Current status of hand-foot-and-mouth disease
Journal of Biomedical Science volume 30, Article number: 15 (2023)
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.
As early as 1957, the characteristic symptoms of fever, vesicular rash on hands and feet caused by Coxsackievirus (CV), primarily CVA16, was first reported in Toronto [1, 2]. In 1959, “hand-foot-and-mouth disease (HFMD)” was initially used to name a disease with essentially the same symptoms as described by Robinson et al. . Over the past few decades, HFMD outbreaks caused by Enterovirus A71 (EV-A71), CVA16, CVA6 and Echoviruses (Echo) were reported frequently around the world . EV-A71, which was first isolated from a child with meningitis in 1969, has also caused widespread outbreaks of HFMD throughout much of the Asia–Pacific region . The disease was generally mild and lasted less than a week in most cases, characterized by fever, a blister-like rash on the hands and feet, and oral ulcers caused by ruptured blisters in the mouth . However, quite a few patients experience fatal neurological or cardiopulmonary complications. Furthermore, recent follow-up studies have shown that severe neurological sequelae may occur in severely recovered patients (Fig. 1) [6,7,8]. Therefore, HFMD has become a significant concern for public health throughout the Asia–Pacific region and beyond. The discovery of tomato flu, a HFMD-like illness caused by enterovirus, in India has brought renewed attention to HFMD outbreaks . This Review focuses on summarizing the current findings regarding HFMD in regards to virology, epidemiology, pathogenesis, and vaccine development in order to better inform clinical practice and public health initiatives.
Etiological characteristics of HFMD
HFMD is caused by Human enteroviruses (EVs) that are members of the Enterovirus genus of the Picornaviridae family . EVs were initially classified into Poliovirus (PV), Echo, CV-A and B, and emerging EVs. Since 1999, EVs have been divided into four categories of Enterovirus A, B, C, and D, in the light of their molecular, biological, and genetic characteristics. Nowadays, over 100 EVs have been reported worldwide . Table 1 lists various pathogens associated with HFMD outbreaks . In the past, EV-A71 and CVA16 were the most frequently reported causes of HFMD prior to 2005. Currently, other EVs such as CVA6 and CVA10 are responsible for a significant proportion of HFMD cases and outbreaks [12, 13]. Although CVB1-5 associated with HFMD had also been mentioned in several reports, the impact of these pathogens on HFMD is still expanding [14, 15].
The viral particle of EVs is symmetrical icosahedron composed of 60 subunits of coat protein and a single-stranded RNA genome (7.5 kb) of positive polarity (Fig. 2) . The open reading frame (ORF) of the viral genome encodes 2194 amino acids (Fig. 2), and the 3′ untranslated region UTR (3'UTR) is followed by a poly-A tail of variable length. The protein encoded by the viral genome mainly include three regions: P1, P2, and P3, of which P1 encodes four structural proteins, VP1-VP4, and the P2 and P3 encode seven non-structural proteins, 2A-2C and 3A-3D, respectively [17, 18]. VP1-VP4 are further involved in virion capsid assembly . Although VP1, VP2 and VP3 are arranged on the outer side of the capsid, VP1 is the main antigen-binding site . Thus, VP1 is a suitable candidate for major serotyping and vaccine development and has been widely used as a target gene for EVs molecular research . Moreover, Physico-chemical characteristics of EVs include resistance to organic solvents such as ether and chloroform and low temperature conditions, and sensitivity to high temperature, chlorinated disinfectants, formaldehyde and ultraviolet etc. .
Epidemic process and influencing factors
The criteria for diagnosing of HFMD, which are widely accepted at present, primarily rely on the patient’s epidemiological history, symptoms additional tests to determine the cause or presence of the disease . This includes examination of the patient's age, the timing of onset, gathering place, and if they had direct or indirect contact with HFMD infections before the onset of the disease . The incubation period of HFMD is mostly 2–10 days, with an average of 3–5 days. The progression of HFMD be divided into 5 stages (rash, neurological dysfunction, early stage of cardiopulmonary failure, cardiopulmonary failure, recovery), and most cases generally only experience the first stage and recover within a week . Clinically, most cases have fever accompanied by rash on hands, feet, mouth, and buttocks . The prevention in patients with severe HFMD depends on the timely and accurate identification of danger signs in the disease progression . The following 7 indicators are considered as risk factors of HFMD severity: (1) high fever; (2) nervous system involvement; (3) abnormal respiratory rate and rhythm; (4) circulatory dysfunction; (5) increased white blood cell count; (6) increased blood glucose; (7) increased blood lactate [21, 23]. In some cases of HFMD, the rash is atypical such as a single site or a maculopapular rash only. Most cases usually need to be differentiated from papular urticaria, chickenpox, herpes zoster, rubella, and herpes simplex caused by other diseases . In addition, neurogenic pulmonary edema (PE) should be distinguished from pneumonia. Clinical samples (pharyngeal swabs, stool or anal swabs, blood, blister fluid, cerebrospinal fluid, etc.) are tested through RT-PCR, virus isolation, neutralizing antibody testing . Subsequently, clinicians diagnosed the suspected patient as a confirmed case of HFMD based on epidemiological history, clinical manifestations, and laboratory nucleic test .
Source of infection
Human is usually considered to be the only reservoir of human EVs, and both cases and asymptomatic infections are the sources of HFMD infection. The virus can be detected in the pharynx and feces of infected individuals in the days before the onset of illness, and is usually most contagious within a week after the onset of symptoms. Therefore, the presence of asymptomatic infections and those in the incubation period may complicate efforts to prevent and control HFMD.
Routes of transmission
Currently, the fecal–oral transmission and contact are considered as the primary transmission routes of HFMD. The potential transmission routes of aerosols and respiratory tract have been proposed based on some animal studies . Further research is required to fully understand and confirm the transmission routes of both aerosol and droplet in human population.
As a common childhood infectious disease, HFMD primarily occurs in children under 5 years old , although HFMD has also been reported in adults . Children are highly susceptible to the EVs due to immature immune system and clustering at the pre-kindergarten stage . China has implemented kindergarten closures to block the transmission of coronavirus disease (COVID-19), indirectly reducing the incidence of HFMD and preventing HFMD outbreaks [29, 30]. In addition to reducing the clustering of susceptible populations and enhancing individual protection, “herd” immunity through vaccination is more effective in reducing population susceptibility. The urban area with high EV-A71 transmission in China initiated vaccination with inactivated EV-A71 vaccine, a dramatic decline in EV-A71-associated HFMD incidence was observed . Patients, both dominant and recessive infections caused by EVs, can acquire specific immunity, and the neutralizing antibodies can be retained in the body for a long time. EVs can stimulate stronger immune response, but there is almost no cross-immunity between different serotypes. Consequently, multivalent vaccines are urgently needed to further improve herd immunity.
Spectrum of infection
HFMD is always considered as a type of self-limiting infectious disease, and most patients with mild symptoms recover within 1 ~ 2 weeks. Large-scale observational studies showed that There are 5 different outcomes of HFMD: asymptomatic (12.7%), mild (86.2%), severe and critical (1.1%), death (0.03%) , .
Both high and low temperatures were associated with the incidence of HFMD . For example, CVA6 outbreaks usually occur in winter . Precipitation and humidity could provide the necessary water environment and aerosols for virus survival, and protect the virus from harmful factors such as temperature, salinity, and pH . The intensity of UV exposure time also affected the incidence of HFMD . Also, the terrain dominated by mountains or hills with lower atmospheric pressure affects the incidence of HFMD . Recently, a new attention has been attracted to the impact of air pollution on HFMD epidemic. Yu et al. found that exposure to environmental particulate matter increases the risk of children developing HFMD. They believed that these particulates may facilitate virus transmission through airborne infections and that high wind speeds further contribute to the spread of virus-carrying particles . Besides, ozone might affect infectious diseases by inhibiting the ability of virus to exist in the external environment .
Socioeconomic factors are also closely related to the epidemic of HFMD. The incidence of HFMD in urban residents, transportation hub cities, and economically developed areas compared to rural area, this is due to the higher population density and mobility in these areas [26, 38]. Health regulations and large-scale vaccination in educational settings promulgated by the state or government at all levels significantly reduced the incidence of HFMD . The lack of medical insurance coverage and ethnic minorities are all risk factors for HFMD . Rural residents and poverty are both risk factors for HFMD severity, which may be caused by poor sanitation, lower educational attainment, and lower economic status . Furthermore, factors such as being raised at home, having a larger family size, and poor hand hygiene are associated with a higher risk of HFMD transmission [39, 40]. Short interval from onset to hospitalization, hospitalization in a high-level hospital, and treatment by more experienced doctor are protective factors for HFMD severity . Lack of breastfeeding in children with lower immune status may lead to HFMD severity [42, 43]. Extended gatherings of children in schools or daycare centers can facilitate the transmission of HFMD, while taking appropriate breaks during vacation time can serve as a protective measure against it .
The four main EV serotypes causing HFMD outbreaks
HFMD of outbreaks caused by EV-A71
The EV-A71 strain was first isolated in California in 1969 . During 1970–1990, HFMD outbreaks caused by EV-A71 occurred frequently in the United States [45,46,47]. In the European, including Sweden , Bulgaria , Hungary , and the Netherlands , outbreaks of HFMD related to EV-A71 have been monitored. Japan , Brazil  and Australia have also reported a large number of cases of aseptic meningitis and brainstem encephalitis associated with EV-A71. At the end of the twentieth century, EV-A71 activity increased dramatically throughout the Western Pacific region. In 1997, a large outbreak of HFMD caused by EV-A71 strain in Malaysia resulted in 41 fatalities . Next year, Taiwan (China) reported 100,000 cases of HFMD mainly caused by EV-A71, including 400 severe cases and 78 deaths . During the period from 2008 to 2014, a total of 10,717,283 cases (3046 deaths) were reported in China, and the fatality rate was 0.03%. Among survivors, the incidence increased from 37.6/100,000 (2008) to 139.6/100,000 (2013) and had a peak in 2012 at 166.8/100,000. In 2011–2012, a large-scale EV-A71 outbreak in Vietnam resulted in more than 200,000 hospitalizations and 207 deaths . In 2012, EV-A71 infection killed at least 54 children with severe encephalitis in Cambodia (26,690,000). In addition, Russia , South Korea , Singapore , Thailand [60, 61] and Philippines  have also experienced large-scale EV-A71 outbreaks. Recently, European countries such as Denmark , France , Germany , Spain  and Poland  also reported sporadic cases (Fig. 3).
HFMD of outbreaks caused by CVA16
CVA16 was the main pathogen of HFMD outbreaks in England in 1959 and 1994 [3, 68]. There were also CVA16 outbreaks in the United States in 1964 and 1968 [69, 70]. CVA16 infection was also responsible for the 1991 outbreak of HFMD in Sydney, Australia . Subsequently, the Asian-Pacific region includes China [72, 73], Japan , India [75, 76], Taiwan (China) , Vietnam , Singapore [79, 80], and Spain in Europe  reported CVA16 outbreaks. Currently, CVA16 pathogens are frequently detected together with CVA6 and CVA10 [43, 82,83,84].
HFMD outbreaks caused by CVA6
In recent years, the pathogenic spectrum of HFMD has changed with inoculation of EV-A71 vaccines, especially in China. From 2016 to 2018, the proportion of EV-A71 and CVA16 positive was 8.9%, 5.2%, respectively, while the proportion of other EVs was 60.6% among 3559 HFMD cases in Hangzhou, China . Since an outbreak of HFMD caused by CVA6 in Finland in 2008, CVA6 is responsible for a series of HFMD outbreaks in Europe, Northern America, and Asia . In recent years, HFMD outbreaks caused by CVA6 have occurred in the United States [87, 88], Spain , Hungary , France  and the United Kingdom (Fig. 3) . EVs were detected in 2228 HFMD patients in Vietnam from 2008 to 2017, and CVA6 accounted for 28.4%, only second to EV-A71 (31.7%). However, the large-scale HFMD outbreak in Thailand in 2012 showed that in 672 HFMD cases, 221 (32.9%) were caused by CVA6 . In 2011, the National Epidemiological Surveillance System of Infectious Diseases of Japan reported an increase rate of CVA6 detection in HFMD cases . In the massive HFMD epidemic that occurred in Japan in 2017, CVA6 was the primary pathogen responsible for the illness of 6,173 patients . In addition, Singapore , New Zealand  and Malaysia  have also reported HFMD CVA6 is the dominant strain of HFMD outbreaks. Since 2013, CVA6-associated HFMD has been on the rise in parts of China [97,98,99,100]. Unlike HFMD caused by other EVs serotypes, CVA6-associated HFMD presents a more severe and extensive rash, and is also characterized by a higher incidence in adults, winter onset, and a tendency to shed arm after recovery [34, 101, 102].
HFMD of outbreaks caused by CVA10
The prototype strain of CVA10, Kowalik (GenBank ID: AY421767), was isolated in the United States in 1950 . In May 1961, the CVA10 strain was also isolated in 40 children with HFMD reported in New Zealand . The first detailed outbreak of CVA10 occurred in Japan between July 1981 and January 1982. Thirty seven clinical HFMD cases were examined for virology and serology, and CVA10 was detected in 18 cases . Subsequently, Asia, Europe, Africa, and Oceania successively reported HFMD associated with CVA10 co-transmitted with CVA6 (Fig. 3). In 2008, clinical specimens were obtained from 317 HFMD cases in Finland, including adults and children, and the proportion of CVA10 (28%) was only second to CVA6 (71%) . The HFMD epidemic surveillance in Singapore in 2008 showed that the detection rate of CVA10 (11.8%) ranked third, followed by CVA6 (23.5%) and EV-A71 (21.6%) . A French sentinel surveillance data study conducted in 2010 reported that CVA10 (39.9%) was the leading serotype responsible for HFMD . In Asia, CVA10 was also the most common pathogen in HFMD cases monitored in Korea in 2008 . In a prospective cohort study in 2016, a higher proportion of CVA10 was detected in HFMD cases . There are different levels of CVA10 detection rates in HFMD patients across China. CVA10 (25%), CVA6 (29.8%), and CVA16 (32.5%) were the most common serotypes  in HFMD patients in Guangdong Province in 2018. In Xiamen, from 2009 to 2015, the proportion of CVA10 in cases of HFMD was not particularly high (1.08–7.09%). However, the detection rate of CVA10 in severe HFMD cases was significantly higher than in previous years . From 2016 to 2020, a total of 9952 sporadic HFMD cases in Shanghai were collected and CVA10 was the fourth major epidemic pathogens, with a total positive rate of 2.78% .
