Materiały źródłowe

• #1 Hand, Foot, and Mouth Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK431082/

  Hand, foot, and mouth disease (HFMD) is a common viral illness that usually affects infants and children but can also affect adults. The cause of HFMD is coxsackievirus A type 16 in most cases, but many other strains of coxsackieviruses and Enteroviruses can also cause the infection. The coxsackievirus is a member of the Picornaviridae family, which includes non-enveloped single-stranded RNA viruses. […] The spread of the human enterovirus is mediated by oral ingestion of the shed virus from infected hosts’ gastrointestinal or upper respiratory tract or via vesicle fluid or oral secretions. Patients tend to be most infectious in the first week of the disease, with an incubation period ranging between 3 to 6 days. After ingestion, the virus replicates in the lower intestine and pharynx lymphoid tissue and spreads to the regional lymph nodes. This can be spread to multiple organs, including the central nervous system, heart, liver, and skin.

• #2 Hand-Foot-and-Mouth Disease: Rapid Evidence Review | AAFP

  https://www.aafp.org/pubs/afp/issues/2019/1001/p408.html

  Hand-foot-and-mouth disease is caused by human enteroviruses and coxsackieviruses. Outbreaks can occur in the spring to fall and are common in North America, and most cases occur in patients younger than 10 years. Hand-foot-and-mouth disease is transmitted by fecal-oral, oral-oral, and respiratory droplet contact. Patients present with a low-grade fever, a maculopapular or papulovesicular rash on the hands and soles of the feet, and painful oral ulcerations. Lesions usually resolve in seven to 10 days; however, in rare cases, patients may have neurologic or cardiopulmonary complications. […] Hand-foot-and-mouth disease is a common viral disease that presents in primary care. This article presents a brief summary and review of the etiology, clinical features, diagnosis, prognosis, and evidence for the care of patients with hand-foot-and-mouth disease.

• #2 Hand-Foot-and-Mouth Disease: Rapid Evidence Review | AAFP

  https://www.aafp.org/pubs/afp/issues/2019/1001/p408.html

  The diagnosis of hand-foot-and-mouth disease should be based on presentation of a maculopapular or papulovesicular rash on the hands and soles of the feet and painful oral ulcerations. […] The patient is most infectious during the first week of illness; however, an active virus may be present in the stool for up to four to eight weeks. […] Hand-foot-and-mouth disease is a clinical diagnosis based on the presentation of a low-grade fever with a maculopapular or papulovesicular rash on the hands and soles of the feet and by painful oral ulcerations. […] Rare neurologic complications can occur such as aseptic meningitis, acute flaccid paralysis, and encephalomyelitis, especially with enterovirus 71. […] Management is supportive and directed toward the relief of pain, lowering of fever, and adequate oral hydration because of the self-limiting nature of hand-foot-and-mouth disease.

• #3 Immunopathogenesis and Virus–Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5713468/

  Enterovirus 71 (EV71) is a global infectious disease that affects millions of people. The virus is the main etiological agent for hand, foot, and mouth disease with outbreaks and epidemics being reported globally. […] Despite on-going efforts, little is known about the pathogenesis of EV71, how the host immune system responds to the virus and the molecular mechanisms behind these responses. Moreover, current animal models remain limited, because they do not recapitulate similar disease patterns and symptoms observed in humans. In this review the role of the host-viral interactions of EV71 are discussed together with the various models available to examine: how EV71 utilizes its proteins to cleave host factors and proteins, aiding virus replication; how EV71 uses its own viral proteins to disrupt host immune responses and aid in its immune evasion. These discoveries along with others, such as the EV71 crystal structure, have provided possible targets for treatment and drug interventions.

• #3 Immunopathogenesis and Virus–Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5713468/

  Enterovirus 71 has been found all over the world with different symptoms and clinical manifestations seen during different outbreaks. […] However, there is still much that is unknown about the interactions of this virus and more studies are required in this area to fully unravel the complete mechanism of EV71. […] The main route of transmission is through the fecal-oral route, however, it can also be spread through contact with virally contaminated vesicular fluid, surfaces, fomites and oral secretions as well as respiratory droplets. […] Evidence suggests that the initial phase of replication occurs in lymphoid tissues of the tonsillar crypt and in the Peyers patches of the small intestine. The virus undergoes further replication in the adjacent lymph nodes and this often leads to a mild viremia. In the majority of patients, viral infection is controlled at this point and the patients remain asymptomatic. However, if the viral infection is not controlled, the virus will then reaches high titres, and disseminate to the skin and mucous membranes to cause HFMD. In a small proportion of patients, EV71 can also enter the CNS and cause severe complications.

• #3 Immunopathogenesis and Virus–Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5713468/

  Viral proteases are vital for the processing of most viral polyproteins. EV71 relies on its two proteases, 2A and 3C, to cleave viral protein precursors into their functional forms. […] These proteases not only cleave viral proteins, they can also cleave host proteins to aid in immune evasion. […] Enterovirus 71’s ability to interrupt, intercept and disrupt the host immune response is critical to the survival and propagation of the virus, and whilst this has a negative effect for the patients, it gives an insight into possible areas that could be targeted to disrupt virus biology.

