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Human Enterovirus 71 Disease In Sarawak, Malaysia: A Prospective Clinical, Virological, and Molecular Epidemiological Study
... The co-circulation of different serotypes and alternation between enterovirus A71 (EV-A71) and coxsackievirus A (CV-A ) was commonly observed during HFMD epidemics [1][2][3][4]. However, co-infection is not a primary cause of severe forms [5,6]. Epidemics could be due to both the accumulation of susceptible individuals in the community, patients are mostly young children under five and introduction of new genotypes or strains [7]. ...
... The theoretical time of the end of a wave is therefore t=+∞. 6 The parameter is an under estimation of this date. It is defined as: τ * = inf{t/|Xm(t) − N| < ϵ}. ...
An HFMD outbreak spread over the city of Hải Phòng from Summer 2011 to Autumn 2012. This epidemic was chosen because it was the very first HFMD epidemic in North Vietnam, eliminating thus interferences with previous outbreaks. This epidemic displayed 3 separate waves. A complete dataset was collected for more than 9500 patients during this period, which enabled us to analyze this epidemic at different scales. Access to the healthcare system was crucial during this period, with a reorganization of the system in February-March 2012. An analysis at commune level enables us to track the epidemic along certain communication routes. The three-waves structure reveals a wide disparity at district level. We develop a mathematical model showing high accuracy at the adjustment of data for both the total number of cases and for the number of cases per week. As a consequence, the model was able to accurately determine the dates of beginning and end of each wave and to show that they overlapped. Using mathematical functions associated with this model, it was possible to calculate the probability for a patient to belong to a specific wave.
... 74.5% had mild HFMD; 11.5% had severe HFMD with no CNS complication; and 14% had HFMD with CNS involvement. There are three (0.4%) out of 725 children were died throughout the study (7). ...
... HEV-71 caused large outbreaks of hand-foot-and-mouth disease with central nervous system complication (CNS). Children at young age were prone to have severe fever, vomiting and hyperglycaemia when they were According to Table 3, patients with CNS disease were more likely to have symptoms like fever, dehydration, unconsciousness, or neck stiffness instead of mouth ulcers which more prone towards non-CNS HFMD patient (7). CNS pathology has been considered to contribute for the disease progress. ...
A major outbreak of HFMD virus reported in Sarawak, Malaysia involving 29 fatal cases. This this study explore, epidemiology and clinical characteristics of HFMD in Sarawak which aims to study the trend of HFMD outbreak in Sarawak as well to create awareness
among the community on the severity of HFMD. A search strategy was employed to obtain relates study. Only two studies fit the inclusion criteria that focused on the HFMD outbreak in Sarawak where the recruited patients were children <6 years old. Those studies explain
clinical symptoms and duration of HFMD were due to rapid onset and progression of the brain-stem encephalitis. Apart from that, abnormal coagulation profile and gastrointestinal profile may contribute to the disease progression.
Keywords: HFMD, Sarawak, Malaysia, virus
... The outbreak in Malaysia in 1997 was caused by a mixture of EV-A71 subgenotypes B3, B4, C1, and C2, of which B3 had the highest prevalence; however, subgenotypic replacements with B4 and C1 were observed in 2000 (Herrero et al., 2003;Huang et al., 2011;Yip et al., 2013;NikNadia et al., 2016). In addition, genotypic replacement with EV-A71 B5 was first documented in Malaysia in the 2003 outbreak (Ooi et al., 2007). In Taiwan, where the large outbreak in 1998 was caused by EV-A71 C2, a shift to the B4 subgenotype was recognized in the 2000 outbreak Kung et al., 2007;Chia et al., 2014). ...
... This finding implies that these B5 strains might have different origins. EV-A71 subgenotype B5 was predominantly found in Malaysia and Japan in 2003 (Mizuta et al., 2005;Ooi et al., 2007), Singapore in 2006(Ang et al., 2009Wu et al., 2010;Huang et al., 2015a,b), and Taiwan in 2008(Huang et al., 2009Wu et al., 2013). The B5 subgenotype first appeared in China in 2008 (strain EV71/Xiamen/2009, GenBank accession number JN964686) (Zhang et al., 2013); nevertheless, C4 has been the most common subgenotype circulating in China since its emergence in 1998 up to the present day. ...
Background
Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) are the major causative agents of hand, foot and mouth disease (HFMD) worldwide, particularly in the Asia-Pacific region. Several strains have emerged, circulated, and faded out over time in recent decades. This study investigated the EV-A71 and CV-A16 circulating strains and replacement of genotypes/subgenotypes in Thailand during the years 2000–2017.
Methods
The complete VP1 regions of 92 enteroviruses obtained from 90 HFMD patients, one asymptomatic adult contact case, and one encephalitic case were sequenced and investigated for serotypes, genotypes, and subgenotypes using a phylogenetic analysis.
Results
The 92 enterovirus isolates were identified as 67 (72.8%) EV-A71 strains comprising subgenotypes B4, B5, C1, C2, C4a, C4b and C5, and 25 (27.2%) CV-A16 strains comprising subgenotypes B1a and B1b. Genotypic/subgenotypic replacements were evidenced during the study period. EV-A71 B5 and C4a have been the major circulating strains in Thailand for more than a decade, and CV-A16 B1a has been circulating for almost two decades.
Conclusions
This study provides chronological data on the molecular epidemiology of EV-A71 and CV-A16 subgenotypes in Thailand. Subgenotypic replacement frequently occurred with EV-A71, but not CV-A16. Monitoring for viral genetic and subgenotypic changes is important for molecular diagnosis, vaccine selection, and vaccine development.
... Te introduction of molecular genetic tests and sequencing schemes for genotyping enteroviruses has expanded our understanding of the epidemiology of enteroviruses and led to the discovery of coinfection. Coinfection is most often detected in patients with HFMD syndrome and can reach 34%, while simultaneous persistence of diferent serotypes can aggravate the severity of the infection and lead to atypical cases involving the respiratory and cardiovascular systems [40][41][42]. In the current study, we did not record any specifc clinical course in patients with coinfections, which may be due to the limited sample size. ...
Enteroviral infection is a common cause of aseptic meningitis, herpangina, and hand, foot, and mouth disease in children. Limited data are available on the enteroviral subtypes associated with hospitalization for these conditions in Kazakhstan. We collected cerebrospinal fluid (CSF) and nasopharyngeal swabs (NSW) from children (N = 152, median age = 8 years) hospitalized with symptoms of aseptic meningitis (AM, N = 139) or herpangina (HA, N = 13) disease. We then genotyped enteroviral subtypes associated with AM (n = 50) and HA (n = 9) using next-generation sequencing (NGS) on the viral protein 1 (VP1), followed up by whole-genome sequencing of the isolated viral species. All identified EVs were species B EV, consisting of five echoviruses (E6, E9, E11, E21, and E25) and three coxsackieviruses (CVA9, CVB3, and CVB5) serotypes within the cohort. The most abundant EVs were CVA9 (38.5%), CVB5 (21.5%), and E6 (13.8%). Most HA samples (6/9) were genotyped with coxsackievirus CVA9, while AM was associated with a variety of both echovirus and coxsackievirus serotypes. The results suggest that coxsackievirus CVA9 may be the dominant serotype circulating in the HA population, while AM is more diverse in terms of circulating echovirus and coxsackievirus serotypes. Further studies are needed to determine the clinical implications of these findings and to investigate potential differences in disease severity or outcomes associated with different EV serotypes.
... The co-circulation of different serotypes and alternation between enterovirus A71 (EV-A71) and coxsackievirus A (CV-A) was commonly observed during HFMD epidemics [1][2][3][4]. However, co-infection is not a primary cause of severe forms [5,6]. Epidemics could be due to both the accumulation of susceptible individuals in the community, since patients are mostly young children under five, and the introduction of new genotypes or strains [7]. ...
An HFMD outbreak spread over the city of Hải Phòng from summer 2011 to autumn 2012. This epidemic was chosen because it was the very first HFMD epidemic in North Vietnam, eliminating thus interferences with previous outbreaks. This epidemic displayed three separate waves. A complete dataset was collected for more than 9500 patients during this period, which enabled us to analyze this epidemic at different scales. Access to the healthcare system was crucial during this period, which was possible due to a reorganization of the system in February–March 2012. An analysis at the commune level enabled us to track the epidemic along certain communication routes. The three-waves structure reveals a wide disparity at the district level. We developed a mathematical model showing high accuracy at the adjustment of data for both the total number of cases and for the number of cases per week. As a consequence, the model was able to accurately determine the dates of the beginning and end of each wave and to show that they overlapped. Using mathematical functions associated with this model, it was possible to calculate the probability for a patient to belong to a specific wave.
... However, EV-A71 is a highly neurotropic virus and EV-A71 infection can develop various neurological complications, including brainstem encephalitis, aseptic meningitis, acute flaccid paralysis, and neurogenic pulmonary edema, in some severe cases. 5,6 Although three inactivated EV-A71 vaccines have been licensed in China, clinical cross protection against other genogroups has not been fully demonstrated, and more appropriate animal data should be evaluated to support the breadth of protection. [7][8][9] Therefore, small molecule drugs with novel structure are particularly attractive for complex variants of EV-A71. ...
Human enterovirus A71 (EV‐A71) is a significant etiological agent responsible for epidemics of hand, foot, and mouth disease (HFMD) in Asia‐Pacific regions. There are presently no licensed antivirals against EV‐A71, and the druggable target for EV‐A71 remains very limited. The phenotypic hit 10,10′‐bis(trifluoromethyl) marinopyrrole A derivative, herein termed MPA‐CF3, is a novel potent small‐molecule inhibitor against EV‐A71, but its pharmacological target(s) and antiviral mechanisms are not defined. Here, quantitative chemoproteomics deciphered the antiviral target of MAP‐CF3 as host factor coatomer subunit zeta‐1 (COPZ1). Mechanistically, MPA‐CF3 disrupts the interaction of COPZ1 with the EV‐A71 nonstructural protein 2C by destabilizing COPZ1 upon binding. The destruction of this interaction blocks the coatomer‐mediated transport of 2C to endoplasmic reticulum, and ultimately inhibits EV‐A71 replication. Taken together, our study disclosed that MPA‐CF3 can be a structurally novel host‐targeting anti‐EV‐A71 agent, providing a structural basis for developing the COPZ1‐targeting broad‐spectrum antivirals against enteroviruses. The mechanistic elucidation of MPA‐CF3 against EV‐A71 may offer an alternative COPZ1‐involved therapeutic pathway for enterovirus infection.
... The introduction of molecular genetic tests and sequencing schemes for genotyping enteroviruses has expanded our understanding of the epidemiology of enteroviruses and led to the discovery of co-infection. Co-infection is most often detected in patients with HFMD syndrome and can reach 34%, while simultaneous persistence of different serotypes can aggravate the severity of the infection and lead to atypical cases involving the respiratory and cardiovascular systems (Ooi et al., 2007;Yang et al., 2011;de Sousa et al., 2021;Guo et al., 2022). In current study, we did not record any speci c clinical course in patients with coinfections, which may be due to the limited sample size. ...
Enteroviral infection is a common cause of aseptic meningitis, herpangina, and hand, foot, and mouth disease in children. Limited data are available on the enteroviral subtypes associated with hospitalization for these conditions in Kazakhstan. We collected cerebrospinal fluid (CSF) and nasopharyngeal swabs (NSW) from children (N=152, median age=8 years) hospitalized with symptoms of aseptic meningitis (AM, N=139) or herpangina (HA, N=13) disease. We then genotyped enteroviral subtypes associated with AM (n=50) and HA (n=9) using next-generation sequencing (NGS) on the viral protein 1 (VP1), followed up by whole-genome sequencing of the isolated viral species. All identified EVs were species B EV, consisting of five echovirus (E6, E9, E11, E21 and E25) and three coxsackievirus (CVA9, CVB3 and CVB5) serotypes within the cohort. The most abundant EVs were CVA9 (38.5%), CVB5 (21.5%) and E6 (13.8%). Most HA samples (6/9) were genotyped with coxsackievirus CVA9, while AM was associated with a variety of both echovirus and coxsackievirus serotypes.
The results suggest that coxsackievirus CVA9 may be the dominant serotype circulating in the HA population, while AM is more diverse in terms of circulating echovirus and coxsackievirus serotypes. Further studies are needed to determine the clinical implications of these findings and to investigate potential differences in disease severity or outcomes associated with different EV serotypes.
... [6] Onychoptosis (nail shedding) is also reported to be one of the characteristic features of HFMD. [7,8] Lesions usually subside in 5-7 days. HFMD is usually a mild illness but sometimes may progress to cause meningitis, encephalitis, and polio-like paralysis. ...