Genetic evolution of EVs
EV-A71, CVA16, CVA6 and CVA10 are the 4 major EVs that cause HFMD worldwide. There are no standardized criteria for the classification of subtype, and the different studies on the prevalent types of HFMD use distinct system of sub‐type classification . Bayesian phylogenetic methods with an integrated molecular clock were introduced a decade ago and provided unprecedented opportunities for phylogenetic analysis. In the Review, a difference of at least 15% in the entire VP1 nucleotide sequences is used to distinguish genotypes (Fig. 4) . The sequences were used to identify the serotypes/sub-genotypes using the online Enterovirus Genotyping Tool (http://www.rivm.nl/mpf/enterovirus/typingtool) or a BLAST search. In the case of CVA6 and CVA10, we consult other studies to ensure that the selected strains are representative [110, 113]. The genetic evolution of EV-A71 virus can be divided into seven genotypes (A-G), with genotypes B and C further divided into sub-genotypes B0-B5 and C1-C5, respectively . Genotype A includes the prototype strain (BrCr) isolated in 1969 . C4 and C1 sub-genotypes have developed into the most predominant strain and sub-genotypes C4 circulate mainly in eastern and southeast Asia, whereas C1 are prevalent in Europe [64, 114]. D-G genotypes are relatively rare strains and have been identified in India , Africa  and Madagascar . There are also several strains that can’t be typed in the online enterovirus Genotyping Tool (defined by some scholars C0: AF135934.1, H: ON646273.1). CVA16 is divided into 2 genogroups A and B with genogroup B being further divided into B1 and B2. Sub-genotype B1 can be further divided into clusters B1a, B1b, and B1c. B1a and B1b can be found in China, Malaysia, Thailand, Australia, Vietnam, and France, Japan et al., which indicate that they co-evolve and co-circulate all over the world [118, 119]. Recently, new genogroups (C and D named by some scholars) have been reported in Peru, France, and China [120,121,122]. Our results revealed that CVA6 strains could be divided into 6 genotypes designated as A to F, and D genotypes could be further subdivided into D1-3 sub-genotypes. In recent years, the D genotype, particularly D3 sub-genotype, has become the dominant sub-genotype circulating in Southeast Asia and Europe [20, 123]. CVA10 is assigned into 7 genogroups, including genogroup A to genogroup G. Genogroup A is the prototype Kowalik strain isolated in 1950 in the United States . Genogroup B, mainly consisted of CVA10 in China, is assigned to genogroup G. Genogroup C and D include isolates from Russia, Viet Nam, France, America, as well as the latest isolates from Mainland China, which is the predominant circulating strain worldwide . Genogroup E and F mainly circulate in India  and Russia . A study on the prevalence of HFMD-associated EVs in China found that more than 98% of EV-A71 sequences belonged to the C4 sub-genotype, with the EV-A71-C4.1 strain having the largest proportion, the longest epidemic period, and the widest geographical distribution. The most predominant strain of CVA16 was CVA16-B1.1, which was widely found in East, Southern, and Northern China. Approximately 95.6% of CVA6 strains belonged to the D genotype and were mainly prevalent in the Eastern, Northern, and Southern regions of China. Most of the CVA10 strains in China belonged to the C sub-genotype and were mainly found in Eastern China . Furthermore, recombination events between other EVs and increased detection rates of these EVs in HFMD samples have been a significant factor in recent HFMD outbreaks. A study of the genome sequence of a novel CVB2 (YN31V3) associated with HFMD found that YN31V3 was likely a recombinant, closely related to CVB2 strains and other EV-B strains . The phylogenetic analysis of CVB3 sequences form the China national HFMD surveillance and global surveillance showed multiple recombination events were present among CVB3 strains circulating globally . Taken together, for evolutionary pressure and frequent recombination, the pathogens of HFMD have evolved into a variety of EVs genotypes with specific temporal and spatial distributions, and further genomic analysis and continuous molecular epidemiological surveillance are helpful for disease control and prevention.
The Viral receptors play a crucial role in the initial stage of infection. The first requirement for virus entry is to bind to the appropriate receptors on the host cells surface, triggering the next step of endocytosis. The availability of receptors often restricts viral infection and influence tissue and species specificity [129, 130]. Currently, most of receptors for EVs belong to the immunoglobulin superfamily (IgSF), which are type I transmembrane glycoproteins . As summarized in Table 2, human scavenger receptor class B member 2 (hSCARB2) , P-selectin glycoprotein ligand-1 (PSGL-1) , Annexin II , Heparan sulfate  are identified to be the main receptors of EV-A71, and KREMEN1 was confirmed as a host entry receptor for CVA2, CVA3, CVA4, CVA5, CVA6, CVA7, CVA10, CVA14, CVA16 [136, 137]. EVs interact with host-encoded counterpart receptors and then undergo uncoating, pore formation, and release their genome into the cytosol . EV-A71 binds to hSCARB2, and triggers a clathrin- and dynamin-dependent endocytosis to facilitate viral entry . hSCARB2 and KREMEN1 bind to the canyons at the adaptor-sensor region of EV-A71 and CVA10, respectively, which can also facilitate viral entry [137, 140]. hSCARB2 also induces EV-A71 uncoating under acidic conditions [140,141,142]. Additionally, the human tryptophan-tRNA synthetase (hWARS) induced by interferon (IFN)-γ has also been recognized as a crucial factor in the entry of EVs . The diversity of receptors and various modes of binding promote EVs infection.
Human intestinal cells permit infection by EVs such as CVB3 and EV-A71, and can facilitate their replication and release . EV-A71 infects the intestinal epithelium through the apical surface, with a preference for infecting goblet cells. hSCARB2, expressed as an integral membrane protein in goblet cells and localized in intracellular vesicles, provides the necessary condition for viral infection . Although intestinal epithelium induces type IFNs secretion to limit viral replication, viral infection reduces the expression of goblet cells-derived mucins, and alters goblet cell function . Therefore, the targeting of goblet cells by EV-A71 for intestinal infection is likely driven by the enrichment of hSCARB2 in secretory vesicles within these cells, which exposes the receptor through apical mucus release . It is possible that EVs attach to the apical surface using SA glycoproteins and SA-containing glycolipids with SA-linked glycans or dependent decay accelerating factors [147, 148]. Moreover, the tonsillar crypt squamous epithelium, which supports active viral replication, is also an important site for EV-A71 invasion and replication, and is an important source of viral shedding in blood . EVs that invade host cells rapidly complete the viral life cycle (Fig. 2). Subsequently, the virus is released from host cells through a traditional cytolytic manner, and packaged within exosomes, which promote virus spread without causing cell lysis [150, 151]. EVs replicate profusely in cells at the initial site of infection, and then spread to adjacent lymphoid tissues, and next spread to the circulation and target tissues, eventually developing varying degrees of viremia . The proportion of cases with HFMD suffering from viremia is correlated with the duration of complications. In patients with mild HFMD, viremia that occurs improves as symptoms diminish . If viral replication and transmission are controlled at this stage, most infected children will be asymptomatic. However, higher viral loads lead to the development of HFMD as long as the viral infection in the host continues to develop . Together, the virus replicates in the gut early in the infection, and then spreads to the spinal cord, brain, and muscles later in the infection . A part of patients with HFMD develop into more serious complications, including encephalitis, aseptic meningitis, acute flaccid paralysis, and cardiopulmonary failure [156, 157]. The central nervous system (CNS) damage is very common in severe HFMD cases complicated with encephalitis, aseptic meningitis . Clinical reports and animal necropsy studies related to HFMD have revealed the presence of EV antigens in neurons at various locations within the CNS. This suggests that the virus may invade the CNS by compromising the blood–brain barrier (BBB), traveling backwards along nerves, or hijacking immune cells as a means of transportation [152, 158, 159]. Among them, retrograde axonal transport is currently considered as the main pathway for the EVs to invade CNS [160, 161]. Ohka et al. have confirmed through experiments in microfluidic devices that hSCARB2 is necessary for the retrograde axonal transport of EV-A71 . Autopsy pathology revealed significant perivascular intussusception, infiltration of inflammatory cells into the parenchymal, and microglial nodules in the affected CNS. This may have been caused by EVs entering the CNS and infecting neurons, glial cells, the brain stem, the dentate nucleus, and the hypothalamus, ultimately leading to nerve damage .
Innate immune evasion by EVs
The initial defense against virus is to activate the secretion of IFNs and other antiviral molecules at the site of infection, and to exert their antiviral effects through both autocrine and paracrine mechanisms. The host cell recognizes pathogen-associated molecular patterns (PAMPs) through three pathogen recognition receptors (PRRs): toll-like receptors (TLRs), retinoic acid-inducible gene (RIG-I)-like receptors (RLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) (Fig. 5) . It was discovered that the TLR7, TLR3 and TLR9 can recognize the single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA) of EVs, which then triggers the recruitment of the toll interlukin-1 receptor (TIR). These leads to the activation of the Toll/IL-1R domain-containing adapter-inducing IFN-β (TRIF), which in turn brings in MyD88 into endosomes to further activate innate immune response [164,165,166,167]. Other findings suggest that ssRNA and dsRNA are also recognized by the RLR, specifically through the interaction of RIG-I and melanoma differentiation-associated gene 5 (MDA5) with mitochondrial antiviral-signaling protein (MAVS) to activate TANK-binding kinase 1 (TBK1) /IKK-ɛ and IKK-α/β/γ. The phosphorylation of TBK1 activates interferon regulatory factor 3 (IRF3) and stimulates the transcription of IFNs genes . NLRP3 (NOD-, LRR- and pyrin domain-containing 3), as a common inflammasome, has also been demonstrated to play a role in the innate immune response to EVs infection . Additionally, some antiviral molecules could enhance the secretion of IFNs, such as ATP1B3, zinc-finger antiviral protein (ZAP) [170, 171]. There are other unknown pathways for EVs to activate the innate immune response. For example, RNA-binding proteins (RBPs) FUS/TLS inhibited viral replication by interacting with EVs RNA, mediating the formation of SGs and promoting the production of antiviral proinflammatory cytokines and IFN-I . IFNs also directly exert antiviral effects and indirectly induce the transmembrane protein TMEM106A to interfere with the binding of viruses to receptors to reduce cell damage [173, 174].
EVs have developed various tactics to suppress the antiviral response that is mediated by IFNs , and the primary impediment to the antiviral pathway is located prior to the production of IFNs. 2Apro and 3Cpro directly inhibit the production of IFNs and the expression of IFNs receptors . EVs mainly act on a variety of protein molecules in the PRR signaling pathway to complete immune evasion. EVs mainly inhibit TLR-dependent signaling mainly by controlling the level of host non-coding RNA (ncRNA) to indirectly influence the TLRs’ ability to sense the host cell, as well as cleaving the downstream molecules MyD88 and TRIF to prevent the IFNs production[176, 177]. 3Cpro could also directly target those key proteins of TLR signaling pathway to inhibit IFNs production . EVs primarily counteract the RLR signaling pathway mainly by directly or indirectly cleaving RIG-I and MDA5, and targeting downstream linker molecules, such as MAVs [179,180,181]. Current evidence supports the conclusion that EV-A71’s 3D RNA polymerase directly interacts with NLRP3 to form a “3D-NLRP3-ASC” ring structure, which promotes the assembly of the NLRP3 inflammasome complex and the secretion of IL-1β . Meanwhile, EV-A71 2Apro and 3Cpro also cleave NLRP3 to counteract inflammasome activation and inhibit IL-1β secretion . In addition, the IFNs and JAK/STAT signaling pathway are also a key step to further expand antiviral immunity . However, EV-A71 2Bpro and 2Apro selectively target the interferon receptor (IFNAR) directly or indirectly, suppressing the nuclear translocation of STAT1/ STAT2 and the level of ISGE, ultimately limiting the performance of IFNs [184,185,186,187,188]. In addition to participating in common innate immune signaling pathways, EVs also directly inhibit antiviral protein molecules like ZAP and acyl-CoA oxidase 1 (ACOX1). They also indirectly target ubiquitinated key proteins, such as Ubc6e, to induce apoptosis and autophagy, which ultimately exacerbates viral infection [171, 189,190,191].
Adaptive immunity to EVs and HFMD
Adaptive immunity also evolved to provide a broader and more sophisticated recognition mechanism to eliminate viruses . Clinical evidence suggests that EVs could elicit neutralizing antibody (NAb) against homotypic viruses . The NAb titers in the serum samples of infected children, collected one day after the symptoms appeared, were more than three times higher than those in healthy children, with the peak occurring at second day . The results of a study investigating the kinetics of EV-A71 NAb response in patients with HFMD showed that the NAb titers rapidly reached a peak within 2 weeks of onset and remained at high levels for 2 years . The study have shown that the serum immunoglobulin IgM (g/L) level of neonatal patients complicated with encephalitis is significantly higher than that of neonatal with lower neurological score . A significant increase in serum and spinal cord IgM and IgG was also observed in EV-A71-infected mice . However, another study found that there is no significant difference between the NAb titers in serum of patients with different severity of HFMD . However, further research is needed to determine the relationship between the antibody response and the severity of HFMD in patients. Chang et al. believe that it is the cellular immunity response rather than the humoral immunity that has a greater impact on determining the outcome of the EV-A71 infection . The cellular immunity carried out by T cells is essential for maintaining body defense. The autopsy biopsy showed abnormal changes in CD4+T cells and CD8+T cells . Lymphocyte subsets displayed in peripheral blood samples from children infected with EV-A71 showed a decrease in the total number of Th (helper T cell), Tc (killer T cell) and Treg cells (regulatory T cell), and an increase in the percentage of B cells, Th2 and Th17 cells . Furthermore, Th1/Tc1 and Th17/Treg were significantly increased in children infected with mild and severe HFMD [200, 201]. The fast and efficient immune response is a solid line of defense against viral infection. However, an excessive and dysregulated immune response can trigger a series of chain reactions, mainly manifested as systemic immune dysregulation with a neurogenic component.
Cytokine profiles in HFMD
The levels of cytokines were found to be significantly different among healthy individuals, those with mild HFMD and those with severe HFMD, suggesting a critical role in the progression of the disease and providing potential targets for diagnosis and treatment . Several studies have summarized the cytokines and chemokines associated with severe HFMD, including TNF-α, IFN-γ, IL-1β, IL-18, IL-33, IL -37, IL-4, IL-13, IL-6, IL-12, IL-23, IL-27, IL-35, IL-10, IL-22, IL-17F, IL-8, IP-10, MCP-1, G-CSF, and HMGB1 [202,203,204]. The innate cells that are involved in cytokine production include neutrophils, macrophages, and natural killer (NK) cells. Meanwhile, and adaptive cells that are involved in ‘cytokine storm’ are mainly various of subsets T cells [205, 206]. The systemic inflammation is usually associated with the breakdown of BBB that accompanies CNS injury, which leads to the entry of brain-derived proinflammatory cytokines into the circulation, further activating the inflammatory cascade including complement . For example, among the lymphocyte chemokines detected, high levels of interferon-gamma-inducible protein-10 (IP-10) were found in the plasma and cerebral spinal fluid of patients with severe HFMD . Additional experiments revealed that a deficiency in IP-10 significantly reduced the levels of Mig (monokine induced by IFN-γ) in serum, and levels of IFN-γ and the number of CD8+ T cells in the mouse brain, This, in turn, resulted in an increase mortality rate of EV-A71-infected mice . In addition, the chemokine (C-X-C motif) ligand (CXCL)10 was dramatically upregulated in EV-positive meningoencephalitis group . Our previous study suggested that CXCL10 was highly expressed in the vital organs (brain, lung, heart, and skeletal muscle) of CV-A2-infected mice. Further interference with the CXCL10/CXCR3 axis was found to reduce the levels of leukocytes, neutrophils, and macrophages in the organs of mice that were critically ill . Critical HFMD patients showed a decreased in peripheral blood lymphocytes, a depletion of CD4+and CD8+T lymphocytes, and a decline cellular immunity . Ultimately, the immune system collapses and multiple organs of the host are damaged, leading to irreversible multi-organ failure and death.