• #3 Immunopathogenesis and Virus–Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5713468/

  After gaining entry to the brain and CNS, EV71 causes neuronal and astrocytic cell death, which in turn leads to the CNS immune and inflammatory response and brainstem encephalitis. […] This leads to the mass release of certain cytokines, known as a cytokine storm. There have been many cytokines implicated in EV71 brainstem encephalitis which have been reported to be significantly increased in patients that suffer from pulmonary oedema. […] Enterovirus 71 is mainly detected via the RLRs; RIG-I, melanoma differentiation-associated protein 5 (MDA5), and TLR3. The binding of EV71 to the RLRs sets off a signaling cascade activating mitochondrial antiviral-signalling protein (MAVS). […] This phosphorylation causes these two IRF molecules to dimerise, causing the formation of hetero- and homodimers, which translocate to the nucleus and bind to interferon stimulate response elements (ISREs). This leads to the expression of type I interferon genes.

• #4 Hand-foot-and-mouth disease – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/hand-foot-and-mouth-disease/symptoms-causes/syc-20353035

  Hand-foot-and-mouth disease is most commonly caused by a coxsackievirus. […] The most common cause of hand-foot-and-mouth disease is infection from coxsackievirus 16. This coxsackievirus belongs to a group of viruses called nonpolio enteroviruses. Other types of enteroviruses also may cause hand-foot-and-mouth disease. […] Most people get the coxsackievirus infection and hand-foot-and-mouth disease through the mouth. The illness spreads by person-to-person contact with an infected person’s: Nose secretions or throat discharge, Saliva, Fluid from blisters, Stool, Respiratory droplets sprayed into the air after a cough or sneeze. […] Hand-foot-and-mouth disease is most common in children in child care. That’s because young children need frequent diaper changes and help using the toilet. They also tend to put their hands in their mouths.

• #4 Hand-foot-and-mouth disease – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/hand-foot-and-mouth-disease/symptoms-causes/syc-20353035

  Your child is most contagious during the first week of having hand-foot-and-mouth disease. But the virus can remain in the body for weeks after the symptoms go away. That means your child still can infect others. […] Hand-foot-and-mouth disease typically affects young children, but anyone can get it. […] Sometimes the enterovirus that causes hand-foot-and-mouth disease enters the brain and causes serious complications: Viral meningitis. This is a rare infection and inflammation of the membranes (meninges) and cerebrospinal fluid surrounding the brain and spinal cord. Encephalitis. This severe and potentially life-threatening disease involves brain inflammation. Encephalitis is rare.

• #5 Hand, foot and mouth disease (HFMD) | Epidemic Control Toolkit

  https://epidemics.ifrc.org/manager/disease/hand-foot-and-mouth-disease-hfmd

  HFMD infects children in particular and is often caused by a group of Enteroviruses, Coxsackie and Enterovirus 71 being the most common. […] Rarely, HFMD can lead to serious complications including viral meningitis and other central nervous system conditions such as encephalitis and paralysis and/or fluid in the lungs (pulmonary oedema). […] Coxsackievirus A16 and other coxsackieviruses, Enterovirus 71 (EV71). […] People with HFMD are usually most contagious during the first week of illness. For EV71, viral shedding from the throat can occur up to two weeks after an acute EV71 infection, and virus can be isolated from stools for up to 11 weeks. […] Most cases of the disease are harmless. But complications may occur with neurological symptoms such as meningitis, encephalitis and polio-like paralysis.

• #6 Hand-Foot-and-Mouth Disease in Adults – Clinical Advisor

  https://www.clinicaladvisor.com/home/topics/infectious-diseases-information-center/hand-foot-and-mouth-disease-in-adults/

  Although affected people are most contagious during the first week, they can remain infectious for approximately 4 to 8 weeks after the onset of illness because of residual viral shedding in stool. […] HFMD is usually diagnosed by history and physical examination. […] The rash usually consists of papules and vesicles, 2 to 6 mm in size, on the gingiva, buccal mucosa, tongue, and pharynx. Lesions may also be found on the skin of the hands, feet, buttocks, and genitalia. […] A culture specimen can be sent for laboratory analysis, but this is not always readily available and is rarely done. The virus is found and can be cultured from skin or oral lesions or from stool specimens. […] Polymerase chain reaction (PCR) and microarray technology can be used to identify the causative virus. […] The treatment of HFMD is supportive and includes consideration of reducing transmission.