HFMD is a childhood viral disease initiated by enteroviruses (EVs). Symptoms are initiated with mild-to-moderate fever of short duration followed by oral and skin lesions. Skin lesions are papulovesicular which appears on palms/soles of feet, hands, knees, and elbows. Oral lesions appear as vesicles producing multiple small superficial ulcers. Disease is usually mild illness but sometimes progresses in severe form as meningitis, encephalitis, and polio-like paralysis. Etiological agents of the disease belong to Picornaviridae family. The causative viral agents are from genus human enterovirus (HEV) such as enterovirus-A 71 (EV-A71), coxsackievirus –A6 (CV-A6), CV-A10, CV-A16. Coxsackievirus A-16 (CV-A16) and enterovirus A-71 (EV-A71) are the major etiological agents of this disease, among children reported globally. In India, studies conducted on HFMD cases revealed CV-A16 as a major EV type and under circulation over a period of time. Molecular studies of different CV-A16 isolates and the viral kinetic studies conducted on organ tissues of experimental mouse model with complete VP1 gene sequencing revealed presence of B1c sub genotype which is currently in circulation. Genetic changes observed at nucleotide and amino acid level in vital organs of experimental infected mice model might predict some targets and can act as markers of virulence. Mice infected with CV-A16 strains revealed progressive pathological changes in mice organs. Major affected organs were to be as brain, heart, intestine, and skeletal muscles. The present review focuses on HFMD caused by CV-A16 with epidemiological, molecular, pathogenesis and need of antivirals against the disease.
... In previous outbreak of HFMD, IVIG was used on a presumptive basis for the treatment of severe cases [223,[241][242][243]. Recently, some anecdotal evidence suggests that the use of IVIG in the early stage of HFMD can significantly improve the progression of the disease and reduce mortality [244,245]. ...
Hand-foot-and-mouth disease (HFMD) is a viral illness commonly seen in young children under 5 years of age, characterized by typical manifestations such as oral herpes and rashes on the hands and feet. These symptoms typically resolve spontaneously within a few days without complications. Over the past two decades, our understanding of HFMD has greatly improved and it has received significant attention. A variety of research studies, including epidemiological, animal, and in vitro studies, suggest that the disease may be associated with potentially fatal neurological complications. These findings reveal clinical, epidemiological, pathological, and etiological characteristics that are quite different from initial understandings of the illness. It is important to note that HFMD has been linked to severe cardiopulmonary complications, as well as severe neurological sequelae that can be observed during follow-up. At present, there is no specific pharmaceutical intervention for HFMD. An inactivated Enterovirus A71 (EV-A71) vaccine that has been approved by the China Food and Drug Administration (CFDA) has been shown to provide a high level of protection against EV-A71-related HFMD. However, the simultaneous circulation of multiple pathogens and the evolution of the molecular epidemiology of infectious agents make interventions based solely on a single agent comparatively inadequate. Enteroviruses are highly contagious and have a predilection for the nervous system, particularly in child populations, which contributes to the ongoing outbreak. Given the substantial impact of HFMD around the world, this Review synthesizes the current knowledge of the virology, epidemiology, pathogenesis, therapy, sequelae, and vaccine development of HFMD to improve clinical practices and public health efforts.
... Well known as the cause of several childhood diseases such as hand-foot-mouth disease and herpangina, enterovirus is one of the common etiologies of viral myocarditis in children (1) . EV71 is unique among all strains of the enterovirus as several epidemics in the past indicated that it is associated with varieties of cardiopulmonary and neurologic manifestations, such as encephalitis, myocardial dysfunction, non-cardiogenic pulmonary edema, and autonomic dysfunction (2,3) . While pulmonary edema is the most common cause of death in children with EV71 infection, the causes of this are still unclear (2) . ...
Ectopic atrial tachycardia (EAT) is one of the most common arrhythmias causing ventricular dysfunction in children. In most case of EAT, no identifiable etiology is found. While viral myocarditis is often thought to be the cause of EAT in some patients, there is little evidence of the association. The authors report a reversible myocardial dysfunction and heart failure concurrent with EAT in a child with enterovirus 71 (EV71) infection. Case Report The present study was approved by the Institutional Review Board (IRB), Faculty of Medicine, Chulalongkorn University (IRB No.033/64). A previously healthy 11-year-old boy presented with progressive dyspnea for one week with a history of an upper respiratory tract infection two weeks earlier. Physical examination on admission showed an alert child with tachypnea, tachycardia with a heart rate of 180 to 190 bpm, and normal blood pressure at 98/60 mmHg. There was lateral shifting of the apical cardiac impulse without significant cardiac murmur, crepitation in both lungs, slight hepatomegaly, and pitting edema on both legs. Neurological evaluation was normal. Chest X-ray showed cardiomegaly with pulmonary venous congestion (Figure 1A). Echocardiography revealed normal cardiac anatomy including coronary arteries, marked dilatation of left ventricle with severely impaired left ventricular function as the left ventricular ejection fraction (LVEF) was 20%, and no pericardial effusion (Figure 1B). Electrocardiography (ECG) showed a regular narrow QRS tachycardia with long R-P and short P-R, rate 180 to 190 bpm, abnormal ST-T change in left precordial leads and an abnormal P wave morphology, consistent with EAT (Figure 2). Blood tests showed elevated troponin-T of 0.08 ng/ mL when the normal is 0.013 to 0.025 ng/mL, and NT-pro BNP of 8,395 pg/mL when the normal is 25 to 160 pg/mL. Viral study (PCR) in stool was positive The authors reported a rare case of ectopic atrial tachycardia (EAT) with reversible myocardial dysfunction associated with enterovirus 71 (EV71) infection. A previously healthy 11-year-old boy presented with progressive heart failure. An initial ECG revealed a regular narrow QRS tachycardia with abnormal P wave morphology. Echocardiography showed severely impaired left ventricular function (LVEF 20%). Viral study (PCR) in stool was positive for EV71. Treatment with inotropic support, amiodarone, and carvedilol resulted in gradual restoration of sinus rhythm over 10 days. Cardiac function returned to normal within three months. EV71 can cause EAT along with other complications and should be considered in patients with persistent tachycardia and cardiac dysfunction. Recognizing this arrhythmia led to proper management to control ventricular rate, then termination of the tachycardia and gradual restoration of ventricular function to normal.
... Therefore, it may suggest that the immune system plays an important role in causing HFMD severe cases. At the same time, there is still much unknown about the interaction of this virus with hosts, and more studies are required to fully uncover the mechanism of EV71 [10][11][12][13][14]. A study conducted by Shen et al. in 2021 had investigated the potential link between severe HFMD and the host intestinal microbiota [15]. ...
Hand, foot, and mouth disease (HFMD) is a common children infectious disease caused by human enteroviruses. Most of the cases have minimal symptoms, however, some patients may develop serious neurological, cardiac complications, or even death. The pathological mechanism leading to severe HFMD is not clearly understood, and the immunological status of the individual patient may play an important role. Transcriptomes of peripheral blood mononuclear cells from EV71-infected patients (n = 45) and healthy controls (n = 36) were examined. Immune pathways were up-regulated in patients with mild disease symptoms (n = 11, M) compared to the healthy controls (n = 36, H), demonstrating an effective anti-viral response upon EV71 infection. However, in patients with severe symptoms (n = 23, S) as well as severe patients following treatment (n = 11, A), their innate and acquired immune pathways were down-regulated, indicating a global immunity suppression. Such immune suppression characteristics could thus provide an opportunity for early EV-71 infection prognosis prediction. Based on our cohort, an SVM model using RNA-seq expression levels of five genes (MCL1, ZBTB37, PLEKHM1P, IFNAR2 and YEATS2) was developed and achieved a high ROC-AUC (91·3%) in predicting severe HFMD. Meanwhile, qPCR fold-changes method was performed based three genes (MCL1, IFNAR2 and YEATS2) on additional cohort. This qPCR method achieved a ROC-AUC of 78.6% in predicting severe HFMD, which the patients could be distinguished in 2-3 h. Therefore, our models demonstrate the possibility of HFMD severity prediction based on the selected biomarkers that predict severe HFMD effectively.
... Among these, 19 genotypes are known to infect humans. Molecular epidemiological studies related to HFMD have shown that CV-A6, CV-A16, and EV-A71 are the dominant genotypes, especially in many Asian countries [26][27][28]. Similar to other EVs, CV-A6 has a non-segmented positive single-stranded RNA genome of approximately 7534 nucleotides (nt), which contains a single open reading frame (ORF). ...
Coxsackievirus (CV)-A6 infections cause hand, foot, and mouth disease (HFMD) in children and adults. Despite the serious public health threat presented by CV-A6 infections, our understanding of the mechanisms by which new CV-A6 strains emerge remains limited. This study investigated the molecular epidemiological trends, evolutionary dynamics, and recombination characteristics of CV-A6-associated HFMD in Thailand between 2019 and 2022. In the HFMD patient samples collected during the 4-year study period, we identified enterovirus (EV) RNA in 368 samples (48.7%), of which CV-A6 (23.7%) was the predominant genotype, followed by CV-A4 (6%), EV-A71 (3.7%), and CV-A16 (3.4%). According to the partial viral protein (VP) 1 sequences, all these CV-A6 strains belonged to the D3 clade. Based on the viral-RNA-dependent RNA polymerase (RdRp) gene, four recombinant forms (RFs), RF-A (147, 84.5%), RF-N (11, 6.3%), RF-H (1, 0.6%), and newly RF-Y (15, 8.6%), were identified throughout the study period. Results from the similarity plot and bootscan analyses revealed that the 3D polymerase (3Dpol) region of the D3/RF-Y subclade consists of sequences highly similar to CV-A10. We envisage that the epidemiological and evolutionarily insights presented in this manuscript will contribute to the development of vaccines to prevent the spread of CV-A6 infection.
... La traduction du cadre de lecture aboutit à une polyprotéine qui subit une série de clivages co-traductionnels afin de générer 11 protéines [68]. provoquer une paralysie flasque de type poliomyélitique [20,22,58]. Il pourrait avoir une valeur pronostique car, dans le cas d'une infection à entérovirus 71 chez l'enfant, une atteinte du système nerveux central accompagnée de complications cardiopulmonaires peut s'accompagner de séquelles neurologiques et cognitives [16]. ...
Nonpolio enteroviruses can be reliably identified with molecular and computer tools for taxonomic, diagnostic and epidemiologic purposes. Seroneutralization tests can efficiently be replaced by genotyping assays using the VP1 capsid protein encoding gene to identify enterovirus strains isolated in cell cultures. Genotyping showed the close genetic relatedness between human enterovirus serotypes and animal enteroviruses and also rhinoviruses currently classified in a separate genus within the Picornaviridae family. Enterovirus genotyping can be done prospectively within 2 to 5 days in a greater number of meningitis patients, using cerebrospinal fluid specimens and hence can help in providing a prompt response to health alert. In the molecular epidemiology of human enteroviruses, recent advances were made by investigating genetic diversity within individual serotypes (genotypes, lineages) and the patterns of circulation and transmission of virus variants involved in epidemics (echovirus 30, enterovirus 71). The observation of epidemiologic features such as the frequent viral immigration of strains from different geographical origins speaks in favour of developing molecular identification of enteroviruses. Recombinant enterovirus strains can also be identified by genotyping. Homologous recombination is a major contributor to the genetic diversity in enteroviruses. Molecular signatures of recombination events are observed in circulating strains, suggesting the occurrence of frequent co-infections during their circulation within the general population. The role of genetic recombination in the emergence of virus variants and its involvement in the epidemiology of human enteroviruses should be investigated.
... 26 At present, based on the sequence analysis of the VP1 gene, people have a deep understanding of the evolution and molecular epidemiology of enterovirus circulating strains. Studies have shown that in the Asia-Pacific countries, there has been a shift between enterovirus EV-A71 genotypes B and C. 27,28 Phylogenetic tree analysis shows that the prototype strain BrCr (genotype A) is the most different strain from others. The "vaccine strain" and the three epidemic strains belong to the C4a genotype, and the "vaccine strain" has a certain homology with the inactivated vaccine strain in mainland China. ...
Hand, foot and mouth disease was mainly caused by EV-A71 virus. The main antigen structure of VP1 region of EV-A71 was easily varied. Here, we investigated the seroprevalence of EV-A71 based on a large group of healthy individuals in Beijing, China, in order to study the effectiveness of EV-A71 vaccine in a real-world setting. BrCr and the clinical strain isolated from the Chinese mainland in 2008 (“vaccine strain:”CMU4232/BJ/CHN/2008), EV-A71 C4 epidemic strains isolated in 2010, 2013, and 2016, were tested for neutralizing antibodies (NtAb) in every year. Phylogenetic tree analysis of the EV-A71 strains above, as well as amino acid composition homologous sequence analysis were applied. The “vaccine strain” has 83.0% homology with FY23, H07 and FY7VP5. It belongs to the same branch of C4a as 10 C4, 13 C4 and 16 C4, and differs from the amino acid sites 283 and 293 of 16 C4. Compared with “vaccine strains,” there was a significant difference between the 50–59 years old age group when the NtAb titer of 16 C4 strain was 1:512-1:1024. Our results suggest that changes in the functional epitopes of NtAb caused by amino acid 283 and 293 loci in EV-A71 strains may affect the production of neutralizing antibodies.
