A common acute viral illness predominantly affecting children under 5 years old, caused by enteroviruses (most commonly Coxsackievirus A16 and Enterovirus A71), characterized by fever, oral enanthema (painful mouth ulcers), and a vesicular exanthem on the hands, feet, and buttocks. Usually self-limiting, but EV-A71 strains can cause severe neurological and cardiopulmonary complications.
Conditions with similar clinical presentations that must be differentiated from Hand Foot and Mouth Disease:
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on the pathophysiology of Hand Foot and Mouth Disease. Focus on the molecular and cellular mechanisms underlying disease progression.
Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs
Hand, foot and mouth disease (HFMD) is an acute, highly contagious pediatric infection most commonly caused by Enterovirus A species, including Enterovirus A71 (EV‑A71), coxsackievirus A16 (CV‑A16), coxsackievirus A6 (CV‑A6), and coxsackievirus A10 (CV‑A10). Severe HFMD is classically associated with EV‑A71 and features neurologic involvement (e.g., brainstem encephalitis) and cardiopulmonary complications (notably pulmonary edema), whereas most infections are self-limited mucocutaneous disease. Recent surveillance has shown a post‑EV‑A71 vaccine shift toward CV‑A6/CV‑A10 as dominant causes of HFMD in multiple Chinese settings (yang2023molecularepidemiologyand pages 1-2, yuan2024epidemiologicalandetiological pages 1-2, xia2024clinicalaetiologicaland pages 1-2).
Current understanding (unifying concept). HFMD pathophysiology is best conceptualized as (i) mucosal entry and early replication, (ii) viremia and tissue dissemination, (iii) host innate and adaptive immune responses (and viral evasion), and (iv) in a subset, neuroinvasion with blood–brain barrier (BBB) dysfunction and brainstem injury leading to systemic inflammatory and neurogenic cardiopulmonary collapse (zhu2023currentstatusof pages 11-12, ji2024thekeymechanisms pages 7-8, ji2024thekeymechanisms pages 12-13).
Note on ontology identifiers. MONDO ID was not available in the retrieved sources; this report provides ontology-ready terms (GO/CL/UBERON/HP/CHEBI) where possible based on the cited mechanistic literature.
Receptor-mediated entry is multi-step and cell-type dependent. A key 2024 mechanistic advance is strong evidence that EV‑A71 uses distinct factors for (a) cell-surface attachment/internalization versus (b) intracellular uncoating.
This attachment–uncoating separation refines older “single receptor” models and implies that receptor expression and endolysosomal trafficking biology are central determinants of tissue tropism and severity (nishimura2024enterovirusa71does pages 1-2, nishimura2024enterovirusa71does pages 2-4).
A complementary 2024 pathogenesis study highlights host regulation of receptor availability: TRIB3 promotes EV‑A71 infection, in part by maintaining “the metabolic stability of…SCARB2…to enhance the infectious entry and spreading of the virus” (Emerging Microbes & Infections; Jan 2024; https://doi.org/10.1080/22221751.2024.2307514) (wang2024tribblespseudokinase3 pages 1-2).
Visual synthesis (authoritative review figure/table). Zhu et al. (J Biomed Sci; Feb 2023; https://doi.org/10.1186/s12929-023-00908-4) provide (i) a table of major enterovirus receptors (including SCARB2 and PSGL‑1) and (ii) a schematic of innate immune evasion mechanisms relevant to HFMD pathogenesis (zhu2023currentstatusof media ba7d7b3e, zhu2023currentstatusof media 86593dfb).
Entry sites and early replication. EV‑A71 infection begins at mucosal epithelial surfaces of the gastrointestinal and respiratory tracts in the early phase of infection (wei2024recentprogressin pages 2-4).
Progression to systemic disease. Severe HFMD is linked to CNS involvement—particularly brainstem structures—and downstream dysautonomia and inflammation (ji2024thekeymechanisms pages 7-8, zhu2023currentstatusof pages 11-12). Ji et al. (Infectious Medicine; Sep 2024; https://doi.org/10.1016/j.imj.2024.100124) describe clinical progression consistent with a systemic dissemination step: “primary and a secondary viremia after ~4–5 days enabling systemic/CNS spread” (ji2024thekeymechanisms pages 7-8).
BBB disruption as a gateway to CNS disease. Multiple mechanisms converge on BBB compromise:
Neural routes and extracellular vesicles. Ji et al. further summarize evidence for neural spread (e.g., retrograde axonal transport) and non-lytic dissemination via exosomes/small extracellular vesicles that can enable CNS entry without overt BBB destruction (ji2024thekeymechanisms pages 7-8, ji2024thekeymechanisms pages 12-13).
Mechanistically, severe disease reflects both antiviral responses and viral suppression of those responses.
Key innate-sensing nodes. A 2024 review of EV‑A71 innate immunity (International Journal of Molecular Sciences; May 2024; https://doi.org/10.3390/ijms25115688) summarizes canonical sensing and signaling engaged by EV‑A71, including endosomal TLR3/TLR7 and cytosolic RIG‑I/MDA5→MAVS leading to IRF3/IRF7 and NF‑κB activation and downstream type I interferon signaling via IFNAR→JAK/STAT (wei2024recentprogressin pages 2-4).
Viral antagonism of interferon and inflammasome. Zhu et al. (J Biomed Sci; Feb 2023; https://doi.org/10.1186/s12929-023-00908-4) provide multiple examples of EV‑A71 immune evasion/rewiring:
These observations map HFMD severity to dysregulation of innate antiviral and inflammatory cascades (type I IFN signaling, NF‑κB activation, inflammasome activation) rather than viral cytopathicity alone (zhu2023currentstatusof pages 11-12, wei2024recentprogressin pages 2-4).
A 2023 proteomics+metabolomics study provides direct evidence that EV‑A71 reprograms glycolysis:
This supports a host-directed therapeutic concept (metabolic intervention) in addition to antiviral approaches (shi2023proteomicandmetabonomic pages 12-13).
Primary mechanistic nodes supported by the retrieved evidence include:
Representative processes supported in the retrieved sources include:
Key subcellular sites implicated include:
Exposure typically occurs through fecal–oral and/or respiratory routes, with early replication at GI/respiratory mucosa (wei2024recentprogressin pages 2-4).
A subset of cases progress beyond localized mucocutaneous disease, with systemic dissemination enabling access to secondary tissues including muscle and CNS; Ji et al. summarize a clinical timeline including a secondary viremia around 4–5 days (ji2024thekeymechanisms pages 7-8).
Host PRR signaling (TLRs and RIG‑I/MDA5) drives IFN and cytokine responses, while EV‑A71 employs multiple evasion strategies (IFNAR/STAT interference; RIG‑I cleavage; inflammasome modulation) (wei2024recentprogressin pages 2-4, zhu2023currentstatusof pages 11-12).
In CV‑A16, IP‑10 (CXCL10) is induced early and promotes TNF‑α, which reduces junctional proteins and facilitates virus entry into the CNS (hu2024ip10actsearly pages 1-2). Broader HFMD literature synthesis implicates additional BBB-disruptive pathways (e.g., MMP‑9) (ji2024thekeymechanisms pages 7-8, ji2024thekeymechanisms pages 12-13).
Brainstem infection/damage is linked to sympathetic hyperactivation and a catecholamine “storm,” driving pulmonary microvascular leakage and cardiopulmonary failure. Ji et al. report marked catecholamine elevation in severe cases and mechanistic links to pulmonary edema: excessive catecholamines increase pulmonary permeability and can induce cardiomyocyte injury (ji2024thekeymechanisms pages 7-8). Zhu et al. similarly connect cardiopulmonary failure to brainstem-mediated hypercatecholaminemia (zhu2023currentstatusof pages 11-12).
The most concrete 2024 mechanistic advance in this corpus is the demonstration that EV‑A71 does not rely on cell-surface SCARB2 for attachment; instead, SCARB2 acts intracellularly in endolysosomes for uncoating. Key quotes include SCARB2 being “within the cytoplasm, but not on the cell surface” and “highly concentrated in lysosomes and late endosomes…likely to trigger acid-dependent uncoating” (Nishimura et al., Feb 2024, PLOS Pathogens; https://doi.org/10.1371/journal.ppat.1012022) (nishimura2024enterovirusa71does pages 1-2, nishimura2024enterovirusa71does pages 2-4).
Hu et al. (Nov 2024; Frontiers in Immunology; https://doi.org/10.3389/fimmu.2024.1374447) provide direct mechanistic evidence that the IP‑10/TNF‑α axis reduces BBB junctional proteins and increases CNS entry during CV‑A16 infection, with anti‑IP‑10 or anti‑TNF‑α improving outcomes in a suckling mouse model (hu2024ip10actsearly pages 1-2).