• #6 Hand-Foot-and-Mouth Disease in Adults – Clinical Advisor

  https://www.clinicaladvisor.com/home/topics/infectious-diseases-information-center/hand-foot-and-mouth-disease-in-adults/

  HFMD is a communicable disease caused by enteroviruses most commonly coxsackievirus (CV) A16 or enterovirus (EV) 71.1 It was first described in 1958 during an outbreak in Toronto, Ontario, Canada, and most commonly occurs in children. HMFD is transmitted via fecal-oral, oral-oral, and respiratory routes. The virus can be found in the saliva, sputum, nasal mucus, blister fluid, and stool of an infected person. The virus quickly spreads through close personal contact, droplets in the air, contact with feces, or contact with contaminated objects, such as doorknobs and toys. Less commonly, HFMD can be transmitted if someone swallows poorly treated water in a swimming pool that has been contaminated with stool containing the virus. […] The virus has an incubation period of 4 to 6 days, after which fever, malaise, sore throat with vesicles, and then hand vesicles develop. Viremia occurs as the virus replicates at sites, such as the skin, mucous membranes, central nervous system, and other organs.

• #7 Hand, Foot And Mouth Disease

  https://www.pediatriconcall.com/articles/alternative-medicine/hand-foot-and-mouth-disease/hand-foot-and-mouth-disease-introduction

  The virus particles are implanted initially in the buccal and ileal mucosa. From here, they spread into the bloodstream via the regional lymph nodes. Within 72 hours, viremia is established and the virus reaches the skin and oral mucosa causing the characteristic lesions. […] The disease occurs both sporadically as well as in the form of epidemics.

• #8 Current status of hand-foot-and-mouth disease | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-023-00908-4

  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. 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. 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. 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. 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. Among them, retrograde axonal transport is currently considered as the main pathway for the EVs to invade CNS. 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.

• #8 Current status of hand-foot-and-mouth disease | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-023-00908-4

  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. 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. 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. hSCARB2 also induces EV-A71 uncoating under acidic conditions. Additionally, the human tryptophan-tRNA synthetase (hWARS) induced by interferon (IFN)- 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.

• #9 Hand-foot-and-mouth disease pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Hand-foot-and-mouth_disease_pathophysiology

  HFMD outbreaks typically occur during summer and autumn months in the United states. […] The exact pathogenesis of HFMD is not fully understood. The pathogenesis of HFMD caused by EV71 includes: EV71 replicates in the lymphoid tissues of the oropharyngeal cavity(tonsils), small bowel(payer’s patches) and regional lymph nodes(deep cervical and mesenteric nodes) leading to a mild viremia. Most of the viruses are destroyed in these lymphatic tissues and the patients remain asymptomatic. Patients present with clinical symptoms when the virus disseminates to other organs like reticuloendothelial system(liver, spleen, bone marrow, lymph node), heart, lung, pancreas, skin, mucous membranes and CNS. […] The pathogenesis of EV71 depends on following factors: Viral virulence factors are still unknown. […] The relationship between pathogenesis and distribution of viral entry receptors (scavenger receptor B2, P-selectin glycoprotein ligand-1 and sialic acid-linked glycans) and host factors, such as gender and age group, is unknown.

• #10 Hand-Foot-and-Mouth Disease (HFMD): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/802260-overview

  Infection generally occurs via the fecal-oral route or via contact with skin lesions and oral secretions. Viremia develops, followed by invasion of the skin and mucous membranes. Widespread apoptosis likely results in the characteristic lesion formation. […] Hand-foot-and-mouth disease caused by EV-71 has a higher incidence of neurologic involvement, including a poliolike syndrome, aseptic meningitis, encephalitis, encephalomyelitis, acute cerebellar ataxia, acute transverse myelitis, Guillain-Barr syndrome, opsomyoclonus syndrome, and benign intracranial hypertension. These neurologic complications have been attributed to either immunopathology or virus-induced damage to gray matter. […] There appears to be a strong association between severe illness and coxsackievirus A6 and enterovirus -A71 infections.

• #11 Hand, Foot, and Mouth disease (HFMD): Enteroviral vesicular stomatitis – DermNet

  https://dermnetnz.org/topics/hand-foot-and-mouth-disease

  Enteroviral vesicular stomatitis (HFMD) is usually caused by the Coxsackie virus, most commonly the A16 subtype. […] Enterovirus 71 infection is associated with more severe infections that may involve the heart, lungs, and can also cause inflammation of the lining of the brain (meningitis). […] Transmission occurs via direct contact with blister fluid or droplets spread from the mouth. […] The virus can be shed in faeces and saliva for several weeks. […] Serious enteroviral infection can lead to: widespread blistering, enteritis, myocarditis, inflammation of the brain and or the lining of the brain (meningoencephalitis), loss of nerve function in a limb (acute flaccid paralysis), pulmonary oedema and pneumonia, haemorrhagic conjunctivitis. […] Meningoencephalitis, thrombocytopenia, disseminated intravascular coagulopathy, cardiomyopathy and hepatitis in the newborn have rarely been described. […] Skin biopsy of a blister shows acral skin with lymphocytic infiltrates at the epidermis. The infiltrate is associated with keratinocyte apoptosis in early lesions. […] See hand, foot, and mouth disease pathology for more information.