... Shedding from the gastrointestinal tract has been shown to be ongoing for weeks after clinical recovery. 34 This highlights the importance of testing stool and respiratory specimens in patients with central nervous system manifestations. 35,36 In addition, 5 0 UTR genotyping would still have a role in testing of CSF as the sensitivity is superior to the other typing methods. ...
Enteroviruses (EV) commonly cause hand, foot and mouth disease (HFMD), and can also cause potentially fatal neurological and systemic complications. In our laboratory, sequencing 5′ untranslated region (UTR) of the viral genome has been the routine method of genotyping EVs. During a recent localised outbreak of aseptic meningitis, sequencing the 5′UTR identified the causative virus as EV-A71, which did not fit with the clinical syndrome or illness severity. When genotyped using a different target gene, VP1, the result was different. This led us to evaluate the accuracy of the two different target genome regions and compare them against whole genome sequencing (WGS).
We aimed to optimise the algorithm for detection and characterisation of EVs in the diagnostic laboratory. We hypothesised that VP1 and WGS genotyping would provide different results than 5′UTR in a subset of samples.
Clinical samples from around New South Wales which were positive for EV by commercial polymerase chain reaction (PCR) assays were genotyped by targeting three different viral genome regions: the 5′UTR, VP1 and WGS. Sequencing was performed by Sanger and next generation sequencing. The subtyping results were compared.
Of the 74/118 (63%) samples that were successfully typed using both the 5′UTR and the VP1 method, the EV typing result was identical for 46/74 (62%) samples compared to WGS as the gold standard. The same EV group but different EV types were found in 22/74 (30%) samples, and 6/74 (8%) samples belonged to different EV groups depending on typing method used.
Genotyping with WGS and VP1 is more accurate than 5′UTR. Genotyping by the 5′UTR method is very sensitive, but less specific.
... We did not isolate EV71, which seems to be the most neurotropic and the one most frequently involved in the genesis of brainstem encephalitis (28). In our patient with brainstem lesions, we isolated echovirus 30, but such lesions were considered secondary to perinatal asphyxia, according to the radiological characteristics and the history of the patient. ...
Background
Non-polio-enteroviruses (EV) and human parechoviruses (HPeV) are small RNA viruses, which in newborns cause infections with a wide range of severity. Today molecular biology tools allow us to diagnose viral meningitis in neonates, sparing patients from useless antibiotics. Data on neurodevelopmental outcome of children who contract enterovirus meningitis in early childhood are still limited in the literature.AimsTo evaluate the neurodevelopmental outcome of newborns with documented enterovirus and parechovirus meningitis contracted within the first months of life.Methods
Enterovirus and parechovirus were detected on cerebrospinal fluid (CSF) and plasma by RT-PCR. The virological typing was done according to WHO recommendations. During the hospitalization each neonate underwent many diagnostic and instrumental examinations, to evaluate any neurological lesions attributable to the infection. After the discharge children entered in an outpatient interdisciplinary assessment process, comprehensive of the administration of Bayley III scales up to 12 months old.ResultsWe observed longitudinally 30 children, born at term (mean GA 39.7 ± 0.8 weeks, mean birthweight was 3,457 ± 405 grams), who contracted enterovirus and parechovirus meningitis within the first month of life (mean age at diagnosis was 15.8 ± 7.33 days). We were able to perform the genetic typing only on 15/30 (50.0%) cerebrospinal fluid (CSF) samples from 15 neonates. We found MRI anomalies in 9/26 observed neonates (34.6%): one of them presented brainstem abnormality that are specific of enteroviral central nervous system (CNS) involvement. During the follow up children displayed an overall normal neurodevelopment and no deficit in visual and hearing areas. The mean cognitive (105.19 ± 8.71), speech (100.23 ± 8.22) and motor (97.00 ± 8.98) composite scores, assessed by Bayley III, were normal in 29/30 (96.7%). Despite this, children with pathological brain magnetic resonance imaging (MRI) scored significantly lower (p = 0.01) than children with normal brain MRI on cognitive subscale at 12 months of life.Conclusions
Early enterovirus infections can be associated to brain MRI abnormalities, more frequently the earlier the infection. Although within a normal range, our children with pathological brain MRI scored significantly lower than those with normal brain MRI on cognitive subscale at 12 months of life.
... Subgenogroup C4 is associated with a higher incidence of Central Nervous System (CNS) infections and a longer duration of spread (Fu et al, 2020;Nhan et al, 2020). Subgenogroup B5 has also been reported to cause CNS infections (Ooi et al, 2007). EV71 can recombine with other viruses gaining new traits (Simmonds, 2010;Yip et al, 2013). ...
Enterovirus 71 (EV71), a member of the picornaviridae family, is a main cause of hand, foot and mouth disease (HFMD), some subgenogroups have been associated with serious complications, such as encephalitis, meningitis, delayed neurological development, reduced cognitive function and a poliomyelitis-like paralysis. We reported here the findings of subgenogroup analysis of enterovirus A-71 in a sibling of a fatal case of HFMD in Jakarta, Indonesia and found it to be subgenogroup B5.
... It should be noted, that in one case we found two EVs (E30 and E6) in the CSF specimen of an elderly man. Coinfections with more than one virus are widely described in the literature [39][40][41][42]. Some authors suggest that simultaneous infection by more than one virus generates more severe symptoms [43] and that infection by more than one genotype can generate recombination events between different species [4,44], giving rise to new variants. ...
There is a growing interest in echovirus 30 (E30), an enterovirus responsible for neurological disease and hospitalization. There are multiple studies of outbreaks, but few that study the epidemiology over long periods of time. Our study aims to describe the clinical, epidemiological and microbiological characteristics of a series of E30 infections detected over 26 years. Data were retrospectively collected from a database of all enterovirus infections identified in our laboratory. They were detected by viral isolation or nucleic acid detection in patients presenting with respiratory or neurological infections, rash, sepsis-like syndrome, or gastroenteritis. Enterovirus genotyping was performed by amplification of the VP1 gene using RT-nested PCR, followed by sequencing and BLAST analysis. Of the 2402 enterovirus infections detected, 1619 were linked to at least one genotype and 173 were caused by E30. Clinical information was available for 158 (91.3%) patients. E30 was associated with neurological infection in 107 (67.8%) cases and it was detected almost every year. Phylogenetic analysis was performed with 67 sequences. We observed that E30 strains circulating in Catalonia from 1996 to 2016 belong to two lineages (E and F), although the majority cluster was in F. In 2018, lineage I emerged as the dominant lineage.
... Hand, foot, and mouth disease (HFMD) is caused by acute enterovirus infections and is common among children, in Asian-Pacific regions [32][33][34][35]. Human enteroviruses (HEV) originally consisted of polioviruses, coxsackie viruses group A and B (CVA and CVB), echoviruses and the numbered enteroviruses. ...
MALDI-TOF-MS has essentially delivered more than expected with respect to clinical pathogens. Viruses are the most versatile entities of clinical pathogens that have challenged well-established microbiological methodologies. This review evaluates the existing scenario with respect to MALDI TOF-MS analytical technique in the successful analysis of viral pathogens. The milestones achieved with respect to detection and identification of COVID-19 has been presented. The fact that only a handful of scattered applications for COVID-19 exist has been pointed out in the review. Further, the lapses in the utilization of the available state-of-the art MALDI-TOF-MS variants/benchmark sophistications for COVID-19 analysis, are highlighted. When the world is seeking for rapid solutions for early, sensitive, rapid COVID-19 diagnosis, maybe MALDI-TOF-MS, may be the actual ‘gold standard’. Reverting to the title, this review emphasizes that there is a need for extrapolating MALDI-TOF-MS for COVID-19 analysis and this calls for urgent scientific attention.
... The virus was first isolated in 1969 from patients with cutaneous symptoms of central nervous system (CNS) infections in California, United States. 4 The EV71 was then discovered in Bulgaria and Hungary, where patients had CNS infections that resulted in cardio-respiratory failure and acute flaccid paralysis. 5 In 1998, the most genuine flare-up happened in Taiwan and was caused by EV71 contamination infecting more than 120,000 individuals and 78 demises. ...
Enterovirus 71 (EV71) is an infectious virus affecting all age groups of people around the world. It is one of the major aetiologic agents for HFMD (hand, foot and mouth disease) identified globally. It has led to many outbreaks and epidemics in Asian countries. Infection caused by this virus that can lead to serious psychological problems, heart diseases and respiratory issues in children younger than 10 years of age. Many studies are being carried out on the pathogenesis of the virus, but little is known. The host immune response and other molecular responses against the virus are also not clearly determined. This review deals with the interaction between the host and the EV71 virus. We discuss how the virus makes use of its proteins to affect the host’s immunity and how the viral proteins help their replication. Additionally, we describe other useful resources that enable the virus to evade the host’s immune responses. The knowledge of the viral structure and its interactions with host cells has led to the discovery of various drug targets for the treatment of the virus. Additionally, this review focusses on the antiviral drugs and vaccines developed by targeting various viral surface molecules during their infectious period. Furthermore, it is asserted that the improvement of prevailing vaccines will be the simplest method to manage EV71 infection swiftly. Therefore, we summarise numerous vaccines candidate for the EV71, such as the use of an inactivated complete virus, recombinant VP1 protein, artificial peptides, VLPs (viral-like particles) and live attenuated vaccines for combating the viral outbreaks promptly.
... Moreover, coxsackievirus A4 (CV-A4) and A10 (CV-A10) have become increasingly common in recent years, which has coincided with the emergence of more severe cases of HFMD. Although EV71 has been one of the major causative agents for severe cases of HFMD in the last decade, the relationship between different genotypes of enteroviruses and disease severity remains unclear [6][7][8][9][10]. Patients with severe symptoms usually develop neurological and systemic complications rapidly. ...
Background
The incidence of hand foot and mouth disease (HFMD) has increased in recent years, making it a very common childhood illness worldwide. The relationship between different enterovirus genotypes and disease severity is not clearly understood. Given that enteroviruses are transmitted through the gastrointestinal tract, we hypothesized that variation in intestinal microorganisms of the host might play a role in the prognosis of HFMD.
Methods
We carried out a meta-transcriptomic-wide association study of fecal samples obtained from a cohort of children (254 patients, 227 tested positive for enterovirus, including 16 patients co-infectied with 2 kinds of enterovirus) with mild and severe HFMD and healthy controls.
Results
We found there was no significant difference in the amount of each virus type between the mild and severe cases. Genes of enterovirus 71 (EV71) and coxsackievirus A (CV-A) from the severe and mild cases did not show significant clustering. Clostridium sp. L2-50 and Bacteroides stercoris ATCC 43183 were enriched in the guts of children with severe HFMD and KEGG enrichment was found between mild and severe cases.
Conclusions
Intestinal microorganisms appear to interact with enterovirus to determine the progression of HFMD. Genes of Bacteroides and Clostridium may be used as predictive markers for a more efficient prognosis and intervention. The enrichment of intestinal bacteria genes with functions may facilitate the development of severe symptoms for HFMD patients.
... www.nature.com/scientificreports/ Several researchers have characterized EV71 and CVA16 strains from HFMD cases in Peninsular Malaysia and Sarawak [10][11][12][13] . Although a number of HFMD outbreaks have been reported in Sabah, information on the genetic characteristics of these strains in Sabah is limited. ...
Hand, foot, and mouth disease (HFMD) is endemic in Malaysia, with the number of cases increasing. Sabah has experienced several HFMD outbreaks, but information on the epidemiology and molecular characteristics of responsible viruses is scarce. In this study, data of 17,574 reports of HFMD cases in Sabah from 2015 to 2019 were extracted from a public health disease surveillance system and analyzed. Twenty-one swab samples from 13 children were collected from Beaufort, Sabah, during an outbreak in August 2018 for detection and serotyping of causative viruses by semi-nested reverse transcription-polymerase chain reaction (snRT-PCR) of the VP4–VP2 region and consensus degenerate hybrid oligonucleotide primer PCR of the VP1 region, respectively. Nucleotide sequencing and phylogenetic analysis were conducted by the neighbor-joining method. The average annual incidence of HFMD was 94.3 per 100,000 people, with the greatest yearly increase between 2017 and 2018. Swabs from six children were tested positive for enterovirus, of which five were positive for CVA16 and one for EV71. All CVA16 strains belonged to sub-genotype B1a, and the EV71 strain belonged to sub-genotype B5. Phylogenetic analyses indicate that enterovirus genotype shift might be responsible for the increasing trend of HFMD in Sabah, however, further study is needed.
... Most of the viral meningitis cases recorded worldwide are due to an infection with non-polio enteroviruses (NPEV) and in total are more than 3 times more frequent than cases of bacterial meningitis. The infection is more likely to be found in young children and is transmitted via the oral-faecal route [41,42]. In most cases the early phase of the infection shows low severity, however as the infection progresses the virus may cause severe infection to the CNS [43]. ...