Mechanisms of neurological damage and cardiopulmonary failure
Fatal complications of infections affecting the nervous system are directly or indirectly linked to damage of nerve cells. EV-A71 3Cpro directly cleaves the host DNA repair enzyme poly (ADP-ribose) polymerase and induces apoptosis . EV-A71 3Dpro indirectly induces apoptosis and inflammation by downregulates ACOX1 expression and promotes reactive oxygen species (ROS) generation [191, 214]. The CNS damage is not only related to viral replication, but frequently associated with immune activation . Recent discoveries indicate that nerve cells that express TLR7, TLR3, TLR8, and TLR9 can rapidly induce the secretion of IFNs in response to infection with EVs, which provides antiviral protection [164,165,166,167]. For instance, EV-A71 triggers a response in glia cells that involves the production of Interleukin-12p40 through TLR9 signaling, leading to the generation of neurotoxic Inducible Nitric Oxide Synthase (iNOS)/Nitric Oxide (NO), resulting in encephalitis . In addition, the Janus kinase (JAK)-signal transducer of activators of transcription (STAT) pathway also regulates the expression of IFNs [184, 187]. Conversely, the virus antagonizes the antiviral response of nerve cells by cleaving RIG-I, which further inhibits the JAK/STAT signaling pathway [217, 218].
PE is one of the most serious complications of HFMD aside for encephalitis, and is the primary reason of rapid death of patients with severe HFMD [212, 219]. The development of PE is closely linked to inflammation in the CNS and ‘cytokine storm’ that is triggered by abnormally high depletion of IL-10, IL-13, IFN-γ and a depletion of lymphocyte in plasma [207, 212]. The currently recognized pathogenesis of fulminant PE is neurogenic [219,220,221,222]. Autopsy results showed extensive inflammatory in the CNS with severe PE . A clinical study in Taiwan showed a significant correlation between CNS involvement and PE in children infected with EV-A71 . Similarly, acute PE caused by Japanese encephalitis is associated with disruption of the anti-hypertensive mechanisms in the medulla of the CNS . In the development of HFMD, damage to CNS leads to immune disorders, which are primarily manifested by the excessive release of catecholamines and cytokines [8, 207, 212]. Wu et al. proposed that the further increase in pulmonary vascular permeability caused by inflammatory response is the underlying cause of PE . The CVA6-infected mice and EV-A71-infected hSCARB2 KI mice exhibited significant PE and hemorrhage, with the infiltration of neutrophil and monocyte in brain and spinal cord [226, 227]. In CVA2-infected mouse model, endothelial dysfunction, local inflammation, and enhanced vascular permeability were confirmed to be involved in accelerating acute lung injury . Cardiac damage caused by EVs mainly progresses to acute heart failure (AHF) and myocarditis. During the HFMD outbreak in Taiwan in 1997, some severe patients presented with AHF . The main cause of AHF in patients is acute left ventricular dysfunction and regional wall motion abnormalities . The underlying cause of cardiac damage may be hypercatecholamineremia caused by brainstem encephalitis, which further leads to the cardiotoxicity of AHF [231, 232]. Myocardial cell necrosis is rarely observed in cardiac autopsy of EV-A71-infected patients . In recent years, the emerging CVB3 among children infected with EVs has garnered increased attention . As the most common pathogen causing viral myocarditis, CVB3 seems to promote cardiac function damage mainly by inducing myocardial apoptosis and necrosis . Despite Lucie et al. not providing a comprehensive explanation of a fatal case of CVA2-related myocarditis in France, our colleagues noticed significant inflammatory and swelling in the heart of a mouse model infected with CVA2 [235, 236].
Unfortunately, there are currently no established antiviral treatments for HFMD and no specific clinical management and treatment methods have been established. For common cases, general treatment is usually used, isolating patients to avoid cross-infection, and taking good oral and skin care to avoid contamination. According to the development of HFMD, the treatment corresponding to the intervention of critical patients usually includes antiviral therapy, immunoglobulin therapy, respiratory and circulatory system support, etc.
IFN-α, and ribavirin treatment have shown positive effect in antiviral management of HFMD to some extent [237, 238]. Various drugs, like antiviral peptides, small molecules, have been identified promising candidates, but their full pre-clinical validation have yet to be reported [239, 240].
Intravenous immunoglobulin (IVIG)
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]. Compared with conventional therapy alone, conventional therapy combined with IVIG had shorter fever clearance time, shorter rash regression time, and shorter clinical cure time .
Mechanical ventilation is the most effective treatment to improve oxygen supply to the body . The application of indications and the withdrawal indications are described in Chinese guidelines for the diagnosis and treatment of HFMD (2018) . If they occur seizures (frequent myoclonic jerks), routine anti-convulsant may be considered, such as sedation (e.g., midazolam) and/or anticonvulsants (e.g., phenytoin).
Treatment of catecholamine storm
Early application of esmolol can effectively stabilize the vital signs of severe HFMD by reducing serum catecholamine concentration, alleviating myocardial damage, improving cardiac function, and reducing inflammatory response. The phentolamine can reduce mortality and relieves the symptoms of EV-A71-induced PE, which is a potential therapeutic agent for neurogenic PE .
Multiple inotropes to support cardiac function (milrinone, dobutamine, dopamine, epinephrine) have been applied in the clinical treatment . Among them, Milrinone exhibits immunoregulatory and anti-inflammatory effects in the management of systemic inflammatory response in severe cases . If the above drugs prove ineffective, vasopressin or levosimendan can be considered .
Intracranial pressure control
Mannitol is commonly used to reduce increased intracranial pressure, the combination with hypertonic saline or diuretics may be considered for patients with severe intracranial hypertension [21, 250].
Traditional Chinese medicine
The combined Chinese medicine and chemistry medicine therapy achieve a better therapeutic efficacy in the treatment of severe HFMD than the chemistry medicine therapy alone . The addition of Andrographolide Sulfonate and S. baicalensis to conventional therapy also reduces the occurrence of major complications, relieves fever, and attenuates oral lesions and rashes [252, 253].
A retrospective observational study showed that continuous veno-venous hemodiafiltration could improve cardiovascular function . Extracorporeal life support, including extracorporeal membrane oxygenation (ECMO), is last rescue treatment for patients who have failed to routine symptomatic and supportive treatment [8, 21].
Taken together, the main approach to treating severe cases of HFMD is mainly through supportive and symptom-relieving measures. There is a need to carry out more clinical studies to gather more evidence to improve the clinical management of severe cases.
Long-term sequelae of HFMD
Severe HFMD occurs mainly affects preschool children under the age of 5, a crucial stage in their growth and development. Although treatment advancements have led to a decrease in acute mortality, there are still concerns about the potential possible short-term or long-term impacts (Fig. 1).
A substantial burden of neurological sequelae following HFMD has been given more attention, especially in severe cases [6, 255, 256]. Among patients who experienced cardiopulmonary failure after CNS involvement, the proportion with subsequent sequelae (facial nerve palsy, limb weakness and atrophy, dysphagia, central hypoventilation, seizure, and psychomotor retardation) was significantly higher compared to those who only CNS involvement. The clinical severity of CNS involvement was significantly related to the children’s neurodevelopment (a delay in the gross motor and personal-social categories, delayed neurodevelopment) [257,258,259,260]. Serious virus-associated CNS infection during childhood appear to be associated with the later mental disorders, like attention-deficit hyperactivity disorder (ADHD) diagnosis alongside social/communication/emotion problems and autistic features [261,262,263]. Some severe EV-A71 infected patients may experience impaired speech and language skills due to subcortical white matter involvement in the acute stage [258,259,260]. Long-term functional neurological morbidity is associated with the involvement of medulla oblongata, gray matter in the brainstem or spinal cord, which may be closely monitored for early intervention and meticulous management [258, 264, 265].
HFMD-related eye involvement presents variable signs, including pseudomembranous conjunctivitis , outer retinitis  and maculopathy , which is only observed in young adult patients in both sexes and always unilaterally. Despite self-limited nature and complete visual recovery in most cases later than resolution of HFMD symptoms (several weeks to months), some cases may have residual visual loss.
Delayed skin and nail change, such as desquamation of palms and soles [269, 270], Beau’s lines, or onychomadesis , have also been observed in some severe EV-A71 infected patients. Nail change, mainly presenting as onychomadesis involving toenails or fingernails, is usually observed among 1–2 months after the onset of HFMD and lasted for 1–8 weeks, most for approximately 4 weeks and the changes are more likely to occur synchronously . It can occur in both children and adults [273, 274]. The pathogens associated with nail abnormalities in HFMD patients are various, but mainly caused by CVA6 . Nail change is usually self-limited with spontaneous healed requiring no treatment for all patients [275, 276].
In addition to focusing on the common health effects of HFMD, other health problems should not be ignored. Allergic diseases: a population-based cohort study has revealed that children suffered from HFMD had decreased risks of asthma . In contrast, another retrospective cohort study found that the risk of asthma was higher in children with herpangina and HFMD . Diabetes: One adult patient with severe atypical HFMD associated with CVA6 viremia showed impaired glucose tolerance after 2-year follow-up . Heart diseases: A population-based cohort study has showed meningitis caused by herpangina/HFMD is the main disease associated with a higher risk of Kawasaki disease . Idiopathic ventricular tachycardia, degenerative aortic valve disease, degenerative mitral valve disease, may be considered as sequelae of CVA6 infection in adults . Nephropathy: A large national cohort study showed that children infected with EVs, particularly coxsackieviruses, had a significantly increased risk of developing nephrotic syndrome . Leukemia: The risk of leukemia was significantly lower in the EVs-infected cohort, and herpangina/HFMD was the main disease reduced the risk of leukemia . Long-term follow-up programs are crucial for early recognition of possible sequelae and early intervention in children who have suffered from HFMD, especially at a young age. Further studies are needed to better understand the pathogenesis of HFMD and its impact on sequelae.
Vaccination is considered the most effective and cost-effective approach to control the incidence of HFMD. Currently, there are monovalent and polyvalent vaccines available against the HFMD pathogen. The monovalent vaccines consist mainly of inactivated whole virus vaccines, synthetic peptide and protein vaccines , recombinant subunit vaccines , and recombinant virus-vector vaccine . Currently, the most readily available inactivated whole virus vaccines for EV71 are produced by Sinovac, Vigo, and the Chinese Academy of Medical Sciences (CAMS). Results from a randomised, double-blind phase 3 trial in China showed that the inactivated EV71 vaccine has a 97.4% efficacy rate . The monovalent inactivated virus vaccine candidates for CVA16, CVA10, CVA6, and CVA5 have only been studied in animal models and lack clinical evidence of protection [287,288,289,290]. However, the limited scope of protection offered by monovalent vaccines, which are specific to one genotype, means that they do not provide protection against other EVs-associated cases of HFMD. Therefore, the most effective approach for reducing the incidence of HFMD is to use polyvalent vaccines that have been developed through the combination of effective monovalent vaccines or by constructing chimeric vaccines with different virus serotypes, which can provide better cross-reactivity and protection. Polyvalent vaccines, which aim to improve cross-reactivity, consist mainly of inactivated polyvalent vaccines, polyvalent virus-like particle vaccines, innovative chimeric vaccines, and recombinant virus-vector vaccines. Currently, the inactivated polyvalent vaccines, including bivalent, trivalent, and quadrivalent vaccines, have mainly been tested for their protective effects in animal studies. Vaccines formulated by combining inactivated EV-A71 and CVA16 viruses induced specific immunity against EV-A71 and CVA16 infections in animal models [291, 292]. The CVA6 and CVA10 inactivated whole virus bivalent vaccines have been shown to elicit high levels of neutralizing antibodies in mice . The induction of a strong neutralizing antibody response and cell-mediated immune response was also shown to occur with the administration of inactivated whole virus trivalent vaccines [294, 295]. The antigen-specific and persistent serum antibody responses by quadrivalent vaccines were comparable to those by the respective monovalent vaccines . In addition, polyvalent virus-like particles, novel chimeric vaccines, and recombinant virus-vector vaccines have all shown to induce broad protective effects and enhance systemic immune responses . Antigenic peptide-based vaccine development and DNA/RNA vaccine technology be also applied for future exploration of polyvalent vaccines [298, 299]. However, it is important to carefully consider the inclusion of appropriate strains and to thoroughly evaluate the immunogenicity and immune interactions when developing multivalent vaccines.
The World Health Organization (WHO) primarily manages the existing global surveillance network for poliovirus, but has not yet established a specialized network to monitor HFMD or EVs. The National Enterovirus Surveillance System (NESS), established in the United States as a passive and laboratory-based system, has been used to track EVs reports since the 1960s, and provides the most comprehensive data for monitoring HFMD . The Asia–Pacific Network for Enterovirus Surveillance (APNES) was established in 2017 through collaboration between academic institutions and hospitals in the Cambodia, Malaysia, Vietnam, and Taiwan region . However, the efficiency of the system is limited due to its limited coverage and the absence of a unified governing body. In 2008, HFMD was incorporated into China’s notifiable infectious disease reporting system. In order to better prevent and control HFMD, China has gradually established and improved a nationwide monitoring network system for HFMD laboratories, with prefecture-level laboratories, provincial-level laboratories, and national-level laboratories as the main body. Most European countries have established national surveillance systems for laboratory-based detection of EVs. Currently, the Prospective, Multicenter and Cross-sectional Hospital Pilot Non-Polio Enterovirus Network program, which was jointly established by several European countries, is set to become operational in 2022 . Laboratory-based disease surveillance networks can result in inefficient use of limited typing resources. Therefore, more optimized monitoring programs have been developed and applied to estimate HFMD incidence and optimize serotype estimation . However, based on epidemiological data from dynamic surveillance of EVs that may cause HFMD, there has been a rise in the incidence of HFMD associated with some non-EV-A71/CVA EVs infections . In recent years, the increasing occurrence of multiple EV infections and novel patterns of recombinant EV infections in patients with HFMD highlights the need for more vigilant pathogen surveillance of HFMD, especially in regards to emerging and co-infected pathogens .
In this Review, we systematically summarize the current knowledge on virology, epidemiology, pathogenesis, long-term sequelae of HFMD. Finally, as we assemble and interpret this evolving knowledge base, we need to understand which approaches to prevention and treatment, in this context, are most feasible and cost-effective, requiring a concerted effort between basic medical researchers and pediatricians. Overall, our study provides all relevant knowledge and the latest progress of HFMD, which will better inform health care and policy.
Availability of data and materials
All relevant data are within the manuscript and its additional files.