• #12 Foot-and-Mouth Disease (FMD) | Iowa State University

  https://vetmed.iastate.edu/vdpam/about/focus-areas/swine/swine-disease-manual/index-diseases/foot-mouth-disease

  Foot and mouth disease virus adheres to the mucosa of the respiratory tract, the usual site of virus entry. Macrophages are believed to transport virus to secondary sites that include epithelium, mucosa and myocardium. In secondary sites, the virus replicates, then a marked viremia develops and the virus infects epithelium at many other sites. Within a few days vesicles develop, usually at sites of mechanical stress. In swine, common vesicle sites include the snout, mouth, tongue, and especially the feet. In cattle, the FMD virus affects the mammary gland epithelium and virus is shed in milk for a prolonged period. Although unproven, similar shedding may occur in swine. […] The FMD virus often causes severe myocardial necrosis in neonatal and young pigs. This often leads to sudden deaths from myocardial failure. The mottled myocardial lesions sometimes are referred to as tiger-heart lesions and are useful in diagnosis.

• #13 A case of sore throat and vesicular hand lesions

  https://www1.racgp.org.au/ajgp/2024/march/a-case-of-sore-throat-and-vesicular-hand-lesions

  Hand, foot and mouth disease is a highly contagious viral infection that primarily affects children under the age of five years. However, cases have also been reported in adults. Hand, foot and mouth disease is caused by enteroviruses, most commonly coxsackievirus A16 and enterovirus 71. Hand, foot and mouth disease typically presents with symptoms such as fever, sore throat and a characteristic rash on the hands, feet and mouth. The rash can be macular, papular or vesicular in nature and lesions might also be present on the buttocks and genitals. […] The exact reasons why hand, foot and mouth disease affects adults less severely than children are not fully understood. However, it is believed that adults might have some level of immunity from previous exposure to enteroviruses, which can provide some protection against the disease.

• #13 A case of sore throat and vesicular hand lesions

  https://www1.racgp.org.au/ajgp/2024/march/a-case-of-sore-throat-and-vesicular-hand-lesions

  Diagnosis is usually based on clinical presentation. In some cases, laboratory testing (throat swabs or stool polymerase chain reaction) might be done to confirm the presence of the enterovirus, though this is rarely done. […] Management of hand, foot and mouth disease in adults is similar to that in children. Adults with hand, foot and mouth disease should focus on relieving symptoms and preventing the spread of the virus. This can be done by practising good hygiene, such as regularly washing hands with soap and water, using hand sanitisers and avoiding close contact with others who might be susceptible to the virus. […] There is no specific treatment for hand, foot and mouth disease in adults because it is a self-limiting condition that resolves on its own within 7-10 days.

• #14 Human enterovirus 71 and hand, foot and mouth disease | Epidemiology & Infection | Cambridge Core

  https://www.cambridge.org/core/journals/epidemiology-and-infection/article/human-enterovirus-71-and-hand-foot-and-mouth-disease/21C9DD3DD0FE6DEE803F8F911BB8942E

  Hand, foot and mouth disease (HFMD) is generally a benign febrile exanthematous childhood disease caused by human enteroviruses. […] Serious outbreaks with neurological and cardiopulmonary complications caused by human enterovirus 71 (HEV-71) seem to be commoner in the Asian Pacific region than elsewhere in the world. […] Vaccine development could be hampered by the general mildness of the illness and rapid genetic evolution of the virus. […] Monitoring of this disease and its epidemiology in the densely populated Asia Pacific epicentre is important for the detection of emerging epidemics due to enteroviruses. […] At least three human cellular receptors of HEV-71 have recently been identified. […] Cells expressing the ligand include circulating leukocytes, dendritic cells, tissue macrophages (such as those in liver, lung, bowel, and Langerhans cells in the skin) and myeloid progenitor cells. […] The ubiquity of HEV-71 receptors in different organs may account for the systemic nature of HEV-71 infection in severe cases and the predilection for involvement of the central nervous system (CNS).

• #14 Human enterovirus 71 and hand, foot and mouth disease | Epidemiology & Infection | Cambridge Core

  https://www.cambridge.org/core/journals/epidemiology-and-infection/article/human-enterovirus-71-and-hand-foot-and-mouth-disease/21C9DD3DD0FE6DEE803F8F911BB8942E

  Both polioviruses and HEV-71 are neurotropic, thus explaining their propensity to cause neurological complications such as acute flaccid paralysis. […] The virus may enter the CNS via the motor pathway of the peripheral nervous system, possibly through retrograde axonal transport. […] Experimental evidence suggested that HEV-71-infected cells (including neurons and Vero cells) undergo apoptosis through a variety of pathways. […] The inflammatory response is characterized by perivascular mononuclear cell infiltration. […] The myocardium showed coagulative myocytolysis and myofibrillar degeneration, which suggested that the pathogenesis is one of neurogenic cardiac damage rather than direct involvement by infection. […] The rapid progression to neurological and cardiopulmonary complications after the onset of HEV-71-associated disease (usually within 3-5 days) suggests that viral replication and direct cytopathic effects of the virus on the host cells are important in the pathogenesis of severe manifestations. […] There is currently no specific antiviral approved for HEV-71 infections.