Shi et al. (Nov 2023; PROTEOMICS; https://doi.org/10.1002/pmic.202200362) show glycolysis activation during EV‑A71 infection and that DCA or ENO1 knockdown suppresses infection (shi2023proteomicandmetabonomic pages 12-13).
Multiple surveillance studies show EV‑A71 reductions and increasing dominance of CV‑A6/CV‑A10:
These epidemiologic shifts are critical to “real-world implementation” because they create vaccine/therapeutic pressure toward multivalent approaches beyond EV‑A71-only strategies (yang2023molecularepidemiologyand pages 1-2, yuan2024epidemiologicalandetiological pages 1-2).
Real-world surveillance supports a sharp decrease in EV‑A71 detections and severe HFMD after EV‑A71 vaccine rollout (e.g., post‑2016 trends in multiple Chinese datasets) (yang2023molecularepidemiologyand pages 1-2, dai2024epidemiologyandetiology pages 4-6). However, non‑EV‑A71 serotypes now dominate detected cases in many settings, implying that single-serotype vaccination is insufficient to fully control HFMD burden (yang2023molecularepidemiologyand pages 1-2, yuan2024epidemiologicalandetiological pages 1-2, dai2024epidemiologyandetiology pages 4-6).
These are not established clinical standards of care in the retrieved sources, but represent mechanistically grounded directions.
Mechanistic convergence. Across pathogens, severe HFMD appears to converge on BBB compromise, neuroinflammation, and autonomic dysregulation rather than only higher peripheral viral replication. The IP‑10/TNF‑α → tight junction loss mechanism (CV‑A16) provides a testable causal chain from innate immune signaling to BBB dysfunction and neuroinvasion (hu2024ip10actsearly pages 1-2). The catecholamine-storm mechanism provides a plausible bridge from brainstem injury to pulmonary edema and rapid deterioration (ji2024thekeymechanisms pages 7-8, zhu2023currentstatusof pages 11-12).
Host genetics as an outcome modifier. Case-control genetic studies support the concept that host receptor variants influence severity (SCARB2 SNPs protective; PSGL‑1 VNTR modest risk) (duan2023theeffectsof pages 1-2, wang2024correlationsofpsgl1 pages 2-4).
Implication for future countermeasures. The consistent shift to CV‑A6/CV‑A10 dominance (while EV‑A71 remains a key severe pathogen) suggests that multivalent vaccines and broad-spectrum antivirals/host-directed therapies are likely necessary for durable control (yang2023molecularepidemiologyand pages 1-2, yuan2024epidemiologicalandetiological pages 1-2, dai2024epidemiologyandetiology pages 4-6).
| Category | Entity | Role in HFMD Pathophysiology | Key Evidence |
|---|---|---|---|
| Gene/Protein | SCARB2 (HGNC:1664) | Primary intracellular receptor facilitating viral uncoating in acidic endosomes/lysosomes; SNPs associated with reduced severity. | (wei2024recentprogressin pages 2-4, nishimura2024enterovirusa71does pages 6-9, nishimura2024enterovirusa71does pages 1-2, duan2023theeffectsof pages 1-2, duan2023theeffectsof pages 6-7) |
| Gene/Protein | SELPLG / PSGL-1 (HGNC:10720) | Major attachment receptor on leukocytes directing viral tropism; VNTR polymorphisms linked to severe disease susceptibility. | (wei2024recentprogressin pages 2-4, nishimura2024enterovirusa71does pages 6-9, nishimura2024enterovirusa71does pages 2-4, wang2024correlationsofpsgl1 pages 2-4, wang2024correlationsofpsgl1 pages 1-2) |
| Gene/Protein | CXCL10 / IP-10 (HGNC:10636) | Pro-inflammatory chemokine elevated early in infection that drives TNF-alpha production and blood-brain barrier disruption. | (ji2024thekeymechanisms pages 12-13, zhu2023currentstatusof pages 11-12, hu2024ip10actsearly pages 1-2) |
| Gene/Protein | TNF / TNF-alpha (HGNC:11892) | Cytokine induced by IP-10 that reduces endothelial tight junction proteins (Claudin5, Occludin), promoting neuroinvasion. | (hu2024ip10actsearly pages 1-2, zhu2023currentstatusof pages 11-12) |
| Gene/Protein | NLRP3 (HGNC:16400) | Inflammasome component bounded by viral 3D polymerase to form a complex promoting IL-1beta secretion. | (zhu2023currentstatusof pages 11-12, wei2024recentprogressin pages 2-4, zhu2023currentstatusof media ba7d7b3e) |
| Gene/Protein | ENO1 (HGNC:3350) | Glycolytic enzyme upregulated by EV-A71 to reprogram host metabolism and support viral replication. | (shi2023proteomicandmetabonomic pages 1-2, shi2023proteomicandmetabonomic pages 12-13) |
| Gene/Protein | TRIB3 (HGNC:16228) | Host pseudokinase that maintains SCARB2 metabolic stability, enhancing viral entry and spread. | (wang2024tribblespseudokinase3 pages 1-2) |
| Gene/Protein | MMP9 (HGNC:7176) | Matrix metalloproteinase implicated in disrupting junctional complexes at the blood-brain barrier. | (ji2024thekeymechanisms pages 12-13, ji2024thekeymechanisms pages 7-8) |
| Gene/Protein | IFNAR1 / IFNAR2 | Type I interferon receptor subunits targeted by viral proteases to evade innate immune signaling. | (wei2024recentprogressin pages 2-4) |
| Gene/Protein | VIM / Vimentin (HGNC:12692) | Cell surface attachment receptor upregulated by viral VP1, facilitating BBB penetration. | (ji2024thekeymechanisms pages 7-8, hu2024ip10actsearly pages 1-2) |
| Pathway (GO) | Type I interferon signaling pathway (GO:0060337) | Antiviral response pathway suppressed by viral cleavage of RIG-I, MAVS, and inhibition of STAT nuclear translocation. | (zhu2023currentstatusof pages 11-12, wei2024recentprogressin pages 2-4, zhu2023currentstatusof media ba7d7b3e) |
| Pathway (GO) | Glycolytic process (GO:0006096) | Metabolic pathway activated/reprogrammed by virus via ENO1 upregulation to support replication. | (shi2023proteomicandmetabonomic pages 1-2, shi2023proteomicandmetabonomic pages 12-13) |
| Cellular Component | Lysosome (GO:0005764) / Late Endosome (GO:0005770) | Acidic compartments where SCARB2 resides and triggers the critical viral uncoating step. | (nishimura2024enterovirusa71does pages 6-9, nishimura2024enterovirusa71does pages 1-2, nishimura2024enterovirusa71does pages 13-15, nishimura2024enterovirusa71does pages 10-13) |
| Cellular Component | Inflammasome complex (GO:0061702) | Multiprotein complex (3D-NLRP3-ASC) engaged to drive cytokine storm and inflammation. | (zhu2023currentstatusof pages 11-12, wei2024recentprogressin pages 2-4) |
| Cellular Component | Tight junction (GO:0005923) | Endothelial barrier structure degraded by IP-10/TNF-alpha-mediated downregulation of ZO-1/Occludin. | (hu2024ip10actsearly pages 1-2) |
| Chemical Entity | Norepinephrine (CHEBI:18357) | Major mediator of the "catecholamine storm" causing neurogenic pulmonary edema and cardiac failure. | (ji2024thekeymechanisms pages 7-8, zhu2023currentstatusof pages 11-12) |
| Chemical Entity | Dichloroacetic acid (CHEBI:41879) | Glycolysis inhibitor shown to suppress EV-A71 infection in vitro. | (shi2023proteomicandmetabonomic pages 1-2, shi2023proteomicandmetabonomic pages 12-13) |
| Anatomy | Blood-brain barrier (UBERON:0000202) | Physical barrier compromised by viral proteins (VP1) and host cytokines, facilitating neuroinvasion. | (ji2024thekeymechanisms pages 12-13, ji2024thekeymechanisms pages 7-8, hu2024ip10actsearly pages 1-2) |
| Anatomy | Brainstem (UBERON:0002298) | Critical CNS region infected via neural routes, triggering autonomic dysfunction and catecholamine surge. | (ji2024thekeymechanisms pages 7-8, zhu2023currentstatusof pages 11-12) |
| Phenotype | Pulmonary edema (HP:0002104) | Severe complication resulting from brainstem damage and subsequent sympathetic hyperactivation. | (ji2024thekeymechanisms pages 12-13, ji2024thekeymechanisms pages 7-8) |
Table: A structured mapping of key molecular entities, biological processes, and anatomical sites involved in Hand, Foot, and Mouth Disease pathophysiology, linked to ontology categories and recent supporting evidence.