China Food and Drug Administration
Open reading frame
Human scavenger receptor class B member 2
P-selectin glycoprotein ligand-1
Pathogen-associated molecular patterns
Pathogen recognition receptors
Retinoic acid-inducible gene
Nucleotide-binding oligomerization domain
The toll interlukin-1 receptor
The Toll/IL-1R domain-containing adapter-inducing IFN-β
Melanoma differentiation-associated gene 5
Mitochondrial antiviral-signaling protein
TANK-binding kinase 1
Interferon regulatory factor 3
Zinc-finger antiviral protein
Acyl-CoA oxidase 1
The chemokine ligand
Reactive oxygen species
Signal transducer of activators of transcription
Acute heart failure
Extracorporeal membrane oxygenation
Attention-deficit hyperactivity disorder
The Chinese Academy of Medical Sciences
National Enterovirus Surveillance System
The World Health Organization
The Asia–Pacific Network for Enterovirus Surveillance
Robinson CR, Doane FW, Rhodes AJ. Report of an outbreak of febrile illness with pharyngeal lesions and exanthem: Toronto, summer 1957; isolation of group A Coxsackie virus. Can Med Assoc J. 1958;79(8):615–21.
Clarke M, Hunter M, Mc NG, Von Seydlitz D, Rhodes AJ. Seasonal aseptic meningitis caused by Coxsackie and ECHO viruses, Toronto, 1957. Can Med Assoc J. 1959;81(1):5–8.
Alsop J, Flewett TH, Foster JR. “Hand-foot-and-mouth disease” in Birmingham in 1959. Br Med J. 1960;2(5214):1708–11.
Bubba L, Broberg EK, Jasir A, Simmonds P, Harvala H. Circulation of non-polio enteroviruses in 24 EU and EEA countries between 2015 and 2017: a retrospective surveillance study. Lancet Infect Dis. 2020;20(3):350–61.
Schmidt NJ, Lennette EH, Ho HH. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis. 1974;129(3):304–9.
Chang LY, Lin HY, Gau SS, Lu CY, Hsia SH, Huang YC, Huang LM, Lin TY. Enterovirus A71 neurologic complications and long-term sequelae. J Biomed Sci. 2019;26(1):57.
Gonzalez G, Carr MJ, Kobayashi M, Hanaoka N, Fujimoto T. Enterovirus-associated hand-foot and mouth disease and neurological complications in Japan and the rest of the world. Int J Mol Sci. 2019;20(20).
Hsia SH, Lin JJ, Chan OW, Lin TY. Cardiopulmonary failure in children infected with Enterovirus A71. J Biomed Sci. 2020;27(1):53.
Chavda V.P., Patel K. and Apostolopoulos V. Tomato flu outbreak in India. Lancet Respir Med. 2022.
Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis. 2010;10(11):778–90.
Huang J, Liao Q, Ooi MH, Cowling BJ, Chang Z, Wu P, Liu F, Li Y, Luo L, Yu S, Yu H, Wei S. Epidemiology of recurrent hand, foot and mouth disease, China, 2008–2015. Emerg Infect Dis. 2018; 24(3).
Hoang MTV, Nguyen TA, Tran TT, Vu TTH, Le NTN, Nguyen THN, Le THN, Nguyen TTH, Nguyen TH, Le NTN, Truong HK, Du TQ, Ha MT, Ho LV, Do CV, Nguyen TN, Nguyen TMT, Sabanathan S, Phan TQ, Van Nguyen VC, Thwaites GE, Wills B, Thwaites CL, Le VT, van Doorn HR. Clinical and aetiological study of hand, foot and mouth disease in southern Vietnam, 2013–2015: inpatients and outpatients. Int J Infect Dis IJID. 2019;80:1–9.
Zhao TS, Du J, Sun DP, Zhu QR, Chen LY, Ye C, Wang S, Liu YQ, Cui F, Lu QB. A review and meta-analysis of the epidemiology and clinical presentation of coxsackievirus A6 causing hand-foot-mouth disease in China and global implications. Rev Med Virol. 2020;30(2): e2087.
Gopalkrishna V, Patil PR, Patil GP, Chitambar SD. Circulation of multiple enterovirus serotypes causing hand, foot and mouth disease in India. J Med Microbiol. 2012;61(Pt 3):420–5.
Yao X, Bian LL, Lu WW, Li JX, Mao QY, Wang YP, Gao F, Wu X, Ye Q, Li XL, Zhu FC, Liang Z. Epidemiological and etiological characteristics of herpangina and hand foot mouth diseases in Jiangsu, China, 2013–2014. Hum Vaccin Immunother. 2017;13(4):823–30.
Plevka P, Perera R, Cardosa J, Kuhn RJ, Rossmann MG. Crystal structure of human enterovirus 71. Science. 2012;336(6086):1274.
McMinn PC. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev. 2002;26(1):91–107.
Chen J, Zhang C, Zhou Y, Zhang X, Shen C, Ye X, Jiang W, Huang Z, Cong Y. A 3.0-Angstrom resolution cryo-electron microscopy structure and antigenic sites of coxsackievirus A6-like particles. J Virol. 2018;92(2).
Huang SC, Hsu YW, Wang HC, Huang SW, Kiang D, Tsai HP, Wang SM, Liu CC, Lin KH, Su IJ, Wang JR. Appearance of intratypic recombination of enterovirus 71 in Taiwan from 2002 to 2005. Virus Res. 2008;131(2):250–9.
Fu X, Wan Z, Li Y, Hu Y, Jin X, Zhang C. National epidemiology and evolutionary history of four hand, foot and mouth disease-related enteroviruses in China from 2008 to 2016. Virol Sin. 2020;35(1):21–33.
Li XW, Ni X, Qian SY, Wang Q, Jiang RM, Xu WB, Zhang YC, Yu GJ, Chen Q, Shang YX, Zhao CS, Yu H, Zhang T, Liu G, Deng HL, Gao J, Ran XG, Yang QZ, Xu BL, Huang XY, Wu XD, Bao YX, Chen YP, Chen ZH, Liu QQ, Lu GP, Liu CF, Wang RB, Zhang GL, Gu F, Xu HM, Li Y, Yang T. Chinese guidelines for the diagnosis and treatment of hand, foot and mouth disease (2018 edition). World J Pediatr. 2018;14(5):437–47.
Cox B, Levent F. Hand, foot, and mouth disease. JAMA. 2018;320(23):2492.
Fang Y, Wang S, Zhang L, Guo Z, Huang Z, Tu C, Zhu BP. Risk factors of severe hand, foot and mouth disease: a meta-analysis. Scand J Infect Dis. 2014;46(7):515–22.
Xing W, Liao Q, Viboud C, Zhang J, Sun J, Wu JT, Chang Z, Liu F, Fang VJ, Zheng Y, Cowling BJ, Varma JK, Farrar JJ, Leung GM, Yu H. Hand, foot, and mouth disease in China, 2008–12: an epidemiological study. Lancet Infect Dis. 2014;14(4):308–18.
Hoorn B, Tyrrell DA. On the growth of certain “newer” respiratory viruses in organ cultures. Br J Exp Pathol. 1965;46:109–18.
Wang Y, Zhao H, Ou R, Zhu H, Gan L, Zeng Z, Yuan R, Yu H, Ye M. Epidemiological and clinical characteristics of severe hand-foot-and-mouth disease (HFMD) among children: a 6-year population-based study. BMC Public Health. 2020;20(1):801.
Ben-Chetrit E, Wiener-Well Y, Shulman LM, Cohen MJ, Elinav H, Sofer D, Feldman I, Marva E, Wolf DG. Coxsackievirus A6-related hand foot and mouth disease: skin manifestations in a cluster of adult patients. J Clin Virol. 2014;59(3):201–3.
Li P, Rui J, Niu Y, Xie F, Wang Y, Li Z, Liu C, Yu S, Huang J, Luo L, Deng B, Liu W, Yang T, Li Q, Chen T. Analysis of HFMD transmissibility among the whole population and age groups in a large City of China. Front Public Health. 2022;10: 850369.
Zhao Z, Zheng C, Qi H, Chen Y, Ward MP, Liu F, Hong J, Su Q, Huang J, Chen X, Le J, Liu X, Ren M, Ba J, Zhang Z, Chang Z, Li Z. Impact of the coronavirus disease 2019 interventions on the incidence of hand, foot, and mouth disease in mainland China. Lancet Reg Health West Pac. 2022;20: 100362.
Shen L, Sun M, Song S, Hu Q, Wang N, Ou G, Guo Z, Du J, Shao Z, Bai Y, Liu K. The impact of anti-COVID-19 nonpharmaceutical interventions on hand, foot, and mouth disease-A spatiotemporal perspective in Xi’an, northwestern China. J Med Virol. 2022;94(7):3121–32.
Head JR, Collender PA, Lewnard JA, Skaff NK, Li L, Cheng Q, Baker JM, Li C, Chen D, Ohringer A, Liang S, Yang C, Hubbard A, Lopman B, Remais JV. Early evidence of inactivated enterovirus 71 vaccine impact against hand, foot, and mouth disease in a major center of ongoing transmission in China, 2011–2018: a longitudinal surveillance study. Clin Infect Dis. 2020;71(12):3088–95.
Esposito S, Principi N. Hand, foot and mouth disease: current knowledge on clinical manifestations, epidemiology, aetiology and prevention. Eur J Clin Microbiol Infect Dis. 2018;37(3):391–8.
Zhang R, Lin Z, Guo Z, Chang Z, Niu R, Wang Y, Wang S, Li Y. Daily mean temperature and HFMD: risk assessment and attributable fraction identification in Ningbo China. J Expo Sci Environ Epidemiol. 2021;31(4):664–71.
Bian L, Wang Y, Yao X, Mao Q, Xu M, Liang Z. Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide. Expert Rev Anti Infect Ther. 2015;13(9):1061–71.
Rui J, Luo K, Chen Q, Zhang D, Zhao Q, Zhang Y, Zhai X, Zhao Z, Zhang S, Liao Y, Hu S, Gao L, Lei Z, Wang M, Wang Y, Liu X, Yu S, Xie F, Li J, Liu R, Chiang YC, Zhao B, Su Y, Zhang XS, Chen T. Early warning of hand, foot, and mouth disease transmission: a modeling study in mainland, China. PLoS Negl Trop Dis. 2021;15(3): e0009233.
Cheng Q, Bai L, Zhang Y, Zhang H, Wang S, Xie M, Zhao D, Su H. Ambient temperature, humidity and hand, foot, and mouth disease: a systematic review and meta-analysis. Sci Total Environ. 2018;625:828–36.
Bo Z, Ma Y, Chang Z, Zhang T, Liu F, Zhao X, Long L, Yi X, Xiao X, Li Z. The spatial heterogeneity of the associations between relative humidity and pediatric hand, foot and mouth disease: evidence from a nation-wide multicity study from mainland China. Sci Total Environ. 2020;707: 136103.
Gao Y, Wang H, Yi S, Wang D, Ma C, Tan B, Wei Y. Spatial and temporal characteristics of hand-foot-and-mouth disease and their influencing factors in Urumqi, China. Int J Environ Res Public Health. 2021;18(9):4919.
Zhang D, Li Z, Zhang W, Guo P, Ma Z, Chen Q, Du S, Peng J, Deng Y, Hao Y. Hand-washing: the main strategy for avoiding hand, foot and mouth disease. Int J Environ Res Public Health. 2016;13(6):610.
Guo N, Ma H, Deng J, Ma Y, Huang L, Guo R, Zhang L. Effect of hand washing and personal hygiene on hand food mouth disease: a community intervention study. Medicine (Baltimore). 2018;97(51): e13144.
Chen S, Yi K, Chen X, Li L, Tan X. A simple scoring system for quick, accurate, and reliable early diagnosis of hand, foot, and mouth disease. Med Sci Monit. 2018;24:8627–38.
Lin H, Sun L, Lin J, He J, Deng A, Kang M, Zeng H, Ma W, Zhang Y. Protective effect of exclusive breastfeeding against hand, foot and mouth disease. BMC Infect Dis. 2014;14:645.
Upala P, Apidechkul T, Suttana W, Kullawong N, Tamornpark R, Inta C. Molecular epidemiology and clinical features of hand, foot and mouth disease in northern Thailand in 2016: a prospective cohort study. BMC Infect Dis. 2018;18(1):630.
Xie C, Wen H, Yang W, Cai J, Zhang P, Wu R, Li M, Huang S. Trend analysis and forecast of daily reported incidence of hand, foot and mouth disease in Hubei, China by Prophet model. Sci Rep. 2021;11(1):1445.
Deibel R, Gross LL, Collins DN. Isolation of a new enterovirus (38506). Proc Soc Exp Biol Med. 1975;148(1):203–7.
Melnick JL. Enterovirus type 71 infections: a varied clinical pattern sometimes mimicking paralytic poliomyelitis. Rev Infect Dis. 1984;6(Suppl 2):S387-390.
Bible JM, Iturriza-Gomara M, Megson B, Brown D, Pantelidis P, Earl P, Bendig J, Tong CY. Molecular epidemiology of human enterovirus 71 in the United Kingdom from 1998 to 2006. J Clin Microbiol. 2008;46(10):3192–200.
Shindarov LM, Chumakov MP, Voroshilova MK, Bojinov S, Vasilenko SM, Iordanov I, Kirov ID, Kamenov E, Leshchinskaya EV, Mitov G, Robinson IA, Sivchev S, Staikov S. Epidemiological, clinical, and pathomorphological characteristics of epidemic poliomyelitis-like disease caused by enterovirus 71. J Hyg Epidemiol Microbiol Immunol. 1979;23(3):284–95.
Iacazio G, Martini D, Faure B, N’Guyen MH. Isolation and characterisation of 8-hydroxy-3Z,5Z-tetradecadienoic acid, a putative intermediate in Pichia guilliermondii gamma-decalactone biosynthesis from ricinoleic acid. FEMS Microbiol Lett. 2002;209(1):57–62.
Nagy G, Takatsy S, Kukan E, Mihaly I, Domok I. Virological diagnosis of enterovirus type 71 infections: experiences gained during an epidemic of acute CNS diseases in Hungary in 1978. Adv Virol. 1982;71(3):217–27.
van der Sanden S, Koopmans M, Uslu G, van der Avoort H, Dutch Working Group for Clinical V. Epidemiology of enterovirus 71 in the Netherlands, 1963 to 2008. J Clin Microbiol. 2009;47(9):2826–33.
Ishimaru Y, Nakano S, Yamaoka K, Takami S. Outbreaks of hand, foot, and mouth disease by enterovirus 71. High incidence of complication disorders of central nervous system. Arch Dis Child. 1980;55(8):583–8.
Takimoto S, Waldman EA, Moreira RC, Kok F, Pinheiro Fde P, Saes SG, Hatch M, de Souza DF, Carmona Rde C, Shout D, de Moraes JC, Costa AM. Enterovirus 71 infection and acute neurological disease among children in Brazil (1988–1990). Trans R Soc Trop Med Hyg. 1998;92(1):25–8.
Chua KB, Kasri AR. Hand foot and mouth disease due to enterovirus 71 in Malaysia. Virol Sin. 2011;26(4):221–8.
Liu CC, Tseng HW, Wang SM, Wang JR, Su IJ. An outbreak of enterovirus 71 infection in Taiwan, 1998: epidemiologic and clinical manifestations. J Clin Virol. 2000;17(1):23–30.