• #14 Human enterovirus 71 and hand, foot and mouth disease | Epidemiology & Infection | Cambridge Core

  https://www.cambridge.org/core/journals/epidemiology-and-infection/article/human-enterovirus-71-and-hand-foot-and-mouth-disease/21C9DD3DD0FE6DEE803F8F911BB8942E

  With the observation that neutralizing antibodies offer protection against infection and mortality in humans and animal models, vaccination is an obvious pathway towards prevention of HEV-71 infection and epidemics. […] The generally mild disease manifestations, prevalence and lack of monitoring in some developing countries means the incentive for vaccine development could be low.

• #15 The Pathogenesis of Foot-and-Mouth Disease Virus Infection:…

  https://sciendo.com/it/article/10.2478/aite-2024-0013?tab=article

  The entry of FMDV into host cells is mediated by the interaction between the viral capsid proteins and the cellular receptors. FMDV can use different receptors, depending on the host species and the virus strain. The main receptors for FMDV are integrins, which are heterodimeric transmembrane glycoproteins that mediate cell-cell and cell-matrix adhesion. […] The binding of FMDV to receptors triggers a series of events that lead to the internalization of the virus into endosomes. FMDV can enter cells by different endocytic pathways, such as clathrin-mediated endocytosis, caveolae-mediated endocytosis, macropinocytosis, or lipid raft-dependent endocytosis. […] The replication of FMDV takes place in the cytoplasm of infected cells. The viral RNA serves as both mRNA and template for RNA synthesis. The viral RNA is translated into a polyprotein by host ribosomes in a cap-independent manner. The polyprotein is then processed by viral proteases into structural and non-structural proteins. The structural proteins form pentamers that assemble into empty capsids or progeny virions in association with viral RNA.

• #15 The Pathogenesis of Foot-and-Mouth Disease Virus Infection:…

  https://sciendo.com/it/article/10.2478/aite-2024-0013?tab=article

  The exit of FMDV from infected cells can occur by two mechanisms: cell lysis or cell-to-cell transmission. Cell lysis is the result of the cytopathic effect of FMDV, which causes the disruption of the plasma membrane and the release of viral particles into the extracellular space. Cell-to-cell transmission is a more efficient and rapid way of spreading FMDV within a tissue or an organism. […] FMDV has indeed developed numerous strategies to evade the immune response, especially the type I IFN response. Viral proteins target this innate antiviral response at different levels, ranging from blocking the detection of viral RNAs to inhibiting the expression of ISGs. […] FMDV can modulate the expression and function of ISGs, such as PKR, OAS, RNase L, MxA, viperin, and tetherin. Additionally, FMDV can affect the adaptive immune response by reducing the surface expression of MHC class I molecules on infected cells, causing transient lymphopenia in swine, and impairing the maturation and function of dendritic cells.

• #15 The Pathogenesis of Foot-and-Mouth Disease Virus Infection:…

  https://sciendo.com/it/article/10.2478/aite-2024-0013?tab=article

  The pathogenesis of FMDV infection involves complex interactions between the virus and the host immune system at different levels: cellular, tissue, organ, and systemic. The virus enters the host through the respiratory or oral mucosa and replicates in the epithelial cells, causing cell lysis and tissue damage. The virus then spreads through the bloodstream (viremia) to other epithelial sites, where it causes secondary vesicles. The host immune system responds to the viral infection by activating both innate and adaptive immune mechanisms, such as interferons (IFNs), cytokines, natural killer cells, macrophages, dendritic cells, B cells, and T cells. However, FMDV has evolved several strategies to evade immune recognition and elimination by the host. These include antigenic variation, receptor switching, immune suppression, and subversion of innate and adaptive responses. Understanding the pathogenesis of FMDV infection and the mechanisms of immune evasion employed by the virus is essential for developing effective vaccines and therapeutics against this important animal disease.

• #16 The immune mechanism of intestinal tract Toll-like receptor in mediating EV71 virus type severe hand-foot-and-mouth disease and the MAPK pathway

  https://www.spandidos-publications.com/10.3892/etm.2017.4245

  Immunological response is thought to play a crucial role in the development of a severe hand-foot-and-mouth disease (HFMD) infection in children, but the mechanisms remain largely unknown. […] The present study was designed to analyze the immune mechanisms of intestinal TLRs and the MAPK signaling pathway after severe HFMD EV71 infection. […] The immune function of organisms are activated after EV71 infection and secreted cytokine levels by a variety of immune cells increase. […] TLRs are considered the most important pattern recognition molecules in vivo, after a viral infection, a conformational change occurs in them, which leads to activation of a signal transduction through the MyD88-dependent and MyD88-independent pathways. […] The present study found that the expression levels of the TLR3, TLR4, TLR7 and TLR8 mRNAs in PBMCs of children in the severe disease group were significantly higher than those in the mild disease and the control groups.