Despite significant advances in the understanding of the pathogenesis of viral meningitis, infection with non-polio enteroviruses (NPEV) has an increasing disease burden worldwide. This dissertation hopes to contribute to further deepening the understanding of the disease for a successful containment of the disease in the future. Viral meningitis can be caused by infection with Echovirus (E) 30 (E-30) of the central nervous system (CNS) at the level of the blood-cerebrospinal fluid barrier (BCSFB). This infection causes neuroinflammation resulting in immune cell migration. Clinical analysis suggests that in the cerebrospinal fluid a pleocytosis of predominantly polymorphonuclear granulocytes (PMN) occurs in the early phase of infection, followed by a monocuclear cell population. Within the scope of this thesis we analysed the sequential transmigration of PMN and CD3+ T-lymphocytes across an E-30 Bastianni- infected human BCSFB in vitro. The results show that migration of PMN through human choroid plexus papilloma (HIBCPP) cells was significantly increased when CD3+ T-lymphocytes were present. In contrast, PMN were not able to promote T-lymphocyte migration. Chemokine expression was affected by E-30 infection with an upregulation of CXCL 3 and CXCL 11. The secretion of these and other chemokines was mainly directed towards the basolateral HIBCPP cell side, except for IL-7 where apical secretion was dominant. In the next step we were utilizing three clinical outbreak strains and the prototypic E-30 Bastianni strain and we were able to show strain dependent effect on the epithelial cell barrier function and morphology. The strains 13-759 and 14-397 did not cause significant effects on the barrier integrity of the HIBCPP cells. E-30 Bastianni and outbreak strain 13-311 caused significant decrease in the transepithelial electrical resistance of the epithelial cell barrier. These two strains were the only variants causing visible alteration of the tight junction proteins ZO1 and Occludin and the adherence junction protein E-cadherin. Despite these disruptive effects on the morphology of the epithelial cell barrier, migration of PMN and CD3+ T lymphocytes occurred both via the trans- and paracellular route. Analysis applying electron microscopy and immunofluorescence detected both cell types during and just following their migration across the epithelial cell barrier moving both between and through the HIBCPP cells. Further analysis of the genetic composition identified differences between the strains, but these could not be linked to the differences observed during the infection experiments. Overall, we showed enhanced PMN migration across the infected epithelial cell layer in the presence of CD3+ T-lymphocytes and an intriguing chemokine release pattern. Further, we were able to show E-30 strain specific effects on human epithelial cell barrier integrity. The strains caused particular morphological changes to the junctional proteins, however, migration of leukocytes occurred both trans and paracellularly. We were able to identify E-30 strain-specific effects on the epithelial cell barrier and contribute to the understanding of immune cell migration in viral meningitis.
... In enteroviral meningitis, virus may also be detected by throat swabs, in stool, or skin vesicles if present. 261,262 How should viral meningitis be treated? ...
Background
Bacterial meningitis has significant mortality but frontline doctors will see it infrequently. Therefore, UK guidance on meningitis in adults, with auditable standards, was revised in 2016. We undertook a national audit to assess adherence to the guidelines.
Methods
Patients with community acquired meningitis were identified through coding or laboratory data. Audit standards, including immediate management, diagnostics and treatment, were evaluated by notes review.
Results
Notes from 1472 patients with meningitis were reviewed – 309/1472 (21%) had bacterial aetiology, 615/1472 (42%) viral, 548/1472 (37%) unidentified aetiology. Only 50% of patients had blood cultures taken within one hour of admission and just 2% had a lumbar puncture (LP) within the first hour. 27% received antibiotics within one hour. Most patients received ceftriaxone or cefotaxime but only 37% of over-60s received empirical anti-listeria antibiotics. 26% of patients who had antibiotics were given adjunctive steroids. Half had CSF microscopy within two hours of LP. Less than a third had pneumococcal and/or meningococcal PCR on cerebrospinal fluid. Only 44% had an HIV test. 62% had unnecessary neuroimaging before LP. Overall mortality was 3% - 16% in pneumococcal disease and 8% in meningococcal meningitis. There was a trend toward improved survival in patients with pneumococcal meningitis who received dexamethasone [85/96 (88%)] compared to those who did not [57/73 (78%)] (p=0.066).
Conclusions
Adherence to the meningitis guidelines is inadequate, potentially compromising patient safety. Improvements in guideline dissemination, novel educational resources and clinician and patient engagement are required if we are to increase guideline adherence and improve outcome.
... Several studies indicated that pneumonoedema/pneumorrhagia was the major cause of death for critical and severe HFMD [38,39]. Fulminant neurogenic pneumonoedema was found in HFMD-related deaths in Malaysia [40,41], and it may be caused by the damage to certain areas of the brainstem or an increase in pulmonary vascular pressure and pulmonary endothelial permeability [42]. This study showed that pneumonoedema/pneumorrhagia was associated with the mortality of patients with HFMD. ...
In recent years, outbreaks of hand–foot–mouth disease (HFMD) in China, Singapore and other Western Pacific Region, involving millions of children, have become a big threat to public health. This study aimed to quantitatively assess all qualified studies and identify the risk factors for HFMD death. A systematic search of the databases PubMed, Medline, Embase and the Cochrane Library was performed. Study heterogeneity and publication bias were estimated. Seven case–control studies involving 1641 participants (634 died and 1007 survived) were included in the meta-analysis. Human enterovirus 71 infection, male, age ⩽3 years, vomiting, cyanosis, convulsion, duration of fever ⩾3 days, atypical rashes and abdominal distention were not significantly related to HFMD death ( P ⩽ 0.05). Lethargy (odds ratio (OR) = 6.62; 95% CI 3.61–12.14; I² = 0%; P < 0.0001), pneumonoedema/pneumorrhagia (OR = 4.09; 95% CI 2.44–6.87; I² = 0%; P < 0.0001), seizures (OR = 6.85; 95% CI 2.37–19.74; I² = 0%; P = 0.0004), dyspnoea (OR = 8.24; 95% CI 2.05–33.19; I² = 83%; P = 0.003) and coma (OR = 3.76; 95% CI 1.85–7.67; I² = 0%; P = 0.0003) were significantly associated with HFMD death, which were risk factors for HFMD death.
... Hand, foot and mouth disease (HFMD) is commonly reported in children under 5 years across East and Southeast Asia during the hot and humid season. 1 Based on the Chinese National Enhanced Surveillance System, annual HFMD outbreaks have occurred since 2008, and 18.2 million HFMD cases and 3.6 thousand deaths associated with HFMD have been reported in mainland China. 2 Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the most common pathogens causing HFMD, while EV71 is more neurotropic than CA16. [3][4][5][6][7] According to reports from large-scale prospective studies performed in Sarawak, 8,9 10-30% of hospitalized EV71-associated HFMD patients develop neurological system complications. The results based on national HFMD surveillance during 2008-2015 revealed that 44% of the laboratoryconfirmed HFMD cases in mainland China were caused by EV71; moreover, 74% of severe cases and 93% of fatal HFMD cases were caused by EV71. 10 EV71 vaccination is the most effective approach for preventing EV71-associated HFMD outbreaks. ...
Background: Short-term dynamic changes in neutralizing antibodies against EV71 and EV71-IgM after inactivated EV71 vaccine injection are unknown.
Methods: This study was designed as a randomized, open-label study and was registered at ClinicalTrials.gov (NCT03278132). In total, 120 healthy infants aged 6–35 months were randomized 1:1:1 to provide a second blood sample on day 10, day 20, or day 30 after the first vaccine dose, respectively.
Results: According to the per-protocol set, a rapid immune response against EV71 was observed 10 days after the first EV71 vaccine dose, with antibody titers ≥1:8 in 89.19% of participants (95% CI: 74.58–96.97%) on day 10, in 80.65% (95% CI: 62.53–92.55%) on day 20, in 66.67% (95% CI: 49.03–81.44%) on day 30, and in 100% (95% CI: 96.52%-.) on day 60. Based on an ELISA, the percentages of participants positive for EV71-IgM on day 0 and day 60 were 1.71% (2 out of 117) and 82.86% (87 out of 105), respectively.
Conclusions: The EV71 vaccine could be used for contingency vaccination to further control EV71-associated disease outbreaks. Caution should be taken in using the EV71-IgM test for rapid EV71 infection diagnosis after EV71 vaccine administration.
Clinical Trial Registration: ClinicalTrials.gov NCT03278132
... Since the 1990s, large-scale epidemics have been observed [9]. Since then, EV-A71 infections have caused mortality rates ranging from < 0. 5-19% in Asia-Pacific countries [1,[10][11][12][13][14]. ...
As a neurotropic virus, enterovirus A71 (EV-A71) emerge and remerge in the Asia-Pacific region since the 1990s, and has continuously been a threat to global public health, especially in children. Annually, EV-A71 results in hand-foot-and-mouth disease (HFMD) and occasionally causes severe neurological disease. Here we reviewed the global epidemiology and genotypic evolution of EV-A71 since 1997. The natural selection, mutation and recombination events observed in the genetic evolution were described. In addition, we have updated the antigenicity and virulence determinants that are known to date. Understanding EV-A71 epidemiology, genetic evolution, antigenicity, and virulence determinants can expand our insights of EV-A71 pathogenesis, which may benefit us in the future.
... Countries with reported outbreaks include Malaysia [29], Taiwan [30,31] and Singapore [32]. The overall mortality rate among patients diagnosed with EV-A71-associated HFMD in the Asian-Pacific countries has ranged from < 0.5 to 19% [33][34][35][36]. Since 1997, an unprecedented increase in the number of EV-A71 infection has primarily been attributed to the circulation of two genotypes, B and C. Here, we compile reports of EV-A71 outbreaks in different countries of the Pacific region during the last two decades. ...
Enterovirus A71 (EV-A71) is one of the common causative pathogens for hand foot and mouth disease (HFMD) affecting young children. HFMD outbreak can result in a substantial pediatric hospitalization and burden the healthcare services, especially in less-developed countries. Since the initial epidemic of predominantly EV-A71 in California in 1969, the high prevalence of HFMD in the Asia-pacific region and elsewhere around the world represents a significant morbidity in this age group. With the advent of rapid and accurate diagnostic tools, there has been a dramatic increase in the number of laboratory-confirmed EV-A71 infection over the past two decades. The population, cultural, and socioeconomic diversity among countries in the Asia-Pacific region all influence the transmission and morbidity associated with HFMD. This review summarizes the current state of epidemiology of EV-A71 in Asia-Pacific countries based on the most recent epidemiological data and available information on the prevalence and disease burden. This knowledge is important in guiding the prevention, control and future research on vaccine development of this highly contagious disease of significant socioeconomic implications in public health.
... The largest prospective observational study of several epidemics over 7 years in Sarawak, Malaysia, showed that 10-30% of children with hand-foot-mouth disease due to EV71 also had CNS complications. 7 Brainstem encephalitis accounted for 58% of all neurological complications in the study followed by aseptic meningitis, which was seen in 36% of cases. Neurological involvement is more likely in cases with fever >38.5 C, fever for over 3 days and history of lethargy. ...
Viruses are the commonest cause of childhood meningitis, but outcomes beyond hospital discharge are poorly described. We undertook a systematic literature review of long‐term outcomes following paediatric viral meningitis. A search was carried out using MEDLINE, Embase, and Cochrane Review for studies from 1 January 1990 to 31 December 2018. Studies were included where specific outcome measures were available beyond hospital discharge for children <16 years old with viral meningitis. In total, 3588 papers were identified of which 14 were eligible for inclusion. Four studies reported outcomes in children with nonenterovirus 71 meningitis. A US study of 16 cases demonstrated subtle language difficulties at 3‐year follow‐up in infants in contrast to an Australian study, which revealed no impairment in language. A Fijian study showed that two out of eight cases had sensorineural hearing loss compared with none in a UK cohort of 668 infants. Three studies evaluated outcomes of enterovirus 71 meningitis in China and Taiwan, two showed cases recovered without sequelae, while one demonstrated an increased risk of attention deficit hyperactivity disorder.
Two studies including 141 cases of human parechovirus revealed no evidence of neurodevelopmental sequelae. Conversely, an Australian study demonstrated neurodevelopmental sequelae in 11 out of 77 infants with parechovirus meningitis. Most studies identified in this review demonstrated a high proportion of good clinical outcomes following viral meningitis. However, the data are limited, so robustly conducted neurodevelopmental studies are warranted to inform the evidence‐based management of viral meningitis beyond hospital discharge.
... Therapeutic options for severe HFMD remain limited [1,3,4], despite the rapidly increasing burden of disease in the southeast Asian region over the last two decades, and the life-threatening nature of the clinical syndromes seen in a small proportion of cases [33][34][35][36][37]. In this report we present the findings from two studies examining the efficacy and safety of intravenous MgSO 4 for management of ANS related hypertension in children with HFMD complicated by brainstem encephalitis. ...