Donato C, le Hoi T, Hoa NT, Hoa TM, Van Duyet L, Dieu Ngan TT, Van Kinh N, Vu Trung N, Vijaykrishna D. Genetic characterization of Enterovirus 71 strains circulating in Vietnam in 2012. Virology. 2016;495:1–9.
Akhmadishina LV, Govorukhina MV, Kovalev EV, Nenadskaya SA, Ivanova OE, Lukashev AN. Enterovirus A71 meningoencephalitis outbreak, Rostov-on-Don, Russia, 2013. Emerg Infect Dis. 2015;21(8):1440–3.
Kim SJ, Kim JH, Kang JH, Kim DS, Kim KH, Kim KH, Kim YH, Chung JY, Bin JH, Jung DE, Kim JH, Kim HM, Cheon DS, Kang BH, Seo SY. Risk factors for neurologic complications of hand, foot and mouth disease in the Republic of Korea, 2009. J Korean Med Sci. 2013;28(1):120–7.
Shah VA, Chong CY, Chan KP, Ng W, Ling AE. Clinical characteristics of an outbreak of hand, foot and mouth disease in Singapore. Ann Acad Med Singap. 2003;32(3):381–7.
Puenpa J, Auphimai C, Korkong S, Vongpunsawad S, Poovorawan Y. Enterovirus A71 infection, Thailand, 2017. Emerg Infect Dis. 2018;24(7):1386–7.
Noisumdaeng P, Korkusol A, Prasertsopon J, Sangsiriwut K, Chokephaibulkit K, Mungaomklang A, Thitithanyanont A, Buathong R, Guntapong R, Puthavathana P. Longitudinal study on enterovirus A71 and coxsackievirus A16 genotype/subgenotype replacements in hand, foot and mouth disease patients in Thailand, 2000–2017. Int J Infect Dis IJID. 2019;80:84–91.
Apostol LN, Suzuki A, Bautista A, Galang H, Paladin FJ, Fuji N, Lupisan S, Olveda R, Oshitani H. Detection of non-polio enteroviruses from 17 years of virological surveillance of acute flaccid paralysis in the Philippines. J Med Virol. 2012;84(4):624–31.
Fischer TK, Nielsen AY, Sydenham TV, Andersen PH, Andersen B, Midgley SE. Emergence of enterovirus 71 C4a in Denmark, 2009 to 2013. Euro Surveill. 2014;19(38).
Luciani L, Morand A, Zandotti C, Piorkowski G, Boutin A, Mazenq J, Minodier P, Ninove L, Nougairede A. Circulation of enterovirus A71 during 2019–2020, Marseille, France. J Med Virol. 2021;93(8):5163–6.
Karrasch M, Fischer E, Scholten M, Sauerbrei A, Henke A, Renz DM, Mentzel HJ, Boer K, Bottcher S, Diedrich S, Krumbholz A, Zell R. A severe pediatric infection with a novel enterovirus A71 strain, Thuringia, Germany. J Clin Virol. 2016;84:90–5.
Gonzalez-Sanz R, Casas-Alba D, Launes C, Munoz-Almagro C, Ruiz-Garcia MM, Alonso M, Gonzalez-Abad MJ, Megias G, Rabella N, Del Cuerpo M, Gozalo-Marguello M, Gonzalez-Praetorius A, Martinez-Sapina A, Goyanes-Galan MJ, Romero MP, Calvo C, Anton A, Imaz M, Aranzamendi M, Hernandez-Rodriguez A, Moreno-Docon A, Rey-Cao S, Navascues A, Otero A, Cabrerizo M. Molecular epidemiology of an enterovirus A71 outbreak associated with severe neurological disease, Spain, 2016. Euro Surveill. 2019;24(7).
Wieczorek M, Purzynska M, Krzysztoszek A, Ciacka A, Figas A, Szenborn L. Genetic characterization of enterovirus A71 isolates from severe neurological cases in Poland. J Med Virol. 2018;90(2):372–6.
Bendig JW, Fleming DM. Epidemiological, virological, and clinical features of an epidemic of hand, foot, and mouth disease in England and Wales. Commun Dis Rep CDR Rev. 1996;6(6):R81-86.
Froeschle JE, Nahmias AJ, Feorino PM, McCord G, Naib Z. Hand, foot, and mouth disease (Coxsackievirus A16) in Atlanta. Am J Dis Child. 1967;114(3):278–83.
Adler JL, Mostow SR, Mellin H, Janney JH, Joseph JM. Epidemiologic investigation of hand, foot, and mouth disease. Infection caused by coxsackievirus A 16 in Baltimore, June through September 1968. Am J Dis Child. 1970;120(4):309–14.
Ferson MJ, Bell SM. Outbreak of Coxsackievirus A16 hand, foot, and mouth disease in a child day-care center. Am J Public Health. 1991;81(12):1675–6.
Zou XN, Zhang XZ, Wang B, Qiu YT. Etiologic and epidemiologic analysis of hand, foot, and mouth disease in Guangzhou city: a review of 4,753 cases. Braz J Infect Dis. 2012;16(5):457–65.
Zhu J, Luo Z, Wang J, Xu Z, Chen H, Fan D, Gao N, Ping G, Zhou Z, Zhang Y, An J. Phylogenetic analysis of Enterovirus 71 circulating in Beijing, China from 2007 to 2009. PLoS ONE. 2013;8(2): e56318.
Mori R, Kitahara Y, Takamori M. Studies of hand, foot and mouth disease. Virus isolation in an epidemic in Nobeoka city in 1970. Kansenshogaku Zasshi. 1971;45(3):105–11.
Kar BR, Dwibedi B, Kar SK. An outbreak of hand, foot and mouth disease in Bhubaneswar. Odisha Indian Pediatr. 2013;50(1):139–42.
Palani S, Nagarajan M, Biswas AK, Reesu R, Paluru V. Hand, foot and mouth disease in the Andaman Islands. India Indian Pediatr. 2018;55(5):408–10.
Chang LY. Enterovirus 71 in Taiwan. Pediatr Neonatol. 2008;49(4):103–12.
Van Tu P, Thao NTT, Perera D, Truong KH, Tien NTK, Thuong TC, How OM, Cardosa MJ, McMinn PC. Epidemiologic and virologic investigation of hand, foot, and mouth disease, southern Vietnam, 2005. Emerg Infect Dis. 2007;13(11):1733–41.
Goh KT, Doraisingham S, Tan JL, Lim GN, Chew SE. An outbreak of hand, foot, and mouth disease in Singapore. Bull World Health Organ. 1982;60(6):965–9.
Chan KP, Goh KT, Chong CY, Teo ES, Lau G, Ling AE. Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore. Emerg Infect Dis. 2003;9(1):78–85.
Cabrerizo M, Tarrago D, Munoz-Almagro C, Del Amo E, Dominguez-Gil M, Eiros JM, Lopez-Miragaya I, Perez C, Reina J, Otero A, Gonzalez I, Echevarria JE, Trallero G. Molecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain. Clin Microbiol Infect. 2014;20(3):O150-156.
Lizasoain A, Mir D, Martinez N, Colina R. Coxsackievirus A10 causing hand-foot-and-mouth disease in Uruguay. Int J Infect Dis IJID. 2020;94:1–3.
Nhan LNT, Khanh TH, Hong NTT, Van HMT, Nhu LNT, Ny NTH, Nguyet LA, Thanh TT, Anh NT, Hang VTT, Qui PT, Viet HL, Tung TH, Ha DQ, Tuan HM, Thwaites G, Chau NVV, Thwaites L, Hung NT, van Doorn HR, Tan LV. Clinical, etiological and epidemiological investigations of hand, foot and mouth disease in southern Vietnam during 2015–2018. PLoS Negl Trop Dis. 2020;14(8): e0008544.
Mirand A, Cohen R, Bisseux M, Tomba S, Sellem FC, Gelbert N, Bechet S, Frandji B, Archimbaud C, Brebion A, Chabrolles H, Regagnon C, Levy C, Bailly JL, Henquell C. A large-scale outbreak of hand, foot and mouth disease, France, as at 28 September 2021. Euro Surveill. 2021;26(43).
Wang J, Zhou J, Xie G, Zheng S, Lou B, Chen Y, Wu Y. The epidemiological and clinical characteristics of hand, foot, and mouth disease in Hangzhou, China, 2016 to 2018. Clin Pediatr (Phila). 2020;59(7):656–62.
Blomqvist S, Klemola P, Kaijalainen S, Paananen A, Simonen ML, Vuorinen T, Roivainen M. Co-circulation of coxsackieviruses A6 and A10 in hand, foot and mouth disease outbreak in Finland. J Clin Virol. 2010;48(1):49–54.
Flett K, Youngster I, Huang J, McAdam A, Sandora TJ, Rennick M, Smole S, Rogers SL, Nix WA, Oberste MS, Gellis S, Ahmed AA. Hand, foot, and mouth disease caused by coxsackievirus a6. Emerg Infect Dis. 2012;18(10):1702–4.
Abedi GR, Watson JT, Pham H, Nix WA, Oberste MS, Gerber SI. Enterovirus and human parechovirus surveillance—United States, 2009–2013. MMWR Morb Mortal Wkly Rep. 2015;64(34):940–3.
Bujaki E, Farkas A, Rigo Z, Takacs M. Distribution of enterovirus genotypes detected in clinical samples in Hungary, 2010–2018. Acta Microbiol Immunol Hung. 2020;67(4):201–8.
Sinclair C, Gaunt E, Simmonds P, Broomfield D, Nwafor N, Wellington L, Templeton K, Willocks L, Schofield O, Harvala H. Atypical hand, foot, and mouth disease associated with coxsackievirus A6 infection, Edinburgh, United Kingdom, January to February 2014. Euro Surveill. 2014;19(12):20745.
Puenpa J, Chieochansin T, Linsuwanon P, Korkong S, Thongkomplew S, Vichaiwattana P, Theamboonlers A, Poovorawan Y. Hand, foot, and mouth disease caused by coxsackievirus A6, Thailand, 2012. Emerg Infect Dis. 2013;19(4):641–3.
Fujimoto T, Iizuka S, Enomoto M, Abe K, Yamashita K, Hanaoka N, Okabe N, Yoshida H, Yasui Y, Kobayashi M, Fujii Y, Tanaka H, Yamamoto M, Shimizu H. Hand, foot, and mouth disease caused by coxsackievirus A6, Japan, 2011. Emerg Infect Dis. 2012;18(2):337–9.
Kanbayashi D, Kaida A, Hirai Y, Yamamoto SP, Fujimori R, Okada M, Kubo H, Iritani N. An epidemic of hand, foot, and mouth disease caused by coxsackievirus A6 in Osaka City, Japan, in 2017. Jpn J Infect Dis. 2019;72(5):334–6.
Wu Y, Yeo A, Phoon MC, Tan EL, Poh CL, Quak SH, Chow VT. The largest outbreak of hand; foot and mouth disease in Singapore in 2008: the role of enterovirus 71 and coxsackievirus A strains. Int J Infect Dis. 2010;14(12):e1076-1081.
Hayman R, Shepherd M, Tarring C, Best E. Outbreak of variant hand-foot-and-mouth disease caused by coxsackievirus A6 in Auckland, New Zealand. J Paediatr Child Health. 2014;50(10):751–5.
Nelson BR, Edinur HA, Abdullah MT. Compendium of hand, foot and mouth disease data in Malaysia from years 2010–2017. Data Brief. 2019;24: 103868.
Li J, Zhu R, Huo D, Du Y, Yan Y, Liang Z, Luo Y, Yang Y, Jia L, Chen L, Wang Q, He Y. An outbreak of Coxsackievirus A6-associated hand, foot, and mouth disease in a kindergarten in Beijing in 2015. BMC Pediatr. 2018;18(1):277.
Li Y, Chang Z, Wu P, Liao Q, Liu F, Zheng Y, Luo L, Zhou Y, Chen Q, Yu S, Guo C, Chen Z, Long L, Zhao S, Yang B, Yu H, Cowling BJ. Emerging enteroviruses causing hand, foot and mouth disease, China, 2010–2016. Emerg Infect Dis. 2018;24(10):1902–6.
Lau SKP, Zhao PSH, Sridhar S, Yip CCY, Aw-Yong KL, Chow EYY, Cheung KCM, Hui RWH, Leung RYH, Lai YSK, Wu AKL, To KKW, Woo PCY, Yuen KY. Molecular epidemiology of coxsackievirus A6 circulating in Hong Kong reveals common neurological manifestations and emergence of novel recombinant groups. J Clin Virol. 2018;108:43–9.
Hu L, Maimaiti H, Zhou L, Gao J, Lu Y. Changing serotypes of hand, foot and mouth disease in Shanghai, 2017–2019. Gut Pathog. 2022;14(1):12.
Ramirez-Fort MK, Downing C, Doan HQ, Benoist F, Oberste MS, Khan F, Tyring SK. Coxsackievirus A6 associated hand, foot and mouth disease in adults: clinical presentation and review of the literature. J Clin Virol. 2014;60(4):381–6.
Hoang CQ, Nguyen HD, Ho NX, Vu THT, Pham TTM, Nguyen KT, Nguyen HT, Hoang LT, Clapham H, Nguyen TTT, Phan LT. Incidence of infection of enterovirus 71 and coxsackieviruses A6 and A16 among household contacts of index cases in Dong Thap Province, Southern Vietnam. Biomed Res Int. 2020;2020:9850351.
Oberste MS, Penaranda S, Maher K, Pallansch MA. Complete genome sequences of all members of the species Human enterovirus A. J Gen Virol. 2004;85(Pt 6):1597–607.
Duff MF. Hand-foot-and-mouth syndrome in humans: coxackie A10 infections in New Zealand. Br Med J. 1968;2(5606):661–4.
Itagaki A, Ishihara J, Mochida K, Ito Y, Saito K, Nishino Y, Koike S, Kurimura T. A clustering outbreak of hand, foot, and mouth disease caused by Coxsackie virus A10. Microbiol Immunol. 1983;27(11):929–35.
Mirand A, Henquell C, Archimbaud C, Ughetto S, Antona D, Bailly JL, Peigue-Lafeuille H. Outbreak of hand, foot and mouth disease/herpangina associated with coxsackievirus A6 and A10 infections in 2010, France: a large citywide, prospective observational study. Clin Microbiol Infect. 2012;18(5):E110-118.
Ryu WS, Kang B, Hong J, Hwang S, Kim J, Cheon DS. Clinical and etiological characteristics of enterovirus 71-related diseases during a recent 2-year period in Korea. J Clin Microbiol. 2010;48(7):2490–4.
Xie J, Yang XH, Hu SQ, Zhan WL, Zhang CB, Liu H, Zhao HY, Chai HY, Chen KY, Du QY, Liu P, Yin AH, Luo MY. Co-circulation of coxsackieviruses A-6, A-10, and A-16 causes hand, foot, and mouth disease in Guangzhou city, China. BMC Infect Dis. 2020;20(1):271.
He SZ, Chen MY, Xu XR, Yan Q, Niu JJ, Wu WH, Su XS, Ge SX, Zhang SY, Xia NS. Epidemics and aetiology of hand, foot and mouth disease in Xiamen, China, from 2008 to 2015. Epidemiol Infect. 2017;145(9):1865–74.
