71 infection presented with acute flaccid paralysis of a single similar to paralytic poliomyelitis.

Enterovirus 71-associated hand, foot and mouth diseases with neurologic symptoms, a university hospital experience in Korea, 2009 / 소아과

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.

Positive Selection Analysis of VP1 Genes of Worldwide Human Enterovirus 71 Viruses / 中国病毒学·英文版

Human enterovirus 71 viruses have been long circulating throughout the world. In this study, we performed a positive selection analysis of the VP1 genes of capsid proteins from Enterovirus 71 viruses. Our results showed that although most sites were under negative or neutral evolution, four positions of the VP1 genes were under positive selection pressure. This might account for the spread and frequent outbreaks of the viruses and the enhanced neurovirulence. In particular, position 98 might be involved in neutralizing antibodies, modulating the virus-receptor interaction and enhancing the virulence of the viruses. Moreover, both positions 145 and 241 might correlate to determine the receptor specificity. However, these positions did not display much difference in amino acid polymorphism. In addition, no position in the VP1 genes of viruses isolated from China was under positive selection.