• #16 The immune mechanism of intestinal tract Toll-like receptor in mediating EV71 virus type severe hand-foot-and-mouth disease and the MAPK pathway

  https://www.spandidos-publications.com/10.3892/etm.2017.4245

  Following TLR activation a cascade of events occurs leading especially to MAPK activation. […] The present study found that the expression levels of ERK, JNK and p38 mRNA in PBMCs of pediatric patients, in the severe disease group, were significantly higher than those in the mild disease group and the control group, and, that the TLR3, TLR4, TLR7 and TLR8 mRNA levels in PBMCs were positively correlated with ERK, JNK and p38 mRNA levels. […] From these results, it looks as though the high expression levels of TLR3, TLR4, TLR7 and TLR8 in severe EV71 HFMD regulate cytokine expression by the MAPK pathway and the resulting exaggerated response causes a severe and dangerous syndrome.

• #17 Pathogenic characteristics of hand, foot and mouth disease in Shaanxi Province, China, 2010–2016 | Scientific Reports

  https://www.nature.com/articles/s41598-020-57807-z

  EV-A71 was more frequently detected in deaths and severe cases than in mild cases, while CV-A16 was more frequently detected in mild cases than in severe cases, no CV-A16 was detected in deaths. […] The VP1 coding region contains many important neutralization epitopes and was demonstrated to help identify different serotypes of EVs. […] The phylogenetic tree showed that CV-A6 could be divided into 4 genotypes A to D, and D genotype could be further divided into 3 sub-genotypes D1-D3. Most of the CV-A6 isolates epidemic in China after 2012 belonged to the D3 sub-genotype, and clustered with the international isolates, the results revealed that D3 was the predominant sub-genotype circulated and spread in Europe and Asia during recent years. […] Therefore, we have reason to believe that CV-A6 has been popular and became the dominant pathogen causing HFMD in Shaanxi provinces in 2013 and 2015 due to the importation of European CV-A6.

• #17 Pathogenic characteristics of hand, foot and mouth disease in Shaanxi Province, China, 2010–2016 | Scientific Reports

  https://www.nature.com/articles/s41598-020-57807-z

  Hand, foot, and mouth disease (HFMD) is a common childhood illness caused by enteroviruses. […] The pathogen spectrum of HFMD has changed in 7 years, and the major serotypes EV-A71, CV-A16 and CV-A6 alternated or co-circulated. […] The etiological surveillance of HFMD in Shaanxi Province revealed that the type of pathogens were differenced during 20102016. In 2010, the pathogen of HFMD was the co-epidemic of EV-A71 and CV-A16. In the period of 2011 to 2012, EV-A71 was the major dominant pathogen. In 2013, the proportion of CV-A6 was significantly increased to 40.85%, exceeding that of EV-A71 becoming the dominant pathogen. In 2014, EV-A71 returned to the dominant pathogen of 50.91%. In 2015, CV-A6 was still the main pathogen of HFMD, accounting for 39.49%. In 2016, EV-A71 became the dominant pathogen of HFMD again, accounting for 46.68%. The pathogen spectrum of HFMD in Shaanxi Province varied, the main serotypes appeared alternately, or simultaneously epidemic, presenting a dynamic change.

• #18 Evolving pathogen trends and spatial–temporal dynamics of hand, foot, and mouth disease in Fengxian District, Shanghai (2009–2022) | Scientific Reports

  https://www.nature.com/articles/s41598-024-71389-0

  Hand, foot, and mouth disease (HFMD) is a prevalent acute infectious disease caused by enteroviruses, presenting substantial public health challenges in Shanghai, especially among children. […] The dynamic nature of HFMDs etiology necessitates an ongoing evaluation of its epidemiological and virological trends to inform effective control strategies. […] The findings indicate a distinct seasonal incidence of HFMD in Fengxian District. […] Moreover, the evolving viral landscape warrants accelerated efforts in vaccine development against new strains to reduce HFMD incidence. […] The transmission pathways of HFMD are complex, significantly contributing to the difficulty of controlling outbreaks. […] Initially, EV71 was the predominant pathogen. However, in recent years, there has been a notable increase in the incidence of CoxA6 and CoxA16, which have now surpassed EV71 as the leading pathogens.

• #18 Evolving pathogen trends and spatial–temporal dynamics of hand, foot, and mouth disease in Fengxian District, Shanghai (2009–2022) | Scientific Reports

  https://www.nature.com/articles/s41598-024-71389-0

  This shift indicates a significant change in the pathogen composition within this region. […] The dominance among HFMD pathogens shifted over the study period. Prior to 2016, EV71 and CoxA16 were the most common strains. However, post-2016, CoxA6 cases increased significantly, overtaking EV71 in prevalence. […] This evolution in pathogen composition within Fengxian District mirrors broader trends observed in various other regions across China, underlining the importance of expanding pathogen monitoring efforts.