Wang J, Liu J, Fang F, Wu J, Ji T, Yang Y, Liu L, Li C, Zhang W, Zhang X, Teng Z. Genomic surveillance of coxsackievirus A10 reveals genetic features and recent appearance of genogroup D in Shanghai, China, 2016–2020. Virol Sin. 2022;37(2):177–86.
Lukashev AN, Vakulenko YA, Turbabina NA, Deviatkin AA, Drexler JF. Molecular epidemiology and phylogenetics of human enteroviruses: Is there a forest behind the trees? Rev Med Virol. 2018;28(6): e2002.
Brown BA, Oberste MS, Alexander JP Jr, Kennett ML, Pallansch MA. Molecular epidemiology and evolution of enterovirus 71 strains isolated from 1970 to 1998. J Virol. 1999;73(12):9969–75.
Zhang C, Zhu R, Yang Y, Chi Y, Yin J, Tang X, Yu L, Zhang C, Huang Z, Zhou D. Phylogenetic analysis of the major causative agents of hand, foot and mouth disease in Suzhou City, Jiangsu province, China, in 2012–2013. Emerg Microbes Infect. 2015;4(2): e12.
He Y, Zou L, Chong MKC, Men R, Xu W, Yang H, Yao X, Chen L, Xian H, Zhang H, Luo M, Cheng J, Ma H, Feng Q, Huang Y, Wang Y, Yeoh EK, Zee BC, Zhou Y, He ML, Wang MH. Genetic evolution of Human Enterovirus A71 subgenotype C4 in Shenzhen, China, 1998–2013. J Infect. 2016;72(6):731–7.
Saxena VK, Sane S, Nadkarni SS, Sharma DK, Deshpande JM. Genetic diversity of enterovirus A71, India. Emerg Infect Dis. 2015;21(1):123–6.
Fernandez-Garcia MD, Volle R, Joffret ML, Sadeuh-Mba SA, Gouandjika-Vasilache I, Kebe O, Wiley MR, Majumdar M, Simon-Loriere E, Sakuntabhai A, Palacios G, Martin J, Delpeyroux F, Ndiaye K, Bessaud M. Genetic characterization of enterovirus A71 circulating in Africa. Emerg Infect Dis. 2018;24(4):754–7.
Bessaud M, Razafindratsimandresy R, Nougairede A, Joffret ML, Deshpande JM, Dubot-Peres A, Heraud JM, de Lamballerie X, Delpeyroux F, Bailly JL. Molecular comparison and evolutionary analyses of VP1 nucleotide sequences of new African human enterovirus 71 isolates reveal a wide genetic diversity. PLoS ONE. 2014;9(3): e90624.
Nhu LNT, Nhan LNT, Anh NT, Hong NTT, Van HMT, Thanh TT, Hang VTT, Han DDK, Ny NTH, Nguyet LA, Quy DT, Qui PT, Khanh TH, Hung NT, Tuan HM, Chau NVV, Thwaites G, van Doorn HR, Tan LV. Coxsackievirus A16 in Southern Vietnam. Front Microbiol. 2021;12: 689658.
Hu YF, Jia LP, Yu FY, Liu LY, Song QW, Dong HJ, Deng J, Qian Y, Zhao LQ, Deng L, Huang H, Zhu RN. Molecular epidemiology of coxsackievirus A16 circulating in children in Beijing, China from 2010 to 2019. World J Pediatr. 2021;17(5):508–16.
Hassel C, Mirand A, Farkas A, Diedrich S, Huemer HP, Peigue-Lafeuille H, Archimbaud C, Henquell C, Bailly JL, Network H.F.S. Phylogeography of coxsackievirus A16 reveals global transmission pathways and recent emergence and spread of a recombinant genogroup. J Virol. 2017;91(18).
Wang J, Teng Z, Chu W, Fang F, Cui X, Guo X, Zhang X, Thorley BR, Zhu Y. The emergence and spread of one Coxsackievirus A16 Genogroup D novel recombinant strain that caused a clustering HFMD outbreak in Shanghai, China, 2016. Emerg Microbes Infect. 2018;7(1):131.
Chen L, Yao XJ, Xu SJ, Yang H, Wu CL, Lu J, Xu WB, Zhang HL, Meng J, Zhang Y, He YQ, Zhang RL. Molecular surveillance of coxsackievirus A16 reveals the emergence of a new clade in mainland China. Adv Virol. 2019;164(3):867–74.
Song Y, Zhang Y, Ji T, Gu X, Yang Q, Zhu S, Xu W, Xu Y, Shi Y, Huang X, Li Q, Deng H, Wang X, Yan D, Yu W, Wang S, Yu D, Xu W. Persistent circulation of Coxsackievirus A6 of genotype D3 in mainland of China between 2008 and 2015. Sci Rep. 2017;7(1):5491.
Dalldorf G. The coxsackie virus group. Ann N Y Acad Sci. 1953;56(3):583–6.
Munivenkatappa A, Yadav PD, Nyayanit DA, Majumdar TD, Sangal L, Jain S, Sinha DP, Shrivastava A, Mourya DT. Molecular diversity of Coxsackievirus A10 circulating in the southern and northern region of India [2009-17]. Infect Genet Evol. 2018;66:101–10.
Lukashev AN, Shumilina EY, Belalov IS, Ivanova OE, Eremeeva TP, Reznik VI, Trotsenko OE, Drexler JF, Drosten C. Recombination strategies and evolutionary dynamics of the Human enterovirus A global gene pool. J Gen Virol. 2014;95(Pt 4):868–73.
Zhang M, Xu D, Feng C, Guo W, Fei C, Sun H, Yang Z, Ma S. Isolation and characterization of a novel clade of coxsackievirus B2 associated with hand, foot, and mouth disease in Southwest China. J Med Virol. 2022;94(6):2598–606.
Yang Q, Yan D, Song Y, Zhu S, He Y, Han Z, Wang D, Ji T, Zhang Y, Xu W. Whole-genome analysis of coxsackievirus B3 reflects its genetic diversity in China and worldwide. Virol J. 2022;19(1):69.
Mendelsohn CL, Wimmer E, Racaniello VR. Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell. 1989;56(5):855–65.
Ren RB, Costantini F, Gorgacz EJ, Lee JJ, Racaniello VR. Transgenic mice expressing a human poliovirus receptor: a new model for poliomyelitis. Cell. 1990;63(2):353–62.
Rossmann MG, He Y, Kuhn RJ. Picornavirus-receptor interactions. Trends Microbiol. 2002;10(7):324–31.
Yamayoshi S, Yamashita Y, Li J, Hanagata N, Minowa T, Takemura T, Koike S. Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat Med. 2009;15(7):798–801.
Nishimura Y, Shimojima M, Tano Y, Miyamura T, Wakita T, Shimizu H. Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med. 2009;15(7):794–7.
Yang SL, Chou YT, Wu CN, Ho MS. Annexin II binds to capsid protein VP1 of enterovirus 71 and enhances viral infectivity. J Virol. 2011;85(22):11809–20.
Tan CW, Poh CL, Sam IC, Chan YF. Enterovirus 71 uses cell surface heparan sulfate glycosaminoglycan as an attachment receptor. J Virol. 2013;87(1):611–20.
Staring J, van den Hengel LG, Raaben M, Blomen VA, Carette JE, Brummelkamp TR. KREMEN1 is a host entry receptor for a major group of enteroviruses. Cell Host Microbe. 2018;23(5):636–43.
Zhao Y, Zhou D, Ni T, Karia D, Kotecha A, Wang X, Rao Z, Jones EY, Fry EE, Ren J, Stuart DI. Hand-foot-and-mouth disease virus receptor KREMEN1 binds the canyon of Coxsackie Virus A10. Nat Commun. 2020;11(1):38.
Tuthill TJ, Groppelli E, Hogle JM, Rowlands DJ. Picornaviruses. Curr Top Microbiol Immunol. 2010;343:43–89.
Lin YW, Lin HY, Tsou YL, Chitra E, Hsiao KN, Shao HY, Liu CC, Sia C, Chong P, Chow YH. Human SCARB2-mediated entry and endocytosis of EV71. PLoS ONE. 2012;7(1): e30507.
Zhou D, Zhao Y, Kotecha A, Fry EE, Kelly JT, Wang X, Rao Z, Rowlands DJ, Ren J, Stuart DI. Unexpected mode of engagement between enterovirus 71 and its receptor SCARB2. Nat Microbiol. 2019;4(3):414–9.
Wang X, Peng W, Ren J, Hu Z, Xu J, Lou Z, Li X, Yin W, Shen X, Porta C, Walter TS, Evans G, Axford D, Owen R, Rowlands DJ, Wang J, Stuart DI, Fry EE, Rao Z. A sensor-adaptor mechanism for enterovirus uncoating from structures of EV71. Nat Struct Mol Biol. 2012;19(4):424–9.
Dang M, Wang X, Wang Q, Wang Y, Lin J, Sun Y, Li X, Zhang L, Lou Z, Wang J, Rao Z. Molecular mechanism of SCARB2-mediated attachment and uncoating of EV71. Protein Cell. 2014;5(9):692–703.
Yeung ML, Jia L, Yip CCY, Chan JFW, Teng JLL, Chan KH, Cai JP, Zhang C, Zhang AJ, Wong WM, Kok KH, Lau SKP, Woo PCY, Lo JYC, Jin DY, Shih SR, Yuen KY. Human tryptophanyl-tRNA synthetase is an IFN-gamma-inducible entry factor for Enterovirus. J Clin Invest. 2018;128(11):5163–77.
Drummond CG, Bolock AM, Ma C, Luke CJ, Good M, Coyne CB. Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner. Proc Natl Acad Sci USA. 2017;114(7):1672–7.
Yu P, Gao Z, Zong Y, Bao L, Xu L, Deng W, Li F, Lv Q, Gao Z, Xu Y, Yao Y, Qin C. Histopathological features and distribution of EV71 antigens and SCARB2 in human fatal cases and a mouse model of enterovirus 71 infection. Virus Res. 2014;189:121–32.
Good C, Wells AI, Coyne CB. Type III interferon signaling restricts enterovirus 71 infection of goblet cells. Sci Adv. 2019;5(3):eaau4255.
Shieh JT, Bergelson JM. Interaction with decay-accelerating factor facilitates coxsackievirus B infection of polarized epithelial cells. J Virol. 2002;76(18):9474–80.
Yang B, Chuang H, Yang KD. Sialylated glycans as receptor and inhibitor of enterovirus 71 infection to DLD-1 intestinal cells. Virol J. 2009;6:141.
He Y, Ong KC, Gao Z, Zhao X, Anderson VM, McNutt MA, Wong KT, Lu M. Tonsillar crypt epithelium is an important extra-central nervous system site for viral replication in EV71 encephalomyelitis. Am J Pathol. 2014;184(3):714–20.
Gu J, Wu J, Fang D, Qiu Y, Zou X, Jia X, Yin Y, Shen L, Mao L. Exosomes cloak the virion to transmit Enterovirus 71 non-lytically. Virulence. 2020;11(1):32–8.
Wang Y, Zhang S, Song W, Zhang W, Li J, Li C, Qiu Y, Fang Y, Jiang Q, Li X, Yan B. Exosomes from EV71-infected oral epithelial cells can transfer miR-30a to promote EV71 infection. Oral Dis. 2020;26(4):778–88.
Zhang Y, Cui W, Liu L, Wang J, Zhao H, Liao Y, Na R, Dong C, Wang L, Xie Z, Gao J, Cui P, Zhang X, Li Q. Pathogenesis study of enterovirus 71 infection in rhesus monkeys. Lab Invest. 2011;91(9):1337–50.
Cheng HY, Huang YC, Yen TY, Hsia SH, Hsieh YC, Li CC, Chang LY, Huang LM. The correlation between the presence of viremia and clinical severity in patients with enterovirus 71 infection: a multi-center cohort study. BMC Infect Dis. 2014;14:417.
Chang LY, King CC, Hsu KH, Ning HC, Tsao KC, Li CC, Huang YC, Shih SR, Chiou ST, Chen PY, Chang HJ, Lin TY. Risk factors of enterovirus 71 infection and associated hand, foot, and mouth disease/herpangina in children during an epidemic in Taiwan. Pediatrics. 2002;109(6): e88.
Wang YF, Chou CT, Lei HY, Liu CC, Wang SM, Yan JJ, Su IJ, Wang JR, Yeh TM, Chen SH, Yu CK. A mouse-adapted enterovirus 71 strain causes neurological disease in mice after oral infection. J Virol. 2004;78(15):7916–24.
Ho M, Chen ER, Hsu KH, Twu SJ, Chen KT, Tsai SF, Wang JR, Shih SR. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341(13):929–35.
Lu MY, Lin YL, Kuo Y, Chuang CF, Wang JR, Liao F. Muscle tissue damage and recovery after EV71 infection correspond to dynamic macrophage phenotypes. Front Immunol. 2021;12: 648184.
Hashimoto I, Hagiwara A. Pathogenicity of a poliomyelitis-like disease in monkeys infected orally with enterovirus 71: a model for human infection. Neuropathol Appl Neurobiol. 1982;8(2):149–56.
Wong KT, Munisamy B, Ong KC, Kojima H, Noriyo N, Chua KB, Ong BB, Nagashima K. The distribution of inflammation and virus in human enterovirus 71 encephalomyelitis suggests possible viral spread by neural pathways. J Neuropathol Exp Neurol. 2008;67(2):162–9.
Chen CS, Yao YC, Lin SC, Lee YP, Wang YF, Wang JR, Liu CC, Lei HY, Yu CK. Retrograde axonal transport: a major transmission route of enterovirus 71 in mice. J Virol. 2007;81(17):8996–9003.
Pan H, Yao X, Chen W, Wang F, He H, Liu L, He Y, Chen J, Jiang P, Zhang R, Ma Y, Cai L. Dissecting complicated viral spreading of enterovirus 71 using in situ bioorthogonal fluorescent labeling. Biomaterials. 2018;181:199–209.
Ohka S, Hao Tan S, Kaneda S, Fujii T, Schiavo G. Retrograde axonal transport of poliovirus and EV71 in motor neurons. Biochem Biophys Res Commun. 2022;626:72–8.
Jin Y, Zhang R, Wu W, Duan G. Innate immunity evasion by enteroviruses linked to epidemic hand-foot-mouth disease. Front Microbiol. 2018;9:2422.
Hsiao HB, Chou AH, Lin SI, Chen IH, Lien SP, Liu CC, Chong P, Liu SJ. Toll-like receptor 9-mediated protection of enterovirus 71 infection in mice is due to the release of danger-associated molecular patterns. J Virol. 2014;88(20):11658–70.
Chen KR, Yu CK, Kung SH, Chen SH, Chang CF, Ho TC, Lee YP, Chang HC, Huang LY, Lo SY, Chang JC, Ling P. Toll-like receptor 3 is involved in detection of enterovirus A71 infection and targeted by viral 2A protease. Viruses. 2018;10(12):689.
Luo Z, Su R, Wang W, Liang Y, Zeng X, Shereen MA, Bashir N, Zhang Q, Zhao L, Wu K, Liu Y, Wu J. EV71 infection induces neurodegeneration via activating TLR7 signaling and IL-6 production. PLoS Pathog. 2019;15(11): e1008142.