The retrieved evidence set includes several high-quality mechanistic papers with DOI links and publication dates; however, PMIDs were not present in the provided tool outputs for many items. Below are the URL/DOI and publication month/year as provided by the tool results:
1) Nishimura et al. “Enterovirus A71 does not meet the uncoating receptor SCARB2 at the cell surface.” PLOS Pathogens, Feb 2024. https://doi.org/10.1371/journal.ppat.1012022 (nishimura2024enterovirusa71does pages 1-2)
2) Hu et al. “IP‑10 acts early in CV‑A16 infection to induce BBB destruction…” Frontiers in Immunology, Nov 2024. https://doi.org/10.3389/fimmu.2024.1374447 (hu2024ip10actsearly pages 1-2)
3) Wei et al. “Recent Progress in Innate Immune Responses to Enterovirus A71 and Viral Evasion Strategies.” Int J Mol Sci, May 2024. https://doi.org/10.3390/ijms25115688 (wei2024recentprogressin pages 2-4)
4) Zhu et al. “Current status of hand-foot-and-mouth disease.” Journal of Biomedical Science, Feb 2023. https://doi.org/10.1186/s12929-023-00908-4 (zhu2023currentstatusof pages 11-12)
5) Shi et al. “Proteomic and metabonomic analysis uncovering EV‑A71 reprogramming host cell metabolic pathway.” PROTEOMICS, Nov 2023. https://doi.org/10.1002/pmic.202200362 (shi2023proteomicandmetabonomic pages 1-2)
6) Duan et al. “The effects of SCARB2 and SELPLG gene polymorphisms on EV71 infection…” Biomolecules and Biomedicine, Apr 2023. https://doi.org/10.17305/bb.2023.8948 (duan2023theeffectsof pages 1-2)
7) Wang et al. “Correlations of PSGL‑1 VNTR polymorphism with susceptibility to severe HFMD…” Virology Journal, Aug 2024. https://doi.org/10.1186/s12985-024-02461-4 (wang2024correlationsofpsgl1 pages 2-4)
8) Yang et al. “Molecular epidemiology…HFMD in Chengdu, 2013–2022.” Virology Journal, Sep 2023. https://doi.org/10.1186/s12985-023-02169-x (yang2023molecularepidemiologyand pages 1-2)
9) Xia et al. “Outpatient HFMD in Chengdu, 2019–2022.” BMC Public Health, Dec 2024. https://doi.org/10.1186/s12889-024-20909-8 (xia2024clinicalaetiologicaland pages 1-2)
1) While EV‑A71 and CV‑A16 mechanisms are richly supported in the retrieved full-text evidence, CV‑A6/CV‑A10 molecular receptor usage and CNS mechanisms were not deeply extracted from the available full texts in this run; the report therefore emphasizes shared enterovirus mechanisms and EV‑A71/CV‑A16 exemplars. 2) PMIDs were not surfaced by the tools for many included items; DOIs/URLs and publication dates are provided as substitutes.
References
(yang2023molecularepidemiologyand pages 1-2): Qiuxia Yang, Fang Liu, Li Chang, Shuyu Lai, Jie Teng, Jiaxin Duan, Hui Jian, Ting Liu, and Guanglu Che. Molecular epidemiology and clinical characteristics of enteroviruses associated hfmd in chengdu, china, 2013–2022. Virology Journal, Sep 2023. URL: https://doi.org/10.1186/s12985-023-02169-x, doi:10.1186/s12985-023-02169-x. This article has 43 citations and is from a peer-reviewed journal.
(yuan2024epidemiologicalandetiological pages 1-2): Yongjuan Yuan, Yun Chen, Jian Huang, Xiaoxia Bao, Wei Shen, Yi Sun, and Haiyan Mao. Epidemiological and etiological investigations of hand, foot, and mouth disease in jiashan, northeastern zhejiang province, china, during 2016 to 2022. Frontiers in Public Health, May 2024. URL: https://doi.org/10.3389/fpubh.2024.1377861, doi:10.3389/fpubh.2024.1377861. This article has 12 citations.
(xia2024clinicalaetiologicaland pages 1-2): Maoyao Xia, Yu Zhu, Juan Liao, Shirong Zhang, Denghui Yang, Peng Gong, Shihang Zhang, Guiyu Jiang, Yue Cheng, Jiantong Meng, Zhenhua Chen, Ye Liao, Xiaojing Li, Yilan Zeng, Chaoyong Zhang, and Lu Long. Clinical, aetiological, and epidemiological studies of outpatient cases of hand, foot, and mouth disease in chengdu, china, from 2019 to 2022: a retrospective study. BMC Public Health, Dec 2024. URL: https://doi.org/10.1186/s12889-024-20909-8, doi:10.1186/s12889-024-20909-8. This article has 5 citations and is from a peer-reviewed journal.
(zhu2023currentstatusof pages 11-12): P. Zhu, W. Ji, Dong Li, Zijie Li, Yu Chen, B. Dai, Shujie Han, Shuaiyin Chen, Yuefei Jin, and G. Duan. Current status of hand-foot-and-mouth disease. Journal of Biomedical Science, Feb 2023. URL: https://doi.org/10.1186/s12929-023-00908-4, doi:10.1186/s12929-023-00908-4. This article has 243 citations and is from a domain leading peer-reviewed journal.
(ji2024thekeymechanisms pages 7-8): Wangquan Ji, Peiyu Zhu, Yuexia Wang, Yu Zhang, Zijie Li, Haiyan Yang, Shuaiyin Chen, Yuefei Jin, and Guangcai Duan. The key mechanisms of multi-system responses triggered by central nervous system damage in hand, foot, and mouth disease severity. Infectious Medicine, 3:100124, Sep 2024. URL: https://doi.org/10.1016/j.imj.2024.100124, doi:10.1016/j.imj.2024.100124. This article has 8 citations.
(ji2024thekeymechanisms pages 12-13): Wangquan Ji, Peiyu Zhu, Yuexia Wang, Yu Zhang, Zijie Li, Haiyan Yang, Shuaiyin Chen, Yuefei Jin, and Guangcai Duan. The key mechanisms of multi-system responses triggered by central nervous system damage in hand, foot, and mouth disease severity. Infectious Medicine, 3:100124, Sep 2024. URL: https://doi.org/10.1016/j.imj.2024.100124, doi:10.1016/j.imj.2024.100124. This article has 8 citations.
(nishimura2024enterovirusa71does pages 1-2): Yorihiro Nishimura, Kei Sato, Yoshio Koyanagi, Takaji Wakita, Masamichi Muramatsu, Hiroyuki Shimizu, Jeffrey M. Bergelson, and Minetaro Arita. Enterovirus a71 does not meet the uncoating receptor scarb2 at the cell surface. PLOS Pathogens, 20:e1012022, Feb 2024. URL: https://doi.org/10.1371/journal.ppat.1012022, doi:10.1371/journal.ppat.1012022. This article has 8 citations and is from a highest quality peer-reviewed journal.
(nishimura2024enterovirusa71does pages 2-4): Yorihiro Nishimura, Kei Sato, Yoshio Koyanagi, Takaji Wakita, Masamichi Muramatsu, Hiroyuki Shimizu, Jeffrey M. Bergelson, and Minetaro Arita. Enterovirus a71 does not meet the uncoating receptor scarb2 at the cell surface. PLOS Pathogens, 20:e1012022, Feb 2024. URL: https://doi.org/10.1371/journal.ppat.1012022, doi:10.1371/journal.ppat.1012022. This article has 8 citations and is from a highest quality peer-reviewed journal.
(wang2024tribblespseudokinase3 pages 1-2): Huiqiang Wang, Ke Li, Boming Cui, Haiyan Yan, Shuo Wu, Kun Wang, Ge Yang, Jiandong Jiang, and Yuhuan Li. Tribbles pseudokinase 3 promotes enterovirus a71 infection via dual mechanisms. Emerging Microbes & Infections, Jan 2024. URL: https://doi.org/10.1080/22221751.2024.2307514, doi:10.1080/22221751.2024.2307514. This article has 9 citations and is from a domain leading peer-reviewed journal.