• #19 Risk factors for death from hand–foot–mouth disease: a meta-analysis | Epidemiology & Infection | Cambridge Core

  https://www.cambridge.org/core/journals/epidemiology-and-infection/article/risk-factors-for-death-from-handfootmouth-disease-a-metaanalysis/0AE9B68EAD63FEE315B2D8F2BF8630B2

  Factors associated with severe or fatal HFMD include EV-A71, a high fever of over 39 C for more than 3 days, a raised WBC count 10.8 109/L, vomiting, tachycardia, lethargy, hyperglycaemia and leucocytosis. […] In this study, the risk factors for fatalities were lethargy, pneumonoedema/pneumorrhagia, seizures, dyspnoea and coma. Moreover, EV-A71, male, age, vomiting, cyanosis, convulsion, duration of fever 3 days, atypical rashes and abdominal distention were not associated with fatal HFMD. […] This study showed that pneumonoedema/pneumorrhagia was associated with the mortality of patients with HFMD. […] Lethargy was reported in lots of studies as a predictor of severe HFMD and confirmed in this study. […] The results suggested that lethargy, pneumonoedema/pneumorrhagia, seizures, dyspnoea and coma increased with HFMD deaths. EV-A71 infection, male, vomiting, cyanosis, convulsion, duration of fever 3 days, age, atypical rushes and abdominal distention were not associated with HFMD death.

• #20 The Mechanism of Onychomadesis (Nail Shedding) and Beau’s Lines Following Hand-Foot-Mouth Disease

  https://www.mdpi.com/1999-4915/11/6/522

  Onychomadesis (nail shedding) is defined as the proximal nail plate detached from the proximal nail fold by a whole thickness sulcus. […] However, the mechanism of onychomadesis following HFMD is still unknown. […] There are several hypotheses explaining this temporary inhibition of nail matrix proliferation. […] The first is severe systemic impact and the second, direct injuries of the nail matrix by cutaneous lesions of HFMD, such as vesicles, around the nail matrix; finally, there are specific novel variants of human enteroviruses (HEV) which are virulent, with new kinds of virus–host interactions leading to nail matrix dysfunction. […] The mechanism involved remains unclear today. […] Several hypotheses explained this temporary inhibition of nail matrix proliferation. […] We do believe that direct injuries caused by the cutaneous lesions of HFMD around nail matrix is one of the causes of onychomadesis, although it appears to be not the only one.

• #20 The Mechanism of Onychomadesis (Nail Shedding) and Beau’s Lines Following Hand-Foot-Mouth Disease

  https://www.mdpi.com/1999-4915/11/6/522

  We believe that the evolution of novel CVA6 leads to changes of the virus’s characteristics. This leads to new virus-host interactions and results in different clinical presentations in the host, not only in the atypical presentation during the acute infection stage, but also in the post-syndrome nail changes. […] To sum up, direct injuries by cutaneous lesions of HFMD around the nail matrix is a possible cause for virus-associated onychomadesis. […] Certain novel viruses, including CVA6, are virulent and may damage the nail matrix and lead to the development of onychomychosis. This seems to be the major cause.

• #21 Researchers Uncover Mechanism Behind Nail Shedding Related to Hand-Foot-and-Mouth Disease—-Chinese Academy of Sciences

  https://english.cas.cn/newsroom/research_news/life/202406/t20240611_664957.shtml

  Hand-foot-and-mouth disease (HFMD) is a prevalent viral infection among children, often causing sores in the mouth and a rash on the hands and feet. […] Onychomadesis (nail shedding) is a common post-HFMD pathological phenomenon. Until now, the mechanisms driving this sequela have been poorly understood, making prevention and treatment of post-HFMD onychomadesis challenging. […] In a study published in Journal of Experimental Medicine, the research group led by Prof. George Fu Gao (GAO Fu) from the Institute of Microbiology of the Chinese Academy of Sciences, and the collaborators from Tsinghua University and Southeast University, uncovered the connection between virus-receptor interaction and pathologic phenomenon through the modulation of cell signaling, and the establishment of links between virus infection and post-HFMD onychomadesis.

• #21 Researchers Uncover Mechanism Behind Nail Shedding Related to Hand-Foot-and-Mouth Disease—-Chinese Academy of Sciences

  https://english.cas.cn/newsroom/research_news/life/202406/t20240611_664957.shtml

  Based on previous structural studies, researchers found that Coxsackievirus A10 (CV-A10, a prominent pathogenic virus of HFMD) infection, mimics the action of a known regulatory protein, Dickkopf-related protein 1 (DKK1), which is crucial in managing Wnt/-catenin signaling involved in nail growth. […] They found that by mimicking DKK1, CV-A10 binds to its receptor KREMEN1 and interferes with the Wnt/-catenin signaling pathway by inhibiting LRP6 phosphorylation and -catenin accumulation. This interference leads to dysfunction of cell proliferation and nail stem cell differentiation, which consequently manifests as onychomadesis. […] Importantly, researchers provided convincing evidence that activation of Wnt signaling with the small molecule CHIR99021 could rescue nail stem cell differentiation in digit tips, and holds promising potential as an effective treatment for onychomadesis. […] This study highlights the activation of the Wnt pathway as a potential treatment, and offers new insights into virus-host cellular signaling interactions.