Lin YL, Lu MY, Chuang CF, Kuo Y, Lin HE, Li FA, Wang JR, Hsueh YP, Liao F. TLR7 is critical for anti-viral humoral immunity to EV71 infection in the spinal cord. Front Immunol. 2020;11: 614743.
Rasti M, Khanbabaei H, Teimoori A. An update on enterovirus 71 infection and interferon type I response. Rev Med Virol. 2019;29(1): e2016.
Gong Z, Gao X, Yang Q, Lun J, Xiao H, Zhong J, Cao H. Phosphorylation of ERK-dependent NF-kappaB triggers NLRP3 inflammasome mediated by vimentin in EV71-infected glioblastoma cells. Molecules. 2022;27(13):4190.
Lu Y, Hou H, Wang F, Qiao L, Wang X, Yu J, Liu W, Sun Z. ATP1B3: a virus-induced host factor against EV71 replication by up-regulating the production of type-I interferons. Virology. 2016;496:28–34.
Xie L, Lu B, Zheng Z, Miao Y, Liu Y, Zhang Y, Zheng C, Ke X, Hu Q, Wang H. The 3C protease of enterovirus A71 counteracts the activity of host zinc-finger antiviral protein (ZAP). J Gen Virol. 2018;99(1):73–85.
Xue YC, Ng CS, Mohamud Y, Fung G, Liu H, Bahreyni A, Zhang J, Luo H. FUS/TLS suppresses enterovirus replication and promotes antiviral innate immune responses. J Virol. 2021;95(12).
Sen GC. Viruses and interferons. Annu Rev Microbiol. 2001;55:255–81.
Guo X, Zeng S, Ji X, Meng X, Lei N, Yang H, Mu X. Type I interferon-induced TMEM106A blocks attachment of EV-A71 virus by interacting with the membrane protein SCARB2. Front Immunol. 2022;13: 817835.
Dong Y, Liu J, Lu N, Zhang C. Enterovirus 71 antagonizes antiviral effects of type III interferon and evades the clearance of intestinal intraepithelial lymphocytes. Front Microbiol. 2021;12: 806084.
Ho BC, Yu IS, Lu LF, Rudensky A, Chen HY, Tsai CW, Chang YL, Wu CT, Chang LY, Shih SR, Lin SW, Lee CN, Yang PC, Yu SL. Inhibition of miR-146a prevents enterovirus-induced death by restoring the production of type I interferon. Nat Commun. 2014;5:3344.
Feng N, Zhou Z, Li Y, Zhao L, Xue Z, Lu R, Jia K. Enterovirus 71-induced has-miR-21 contributes to evasion of host immune system by targeting MyD88 and IRAK1. Virus Res. 2017;237:27–36.
Lei X, Sun Z, Liu X, Jin Q, He B, Wang J. Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by Toll-like receptor 3. J Virol. 2011;85(17):8811–8.
Kuo RL, Kao LT, Lin SJ, Wang RY, Shih SR. MDA5 plays a crucial role in enterovirus 71 RNA-mediated IRF3 activation. PLoS ONE. 2013;8(5): e63431.
Rui Y, Su J, Wang H, Chang J, Wang S, Zheng W, Cai Y, Wei W, Gordy JT, Markham R, Kong W, Zhang W, Yu XF. Disruption of MDA5-mediated innate immune responses by the 3C proteins of coxsackievirus A16, coxsackievirus A6, and enterovirus D68. J Virol. 2017;91(13).
Xiao H, Li J, Yang X, Li Z, Wang Y, Rui Y, Liu B, Zhang W. Ectopic expression of TRIM25 restores RIG-I expression and IFN production reduced by multiple enteroviruses 3C(pro). Virol Sin. 2021;36(6):1363–74.
Wang W, Xiao F, Wan P, Pan P, Zhang Y, Liu F, Wu K, Liu Y, Wu J. EV71 3D protein binds with NLRP3 and enhances the assembly of inflammasome complex. PLoS Pathog. 2017;13(1): e1006123.
Koestner W, Spanier J, Klause T, Tegtmeyer PK, Becker J, Herder V, Borst K, Todt D, Lienenklaus S, Gerhauser I, Detje CN, Geffers R, Langereis MA, Vondran FWR, Yuan Q, van Kuppeveld FJM, Ott M, Staeheli P, Steinmann E, Baumgartner W, Wacker F, Kalinke U. Interferon-beta expression and type I interferon receptor signaling of hepatocytes prevent hepatic necrosis and virus dissemination in Coxsackievirus B3-infected mice. PLoS Pathog. 2018;14(8): e1007235.
Han Y, Wang L, Cui J, Song Y, Luo Z, Chen J, Xiong Y, Zhang Q, Liu F, Ho W, Liu Y, Wu K, Wu J. SIRT1 inhibits EV71 genome replication and RNA translation by interfering with the viral polymerase and 5’UTR RNA. J Cell Sci. 2016;129(24):4534–47.
Wang C, Sun M, Yuan X, Ji L, Jin Y, Cardona CJ, Xing Z. Enterovirus 71 suppresses interferon responses by blocking Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling through inducing karyopherin-alpha1 degradation. J Biol Chem. 2017;292(24):10262–74.
Chen B, Wang Y, Pei X, Wang S, Zhang H, Peng Y. Cellular caspase-3 contributes to EV-A71 2A(pro)-mediated down-regulation of IFNAR1 at the translation level. Virol Sin. 2020;35(1):64–72.
Wang H, Yuan M, Wang S, Zhang L, Zhang R, Zou X, Wang X, Chen D, Wu Z. STAT3 regulates the type I IFN-mediated antiviral response by interfering with the nuclear entry of STAT1. Int J Mol Sci. 2019;20(19):4870.
Sun M, Lin Q, Wang C, Xing J, Yan K, Liu Z, Jin Y, Cardona CJ, Xing Z. Enterovirus A71 2B inhibits interferon-activated JAK/STAT signaling by inducing caspase-3-dependent karyopherin-alpha1 degradation. Front Microbiol. 2021;12: 762869.
Gu Z, Shi W, Zhang L, Hu Z, Xu C. USP19 suppresses cellular type I interferon signaling by targeting TRAF3 for deubiquitination. Future Microbiol. 2017;12:767–79.
Wang T, Wang B, Huang H, Zhang C, Zhu Y, Pei B, Cheng C, Sun L, Wang J, Jin Q, Zhao Z. Enterovirus 71 protease 2Apro and 3Cpro differentially inhibit the cellular endoplasmic reticulum-associated degradation (ERAD) pathway via distinct mechanisms, and enterovirus 71 hijacks ERAD component p97 to promote its replication. PLoS Pathog. 2017;13(10): e1006674.
You L, Chen J, Liu W, Xiang Q, Luo Z, Wang W, Xu W, Wu K, Zhang Q, Liu Y, Wu J. Enterovirus 71 induces neural cell apoptosis and autophagy through promoting ACOX1 downregulation and ROS generation. Virulence. 2020;11(1):537–53.
Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S33-40.
Nguyet LA, Thanh TT, Nhan LNT, Hong NTT, Nhu LNT, Van HMT, Ny NTH, Anh NT, Han DDK, Tuan HM, Huy VQ, Viet HL, Cuong HQ, Thao NTT, Viet DC, Khanh TH, Thwaites L, Clapham H, Hung NT, Chau NVV, Thwaites G, Ha DQ, van Doorn HR, Tan LV. Neutralizing antibodies against enteroviruses in patients with hand, foot and mouth disease. Emerg Infect Dis. 2020;26(2):298–306.
Yang C, Deng C, Wan J, Zhu L, Leng Q. Neutralizing antibody response in the patients with hand, foot and mouth disease to enterovirus 71 and its clinical implications. Virol J. 2011;8:306.
Qiu Q, Zhou J, Cheng Y, Zhou Y, Liang L, Cui P, Xue Y, Wang L, Wang K, Wang H, Li P, Chen J, Li Y, Turtle L, Yu H. Kinetics of the neutralising antibody response in patients with hand, foot, and mouth disease caused by EV-A71: a longitudinal cohort study in Zhengzhou during 2017–2019. EBioMedicine. 2021;68: 103398.
Fang Y, Lian C, Huang D, Xu L. Analysis of clinical related factors of neonatal hand-foot-mouth disease complicated with encephalitis. Front Neurol. 2020;11: 543013.
Chang LY, Hsiung CA, Lu CY, Lin TY, Huang FY, Lai YH, Chiang YP, Chiang BL, Lee CY, Huang LM. Status of cellular rather than humoral immunity is correlated with clinical outcome of enterovirus 71. Pediatr Res. 2006;60(4):466–71.
Lin YW, Chang KC, Kao CM, Chang SP, Tung YY, Chen SH. Lymphocyte and antibody responses reduce enterovirus 71 lethality in mice by decreasing tissue viral loads. J Virol. 2009;83(13):6477–83.
Zhao MQ, Wang LH, Lian GW, Lin ZF, Li YH, Guo M, Chen Y, Liu XM, Zhu B. Characterization of lymphocyte subsets in peripheral blood cells of children with EV71 infection. J Microbiol Immunol Infect. 2020;53(5):705–14.
Li S, Cai C, Feng J, Li X, Wang Y, Yang J, Chen Z. Peripheral T lymphocyte subset imbalances in children with enterovirus 71-induced hand, foot and mouth disease. Virus Res. 2014;180:84–91.
Li Q, Wang Y, Bian Z, Gao Y, Zeng Y, Tang L, Tang T, Tian Y, Guo W. Abnormalities of ILC1 in children with hand, foot and mouth disease during enterovirus 71 infection. Virology. 2020;551:36–45.
Zhang W, Huang Z, Huang M, Zeng J. Predicting severe enterovirus 71-infected hand, foot, and mouth disease: cytokines and chemokines. Mediators Inflamm. 2020;2020:9273241.
Zhang Y, Liu H, Wang L, Yang F, Hu Y, Ren X, Li G, Yang Y, Sun S, Li Y, Chen X, Li X, Jin Q. Comparative study of the cytokine/chemokine response in children with differing disease severity in enterovirus 71-induced hand, foot, and mouth disease. PLoS ONE. 2013;8(6): e67430.
Duan G, Yang H, Shi L, Sun W, Sui M, Zhang R, Wang X, Wang F, Zhang W, Xi Y, Fan Q. Serum inflammatory cytokine levels correlate with hand-foot-mouth disease severity: a nested serial case-control study. PLoS ONE. 2014;9(11): e112676.
Avau A, Mitera T, Put S, Put K, Brisse E, Filtjens J, Uyttenhove C, Van Snick J, Liston A, Leclercq G, Billiau AD, Wouters CH, Matthys P. Systemic juvenile idiopathic arthritis-like syndrome in mice following stimulation of the immune system with Freund’s complete adjuvant: regulation by interferon-gamma. Arthritis Rheumatol. 2014;66(5):1340–51.
Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. 2020;383(23):2255–73.
Lin TY, Hsia SH, Huang YC, Wu CT, Chang LY. Proinflammatory cytokine reactions in enterovirus 71 infections of the central nervous system. Clin Infect Dis. 2003;36(3):269–74.
Wang SM, Lei HY, Yu CK, Wang JR, Su IJ, Liu CC. Acute chemokine response in the blood and cerebrospinal fluid of children with enterovirus 71-associated brainstem encephalitis. J Infect Dis. 2008;198(7):1002–6.
Shen FH, Tsai CC, Wang LC, Chang KC, Tung YY, Su IJ, Chen SH. Enterovirus 71 infection increases expression of interferon-gamma-inducible protein 10 which protects mice by reducing viral burden in multiple tissues. J Gen Virol. 2013;94(Pt 5):1019–27.
Sun Z, Li W, Xu J, Ren K, Gao F, Jiang Z, Ji F, Pan D. Proteomic analysis of cerebrospinal fluid in children with acute enterovirus-associated meningoencephalitis identifies dysregulated host processes and potential biomarkers. J Proteome Res. 2020;19(8):3487–98.
Liang R, Chen S, Jin Y, Tao L, Ji W, Zhu P, Li D, Zhang Y, Zhang W, Duan G. The CXCL10/CXCR3 axis promotes disease pathogenesis in mice upon CVA2 infection. Microbiol Spectr. 2022;10(3): e0230721.
Wang SM, Lei HY, Huang KJ, Wu JM, Wang JR, Yu CK, Su IJ, Liu CC. Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema. J Infect Dis. 2003;188(4):564–70.
Li ML, Hsu TA, Chen TC, Chang SC, Lee JC, Chen CC, Stollar V, Shih SR. The 3C protease activity of enterovirus 71 induces human neural cell apoptosis. Virology. 2002;293(2):386–95.
Li H, Bai Z, Li C, Sheng C, Zhao X. EV71 infection induces cell apoptosis through ROS generation and SIRT1 activation. J Cell Biochem. 2020;121(10):4321–31.
Koyuncu OO, Hogue IB, Enquist LW. Virus infections in the nervous system. Cell Host Microbe. 2013;13(4):379–93.
Lai RH, Chow YH, Chung NH, Chen TC, Shie FS, Juang JL. Neurotropic EV71 causes encephalitis by engaging intracellular TLR9 to elicit neurotoxic IL12-p40-iNOS signaling. Cell Death Dis. 2022;13(4):328.
Barral PM, Sarkar D, Fisher PB, Racaniello VR. RIG-I is cleaved during picornavirus infection. Virology. 2009;391(2):171–6.
Chang Z, Wang Y, Bian L, Liu Q, Long JE. Enterovirus 71 antagonizes the antiviral activity of host STAT3 and IL-6R with partial dependence on virus-induced miR-124. J Gen Virol. 2017;98(12):3008–25.
Chang LY, Lin TY, Hsu KH, Huang YC, Lin KL, Hsueh C, Shih SR, Ning HC, Hwang MS, Wang HS, Lee CY. Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth disease. Lancet. 1999;354(9191):1682–6.
Chang LY, Huang YC, Lin TY. Fulminant neurogenic pulmonary oedema with hand, foot, and mouth disease. Lancet. 1998;352(9125):367–8.
Yan JJ, Wang JR, Liu CC, Yang HB, Su IJ. An outbreak of enterovirus 71 infection in Taiwan 1998: a comprehensive pathological, virological, and molecular study on a case of fulminant encephalitis. J Clin Virol. 2000;17(1):13–22.
Hsueh C, Jung SM, Shih SR, Kuo TT, Shieh WJ, Zaki S, Lin TY, Chang LY, Ning HC, Yen DC. Acute encephalomyelitis during an outbreak of enterovirus type 71 infection in Taiwan: report of an autopsy case with pathologic, immunofluorescence, and molecular studies. Mod Pathol. 2000;13(11):1200–5.
Wang SM, Liu CC, Tseng HW, Wang JR, Huang CC, Chen YJ, Yang YJ, Lin SJ, Yeh TF. Clinical spectrum of enterovirus 71 infection in children in southern Taiwan, with an emphasis on neurological complications. Clin Infect Dis. 1999;29(1):184–90.