(zhu2023currentstatusof media ba7d7b3e): P. Zhu, W. Ji, Dong Li, Zijie Li, Yu Chen, B. Dai, Shujie Han, Shuaiyin Chen, Yuefei Jin, and G. Duan. Current status of hand-foot-and-mouth disease. Journal of Biomedical Science, Feb 2023. URL: https://doi.org/10.1186/s12929-023-00908-4, doi:10.1186/s12929-023-00908-4. This article has 243 citations and is from a domain leading peer-reviewed journal.
(zhu2023currentstatusof media 86593dfb): P. Zhu, W. Ji, Dong Li, Zijie Li, Yu Chen, B. Dai, Shujie Han, Shuaiyin Chen, Yuefei Jin, and G. Duan. Current status of hand-foot-and-mouth disease. Journal of Biomedical Science, Feb 2023. URL: https://doi.org/10.1186/s12929-023-00908-4, doi:10.1186/s12929-023-00908-4. This article has 243 citations and is from a domain leading peer-reviewed journal.
(wei2024recentprogressin pages 2-4): Jialong Wei, Linxi Lv, Tian Wang, Wei Gu, Yang Luo, and Hui Feng. Recent progress in innate immune responses to enterovirus a71 and viral evasion strategies. International Journal of Molecular Sciences, 25:5688, May 2024. URL: https://doi.org/10.3390/ijms25115688, doi:10.3390/ijms25115688. This article has 12 citations.
(hu2024ip10actsearly pages 1-2): Yajie Hu, Yunguang Hu, Anguo Yin, Yaming Lv, Jiang Li, Jingyuan Fan, Baojiang Qian, Jie Song, and Yunhui Zhang. Ip-10 acts early in cv-a16 infection to induce bbb destruction and promote virus entry into the cns by increasing tnf-α expression. Frontiers in Immunology, Nov 2024. URL: https://doi.org/10.3389/fimmu.2024.1374447, doi:10.3389/fimmu.2024.1374447. This article has 4 citations and is from a peer-reviewed journal.
(shi2023proteomicandmetabonomic pages 1-2): Huichun Shi, Siyuan Liu, Zhimi Tan, Lin Yin, Liyan Zeng, Tiefu Liu, Shuye Zhang, and Lijun Zhang. Proteomic and metabonomic analysis uncovering enterovirus a71 reprogramming host cell metabolic pathway. Nov 2023. URL: https://doi.org/10.1002/pmic.202200362, doi:10.1002/pmic.202200362. This article has 8 citations and is from a peer-reviewed journal.
(shi2023proteomicandmetabonomic pages 12-13): Huichun Shi, Siyuan Liu, Zhimi Tan, Lin Yin, Liyan Zeng, Tiefu Liu, Shuye Zhang, and Lijun Zhang. Proteomic and metabonomic analysis uncovering enterovirus a71 reprogramming host cell metabolic pathway. Nov 2023. URL: https://doi.org/10.1002/pmic.202200362, doi:10.1002/pmic.202200362. This article has 8 citations and is from a peer-reviewed journal.
(nishimura2024enterovirusa71does pages 10-13): Yorihiro Nishimura, Kei Sato, Yoshio Koyanagi, Takaji Wakita, Masamichi Muramatsu, Hiroyuki Shimizu, Jeffrey M. Bergelson, and Minetaro Arita. Enterovirus a71 does not meet the uncoating receptor scarb2 at the cell surface. PLOS Pathogens, 20:e1012022, Feb 2024. URL: https://doi.org/10.1371/journal.ppat.1012022, doi:10.1371/journal.ppat.1012022. This article has 8 citations and is from a highest quality peer-reviewed journal.
(dai2024epidemiologyandetiology pages 4-6): Bowen Dai, Yu Chen, Shujie Han, Shouhang Chen, Fang Wang, Huifen Feng, Xiaolong Zhang, Wenlong Li, Shuaiyin Chen, Haiyan Yang, Guangcai Duan, Guowei Li, and Yuefei Jin. Epidemiology and etiology of hand, foot, and mouth disease in zhengzhou, china, from 2009 to 2021. Infectious Medicine, 3:100114, Jun 2024. URL: https://doi.org/10.1016/j.imj.2024.100114, doi:10.1016/j.imj.2024.100114. This article has 8 citations.
(duan2023theeffectsof pages 1-2): Feng Yuan Duan, Zeng-Qing Du, Yang Wang, Lan Luo, Li-Jiang Du, Hong Jiang, Yantuanjin Ma, and Yu-Ling Yang. The effects of scarb2 and selplg gene polymorphisms on ev71 infection in hand, foot, and mouth disease. Biomolecules and Biomedicine, 23:815-824, Apr 2023. URL: https://doi.org/10.17305/bb.2023.8948, doi:10.17305/bb.2023.8948. This article has 3 citations.
(wang2024correlationsofpsgl1 pages 2-4): Xia Wang, Jing Qian, Yuqiang Mi, Ying Li, Yu Cao, and Kunyan Qiao. Correlations of psgl-1 vntr polymorphism with the susceptibility to severe hfmd associated with ev-71 and the immune status after infection. Virology Journal, Aug 2024. URL: https://doi.org/10.1186/s12985-024-02461-4, doi:10.1186/s12985-024-02461-4. This article has 2 citations and is from a peer-reviewed journal.
(chen2024molecularevolutionarydynamics pages 1-2): Yu Chen, Shouhang Chen, Yuanfang Shen, Zhi Li, Xiaolong Li, Yaodong Zhang, Xiaolong Zhang, Fang Wang, and Yuefei Jin. Molecular evolutionary dynamics of coxsackievirus a6 causing hand, foot, and mouth disease from 2021 to 2023 in china: genomic epidemiology study. JMIR Public Health and Surveillance, 10:e59604-e59604, Jul 2024. URL: https://doi.org/10.2196/59604, doi:10.2196/59604. This article has 18 citations and is from a peer-reviewed journal.
(duan2023theeffectsof pages 2-3): Feng Yuan Duan, Zeng-Qing Du, Yang Wang, Lan Luo, Li-Jiang Du, Hong Jiang, Yantuanjin Ma, and Yu-Ling Yang. The effects of scarb2 and selplg gene polymorphisms on ev71 infection in hand, foot, and mouth disease. Biomolecules and Biomedicine, 23:815-824, Apr 2023. URL: https://doi.org/10.17305/bb.2023.8948, doi:10.17305/bb.2023.8948. This article has 3 citations.
(nishimura2024enterovirusa71does pages 6-9): Yorihiro Nishimura, Kei Sato, Yoshio Koyanagi, Takaji Wakita, Masamichi Muramatsu, Hiroyuki Shimizu, Jeffrey M. Bergelson, and Minetaro Arita. Enterovirus a71 does not meet the uncoating receptor scarb2 at the cell surface. PLOS Pathogens, 20:e1012022, Feb 2024. URL: https://doi.org/10.1371/journal.ppat.1012022, doi:10.1371/journal.ppat.1012022. This article has 8 citations and is from a highest quality peer-reviewed journal.
(duan2023theeffectsof pages 6-7): Feng Yuan Duan, Zeng-Qing Du, Yang Wang, Lan Luo, Li-Jiang Du, Hong Jiang, Yantuanjin Ma, and Yu-Ling Yang. The effects of scarb2 and selplg gene polymorphisms on ev71 infection in hand, foot, and mouth disease. Biomolecules and Biomedicine, 23:815-824, Apr 2023. URL: https://doi.org/10.17305/bb.2023.8948, doi:10.17305/bb.2023.8948. This article has 3 citations.
(wang2024correlationsofpsgl1 pages 1-2): Xia Wang, Jing Qian, Yuqiang Mi, Ying Li, Yu Cao, and Kunyan Qiao. Correlations of psgl-1 vntr polymorphism with the susceptibility to severe hfmd associated with ev-71 and the immune status after infection. Virology Journal, Aug 2024. URL: https://doi.org/10.1186/s12985-024-02461-4, doi:10.1186/s12985-024-02461-4. This article has 2 citations and is from a peer-reviewed journal.