Background:
Brainstem encephalitis is a serious complication of hand foot and mouth disease (HFMD) in children. Autonomic nervous system (ANS) dysregulation and hypertension may occur, sometimes progressing to cardiopulmonary failure and death. Vietnamese national guidelines recommend use of milrinone if ANS dysregulation with Stage 2 hypertension develops. We wished to investigate whether magnesium sulfate (MgSO4) improved outcomes in children with HFMD if used earlier in the evolution of the ANS dysregulation (Stage 1 hypertension).
Methods:
During a regional epidemic we conducted a randomized, double-blind, placebo-controlled trial of MgSO4 in children with HFMD, ANS dysregulation and Stage 1 hypertension, at the Hospital for Tropical Diseases in Ho Chi Minh city. Study participants received an infusion of MgSO4 or matched placebo for 72 h. We also reviewed data from non-trial HFMD patients in whom milrinone failed to control hypertension, some of whom received MgSO4 as second line therapy. The primary outcome for both analyses was a composite of disease progression within 72 h - addition of milrinone (trial participants only), need for ventilation, shock, or death.
Results:
Between June 2014 and September 2016, 14 and 12 participants received MgSO4 or placebo respectively, before the trial was stopped due to futility. Among 45 non-trial cases with poorly controlled hypertension despite high-dose milrinone, 33 received MgSO4 while 12 did not. There were no statistically significant differences in the composite outcome between the MgSO4 and the placebo/control groups in either study (adjusted relative risk (95%CI) of [6/14 (43%) vs. 6/12 (50%)], 0.84 (0.37, 1.92), p = 0.682 in the trial and [1/33 (3%) vs. 2/12 (17%)], 0.16 (0.01, 1.79), p = 0.132 in the observational cohort). The incidence of adverse events was similar between the groups. Potentially toxic magnesium levels occurred very rarely with the infusion regime used.
Conclusion:
Although we could not demonstrate efficacy in these studies, there were no safety signals associated with use of 30-50 mg/kg/hr. MgSO4 in severe HFMD. Intermittent outbreaks of HFMD are likely to continue across the region, and an adequately powered trial is still needed to evaluate use of MgSO4 in controlling hypertension in severe HFMD, potentially involving a higher dose regimen.
Trial registration:
ClinicalTrials.gov Identifier: NCT01940250 (Registered 22 AUG 2013). Trial sponsor: University of Oxford.
... Most EV infections are asymptomatic, but some may lead to illnesses, ranging from mild to more severe, or even life-threatening, such as hand, foot, and mouth disease (HFMD), aseptic meningitis, encephalitis, myocarditis, pancreatitis, acute flaccid paralysis, and neonatal sepsis 1 . In recent years, outbreaks of HFMD caused by enterovirus A71 (EV-A71) or coxsackievirus A16 have occcured in China and several countries in Southeast Asia [2][3][4][5][6] . To date, there are no approved specific antiviral therapies available to treat diseases caused by EVs. ...
We describe the development, optimisation, and validation of an automated, cell-based and high-throughput screening assay using existing luminescence-based ATPlite reagents for identifying antiviral compounds that inhibit enterovirus replication. Antiviral efficacy was determined by measuring the ATP levels in cells that were protected from the viral cytopathic effect (CPE) by the antiviral compounds pleconaril and rupintrivir. CPE-based assay conditions were optimised at a cell density of 5000 cells/well and a viral infection dose of 100 CCID50 in 384-well plates. The assay exhibited excellent robustness, with Z′-factor values between 0.75 and 0.82, coefficients of variation between 0.33% and 1.45%, and signal-to-background ratios ranging from 6.92 to 22.6 when testing three enterovirus A71 isolates circulating in China. The assay was also suitable for screening other picornaviruses, such as poliovirus, coxsackievirus, echovirus, and parechovirus.
... IVIG has been suggested to treat severe EV infections based on evidence of a possible significant benefit through the reduction of the associated central nervous system (CNS) inflammatory response [7]. Studies [33,34] showed that administration of high-dose IVIG achieved good anecdotal outcomes in EV-A71 outbreaks for severe HFMD subjects. Our previous study [17] also showed changes in outcome by early use of IVIG in outbreaks of EV-A71 infection during 2010 to 2012 in Shanghai. ...
Background
Hand, foot and mouth disease (HFMD) is a transmissible infectious disease caused by human enteroviruses (EV). Here, we described features of children with severe HFMD caused by EV-A71 or coxsackievirus A16 (CV-A16) in Shanghai, China.
Methods
Severe EV-A71 or CV-A16 caused HFMD children admitted to the Xinhua Hospital from January 2014 and December 2016, were recruited retrospectively to the study. Symptoms and findings at the time of hospitalization, laboratory tests, treatments, length of stay and residual findings at discharge were systematically recorded and analyzed.
Results
Of 19,995 children visited clinic service with probable HFMD, 574 children (2.87%) were admitted, 234 children (40.76%) were confirmed with EV-A71 (90/574) or CV-A16 (144/574) disease. Most (91.02%) of the patients were under 5 years. Initial clinical symptoms of EV-A71 and CV-A16 cases were: fever > 39 °C in 81 (90%) and 119 (82.63%), vomiting in 31 (34.44%) and 28 (19.44%), myoclonic twitching in 19 (21.11%) and 11(7.64%), startle in 21 (23.33%) and 20 (13.69%), respectively. Serum levels of interleukin-1β (IL-1β), IL-2, IL-6, IL-8, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) were significantly upregulated in severe HFMD subjects. Forty-seven children (20.08%) treated with intravenous gamma globulin (IVIG) showed decreased duration of illness episodes. All children were discharged without complications.
Conclusions
EV-A71 and CV-A16 accounted 40.76% of admitted HFMD during 2014 to 2016 in Xinhua Hospital. IVIG appeared to be beneficial in shortening the duration of illness episodes of severe HFMD.
Les entérovirus (EV) sont des virus entériques (famille des Picornaviridae) classés parmi quatre espèces taxonomiques (A à D). Les infections à EV symptomatiques sont associées à des atteintes neurologiques, respiratoires, cardiaques, musculaires, cutanéomuqueuses. La maladie pieds-mains-bouche (PMB) se caractérise par une éruption cutanée et des ulcérations buccales chez les enfants de moins 5 ans. L’EVA71 (EVA71) et le coxsackievirus A6 (CVA6) sont parmi les types d’EV de l’espèce A, les plus fréquemment associés à la maladie PMB. En France, l’EVA71 est associé à la recrudescence d’atteintes neurologiques depuis 2016, et le CVA6 est relié à la survenue d’épidémies régulières de maladie PMB. L’objectif de la thèse est de comparer les réémergences épidémiques de ces deux virus par l’analyse comparative des génomes. L’épidémie d’atteintes neurologiques sévères en 2016 a été associée au variant C1v2015 classé dans le sous-génogroupe C1 d’EVA71 et dont l’émergence a été datée en 2010. Le génome de ce virus présente une structure chimérique caractéristique de multiples évènements de recombinaison. Le génome du virus C1v2015 montre des variations notables par rapport à celui des virus antérieurs dans des segments codant des épitopes exposés à la surface des protéines de capside. Nous avons daté en 2013 la survenue d’un évènement de recombinaison qui a remplacé le gène de la polymérase 3Dpol précédant de peu la propagation épidémique du virus en Europe à partir de 2015. Pour étudier le CVA6, nous avons mis au point une méthode de séquençage NGS que nous avons appliquée à des échantillons cliniques recueillis en France entre 2010 et 2018. En France, depuis 2014, les épidémies sont liées au sous-génogroupe D4 qui a émergé globalement en 2004. L’étude du gène 3Dpol permet d’identifier 5 nouvelles formes recombinantes. Les caractéristiques épidémio-cliniques des cas de maladie PMB rapportés en France montrent que l’émergence du CVA6 a été contemporaine de l’augmentation de formes atypiques de la maladie, une tendance aussi observée à l’échelle mondiale. En conclusion, nos travaux montrent l’intérêt de l’analyse des génomes complets d’EV pour comparer les variations moléculaires et retracer l’histoire évolutive et épidémique des virus réémergents.
Enterovirus A71 is a major causative pathogen of hand, foot and mouth disease. It has become a global public health threat, and is especially important for infants and young children in the Asian‐Pacific countries. The enterovirus A71 is a non‐enveloped virus of the Picornaviridae family having a single‐stranded positive‐sense RNA genome of about 7.4 kb which encodes the structural and nonstructural proteins. Currently there are no US FDA‐approved vaccines or antiviral therapy available against enterovirus A71 infection. Although enterovirus A71 vaccines have been licenced in China, clinically approved vaccines for widespread vaccination programs are lacking. Substantial progress has recently been achieved on understanding the structure and function of enterovirus A71 proteins together with information on the viral genetic diversity and geographic distribution. The present review is intended to provide an overview on our current understanding of the molecular biology and epidemiology of enterovirus A71 which will aid the development of vaccines, therapeutics and other control strategies so as to bolster the preparedness for future enterovirus A71 outbreaks.
Introduction: Hand, foot, and mouth disease caused by enterovirus A71 (EV-A71) is more frequently associated with neurological complications and deaths compared to other enteroviruses.
Areas covered: The authors discuss current understanding of the neuropathogenesis of EV-A71 based on various clinical, human, and animal model studies. The authors discuss the important advancements in virus entry, virus dissemination, and neuroinvasion. The authors highlight the role of host immune system, host genetic factors, viral quasispecies, and heparan sulfate in EV-A71 neuropathogenesis.
Expert opinion: Comparison of EV-A71 with EV-D68 and PV shows similarity in primary target sites and dissemination to the central nervous system. More research is needed to understand cellular tropisms, persistence of EV-A71, and other possible invasion routes. EV-A71 infection has varied clinical manifestations which may be attributed to multiple receptors usage. Future development of antivirals and vaccines should target neurotropic enteroviruses. Repurposing drug and immunomodulators used in combination could reduce the severity of EV-A71 infection. Only a few drugs have been tested in clinical trials, and in the absence of antiviral and vaccines (except China), active virus surveillance, good hand hygiene, and physical distancing should be advocated. A better understanding of EV-A71 neuropathogenesis is critical for antiviral and multivalent vaccines development.
Hand, foot and mouth disease (HFMD), caused by enterovirus A71 (EV-A71), presents mild to severe disease, and sometimes fatal neurological and respiratory manifestations. However, reasons for the severe pathogenesis remain undefined. To investigate this, infection and viral kinetics of EV-A71 isolates from clinical disease (mild, moderate and severe) from Sarawak, Malaysia, were characterised in human rhabdomyosarcoma (RD), neuroblastoma (SH-SY5Y) and peripheral blood mononuclear cells (PBMCs). High resolution transcriptomics was used to decipher EV-A71-host interactions in PBMCs. Ingenuity analyses revealed similar pathways triggered by all EV-A71 isolates, although the extent of activation varied. Importantly, several pathways were found to be specific to the severe isolate, including triggering receptor expressed on myeloid cells 1 (TREM-1) signalling. Depletion of TREM-1 in EV-A71-infected PBMCs with peptide LP17 resulted in decreased levels of pro-inflammatory genes for the moderate and severe isolates. Mechanistically, this is the first report describing the transcriptome profiles during EV-A71 infections in primary human cells, and the potential involvement of TREM-1 in the severe disease pathogenesis, thus providing new insights for future treatment targets.
This chapter looks at how enteroviruses are responsible for most cases of viral meningitis where a pathogen is identified; many other viruses can also cause meningitis with considerable geographical and seasonal variation. Their typical presentation is with sudden onset of fever, headache, neck stiffness, and photophobia. There is no change in conscious level. Prognosis is generally good, though recent data suggest not always. Viruses invade and damage the central nervous system in two ways: directly, by infecting the leptomeninges, brain, and spinal cord; and, indirectly, by inducing an immunological reaction resulting in para and postinfectious diseases. In both cases, the terms ‘meningitis’, ‘encephalitis’, and ‘myelitis’ are used alone or in combination.
Rituximab and other B cell depleting agents are increasingly used for haematological, immunological and neurological diseases. In a small minority, immunosuppression leads to increased virulence of normally mild infections. Brainstem encephalitis has been described occurring after infection from enteroviruses, more commonly in the paediatric population, but also in immunosuppressed adults. In this paper, we describe an enteroviral brainstem encephalitis in a rituximab-immunosuppressed patient. The enterovirus identified was Coxsackie A16, which has never yet been reported to cause brainstem encephalitis in an adult.
The goal of this paper was to develop a sandwich ELISA that can detect intact human enterovirus A71 (EV-A71)virus-like particles (VLPs)in vaccines. This assay specifically detected EV-A71 viruses from different sub-genogroups as well as EV-A71 VLPs, and treatment of VLPs with high heat and low pH reduced or completely abolished detection of the VLPs suggesting that the ELISA detected assembled particles. Using a purified VLP as a reference standard, a quantitative sandwich ELISA (Q-ELISA)was established which was used to monitor the yield and purity of the VLPs during manufacturing. Coupled with immunogenicity studies, the Q-ELISA was used to evaluate the performance of the VLPs and formalin-inactivated EV-A71 vaccine. This assay has the potential to play an important role in the development of an efficient process to produce and purify the VLPs and in examining the quality of EV-A71 vaccines.