Hsu YH, Kao SJ, Lee RP, Chen HI. Acute pulmonary oedema: rare causes and possible mechanisms. Clin Sci (Lond). 2003;104(3):259–64.
Wu JM, Wang JN, Tsai YC, Liu CC, Huang CC, Chen YJ, Yeh TF. Cardiopulmonary manifestations of fulminant enterovirus 71 infection. Pediatrics. 2002;109(2):E26.
Jin Y, Sun T, Zhou G, Li D, Chen S, Zhang W, Li X, Zhang R, Yang H, Duan G. Pathogenesis study of enterovirus 71 using a novel human SCARB2 knock-in mouse model. mSphere. 2021;6(2):e01048-e1120.
Li D, Sun T, Tao L, Ji W, Zhu P, Liang R, Zhang Y, Chen S, Yang H, Jin Y, Duan G. A mouse-adapted CVA6 strain exhibits neurotropism and triggers systemic manifestations in a novel murine model. Emerg Microbes Infect. 2022;11(1):2248–63.
Ji W, Hu Q, Zhang M, Zhang C, Chen C, Yan Y, Zhang X, Chen S, Tao L, Zhang W, Jin Y, Duan G. The disruption of the endothelial barrier contributes to acute lung injury induced by coxsackievirus A2 infection in mice. Int J Mol Sci. 2021;22(18):9895.
Lum LC, Wong KT, Lam SK, Chua KB, Goh AY, Lim WL, Ong BB, Paul G, AbuBakar S, Lambert M. Fatal enterovirus 71 encephalomyelitis. J Pediatr. 1998;133(6):795–8.
Huang FL, Jan SL, Chen PY, Chi CS, Wang TM, Fu YC, Tsai CR, Chang Y. Left ventricular dysfunction in children with fulminant enterovirus 71 infection: an evaluation of the clinical course. Clin Infect Dis. 2002;34(7):1020–4.
Fu YC, Chi CS, Chiu YT, Hsu SL, Hwang B, Jan SL, Chen PY, Huang FL, Chang Y. Cardiac complications of enterovirus rhombencephalitis. Arch Dis Child. 2004;89(4):368–73.
Jan SL, Lin MC, Chan SC, Lee HF, Chen PY, Huang FL. Urine catecholamines in children with severe Enterovirus A71 infection: comparison with paediatric septic shock. Biomarkers. 2019;24(3):277–85.
Fu X, Mao L, Wan Z, Xu R, Ma Y, Shen L, Jin X, Zhang C. High proportion of coxsackievirus B3 genotype A in hand, foot and mouth disease in Zhenjiang, China, 2011–2016. Int J Infect Dis. 2019;87:1–7.
Lasrado N, Reddy J. An overview of the immune mechanisms of viral myocarditis. Rev Med Virol. 2020;30(6):1–14.
Molet L, Saloum K, Marque-Juillet S, Garbarg-Chenon A, Henquell C, Schuffenecker I, Peigue-Lafeuille H, Rozenberg F, Mirand A. Enterovirus infections in hospitals of Ile de France region over 2013. J Clin Virol. 2016;74:37–42.
Ji W, Qin L, Tao L, Zhu P, Liang R, Zhou G, Chen S, Zhang W, Yang H, Duan G, Jin Y. Neonatal murine model of coxsackievirus A2 infection for the evaluation of antiviral therapeutics and vaccination. Front Microbiol. 2021;12: 658093.
Huang X, Zhang X, Wang F, Wei H, Ma H, Sui M, Lu J, Wang H, Dumler JS, Sheng G, Xu B. Clinical efficacy of therapy with recombinant human interferon alpha1b in hand, foot, and mouth disease with enterovirus 71 infection. PLoS ONE. 2016;11(2): e0148907.
Lin H, Huang L, Zhou J, Lin K, Wang H, Xue X, Xia C. Efficacy and safety of interferon-alpha2b spray in the treatment of hand, foot, and mouth disease: a multicenter, randomized, double-blind trial. Adv Virol. 2016;161(11):3073–80.
Abzug MJ. The enteroviruses: problems in need of treatments. J Infect. 2014;68(Suppl 1):S108-114.
Lin JY, Kung YA, Shih SR. Antivirals and vaccines for Enterovirus A71. J Biomed Sci. 2019;26(1):65.
Lin TY, Chang LY, Hsia SH, Huang YC, Chiu CH, Hsueh C, Shih SR, Liu CC, Wu MH. The 1998 enterovirus 71 outbreak in Taiwan: pathogenesis and management. Clin Infect Dis. 2002;34(Suppl 2):S52-57.
Wang SM, Lei HY, Huang MC, Su LY, Lin HC, Yu CK, Wang JL, Liu CC. Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis. J Clin Virol. 2006;37(1):47–52.
Ooi MH, Wong SC, Podin Y, Akin W, del Sel S, Mohan A, Chieng CH, Perera D, Clear D, Wong D, Blake E, Cardosa J, Solomon T. Human enterovirus 71 disease in Sarawak, Malaysia: a prospective clinical, virological, and molecular epidemiological study. Clin Infect Dis. 2007;44(5):646–56.
Cai K, Wang Y, Guo Z, Yu H, Li H, Zhang L, Xu S, Zhang Q. Clinical characteristics and managements of severe hand, foot and mouth disease caused by enterovirus A71 and coxsackievirus A16 in Shanghai, China. BMC Infect Dis. 2019;19(1):285.
Liu J, Qi J. Prevalence and management of severe hand, foot, and mouth disease in Xiangyang, China from 2008–2013. J Med Virol. 2020;33:340.
Jiao W, Tan SR, Huang YF, Mu LH, Yang Y, Wang Y, Wu XE. The effectiveness of different doses of intravenous immunoglobulin on severe hand, foot and mouth disease: a meta-analysis. Med Princ Pract. 2019;28(3):256–63.
Wang SM, Liu CC. Enterovirus 71: epidemiology, pathogenesis and management. Expert Rev Anti Infect Ther. 2009;7(6):735–42.
Yan Z, Shang Y, Li F, Xie F, Qian H, Zhang Y, Yue B. Therapeutic efficacy of phentolamine in the management of severe hand, foot and mouth disease combined with pulmonary edema. Exp Ther Med. 2017;13(4):1403–7.
Wang SM. Milrinone in enterovirus 71 brain stem encephalitis. Front Pharmacol. 2016;7:82.
Yang TT, Huang LM, Lu CY, Kao CL, Lee WT, Lee PI, Chen CM, Huang FY, Lee CY, Chang LY. Clinical features and factors of unfavorable outcomes for non-polio enterovirus infection of the central nervous system in northern Taiwan, 1994–2003. J Microbiol Immunol Infect. 2005;38(6):417–24.
Li XH, Li SJ, Xu Y, Wei D, Shi QS, Zhu QX, Yang T, Ding JB, Tian YM, Huang JH, Wang K, Wen T, Zhang X. Effect of integrated Chinese and Western medicine therapy on severe hand, foot and mouth disease: a prospective, randomized, controlled trial. Chin J Integr Med. 2017;23(12):887–92.
Li X, Zhang C, Shi Q, Yang T, Zhu Q, Tian Y, Lu C, Zhang Z, Jiang Z, Zhou H, Wen X, Yang H, Ding X, Liang L, Liu Y, Wang Y, Lu A. Improving the efficacy of conventional therapy by adding andrographolide sulfonate in the treatment of severe hand, foot, and mouth disease: a randomized controlled trial. Evid Based Complement Alternat Med. 2013;2013: 316250.
Lin H, Zhou J, Lin K, Wang H, Liang Z, Ren X, Huang L, Xia C. Efficacy of Scutellaria baicalensis for the treatment of hand, foot, and mouth disease associated with encephalitis in patients infected with EV71: a multicenter, retrospective analysis. Biomed Res Int. 2016;2016:5697571.
Wang C, Cui Y, Zhu Y, Wang F, Rong Q, Zhang Y. Continuous hemodiafiltration as a rescue therapy for patients with cardiopulmonary failure caused by enterovirus-71: a retrospective observational study in a PICU. BMC Infect Dis. 2019;19(1):866.
Jones E, Pillay TD, Liu F, Luo L, Bazo-Alvarez JC, Yuan C, Zhao S, Chen Q, Li Y, Liao Q, Yu H, Rogier van Doorn H, Sabanathan S. Outcomes following severe hand foot and mouth disease: a systematic review and meta-analysis. Eur J Paediatr Neurol. 2018;22(5):763–73.
Ji H, Fan H, Ai J, Shi C, Bi J, Chen YH, Lu XP, Chen QH, Tian JM, Bao CJ, Zhang XF, Jin Y. Neurocognitive deficits and sequelae following severe hand, foot, and mouth disease from 2009 to 2017, in JiangSu Province, China: a long-term follow-up study. Int J Infect Dis. 2022;115:245–55.
Prager P, Nolan M, Andrews IP, Williams GD. Neurogenic pulmonary edema in enterovirus 71 encephalitis is not uniformly fatal but causes severe morbidity in survivors. Pediatr Crit Care Med. 2003;4(3):377–81.
Chang LY, Huang LM, Gau SS, Wu YY, Hsia SH, Fan TY, Lin KL, Huang YC, Lu CY, Lin TY. Neurodevelopment and cognition in children after enterovirus 71 infection. N Engl J Med. 2007;356(12):1226–34.
Tsou YA, Cheng YK, Chung HK, Yeh YC, Lin CD, Tsai MH, Chang JS. Upper aerodigestive tract sequelae in severe enterovirus 71 infection: predictors and outcome. Int J Pediatr Otorhinolaryngol. 2008;72(1):41–7.
Liang L, Cheng Y, Li Y, Shang Q, Huang J, Ma C, Fang S, Long L, Zhou C, Chen Z, Cui P, Lv N, Lou P, Cui Y, Sabanathan S, van Doorn HR, Luan R, Turtle L, Yu H. Long-term neurodevelopment outcomes of hand, foot and mouth disease inpatients infected with EV-A71 or CV-A16, a retrospective cohort study. Emerg Microbes Infect. 2021;10(1):545–54.
Dalman C, Allebeck P, Gunnell D, Harrison G, Kristensson K, Lewis G, Lofving S, Rasmussen F, Wicks S, Karlsson H. Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. Am J Psychiatry. 2008;165(1):59–65.
Gau SS, Chang LY, Huang LM, Fan TY, Wu YY, Lin TY. Attention-deficit/hyperactivity-related symptoms among children with enterovirus 71 infection of the central nervous system. Pediatrics. 2008;122(2):e452-458.
Pedersen EMJ, Kohler-Forsberg O, Nordentoft M, Christensen RHB, Mortensen PB, Petersen L, Benros ME. Infections of the central nervous system as a risk factor for mental disorders and cognitive impairment: a nationwide register-based study. Brain Behav Immun. 2020;88:668–74.
Teoh HL, Mohammad SS, Britton PN, Kandula T, Lorentzos MS, Booy R, Jones CA, Rawlinson W, Ramachandran V, Rodriguez ML, Andrews PI, Dale RC, Farrar MA, Sampaio H. Clinical characteristics and functional motor outcomes of enterovirus 71 neurological disease in children. JAMA Neurol. 2016;73(3):300–7.
Lian ZY, Li HH, Zhang B, Dong YH, Deng WX, Liu J, Luo XN, Huang B, Liang CH, Zhang SX. Neuro-magnetic resonance imaging in hand, foot, and mouth disease: finding in 412 patients and prognostic features. J Comput Assist Tomogr. 2017;41(6):861–7.
Kim YJ, Kim TG. Pseudomembranous conjunctivitis with hand, foot and mouth disease in a pregnant woman: a case report. BMC Ophthalmol. 2021;21(1):113.
Haamann P, Kessel L, Larsen M. Monofocal outer retinitis associated with hand, foot, and mouth disease caused by coxsackievirus. Am J Ophthalmol. 2000;129(4):552–3.
Ng SK, Ebneter A, Gilhotra JS. Atypical findings in delayed presentation of unilateral acute idiopathic maculopathy. Int Ophthalmol. 2013;33(4):387–9.
Wei SH, Huang YP, Liu MC, Tsou TP, Lin HC, Lin TL, Tsai CY, Chao YN, Chang LY, Hsu CM. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346.
Chiu HH, Liu MT, Chung WH, Ko YS, Lu CF, Lan CE, Lu CW, Wei KC. The mechanism of onychomadesis (nail shedding) and beau’s lines following hand-foot-mouth disease. Viruses. 2019;11(6):522.
Akpolat ND, Karaca N. Nail changes secondary to hand-foot-mouth disease. Turk J Pediatr. 2016;58(3):287–90.
Long DL, Zhu SY, Li CZ, Chen CY, Du WT, Wang X. Late-onset nail changes associated with hand, foot, and mouth disease: a clinical analysis of 56 cases. Pediatr Dermatol. 2016;33(4):424–8.
Abramovici G, Keoprasom N, Winslow CY, Tosti A. Onycholysis and subungual haemorrhages in a patient with hand, foot and mouth disease. Br J Dermatol. 2014;170(3):748–9.
Gan XL, Zhang TD. Onychomadesis after hand-foot-and-mouth disease. CMAJ. 2017;189(7):E279.
Tan ZH, Koh MJ. Nail shedding following hand, foot and mouth disease. Arch Dis Child. 2013;98(9):665.
Yuksel S, Evrengul H, Ozhan B, Yuksel G. Onychomadesis-a late complication of hand-foot-mouth disease. J Pediatr. 2016;174:274.
Lee ZM, Huang YH, Ho SC, Kuo HC. Correlation of symptomatic enterovirus infection and later risk of allergic diseases via a population-based cohort study. Medicine (Baltimore). 2017;96(4): e5827.
Yeh JJ, Lin CL, Hsu WH. Effect of enterovirus infections on asthma in young children: a national cohort study. Eur J Clin Invest. 2017;47(12):e12844.
Broccolo F, Drago F, Ciccarese G, Genoni A, Porro A, Parodi A, Chumakov K, Toniolo A. Possible long-term sequelae in hand, foot, and mouth disease caused by Coxsackievirus A6. J Am Acad Dermatol. 2019;80(3):804–6.
Weng KP, Cheng-Chung Wei J, Hung YM, Huang SH, Chien KJ, Lin CC, Huang SM, Lin CL, Cheng MF. Enterovirus infection and subsequent risk of Kawasaki disease: a population-based cohort study. Pediatric Infect Dis J. 2018;37(4):310–5.
Lin JN, Lin CL, Yang CH, Lin MC, Lai CH, Lin HH, Kao CH. Risk of nephrotic syndrome following enteroviral infection in children: a nationwide retrospective cohort study. PLoS ONE. 2016;11(8): e0161004.
Lin JN, Lin CL, Lin MC, Lai CH, Lin HH, Yang CH, Sung FC, Kao CH. Risk of leukaemia in children infected with enterovirus: a nationwide, retrospective, population-based, Taiwanese-registry, cohort study. Lancet Oncol. 2015;16(13):1335–43.
Foo DG, Alonso S, Phoon MC, Ramachandran NP, Chow VT, Poh CL. Identification of neutralizing linear epitopes from the VP1 capsid protein of Enterovirus 71 using synthetic peptides. Virus Res. 2007;125(1):61–8.