(nishimura2024enterovirusa71does pages 13-15): Yorihiro Nishimura, Kei Sato, Yoshio Koyanagi, Takaji Wakita, Masamichi Muramatsu, Hiroyuki Shimizu, Jeffrey M. Bergelson, and Minetaro Arita. Enterovirus a71 does not meet the uncoating receptor scarb2 at the cell surface. PLOS Pathogens, 20:e1012022, Feb 2024. URL: https://doi.org/10.1371/journal.ppat.1012022, doi:10.1371/journal.ppat.1012022. This article has 8 citations and is from a highest quality peer-reviewed journal.
name: Hand Foot and Mouth Disease
creation_date: "2026-03-09T12:00:00Z"
updated_date: "2026-03-10T16:31:31Z"
category: Infectious
description: >-
A common acute viral illness predominantly affecting children under 5 years old,
caused by enteroviruses (most commonly Coxsackievirus A16 and Enterovirus A71),
characterized by fever, oral enanthema (painful mouth ulcers), and a vesicular
exanthem on the hands, feet, and buttocks. Usually self-limiting, but EV-A71
strains can cause severe neurological and cardiopulmonary complications.
disease_term:
preferred_term: hand, foot and mouth disease
term:
id: MONDO:0005779
label: hand, foot and mouth disease
mappings:
mondo_mappings:
- term:
id: MONDO:0005779
label: hand, foot and mouth disease
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: Primary MONDO disease identifier for this hand, foot and mouth disease entry.
parents:
- Enterovirus infection
- Viral exanthem
synonyms:
- HFMD
- Hand-foot-and-mouth disease
classifications:
harrisons_chapter:
- classification_value: infectious disease
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand-foot-and-mouth disease (HFMD) is a viral illness commonly seen in young children under 5 years of age"
explanation: Supports classification of HFMD as an infectious disease.
- classification_value: viral infectious disease
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand-foot-and-mouth disease (HFMD) is a viral illness commonly seen in young children under 5 years of age"
explanation: Confirms HFMD is caused by viral pathogens (enteroviruses).
infectious_agent:
- name: Coxsackievirus A16
description: >-
The most common causative agent of classical HFMD worldwide, typically
associated with mild, self-limiting disease.
infectious_agent_term:
preferred_term: Coxsackievirus A16
term:
id: NCBITaxon:31704
label: Coxsackievirus A16
evidence:
- reference: DOI:10.1186/s12985-023-02169-x
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The proportion of CV-A16 cases decreased from 13.96% in 2013–2015 to 10.84% in 2017–2019 and then to 4.54% in 2020–2022."
explanation: Confirms CV-A16 as a significant HFMD pathogen, though its proportion has been declining.
- name: Enterovirus A71
description: >-
A major causative agent of HFMD associated with severe neurological
complications including brainstem encephalitis, aseptic meningitis,
and acute flaccid paralysis, particularly in young children.
infectious_agent_term:
preferred_term: Enterovirus A71
term:
id: NCBITaxon:39054
label: Enterovirus A71
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "HFMD has been linked to severe cardiopulmonary complications, as well as severe neurological sequelae that can be observed during follow-up."
explanation: Supports EV-A71 as the primary agent associated with severe neurological and cardiopulmonary complications of HFMD.
- name: Coxsackievirus A6
description: >-
An increasingly dominant cause of HFMD outbreaks globally, associated with
atypical presentations including more widespread vesicular rash and
onychomadesis. CV-A6 has become the leading HFMD pathogen in many
Chinese surveillance settings since 2020.
infectious_agent_term:
preferred_term: Coxsackievirus A6
term:
id: NCBITaxon:86107
label: Coxsackievirus A6
evidence:
- reference: DOI:10.1186/s12985-023-02169-x
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Other (non-EV-A71 and non-CV-A16) serotypes accounted for 95.45% during 2020–2022, with CV-A6 accounting for 50.39% and CV-A10 accounting for 10.81%."
explanation: Demonstrates CV-A6 as the dominant HFMD pathogen in recent years.
- reference: DOI:10.2196/59604
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CV-A6 emerged as the major pathogen for HFMD in 2022 (203/732, 27.73%) and 2023 (262/708, 37.01%)."
explanation: Confirms CV-A6 as the leading HFMD pathogen in recent Chinese surveillance.
transmission:
- name: Fecal-oral transmission
description: >-
Primary route of transmission through contact with feces of infected
individuals, facilitated by poor hygiene and close contact in childcare
settings.
evidence:
- reference: PMID:31573162
reference_title: "Hand-Foot-and-Mouth Disease: Rapid Evidence Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand-foot-and-mouth disease is transmitted by fecal-oral, oral-oral, and respiratory droplet contact."
explanation: Directly states fecal-oral transmission as one of the major HFMD transmission routes.
- name: Respiratory droplet transmission
description: >-
Spread via respiratory droplets from coughing or sneezing of infected
individuals.
evidence:
- reference: PMID:31573162
reference_title: "Hand-Foot-and-Mouth Disease: Rapid Evidence Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand-foot-and-mouth disease is transmitted by fecal-oral, oral-oral, and respiratory droplet contact."
explanation: Directly identifies respiratory droplet contact as a transmission route for HFMD.
- name: Oral-oral/direct contact transmission
description: >-
Transmission through close contact with saliva and other oral secretions of
infected persons.
evidence:
- reference: PMID:31573162
reference_title: "Hand-Foot-and-Mouth Disease: Rapid Evidence Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand-foot-and-mouth disease is transmitted by fecal-oral, oral-oral, and respiratory droplet contact."
explanation: Directly identifies oral-oral contact as a transmission route and supports close-contact spread via oral secretions.
pathophysiology:
- name: Receptor-mediated viral entry and endosomal uncoating
description: >-
EV-A71 uses a two-step entry mechanism. PSGL-1 (SELPLG) serves as the
cell-surface attachment receptor on hematopoietic cells, while SCARB2 acts
as an intracellular uncoating receptor within late endosomes and lysosomes,
where acid-dependent genome release occurs. This separation of attachment
and uncoating receptors determines tissue tropism and is a key determinant
of disease severity.
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
biological_processes:
- preferred_term: receptor-mediated endocytosis of virus by host cell
term:
id: GO:0019065
label: receptor-mediated endocytosis of virus by host cell
downstream:
- target: Viremia and systemic dissemination
description: Successful receptor-mediated entry and uncoating are prerequisite upstream steps for productive infection and subsequent systemic spread.
evidence:
- reference: DOI:10.1371/journal.ppat.1012022
supports: PARTIAL
evidence_source: IN_VITRO
snippet: "although both PSGL-1 and SCARB2 are essential for virus infection of Jurkat cells"
explanation: Demonstrates that receptor engagement and SCARB2-dependent uncoating are required for productive infection, making them necessary upstream events for later systemic dissemination.
evidence:
- reference: DOI:10.1371/journal.ppat.1012022
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "SCARB2 is highly concentrated in lysosomes and late endosomes, where it is likely to trigger acid-dependent uncoating of virions, the critical final step of the entry process."
explanation: Demonstrates that SCARB2 acts intracellularly for uncoating rather than as a cell-surface receptor.
- reference: DOI:10.1371/journal.ppat.1012022
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "virus attachment to these cells requires only PSGL-1"
explanation: Shows PSGL-1 is the primary attachment receptor on lymphocytes.
- name: Viremia and systemic dissemination
description: >-
Following initial mucosal replication, enteroviruses undergo primary and
secondary viremia enabling systemic spread to skin, mucous membranes, and
in severe cases the central nervous system. The viremic phase typically
occurs 4-5 days post-infection and determines the extent of disease.
biological_processes:
- preferred_term: symbiont entry into host cell
term:
id: GO:0046718
label: symbiont entry into host cell
downstream:
- target: Enteroviral mucocutaneous injury
description: Hematogenous dissemination seeds peripheral skin and oral mucosal sites where HFMD lesions develop.
evidence:
- reference: PMID:31573162
reference_title: "Hand-Foot-and-Mouth Disease: Rapid Evidence Review."
supports: PARTIAL
evidence_source: OTHER
snippet: "Patients present with a low-grade fever, a maculopapular or papulovesicular rash on the hands and soles of the feet, and painful oral ulcerations."
explanation: The simultaneous involvement of skin and oral mucosa is consistent with systemic viral dissemination to peripheral epithelial sites, though the abstract does not directly measure viremia.
- target: Blood-brain barrier disruption and neuroinvasion
description: Circulating virus reaches the neurovascular interface and gains access to the CNS after traversing the blood-brain barrier.
evidence:
- reference: PMID:40229831
reference_title: "Microvesicles carrying EV71 virions cross BBB through endocytic pathway to induce brain injury."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "qPCR assays showed a higher copy number of EV71 in both blood and brain samples in the mice treated with MVsEV71 compared to those treated with free EV71."
explanation: Directly supports a hematogenous route linking blood-borne EV71 to subsequent brain invasion after BBB crossing.
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "Enteroviruses are highly contagious and have a predilection for the nervous system, particularly in child populations, which contributes to the ongoing outbreak."
explanation: Supports systemic dissemination and neurotropism of enteroviruses following initial infection.