• #22

  https://link.springer.com/article/10.1007/s00430-016-0465-y

  Hand, foot, and mouth disease (HFMD) is a contagious viral disease and mainly affects infants and young children. […] Historically, outbreaks of HFMD were mainly caused by two enteroviruses: the coxsackievirus A16 (CV-A16) and the enterovirus 71 (EV-A71). […] Currently, there is no pharmacological intervention or vaccine available for HFMD. […] Therefore, the development of a globally representative multivalent HFMD vaccine could be the best strategy.

• #23 Salvianolic Acid B Inhibits Hand-Foot-Mouth Disease Enterovirus 71 Replication through Enhancement of AKT Signaling Pathway

  https://www.jmb.or.kr/journal/view.html?uid=5339&vmd=Full

  Hand, foot, and mouth disease (HFMD) is caused by enterovirus 71 (EV71) in infants and children under six years of age. HFMD is characterized by fever, mouth ulcers, and vesicular rashes on the palms and feet. EV71 also causes severe neurological manifestations, such as brainstem encephalitis and aseptic meningitis. […] In this study, we investigated the antiviral effect of salvianolic acid B (SalB) on EV71. […] SalB treatment (100 g/ml) significantly decreased the cleavage of the eukaryotic eIF4G1 protein and reduced the expression of the EV71 capsid protein VP1. […] The Akt signaling pathway, a key component of cell survival and proliferation, was significantly increased in EV71-infected HeLa cells treated with 100 g/ml SalB. […] These results indicate that SalB activates Akt/PKB signaling and inhibits apoptosis in infected HeLa cells.

• #23 Salvianolic Acid B Inhibits Hand-Foot-Mouth Disease Enterovirus 71 Replication through Enhancement of AKT Signaling Pathway

  https://www.jmb.or.kr/journal/view.html?uid=5339&vmd=Full

  In this study, we have discovered that SalB has potent antiviral effects on enterovirus EV71. SalB inhibited proliferation of EV71 in HeLa cells and activated the Akt signaling pathway, which promotes cell survival and proliferation. […] SalB treatment strongly activates Akt, leading to down-regulation of apoptosis through the induction of the anti-apoptotic Bcl-2 pathway. […] In conclusion, we found that SalB activates Akt signaling and the expression of the anti-apoptotic Bcl-2 pathway. It down-regulates apoptosis in EV71-infected HeLa cells and inhibits EV71 replication. These results, therefore, suggest that SalB may be a useful compound when developing new therapeutic agents to treat HFMD.

• #24 Mechanism of Sang-Ju-Yin on Hand, Foot and Mouth Disease Based on Network Pharmacology, International Journal of Chinese Medicine, Science Publishing Group

  https://www.sciencepublishinggroup.com/article/10055111

  Objective: Hand, foot and mouth disease (HFMD) is an acute infectious disease caused by enterovirus 71 (EV71), Coxsackie virus A16 (CA16) and other enteroviruses. […] In this paper, the network pharmacology method was adopted to analyze the main active components and action targets of Sang-Ju-Yin (SJY) and to construct corresponding pathways, and to explore the mechanism of action of SJY in the treatment of HFMD. […] The main active components of SJY are quercetin, luteolin, wogonin, kaempferol, aloe emodin, Licochalcone A. It mainly regulates AKT1, Bax, IKBKB, IL-6, STAT3 and other targets, regulates TNF, influenza A and other signaling pathways to inhibit inflammatory response and regulate immune function, so as to achieve the purpose of treating hand foot mouth disease.

• #25 A literature review and case report of hand, foot and mouth disease in an immunocompetent adult | BMC Research Notes | Full Text

  https://bmcresnotes.biomedcentral.com/articles/10.1186/s13104-016-1973-y

  The main causative agents are CVA16 and EV71. Moreover, outbreaks caused by CVA4, CVA5, CVA6, CVA9, CVA10, CVA12, CVB1, CVB3 and CVB5 have been observed. […] Diagnosing the disease is relatively easy by looking at the clinical features of the disease. […] Although it is not a serious disease, an early diagnosis is important to avoid epidemics on the pediatric population. […] The role of the dentist is important, as he/she is one of the professionals who must help with diagnosis when the patient seeks professional advice for painful oral lesions. […] A surveillance system to predict future outbreaks, appropriate public health measures and research into vaccine development are of vital importance to control HFMD.

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