Enterovirus 71 (EV71)and coxsackievirus A16 (CA16)are common causative agents of mild and self-limiting symptoms of childhood hand, foot, and mouth disease (HFMD). However, some EV71-infected HFMD patients can develop severe neurological and/or fatal cardiopulmonary complications. In Thailand, HFMD associated with the EV71 subgenotypes C4a and B5 were reported to be associated with diverse outcomes. However, variations in enterovirus subgenotypes and virulence factors have not been fully elucidated; this study elucidated these variations in peripheral blood mononuclear cells (PBMCs)exposed to different subgenotypes of isolated enteroviruses for 24 and 48 h. Following infection, viral titers were determined by plaque assay. Infected cells and intracellular cytokines were quantified using flow cytometry, and multiplex assay was used to examine cytokine release. All isolated subgenotypes showed replication capability in PBMCs; specifically, the replication titer of EV71 C4a tended to be higher than titers of EV71 B5 and CA16. Additionally, the infectivity of EV71 B5 was higher in monocytes than in lymphocytes. Compared with EV71 B5, EV71 C4a and CA16 had greater ability to induce intra- and extracellular cytokine responses. These findings provide new insights into variations in cellular immune responses to different EV71 subgenotypes isolated from Thai patients, which should be considered for the development of vaccines and therapeutic agents.
Hand, foot and mouth disease (HFMD) is responsible for a heavy economic and social burden in the Asia-Pacific region. Previous studies have shown that coxsackievirus A6 (CVA6) and coxsackievirus A10 (CVA10) have become the predominant agents of HFMD in mainland China in recent years, replacing enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), although it is unclear if this is consistent throughout China. In this study, samples from 253 HFMD cases were collected in Shenzhen, China, from May 2013 through April 2014 to identify the etiological agent of HFMD. In total, 64.8% (164/253) of HFMD cases were enterovirus positive, in which 81.1% (133/164) were determined to be CVA6. The phylogenetic tree of the partial viral protein 1 sequence showed that the CVA6 isolates were divided into four clusters (Clusters A to D), and cluster D was further divided into four sub-clusters (Clusters D1 to D4). The 133 CVA6 samples isolated in our study were classified into cluster D4, in which the first identified sequence was isolated in Shenzhen in 2008. This study demonstrated that the CVA6 cluster D4, which is predominantly circulating in HFMD in mainland China, may have originated from a local strain identified in 2008 in Shenzhen.
Enterovirus (EV) and Parechovirus (HPeV) are a frequent cause of infection in children. This review gives an overview of possible causes for differences in clinical presentation. EV and HPeV can cause a meningitis with or without pleocytosis. Different possible mechanisms for meningitis without pleocytosis are given. Little is known about the prognosis and long-term effects of EV and HPeV meningitis in children. Only some studies with a small number of children with EV or HPeV meningitis are reported. The different possible mechanisms involved in the neurological outcome after EV or HPeV meningitis will be discussed.
Yongxin Yu is an academician at the Chinese Academy of Engineering and a highly respected person when it comes to Japanese encephalitis (JE) live attenuated vaccine (Fig. 5.1). After the JE vaccine he developed was approved and marketed in 1989, hundreds of million doses have been used, demonstrating the safety and effectiveness of this vaccine under large-scale use. The effectiveness of this vaccine is over 95%, as recognized by the WHO and other international organizations. Academician Yu is one of China’s most famous virologists and experts in biological products; he has received an outstanding contribution award by improving China’s medical health. He is also a renowned scientist in China and in the world with his great contributions. His science is rigorous and realistic; pays attention to the accuracy, reliability, and integrity of the experimental data; and is loved by scientific and technological personnel.
Enteroviruses can cause outbreaks of hand-foot-and-mouth disease (characterized by vesicular lesions on the hands, feet, and oral mucosa) or herpangina, usually without life-threatening manifestations. In 1998 an epidemic of enterovirus 71 infection caused hand-foot-and-mouth disease and herpangina in thousands of people in Taiwan, some of whom died.
We assessed the epidemiologic aspects of this outbreak. Cases of hand-foot-and-mouth disease or herpangina in ambulatory patients were reported to the Taiwan Department of Health by a mean of 818 sentinel physicians. Severe cases in hospitalized patients were reported by 40 medical centers and regional hospitals. Viruses were isolated by 10 hospital laboratories and the department of health.
The sentinel physicians reported 129,106 cases of hand-foot-and-mouth disease or herpangina in two waves of the epidemic, which probably represents less than 10 percent of the estimated total number of cases. There were 405 patients with severe disease, most of whom were five years old or younger; severe disease was seen in all regions of the island. Complications included encephalitis, aseptic meningitis, pulmonary edema or hemorrhage, acute flaccid paralysis, and myocarditis. Seventy-eight patients died, 71 of whom (91 percent) were five years of age or younger. Of the patients who died, 65 (83 percent) had pulmonary edema or pulmonary hemorrhage. Among patients from whom a virus was isolated, enterovirus 71 was present in 48.7 percent of outpatients with uncomplicated hand-foot-and-mouth disease or herpangina, 75 percent of hospitalized patients who survived, and 92 percent of patients who died.
Although several enteroviruses were circulating in Taiwan during the 1998 epidemic, enterovirus 71 infection was associated with most of the serious clinical manifestations and with nearly all the deaths. Most of those who died were young, and the majority died of pulmonary edema and pulmonary hemorrhage.
An outbreak of enterovirus 71 (EV71) infection occurred in Taiwan in 1998. The clinical spectrums and laboratory findings
for 97 patients with virus culture-proven EV71 infections were analyzed. Eighty-seven percent of the patients were younger
than age 5 years. Hand-foot-and-mouth syndrome occurred in 79% of the children and central nervous system (CNS) involvement
in 35%, including nine fatal cases. The predominant neurological presentations were myoclonus (68%), vomiting (53%), and ataxia
(35%). Brain stem encephalitis was the cardinal feature of EV71 CNS involvement during this outbreak. Magnetic resonance imaging
and pathological findings illustrated that the midbrain, pons, and medulla were the target areas. EV71 brain stem encephalitis
can present either with cerebellar signs and an initially mild, reversible course or with overwhelming neurogenic shock and
neurogenic pulmonary edema (NPE) resulting in a fatal outcome. Brain stem encephalitis that progressed abruptly to neurogenic
shock and NPE was indicative of poor prognosis in this epidemic. Early aggressive treatment and close monitoring of the neurological
signs are mandatory to improve the chance of survival.
Enterovirus 71 (EV71) (genus Enterovirus, family Picornaviridae), a common cause of hand, foot, and mouth disease (HFMD), may also cause severe neurological diseases, such as encephalitis and poliomyelitis-like paralysis. To examine the genetic diversity and rate of evolution of EV71, we have determined and analyzed complete VP1 sequences (891 nucleotides) for 113 EV71 strains isolated in the United States and five other countries from 1970 to 1998. Nucleotide sequence comparisons demonstrated three distinct EV71 genotypes, designated A, B, and C. The genetic variation within genotypes (12% or fewer nucleotide differences) was less than the variation between genotypes (16.5 to 19.7%). Strains of all three genotypes were at least 94% identical to one another in deduced amino acid sequence. The EV71 prototype strain, BrCr-CA-70, isolated in California in 1970, is the sole member of genotype A. Strains isolated in the United States and Australia during the period from 1972 to 1988, a 1994 Colombian isolate, and isolates from a large HFMD outbreak in Malaysia in 1997 are all members of genotype B. Although strains of genotype B continue to circulate in other parts of the world, none have been isolated in the United States since 1988. Genotype C contains strains isolated in 1985 or later in the United States, Canada, Australia, and the Republic of China. The annual rate of evolution within both the B and C genotypes was estimated to be approximately 1.35 x 10(-2) substitutions per nucleotide and is similar to the rate observed for poliovirus. The results indicate that EV71 is a genetically diverse, rapidly evolving virus. Its worldwide circulation and potential to cause severe disease underscore the need for additional surveillance and improved methods to identify EV71 in human disease.
From April through June 1997, 29 previously healthy children aged <6 years (median, 1.5 years) in Sarawak, Malaysia, died
of rapidly progressive cardiorespiratory failure during an outbreak of hand, foot, and mouth disease caused primarily by enterovirus
71 (EV71). The case children were hospitalized after a short illness (median duration, 2 days) that usually included fever
(in 100% of case children), oral ulcers (66%), and extremity rashes (62%). The illness rapidly progressed to include seizures
(28%), flaccid limb weakness (17%), or cardiopulmonary symptoms (of 24 children, 17 had chest radiographs showing pulmonary
edema, and 24 had echocardiograms showing left ventricular dysfunction), resulting in cardiopulmonary arrest soon after hospitalization
(median time, 9 h). Cardiac tissue from 10 patients showed normal myocardium, but central nervous system tissue from 5 patients
showed inflammatory changes. Brain-stem specimens from 2 patients were available, and both specimens showed extensive neuronal
degeneration, inflammation, and necrosis, suggesting that a central nervous system infection was responsible for the disease,
with the cardiopulmonary dysfunction being neurogenic in origin. EV71 and possibly an adenovirus, other enteroviruses, or
unknown cofactors are likely responsible for this rapidly fatal disease.
Enterovirus 71 (EV71) causes epidemics of hand, foot, and mouth disease associated with neurological complications in young
children. We report an outbreak of EV71-associated neurological disease that occurred from February through September 1999
in Perth, Western Australia. Fourteen children with culture-proven, EV71-induced neurological disease were identified. Nine
patients (64%) developed severe neurological disease; 4 of these patients developed long-term neurological sequelae. Neurological
syndromes included aseptic meningitis, Guillain-Barré syndrome, acute transverse myelitis, acute cerebellar ataxia, opso-myoclonus
syndrome, benign intracranial hypertension, and a febrile convulsion. Clinical and magnetic resonance imaging data indicated
that immunopathology was a major factor in the pathogenesis of neurological disease in this outbreak. This finding is in contrast
to reports of previous EV71 epidemics, in which virus-induced damage to gray matter was the most frequent cause of neurological
disease.
Enterovirus 71 (EV 71) infections have high neurovirulence and fatality. Immune responses were assessed in 78 patients with
EV 71 infection. EV 71 meningoencephalitis occurred more frequently in younger children and in boys. C-reactive protein levels
were not elevated, although total leukocyte counts were increased in these patients. The CD40-ligand expression on T cells
significantly decreased in children with meningoencephalitis (P=.041). Polymorphism of the cytotoxic T lymphocyte antigen–4
(CTLA-4) at position 49 of exon 1 showed a higher frequency of G/G genotype in patients with EV 71 meningoencephalitis than
in those without meningoencephalitis (18/31 vs. 14/47; P=.045) and in control subjects (18/31 vs. 25/93l; P=.007). Specific
EV 71 neutralizing antibody titers were detectable but did not differ in children with and without meningoencephalitis in
the acute and convalescent stages. Results from this study suggest that younger children with a certain CTLA-4 polymorphism
and altered cellular but not humoral response may be linked to EV 71 meningoencephalitis
Enterovirus 71 (EV71) is a frequent cause of hand, foot, and mouth disease (HFMD) epidemics associated with severe neurological
sequelae in a small proportion of cases. There has been a significant increase in EV71 epidemic activity throughout the Asia-Pacific
region since 1997. Recent HFMD epidemics in this region have been associated with a severe form of brainstem encephalitis
associated with pulmonary edema and high case fatality rates. In this study, we show that four genetic lineages of EV71 have
been prevalent in the Asia-Pacific region since 1997, including two previously undescribed genogroups (B3 and B4). Furthermore,
we show that viruses belonging to genogroups B3 and B4 have circulated endemically in Southeast Asia during this period and
have been the primary cause of several large HFMD or encephalitis epidemics in Malaysia, Singapore, and Western Australia.
Two outbreaks of hand-foot-and-mouth disease (HFMD) occurred in Taiwan between 1998 and 2000. Enteroviruses were isolated
from a total of 1,892 patients in this laboratory during this period. Of the virus isolates, enterovirus 71 (EV71) was diagnosed
in 44.4% of the patients (132 of 297) in 1998, 2% (13 of 646) in 1999, and 20.5% (195 of 949) in 2000. Genetic analyses of
the 5′-untranslated and VP1 regions of EV71 isolates by reverse transcription-PCR and sequencing were performed to understand
the diversity of EV71 in these outbreaks of HFMD. Most EV71 isolates from the 1998 epidemic belonged to genotype C, while
only one-tenth of the isolates were genotype B. Interestingly, all EV71 isolates tested from 1999 to 2000 belonged to genotype
B. This study indicated that two genogroups of EV71 capable of inducing severe clinical illness have been circulating in Taiwan.
Furthermore, the predominant EV71 genotypes responsible for each of the two major HFMD outbreaks within the 3-year period
in Taiwan were different.