- reference: DOI:10.3390/ijms25115688
supports: SUPPORT
evidence_source: OTHER
snippet: "Enterovirus A71 (EV-A71) is a major pathogen causing hand, foot, and mouth disease (HFMD) in children worldwide. It can lead to severe gastrointestinal, pulmonary, and neurological complications."
explanation: Multi-system complications (gastrointestinal, pulmonary, neurological) confirm systemic viral dissemination beyond the initial mucosal site.
- name: Enteroviral mucocutaneous injury
description: >-
Viral cytopathic effects and immune-mediated inflammation in epidermal
keratinocytes produce the characteristic vesicular lesions on hands, feet,
and oral mucosa. Lesion formation involves direct viral lysis of epithelial
cells combined with local inflammatory cell infiltration.
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
locations:
- preferred_term: oral mucosa
term:
id: UBERON:0003729
label: mouth mucosa
biological_processes:
- preferred_term: innate immune response
modifier: INCREASED
term:
id: GO:0045087
label: innate immune response
downstream:
- target: Vesicular exanthem on hands and feet
description: Acral keratinocyte injury and local inflammation produce the characteristic papulovesicular rash.
evidence:
- reference: PMID:31573162
reference_title: "Hand-Foot-and-Mouth Disease: Rapid Evidence Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Patients present with a low-grade fever, a maculopapular or papulovesicular rash on the hands and soles of the feet, and painful oral ulcerations."
explanation: Directly links HFMD mucocutaneous injury to the characteristic vesicular eruption on the hands and feet.
- target: Oral enanthema
description: Viral epithelial injury in the oral mucosa produces painful oral ulcerations.
evidence:
- reference: PMID:31573162
reference_title: "Hand-Foot-and-Mouth Disease: Rapid Evidence Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Patients present with a low-grade fever, a maculopapular or papulovesicular rash on the hands and soles of the feet, and painful oral ulcerations."
explanation: Directly links oral mucosal injury to the painful oral ulcerations of HFMD.
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "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."
explanation: Supports mucocutaneous tropism as the hallmark clinical manifestation.
- name: Innate immune sensing and viral evasion
description: >-
Host pattern recognition receptors (TLR3, TLR7, RIG-I, MDA5) detect viral
RNA and activate MAVS-TBK1-IRF3/7 and NF-kB signaling, inducing type I
interferons and pro-inflammatory cytokines. EV-A71 counteracts these
defenses through viral protease-mediated cleavage of RIG-I, inhibition of
IFNAR/STAT signaling, and modulation of NLRP3 inflammasome activation.
biological_processes:
- preferred_term: type I interferon-mediated signaling pathway
modifier: DYSREGULATED
term:
id: GO:0060337
label: type I interferon-mediated signaling pathway
- preferred_term: defense response to virus
modifier: DYSREGULATED
term:
id: GO:0051607
label: defense response to virus
downstream:
- target: Blood-brain barrier disruption and neuroinvasion
description: Innate sensing pathways induce IP-10/TNF-alpha inflammatory signaling that contributes to BBB damage and CNS entry.
evidence:
- reference: DOI:10.3389/fimmu.2024.1374447
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We observed that the level of IP-10, as well as the TLR3-TRIF-TRAF3-TBK1-NF-κB and RIG-I/MDA5-MAVS-TRAFS-TBK1-NF-κB pathways, which are the upstream of IP-10, were significantly elevated during the course of CV-A16 infection."
explanation: Supports innate antiviral sensing as the upstream driver of the IP-10/TNF-alpha axis that subsequently disrupts the BBB.
evidence:
- reference: DOI:10.3390/ijms25115688
supports: SUPPORT
evidence_source: OTHER
snippet: "The innate immune system, which rapidly detects pathogens via pathogen-associated molecular patterns or pathogen-encoded effectors, serves as the first defensive line against EV-A71 infection. Concurrently, the virus has developed various sophisticated strategies to evade host antiviral responses and establish productive infection."
explanation: Reviews the interplay between innate immune sensing and EV-A71 immune evasion strategies.
- name: Blood-brain barrier disruption and neuroinvasion
description: >-
In severe HFMD, the IP-10 (CXCL10)/TNF-alpha regulatory axis induces
downregulation of endothelial tight junction proteins (Claudin5, Occludin,
ZO-1, VE-cadherin), compromising blood-brain barrier integrity and
facilitating viral entry into the CNS. MMP-9-mediated junctional
disruption provides an additional mechanism of BBB compromise.
cell_types:
- preferred_term: endothelial cell
term:
id: CL:0000115
label: endothelial cell
biological_processes:
- preferred_term: inflammatory response
modifier: INCREASED
term:
id: GO:0006954
label: inflammatory response
locations:
- preferred_term: brainstem
term:
id: UBERON:0002298
label: brainstem
downstream:
- target: Brainstem neuroinflammation
description: Blood-brain barrier breakdown and CNS viral entry amplify inflammatory injury in the brainstem.
evidence:
- reference: DOI:10.3389/fimmu.2024.1374447
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Taken together, this study provides the first evidence that CV-A16 activates the IP-10/TNF-α regulatory axis to cause BBB damage and accelerate the formation of neuroinflammation in infected hosts"
explanation: Supports BBB disruption and neuroinvasion as an upstream driver of CNS neuroinflammation.
evidence:
- reference: DOI:10.3389/fimmu.2024.1374447
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the expression levels of Claudin5, Occludin, ZO-1 and VE-Cadherin were notably decreased in CV-A16-infected HUVECs, but these indicators were restored in CV-A16-infected HUVECs with Eldelumab treatment"
explanation: Demonstrates IP-10-mediated BBB tight junction protein loss during CV-A16 infection.
- reference: DOI:10.3389/fimmu.2024.1374447
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "IP-10 and TNF-α were observed to reduce junctional complexes and enhance virus entry into the CNS"
explanation: Confirms the IP-10/TNF-alpha axis as a mechanism of BBB disruption facilitating neuroinvasion.
- name: Brainstem neuroinflammation
description: >-
After CNS entry, enteroviral infection triggers inflammatory injury in the
brainstem, a key substrate for severe neurologic disease in EV-A71 HFMD.
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
locations:
- preferred_term: brainstem
term:
id: UBERON:0002298
label: brainstem
biological_processes:
- preferred_term: inflammatory response
modifier: INCREASED
term:
id: GO:0006954
label: inflammatory response
downstream:
- target: Brainstem structural injury
description: Persistent inflammatory injury produces clinically detectable brainstem lesions.
evidence:
- reference: PMID:11826236
reference_title: "Cardiopulmonary manifestations of fulminant enterovirus 71 infection."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Magnetic resonance imaging revealed that all 5 infants had brainstem lesions."
explanation: Supports progression from CNS inflammatory disease to structural brainstem injury in severe EV71 infection.
evidence:
- reference: DOI:10.3389/fimmu.2024.1374447
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Taken together, this study provides the first evidence that CV-A16 activates the IP-10/TNF-α regulatory axis to cause BBB damage and accelerate the formation of neuroinflammation in infected hosts"
explanation: Supports inflammatory brain injury as a core CNS event following enteroviral neuroinvasion.
- name: Brainstem structural injury
description: >-
Severe CNS involvement produces radiographically and clinically detectable
brainstem lesions.
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
locations:
- preferred_term: brainstem
term:
id: UBERON:0002298
label: brainstem
downstream:
- target: Brainstem encephalitis
description: Brainstem tissue injury manifests clinically as brainstem encephalitis.
evidence:
- reference: PMID:12831425
reference_title: "Neurogenic pulmonary edema in enterovirus 71 encephalitis is not uniformly fatal but causes severe morbidity in survivors."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Epidemic enterovirus 71 brainstem encephalitis presenting as neurogenic pulmonary edema can be successfully managed in the pediatric intensive care unit"
explanation: Directly links severe EV71 brainstem injury to the brainstem encephalitis phenotype.
- target: Sympathetic nervous system overactivation
description: Brainstem injury disrupts autonomic regulatory centers and precipitates autonomic dysregulation.
evidence:
- reference: PMID:19681701
reference_title: "Enterovirus 71: epidemiology, pathogenesis and management."
supports: SUPPORT
evidence_source: OTHER
snippet: "Destruction of vasomotor in the brainstem by EV71 produces autonomic nervous system dysregulation prior to the pulmonary edema."
explanation: Directly supports brainstem injury as the upstream cause of autonomic dysregulation in severe EV71 disease.
evidence:
- reference: PMID:11826236
reference_title: "Cardiopulmonary manifestations of fulminant enterovirus 71 infection."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Magnetic resonance imaging revealed that all 5 infants had brainstem lesions."
explanation: Provides direct human clinical evidence of brainstem structural injury in fulminant EV71 infection.
- name: Sympathetic nervous system overactivation
description: >-
Brainstem autonomic dysfunction produces excessive sympathetic outflow
during severe EV-A71 CNS disease.
downstream:
- target: Catecholamine excess
description: Sympathetic hyperactivation increases systemic release of norepinephrine and epinephrine.
evidence:
- reference: PMID:26252639
reference_title: "Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71."
supports: PARTIAL
evidence_source: OTHER
snippet: "ANS dysregulation is related to the overactivation of the sympathetic nervous system, which results from catecholamine release."
explanation: Links autonomic dysregulation, sympathetic overactivation, and catecholamine release, supporting this causal transition even though the directionality is summarized in review-style language.
evidence:
- reference: PMID:26252639
reference_title: "Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71."
supports: SUPPORT
evidence_source: OTHER
snippet: "Severe EV71 BE may be complicated with autonomic nervous system (ANS) dysregulation and/or pulmonary edema."
explanation: Supports autonomic dysregulation as a major intermediate event in severe EV71 brainstem disease.
- name: Catecholamine excess
description: >-
Severe EV-A71 CNS disease is accompanied by excess circulating
norepinephrine and epinephrine, consistent with a catecholamine storm.
biological_processes:
- preferred_term: catecholamine secretion
modifier: INCREASED
term:
id: GO:0050432
label: catecholamine secretion
downstream:
- target: Neurogenic pulmonary edema
description: Excess catecholaminergic signaling contributes to pulmonary vascular leak and pulmonary edema.
evidence:
- reference: PMID:26252639
reference_title: "Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The plasma levels of NE and EP were significantly higher in EV71-infected patients with ANS dysregulation and PE than in controls."
explanation: Directly associates catecholamine excess with pulmonary edema in severe EV71 disease.
evidence:
- reference: PMID:28647185
reference_title: "Relationship between catecholamine level and gene polymorphism of β1 adrenergic receptor G1165C in children with EV71 infection in hand foot and mouth disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The plasma norepinephrine level of severe group was significantly higher than the mild group in children with EV71 infection in HFMD (P < 0.05)"
explanation: Demonstrates elevated catecholamine levels in severe EV71 HFMD.
- name: Host metabolic reprogramming by EV-A71
description: >-
EV-A71 reprograms host cell glycolysis by upregulating alpha-enolase (ENO1),
increasing glucose absorption and glycolytic metabolite production to support
viral replication. Glycolysis inhibition through ENO1 knockdown or
dichloroacetic acid (DCA) treatment significantly suppresses viral infection.
biological_processes:
- preferred_term: glycolytic process
modifier: INCREASED
term:
id: GO:0006096
label: glycolytic process
evidence:
- reference: DOI:10.1002/pmic.202200362
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The upregulated proteins are mainly involved in metabolic process, especially in the glycolysis pathway. Alpha-enolase (ENO1) protein was found to increase with temporal dependence following EV71 infection."
explanation: Demonstrates EV-A71-induced glycolytic reprogramming via ENO1 upregulation.
- reference: DOI:10.1002/pmic.202200362
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "EV71 infection was inhibited by depleting ENO1 or using DCA"
explanation: Shows glycolysis inhibition as a potential host-directed therapeutic strategy.
phenotypes:
- category: Integument
name: Vesicular exanthem on hands and feet
frequency: VERY_FREQUENT
description: >-
Small, tender vesicles on an erythematous base appearing on palms, soles,
and sometimes dorsal surfaces of hands and feet.
phenotype_term:
preferred_term: vesicular exanthem on hands and feet
term:
id: HP:0200037
label: Skin vesicle
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "characterized by typical manifestations such as oral herpes and rashes on the hands and feet"
explanation: Confirms vesicular rash on hands and feet as a hallmark feature.
- category: Integument
name: Maculopapular exanthem
frequency: FREQUENT
description: >-
Maculopapular rash that may accompany or precede vesicular lesions,
particularly on buttocks and extremities.
phenotype_term:
preferred_term: maculopapular exanthem
term:
id: HP:0040186
label: Maculopapular exanthema
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand, foot, and mouth disease is characterized by a painful oral enanthem and asymptomatic exanthem on the palms and soles."
explanation: Confirms exanthem on palms and soles as a characteristic feature.
- category: Integument
name: Onychomadesis
frequency: OCCASIONAL
description: >-
Nail shedding occurring weeks after acute HFMD, particularly
associated with Coxsackievirus A6 infections.
phenotype_term:
preferred_term: onychomadesis
term:
id: HP:0025088
label: Onychomadesis
evidence:
- reference: PMID:36226004
reference_title: "Hand, Foot and Mouth Disease: A Single Centre Retrospective Study of 403 New Cases and Brief Review of Relevant Indian Literature to Understand Clinical, Epidemiological, and Virological Attributes of a Long-Lasting Indian Epidemic."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "serotyping identified Coxsackievirus A16 (CV A16) in 83%, Coxsackievirus A6 (CV A6) in 17%"
explanation: CV-A6, known to cause onychomadesis, was identified in 17% of cases in this Indian cohort.
- category: Digestive
name: Oral enanthema
frequency: VERY_FREQUENT
description: >-
Painful vesicles and ulcers on the oral mucosa, tongue, and hard palate,
often appearing 1-2 days after fever onset.
phenotype_term:
preferred_term: oral enanthema
term:
id: HP:0000155
label: Oral ulcer
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "characterized by typical manifestations such as oral herpes and rashes on the hands and feet"
explanation: Confirms oral lesions as a hallmark feature of HFMD.
- category: Digestive
name: Drooling
frequency: OCCASIONAL
description: >-
Excessive drooling in young children secondary to painful swallowing
from oral ulcers.
phenotype_term:
preferred_term: drooling
term:
id: HP:0002307
label: Drooling
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand, foot, and mouth disease is characterized by a painful oral enanthem and asymptomatic exanthem on the palms and soles."
explanation: Painful oral enanthem causes dysphagia and drooling in young children.
- category: Digestive
name: Decreased appetite
frequency: FREQUENT
description: >-
Reduced food intake often due to painful oral ulcers.
phenotype_term:
preferred_term: decreased appetite
term:
id: HP:0004396
label: Poor appetite
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand, foot, and mouth disease is characterized by a painful oral enanthem and asymptomatic exanthem on the palms and soles."
explanation: Painful oral enanthem leads to reduced oral intake and poor appetite.
- category: Digestive
name: Sore throat
frequency: FREQUENT
description: >-
Pharyngeal pain associated with mucosal inflammation and vesicles.
phenotype_term:
preferred_term: sore throat
term:
id: HP:0025439
label: Pharyngitis
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand, foot, and mouth disease is characterized by a painful oral enanthem and asymptomatic exanthem on the palms and soles."
explanation: Painful oral enanthem includes pharyngeal involvement causing sore throat.
- category: Constitutional
name: Fever
frequency: VERY_FREQUENT
description: >-
Low to moderate grade fever typically preceding the rash by 1-2 days.
phenotype_term:
preferred_term: fever
term:
id: HP:0001945
label: Fever
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "the disease is usually benign and resolves in 7 to10 days without sequelae. Given the self-limited nature of most cases, treatment is mainly symptomatic and supportive."
explanation: Fever is part of the self-limited illness requiring symptomatic treatment.
- category: Constitutional
name: Malaise
frequency: FREQUENT
description: >-
General feeling of discomfort and illness during the prodromal and
acute phases.
phenotype_term:
preferred_term: malaise
term:
id: HP:0033834
label: Malaise
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "the disease is usually benign and resolves in 7 to10 days without sequelae."
explanation: Malaise is part of the prodromal and acute symptomatology.
- category: Constitutional
name: Irritability
frequency: FREQUENT
description: >-
Fussiness and irritability in young children, often due to pain
from oral ulcers.
phenotype_term:
preferred_term: irritability
term:
id: HP:0000737
label: Irritability
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Children younger than 5 years are most commonly affected."
explanation: Irritability is a common presentation in young children with painful oral lesions.
- category: Nervous System
name: Aseptic meningitis
frequency: VERY_RARE
description: >-
Viral meningitis occurring as a neurological complication,
predominantly with EV-A71 infection.
phenotype_term:
preferred_term: aseptic meningitis
term:
id: HP:0001287
label: Meningitis
evidence:
- reference: PMID:10029254
reference_title: "Outbreak of severe neurologic involvement associated with Enterovirus 71 infection."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Seven children with encephalitis and five with aseptic meningitis caused by Enterovirus 71 were seen at Otsu Municipal Hospital during the summer of 1997."
explanation: Directly documents aseptic meningitis occurring in children with EV-A71-associated HFMD-spectrum illness.