The most recently discovered enterovirus, enterovirus 71 (EV71), is neurotropic and may cause severe disease and sudden death
in children. In 1998, a large outbreak of enterovirus infection occurred in Taiwan that resulted in 405 severe cases in children
and 78 deaths. Of the 78 children who died, 71 (91%) were <5 years old. EV71 was the primary agent in fatal cases of infection.
Most of these patients died within 1–2 days of admission to the hospital. We hypothesize that EV71 directly attacks the central
nervous system and causes neurogenic pulmonary edema and cardiac decompensation through the mechanism of sympathetic hyperactivity
and inflammatory responses. Early recognition of risk factors and intensive care are crucial to successful treatment of this
fulminant infection. After poliovirus is eradicated, EV71 will become the most important enterovirus that affects children,
and development of a vaccine may be the only effective measure against it.
In Southeast Asia, dengue viruses often co-circulate with other flaviviruses such as Japanese encephalitis virus, and due to the presence of shared antigenic epitopes it is often difficult to use serological methods to distinguish between previous infections by these flaviviruses.
Convalescent sera from 69 individuals who were known to have had dengue or Japanese encephalitis virus infection were tested by western blotting against dengue, Japanese encephalitis and West Nile virus antigens. We determined that individuals who had been infected with dengue viruses had IgG responses against the premembrane protein of dengue viruses but not Japanese encephalitis, whereas individuals who had been infected with Japanese encephalitis had IgG specific for the premembrane protein of Japanese encephalitis virus but not the dengue viruses. None reacted with the premembrane protein of West Nile virus. Using the Pearson Chi Square test, it was determined that the difference between the two groups was highly significant with a p value of <0.001.
The use of flavivirus premembrane protein in seroepidemiological studies will be useful in determining what flaviviruses have circulated in a community.
Singapore experienced a large epidemic of hand, foot and mouth disease (HFMD) in 2000. After reviewing HFMD notifications from doctors and child-care centers, we found that the incidence of HFMD rose in September and declined at the end of October. During this period, 3,790 cases were reported. We performed enteroviral cultures on 311 and 157 specimens from 175 HFMD patients and 107 non-HFMD patients, respectively; human enterovirus 71 (HEV71) was the most frequently isolated virus from both groups. Most of the HFMD patients were </=4 years of age. Three HFMD and two non-HFMD patients died. Specimens from two HFMD and both non-HFMD patients were culture positive for HEV71; a third patient was possibly associated with the virus. Autopsies performed on all three HFMD and one of the non-HFMD case-patients showed encephalitis, interstitial pneumonitis, and myocarditis. A preparedness plan for severe HFMD outbreaks provided for the prompt, coordinated actions needed to control the epidemic.
We report the virological and clinical features of 8 children who presented with adenovirus-associated acute flaccid paralysis
(AFP) during an epidemic of enterovirus type 71 (EV71)-associated hand-foot-and-mouth disease (HFMD) in Sarawak, Malaysia,
in 1997. Neutralization tests and phylogenetic analysis revealed adenovirus type 21 (Ad21), although DNA restriction digests
suggested that this virus was different from the prototype Ad21. Four children had upper-limb monoparesis, 2 had lower-limb
monoparesis (one of whom had changes in the anterior spinal cord noted on magnetic resonance imaging), and 2 had flaccid paraparesis.
At follow-up, 4 children were noted to have made full recoveries and 3 had residual flaccid weakness and wasting. Neurophysiological
investigation revealed a mixture of axonal and demyelinating features in motor and sensory nerves, with denervation. These
findings suggest that Ad21 might cause AFP by anterior horn cell damage or neuropathy of the brachial or lumbosacral plexus.
The occurrence of these unusual adenovirus infections during an outbreak of EV71-associated HFMD suggests that an interaction
between the 2 viruses may have occurred.
Enterovirus 71 (EV71) caused a large outbreak in Taiwan in 1998 with 78 deaths, and smaller outbreaks recurred in 2000 and 2001. The outbreak was recognized because of a large number of hand, foot, and mouth disease cases and the rapid deaths of children with the disease. Virologic and pathologic studies indicated that EV71 was the most important agent related to severe and fatal cases and that a neurogenic inflammatory response was involved in the pathogenesis of cardiopulmonary collapse resulting from fulminant EV71 infection. Seroepidemiologic study suggested that EV71 had circulated for at least 16 years and that the accumulation of susceptible hosts might have triggered the 1998 outbreak. However, a change in EV71 neurovirulence and host genetic susceptibility may also have affected the clinical outcome. The Taiwan outbreak shows that worldwide attention should be paid to such outbreaks, new antiviral drugs should be developed, and that vaccination of children under 5 years of age may be warranted.
This study provides a comprehensive overview of the molecular epidemiology of human enterovirus 71 (HEV71) in the Asia-Pacific region from 1997 through 2002. Phylogenetic analysis of the VP4 and VP1 genes of recent HEV71 strains indicates that several genogroups of the virus have been circulating in the Asia-Pacific region since 1997. The first of these recent outbreaks, described in Sarawak (Malaysian Borneo) in 1997, was caused by genogroup B3. This outbreak was followed by large outbreaks in Taiwan in 1998, caused by genogroup C2, and in Perth (Western Australia) in 1999, where viruses belonging to genogroups B3 and C2 cocirculated. Singapore, Taiwan, and Sarawak had HEV71 epidemics in 2000, caused predominantly by viruses belonging to genogroup B4; however, large numbers of fatalities were observed only in Taiwan. HEV71 was identified during an epidemic of hand, foot and mouth disease in Korea; that epidemic was found to be due to viruses constituting a new genogroup, C3.
Phylogenetic analysis of 45 enterovirus 71 (EV71) isolates for 6 years in Yamagata, Japan, clarified that the annual outbreak
of hand-foot-and-mouth disease was due to four genetically distinct subgenogroups, including a novel “B5.” Our results suggest
that the importation of EV71 from surrounding countries has had a major epidemiological impact on the local community used
in our study.
In Taiwan, enterovirus 71 (EV71) has played an important role in severe enterovirus-related cases every year since the devastating outbreak in 1998. Three genogroups A, B, C occur worldwide; with the B and C genogroups being subdivided into B1-B4 and C1-C4 subgenogroups respectively. To understand the mutation of the EV71 genogroup in Taiwan before and after 1998, a total of 54 worldwide strains were studied including 41 Taiwanese strains obtained in 1986 and 1998-2004. A fragment of 207 bp of the VP4 region was amplified and sequenced. Genetic analysis was performed using MEGA software (version 3.0) for the nucleotide sequence alignment and phylogenetic analysis. In Taiwan, the subgenogroup B1 was predominant before 1998 while subgenogroup C2 was the major etiologic group in 1998 outbreak. A minor etiologic group outbreak in 1998, subgenogroup B4, became predominant during the period from 1999 to 2003. In this study, subgenogroup C4 emerged and became predominant in 2004 in Taiwan. The nucleotide differences between B1 and C2, C2 and B4, B4 and C4 were 20%-26%, 19%-27%, 18%-22%, respectively. Nucleotide sequence alignment revealed 67 substitutions. Most of the substitutions (62/67) were silent mutations. This is the first report about the emergence of EV71 subgenogroup C4 in Taiwan.
A major outbreak of human enterovirus 71-associated hand, foot and mouth disease in Sarawak in 1997 marked the beginning of a series of outbreaks in the Asia Pacific region. Some of these outbreaks had unusually high numbers of fatalities and this generated much fear and anxiety in the region.
We established a sentinel surveillance programme for hand, foot and mouth disease in Sarawak, Malaysia, in March 1998, and the observations of the first 7 years are described here. Virus isolation, serotyping and genotyping were performed on throat, rectal, vesicle and other swabs.
During this period Sarawak had two outbreaks of human enterovirus 71, in 2000 and 2003. The predominant strains circulating in the outbreaks of 1997, 2000 and 2003 were all from genogroup B, but the strains isolated during each outbreak were genetically distinct from each other. Human enterovirus 71 outbreaks occurred in a cyclical pattern every three years and Coxsackievirus A16 co-circulated with human enterovirus 71. Although vesicles were most likely to yield an isolate, this sample was not generally available from most cases and obtaining throat swabs was thus found to be the most efficient way to obtain virological information.
Knowledge of the epidemiology of human enterovirus 71 transmission will allow public health personnel to predict when outbreaks might occur and to plan interventions in an effective manner in order to reduce the burden of disease.
The prevalence of HFMD as well as the causative agents was unknown in peninsular Malaysia prior to May 1997. From May 1997 to June 2001, 585 patients suspected to have enterovirus infections, with 467 patients clinically diagnosed as having HFMD, were investigated in the diagnostic virology unit of the University Malaya Medical Centre. Data from this study showed that HFMD is endemic in Malaysia with the occurrence of two outbreaks during the study period. In each outbreak, a number of viruses were isolated but enterovirus 71 was the main virus isolated in both outbreaks. Echovirus 7 (Eo7) was isolated from 5 patients with HFMD in the second outbreak, a clinical entity that has not been attributed to it previously. Children aged 4 years and below, particularly those between 1 and 2 years of age, were in the main group of patients affected by the illness. HFMD by itself and without neurological involvement was relatively benign and self-limiting. There was no significant difference in the virus isolation rate with respect to gender and ethnic groups. Virus isolation was attempted in a total of 764 clinical specimens consisting of 342 stool specimens, 285 oral secretions specimens and 137 vesicular fluid specimens. Oral specimens gave the highest virus isolation rate (33.3%) followed by vesicular specimens (27.0%). Stool specimens only yielded an isolation rate of 14.0%.
Acute flaccid paralysis remains common among Vietnamese children despite a pronounced fall in the incidence of poliomyelitis.
During 1995, all 22 children presenting with acute flaccid paralysis to a referral centre in Ho Chi Minh City, Vietnam, had virological cultures and antibody measurements done on serum, cerebrospinal fluid, and faeces. A year later the children were reassessed and electrophysiological studies were done.
Wild poliovirus type 1 was isolated from the faeces of only one patient, and non-polio enteroviruses from three patients. 12 (55%) of the 22 children with acute flaccid paralysis had evidence of acute Japanese encephalitis virus (JEV) infection, compared with only one (1%) of 88 age-matched hospital controls (children with diphtheria; p<0.0001). Compared with JEV-negative patients, weakness in JEV-infected children was more rapid in onset, tended to be asymmetrical, but was less likely to involve the arms. All 12 children with JEV infection were febrile at the onset of weakness, seven had acute retention of urine, and ten had CSF pleiocytosis. Seven of eight JEV-negative patients met the case-definition of Guillain-Barré syndrome, compared with only one of 12 JEV-positive children. At follow-up, patients with JEV infection had greater disability and were more likely to have muscle wasting than were JEV-negative children. Nerve conduction and electromyographic studies indicated damage to the anterior horn cells.
JEV causes an acute flaccid paralysis in children that has similar clinical and pathological features to poliomyelitis. In endemic areas, children with acute flaccid paralysis should be investigated for evidence of JEV infection.
Enterovirus 71 has been associated with several outbreaks, as well as sporadic cases, of central nervous system infection and has a worldwide distribution. Seven children with encephalitis and five with aseptic meningitis caused by Enterovirus 71 were seen at Otsu Municipal Hospital during the summer of 1997. The infections were confirmed serologically, although detection of the viral genome in cerebrospinal fluid was unsuccessful. Seven children were diagnosed as having hand-foot-and-mouth syndrome, two were diagnosed as having herpangina, and three patients younger than 12 months old developed no eruptions. The skin or mucosal manifestations of this outbreak demonstrated considerable variation. The Enterovirus 71 strain that caused the outbreak had a strong neurovirulent tendency. Among the patients with encephalitis, symptoms originating from the impairment of diencephalon were seen in four patients, and those originating from cerebellar impairment were seen in two patients. Brain magnetic resonance imaging in one patient revealed an abnormality in the pons. The neurologic manifestations associated with Enterovirus 71 infection may be characterized by involvement of the cerebellum, brainstem, and diencephalon. Enterovirus 71 is one of the pathogenic viruses that cause hand-foot-and-mouth syndrome, as well as a variety of other clinical manifestations. The most important of these is neurologic disease, especially in infants and young children.
This article has no abstract; the first 100 words appear below.
Enteroviruses are members of a family of viruses (the picornaviruses) that commonly infect humans throughout the world. They are associated with a broad range of diseases, including various enanthems and exanthems, hemorrhagic conjunctivitis, myocarditis, pericarditis, several central nervous system syndromes (most commonly aseptic meningitis), and undifferentiated febrile illnesses with or without respiratory tract symptoms. Almost all enteroviral infections are probably either asymptomatic or mild and self-limited. Historically, enteroviruses have been divided into the following subgroups largely on the basis of differences in the range of hosts and pathogenicity: the polioviruses, group A coxsackieviruses, group B coxsackieviruses, and echoviruses. Serologically distinct . . .
Raphael Dolin, M.D.
Harvard Medical School, Boston, MA 02115
In mid-1997, several children died in Sarawak, Malaysia, during an epidemic of enterovirus-71 (EV71) hand, foot, and mouth disease. The children who died had a febrile illness that rapidly progressed to cardiopulmonary failure and the cause was not satisfactorily resolved. We describe the isolation and identification of a subgenus B adenovirus from the children who died.
We studied two groups of children presenting to Sibu Hospital from April 14 to Sept 30, 1997. For children who died, the inclusion criterion was death after febrile illness, and for those who did not die it was acute flaccid paralysis (AFP). Serum and cerebrospinal fluid samples were tested for IgM antibodies to Japanese encephalitis and dengue viruses. Viruses isolated were identified by immunofluorescence, reverse-transcriptase PCR, or PCR and DNA sequencing.
Enterovirus was isolated in three (19%) of 16 children who died and in none of the eight surviving children with AFP. However, an agent that was initially difficult to identify was found in ten (63%) children who died and five (63%) surviving children who had AFP. The agents isolated from ten (66.7%) of these 15 children were eventually identified as adenoviruses and were isolated mainly from clinically important sterile sites or tissues. All the enterovirus-positive children who died had this second agent.
Our data raises doubts that EV71 was the only aetiological agent in these deaths.
In Taiwan, from April to July, 1998, an epidemic of hand, foot, and mouth disease associated with enterovirus 71 (EV71) occurred with fatal complications. We did a clinical study of EV71-related diseases in Taiwan.
We studied 154 children with virus-culture confirmed EV71 infection. Children were divided into three groups: 11 patients with pulmonary oedema; 38 patients with central nervous system (CNS) involvement and no pulmonary oedema; and 105 children without complications. We compared the clinical features, laboratory findings, risk factors, and outcome among these three groups.
Nine children with pulmonary oedema had hand, foot, and mouth disease, one had herpangina, and one had febrile illness with eight children with limb weakness and one with limb hypesthesia. All children had had sudden onset of tachycardia, tachypnoea, and cyanosis 1-3 days after onset of the disease. Nine of 11 children died within 12 h of intubation; one child was braindead within 15 h and died 17 days after intubation; one child was in deep coma and died 3 months later. In children with CNS complication and no pulmonary oedema, one child died of pneumonia after 4 months of ventilator support and four children had sequelae. All 105 children without complications recovered. There was a significant association between CNS involvement and pulmonary oedema (odds ratio 12.4 [95% CI 2.6-60.1], p=0.001). Risk factors for pulmonary oedema after CNS involvement were hyperglycaemia, leucocytosis, and limb weakness. Hyperglycaemia was the most significant prognostic factor for pulmonary oedema (odds ratio 21.5 [3-159], p=0.003).
EV71 can cause hand, foot, and mouth disease, CNS involvement with severe sequelae, and fatal pulmonary oedema. Hyperglycaemia is the most important prognostic factor.
Severe forms of dengue, the most important arboviral infection of man, are associated with haemorrhagic disease and a generalised vascular leak syndrome. The importance of dengue as a cause of neurological disease is uncertain.
During 1995, all patients with suspected CNS infections admitted to a referral hospital in southern Vietnam were investigated by culture, PCR, and antibody measurement in serum and CSF for dengue and other viruses.
Of 378 patients, 16 (4.2%) were infected with dengue viruses, compared with four (1.4%) of 286 hospital controls (odds ratio [95% CI] 3.1 [1.7-5.8]). Five additional dengue positive patients with CNS abnormalities were studied subsequently. No other cause of CNS infection was identified. Seven infections were primary dengue, 13 secondary, and one was not classified. Ten patients had dengue viruses isolated or detected by PCR, and three had dengue antibody in the CSF. 12 of the 21 had no characteristic features of dengue on admission. The most frequent neurological manifestations were reduced consciousness and convulsions. Nine patients had encephalitis. No patient died, but six had neurological sequelae at discharge. Phylogenetic analysis of the four DEN-2 strains isolated mapped them with a DEN-2 strain isolated from a patient with dengue haemorrhagic fever, and with other strains previously isolated in southern Vietnam.
In dengue endemic areas patients with encephalitis and encephalopathy should be investigated for this infection, whether or not they have other features of the disease.
Enteroviruses can cause outbreaks of acute flaccid paralysis (AFP), mimicking wild poliovirus infections. Coxsackie virus A24 has never been implicated and yet it is a virus with high outbreak potential. We describe the association of coxsackie virus A24 with AFP in East Timor.
Human enteroviruses (EVs) are the major cause of a variety of acute and chronic illnesses. Virus isolation and neutralization
tests are usually done to identify the causative virus, but these tests are labor intensive, time consuming, and sometimes
require suckling mice from which certain viruses have been isolated. This study investigated a rapid and reliable method based
on reverse-transcription polymerase chain reaction and phylogenetic analysis. The phylogenetic tree constructed by neighbor-joining
on the basis of the VP4 sequence from 66 prototypes grouped all human EVs into 5 distinct clusters. These clusters correspond
closely to the 5 newly designated species—human EV A-D and poliovirus. The VP4 sequences of 89 isolates from 26 serotypes
obtained over >30 years plus those of 66 prototype strains were analyzed. Each isolate formed a monophyletic cluster along
with its respective prototype strain, allowing for serotype identification (with the exception of E-8). VP4-based classification
appears to be an effective tool for the molecular epidemiology study of EVs.
In 1998, an epidemic of hand-foot-and-mouth disease and herpangina caused by enterovirus 71 occurred in Taiwan, leaving many fatalities and severely handicapped survivors in its wake. The reasons this rather common pathogen would cause such a large-scale epidemic remain unknown. A seroepidemiological survey to elucidate the epidemiological characteristics of this outbreak, including its incidence and case-fatality rates was undertaken. Microneutralization tests for antibodies against enterovirus 71 were used to screen four collections of serum samples: 1) 202 specimens taken from individuals > or = 4 years old in 1994; 2) 245 specimens collected from individuals of all ages in 1997; 3) 1,258 specimens collected from individuals of all ages in 1999; and 4) sera samples from a birth cohort of 81 children who had yearly blood samples taken from 1988-98. After the maternal antibody had declined, the seropositive rates began to increase with age. Approximately half of all children aged 6 years or older were enterovirus 71 seropositive. Significantly higher seropositive rates were noted in 1999 than in 1997, in children aged 0.5-3 years. The incidence of enterovirus 71 infection during the epidemic was estimated to be 13-22%, with the higher rates in younger children. The case-fatality rate was highest (96.96 per 100,000) in infants aged 6-11 months, and declined in older children. The results showed that enterovirus 71 is endemic in Taiwan. The apparent lack of large-scale enterovirus 71 activity in the 3 years before 1998 might have been the prelude to the epidemic's appearance in 1998, and might suggest that enterovirus 71 infection will reappear every few years. The lack of a protective antibody in younger children may account for the high incidence and case-fatality rate in this age group.
Since its discovery in 1969, enterovirus 71 (EV71) has been recognised as a frequent cause of epidemics of hand-foot-and-mouth disease (HFMD) associated with severe neurological sequelae in a small proportion of cases. There has been a significant increase in EV71 epidemic activity throughout the Asia-Pacific region since 1997. Recent HFMD epidemics in this region have been associated with a severe form of brainstem encephalitis associated with pulmonary oedema and high case-fatality rates. The emergence of large-scale epidemic activity in the Asia-Pacific region has been associated with the circulation of three genetic lineages that appear to be undergoing rapid evolutionary change. Two of these lineages (B3 and B4) have not been described previously and appear to have arisen from an endemic focus in equatorial Asia, which has served as a source of virus for HFMD epidemics in Malaysia, Singapore and Australia. The third lineage (C2) has previously been identified [Brown, B.A. et al. (1999) J. Virol. 73, 9969-9975] and was primarily responsible for the large HFMD epidemic in Taiwan during 1998. As EV71 appears not to be susceptible to newly developed antiviral agents and a vaccine is not currently available, control of EV71 epidemics through high-level surveillance and public health intervention needs to be maintained and extended throughout the Asia-Pacific region. Future research should focus on (1) understanding the molecular genetics of EV71 virulence, (2) identification of the receptor(s) for EV71, (3) development of antiviral agents to ameliorate the severity of neurological disease and (4) vaccine development to control epidemics. Following the successful experience of the poliomyelitis control programme, it may be possible to control EV71 epidemics if an effective live-attenuated vaccine is developed.
A large outbreak of poliomyelitis due to poliovirus type 3 (P3) occurred in India in 1999. This raised concerns about oral poliovirus vaccine (OPV) effectiveness, particularly the type 3 component, in preventing clinical disease and offered an opportunity to describe the epidemiology of a P3 outbreak.
We reviewed data collected by the National Polio Surveillance Project to describe the outbreak and conducted a case-control study to determine risk factors for the development of paralytic poliomyelitis. The P3 cases with paralysis onset in 2000 were enrolled with four controls per case, matched for age and neighbourhood.
Of 1126 virologically confirmed poliomyelitis cases reported in 1999, 719 (64%) were due to P3. We enrolled 48 (80%) of 60 cases and 175 matched controls. Age (30.6 months, cases versus 30.4 months, controls) and vaccination status (median 5.8 OPV doses, cases versus 6.1 OPV doses, controls) were similar among cases and controls. The only significant difference between the groups was the proportion that received any injection in the last 30 days prior to paralysis onset or the corresponding reference date for controls (35.4% versus 12.3%, adjusted odds ratio [OR] = 3.9, 95% CI: 1.8-12.5).
Cases and controls had similar vaccination histories. The only significant risk factor for paralytic illness was having received any injection in the 30 days before onset. Our study confirms that injections administered during the poliovirus incubation period can provoke paralytic poliomyelitis. Injections in polio-endemic countries should only be indicated when other therapeutic options have failed or are not available.
A distinctive pattern of enterovirus 71 (EV71) infection, characterized by fever, exanthem, acute pulmonary edema (PE), brainstem encephalitis, and flaccid paresis, affects infants and young children. Most die rapidly owing to respiratory failure and fulminant PE.
The authors report short- and long-term outcome of six survivors of the acute illness.
In the context of acute PE and widespread weakness, recognition of the underlying neurologic disorder was facilitated by the distinctive pattern of MRI signal abnormalities in posterior pons and medulla. EV71-specific PCR of clinical samples helped confirm the diagnosis. Acute PE was managed with mechanical ventilation, afterload reduction, and inotrope support, and resolved completely over days. One patient with minimal neurologic recovery died 9 weeks after disease onset. The other patients have residual neurologic dysfunction, varying from subtle monoparesis to severe bulbar dysfunction, central and peripheral respiratory failure, and flaccid quadriparesis. Faster neurologic recovery was associated with less long-term deficit. Long-term outcome was similar in patients treated with and without pleconaril or IV immunoglobulin. Three long-term survivors treated with IV corticosteroids had less severe long-term neurologic disability than two not treated with steroids.
Acute pulmonary edema and encephalomyelitis occurs with EV71 infection in infants. Long-term neurologic outcome varied from minor, focal weakness to profound, global motor dysfunction with respiratory failure.
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.
Viruses were isolated from clinical samples from patients with HFMD or those with neurological complications. The EV71 isolates were identified by microneutralization assay. The VP4 and/or VP1 regions of recent EV71 isolates were sequenced and subjected to phylogenetic analysis using reference EV71 strains.
The phylogenetic analysis of EV71 isolates from the WPR revealed two major genogroups, B and C, based on the nucleotide sequence alignment of the VP1 or VP4 region. These two major genogroups were further divided into subgenogroups, B1, B2, B3, and B4 and C1, C2, C3 and C4, respectively.
The molecular epidemiological analyses of recent and previous EV71 isolates in the WPR indicated that two major genogroups of EV71 are co-circulating in Australia, Malaysia, Singapore, Taiwan and Japan. Recent EV71 isolates in Mainland China constitute a new distinct genetic cluster, subgenogroup C4. Two major lineages of EV71 are the major causative agents of the present HFMD epidemics in the WPR and both are considered to be neurovirulent.
Isolation of subgenus B adenovirus during a fatal outbreak of enterovirus 71-as-at UNIVERSITY OF PITTSBURGH on
- Cardosa Mj S Krishnan
- Tio Ph
- D Perera
- Wong
- Sc
Cardosa MJ, Krishnan S, Tio PH, Perera D, Wong SC. Isolation of subgenus B adenovirus during a fatal outbreak of enterovirus 71-as-at UNIVERSITY OF PITTSBURGH on March 18, 2015 http://cid.oxfordjournals.org/ Downloaded from 656 @BULLET CID 2007:44 (1 March) @BULLET Ooi et al. sociated hand, foot, and mouth disease in Sibu, Sarawak. Lancet 1999; 354:987–91.
- Chan KP
The 1998 enterovirus 71 outbreak in Taiwan: pathogenesis and management
- TY Lin
- LY Chang
- SH Hsia
Adenovirus-21 associated acute flaccid paralysis during a hand foot and mouth disease outbreak in Sarawak, Malaysia
- MH Ooi
- SC Wong
- D Clear