- category: Nervous System
name: Brainstem encephalitis
frequency: VERY_RARE
description: >-
Severe neurological complication of EV-A71 infection affecting the
brainstem, associated with high mortality and morbidity.
phenotype_term:
preferred_term: brainstem encephalitis
term:
id: HP:0002383
label: Infectious encephalitis
evidence:
- reference: DOI:10.3389/fimmu.2024.1374447
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "IP-10 and TNF-α treatments exacerbated clinical symptoms, mortality and pathological changes in the brain of CV-A16-infected mice, but Anti-IP-10 and Anti-TNF-α treatments alleviated these changes."
explanation: Demonstrates neuroinflammatory mechanisms underlying brainstem encephalitis in an animal model.
- category: Nervous System
name: Acute flaccid paralysis
frequency: VERY_RARE
description: >-
Polio-like acute flaccid paralysis as a severe neurological
complication of EV-A71 infection.
phenotype_term:
preferred_term: acute flaccid paralysis
term:
id: HP:0003470
label: Paralysis
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "the disease may be associated with potentially fatal neurological complications"
explanation: Acute flaccid paralysis is among the severe neurological complications of EV-A71 HFMD.
- category: Nervous System
name: Seizures
frequency: VERY_RARE
description: >-
Seizures occurring as part of CNS involvement in severe HFMD cases.
phenotype_term:
preferred_term: seizures
term:
id: HP:0001250
label: Seizure
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "the disease may be associated with potentially fatal neurological complications"
explanation: Seizures are part of the spectrum of neurological complications in severe HFMD.
- category: Respiratory
name: Neurogenic pulmonary edema
frequency: VERY_RARE
description: >-
Life-threatening pulmonary edema of neurogenic origin, occurring
in severe EV-A71 brainstem encephalitis due to catecholamine storm
and sympathetic hyperactivation.
phenotype_term:
preferred_term: neurogenic pulmonary edema
term:
id: HP:0100598
label: Pulmonary edema
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Circulatory failure secondary to myocardial impairment and neurogenic pulmonary edema secondary to brainstem damage are the main causes of death."
explanation: Confirms neurogenic pulmonary edema as a major cause of death in severe HFMD.
- category: Cardiovascular
name: Myocarditis
frequency: VERY_RARE
description: >-
Cardiac inflammation rarely complicating severe HFMD, particularly
with EV-A71 infection.
phenotype_term:
preferred_term: myocarditis
term:
id: HP:0012819
label: Myocarditis
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Circulatory failure secondary to myocardial impairment and neurogenic pulmonary edema secondary to brainstem damage are the main causes of death."
explanation: Confirms myocardial impairment as a contributor to mortality in severe HFMD.
- category: Metabolism
name: Dehydration
frequency: OCCASIONAL
description: >-
Dehydration from reduced oral intake due to painful mouth ulcers,
particularly in young children.
phenotype_term:
preferred_term: dehydration
term:
id: HP:0001944
label: Dehydration
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand, foot, and mouth disease is characterized by a painful oral enanthem and asymptomatic exanthem on the palms and soles."
explanation: Painful oral enanthem causes reduced fluid intake, leading to dehydration in young children.
genetic:
- name: SCARB2 polymorphisms and disease severity
notes: >-
Single nucleotide polymorphisms in the SCARB2 gene (encoding the intracellular
uncoating receptor for EV-A71) are associated with reduced risk of severe
EV-A71 HFMD. The protective variants (rs74719289 A, rs3733255 T, rs17001551 A)
suggest that host receptor genetics modulate disease outcome.
evidence:
- reference: DOI:10.17305/bb.2023.8948
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SCARB2 polymorphisms (rs74719289, rs3733255 and rs17001551) are related to the severity of EV71 infection (A vs G: OR 0.330; 95% CI 0.115 - 0.947; T vs C: OR 0.336; 95% CI 0.118 - 0.958; and A vs G: OR 0.378; 95% CI 0.145 - 0.984)"
explanation: Demonstrates protective SCARB2 SNPs reducing risk of severe EV-A71 HFMD.
environmental:
- name: Childcare and school settings
description: >-
Close contact in daycare centers and schools facilitates transmission
among young children, the primary affected population.
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Children younger than 5 years are most commonly affected."
explanation: The predominant age group (under 5) is the daycare and preschool population.
- name: Tropical and subtropical climate
description: >-
HFMD shows seasonal peaks in summer and early autumn in temperate
climates, with year-round occurrence in tropical regions.
evidence:
- reference: PMID:36226004
reference_title: "Hand, Foot and Mouth Disease: A Single Centre Retrospective Study of 403 New Cases and Brief Review of Relevant Indian Literature to Understand Clinical, Epidemiological, and Virological Attributes of a Long-Lasting Indian Epidemic."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The major peaks occurred during summers with small peaks in autumns."
explanation: Confirms summer/autumn seasonality of HFMD epidemics.
- name: Poor hygiene and sanitation
description: >-
Inadequate hand hygiene and sanitation increase fecal-oral transmission risk.
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "good personal hygiene are important preventative measures to combat the disease."
explanation: Highlights the role of hygiene in HFMD prevention.
treatments:
- name: Supportive care
description: >-
Primary management is supportive, including adequate hydration,
antipyretics for fever, and analgesics for pain relief.
treatment_term:
preferred_term: supportive care
term:
id: MAXO:0000950
label: supportive care
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "These symptoms typically resolve spontaneously within a few days without complications."
explanation: Supports supportive care as the mainstay of treatment given self-limiting nature.
- name: Antipyretic and analgesic therapy
description: >-
Acetaminophen or ibuprofen for fever and pain management,
particularly for oral ulcer pain.
treatment_term:
preferred_term: antipyretic and analgesic therapy
term:
id: MAXO:0000058
label: pharmacotherapy
evidence:
- reference: PMID:31573162
reference_title: "Hand-Foot-and-Mouth Disease: Rapid Evidence Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Treatment is supportive and directed toward hydration and pain relief as needed with acetaminophen or ibuprofen."
explanation: Directly supports acetaminophen or ibuprofen for symptomatic treatment of HFMD.
- name: EV-A71 inactivated vaccine
description: >-
An inactivated EV-A71 vaccine approved in China provides high-level
protection against EV-A71-related HFMD, but does not protect against
other enterovirus serotypes. Real-world surveillance shows sharp
reductions in EV-A71 detections following vaccine rollout.
treatment_term:
preferred_term: EV-A71 vaccination
term:
id: MAXO:0001017
label: vaccination
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "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."
explanation: Confirms the efficacy and regulatory approval of the EV-A71 vaccine.
- reference: DOI:10.1186/s12985-023-02169-x
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There was a significant reduction in the number and proportion of EV-A71 cases after 2016, from 1713 cases (13.60%) in 2013–2015 to 150 cases (1.83%) in 2017–2019."
explanation: Demonstrates real-world impact of EV-A71 vaccine on reducing EV-A71-associated HFMD.
progression:
- phase: Incubation
incubation_days: 3-6
notes: Asymptomatic period following viral exposure.
evidence:
- reference: PMID:29184105
reference_title: "Estimating the incubation period of hand, foot and mouth disease for children in different age groups."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The incubation period of HFMD was typically described as about 3-7 days but empirical evidence is lacking."
explanation: Supports the expected incubation window for HFMD prior to symptom onset.
- phase: Prodrome
duration_days: 1-2
notes: >-
Low-grade fever, malaise, decreased appetite, and sore throat
before rash onset.
evidence:
- reference: PMID:25528808
reference_title: "[The hand, foot and mouth disease. Clinical premiere in our country]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The onset of the disease was characterized by moderate fever, coryza and spontaneous endobuccal pains followed at a short interval of time by the simultaneous of a papulo-vesicular eruption on hands and feet."
explanation: Supports a short prodromal period with fever and mucosal symptoms preceding the characteristic exanthem.
- phase: Acute mucocutaneous illness
duration_days: 7-10
notes: >-
Oral enanthema appears first, followed by vesicular exanthem on
hands, feet, and buttocks. Lesions typically resolve within 7-10 days.
evidence:
- reference: PMID:31573162
reference_title: "Hand-Foot-and-Mouth Disease: Rapid Evidence Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "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"
explanation: Directly supports the acute exanthem/enanthem phase and its typical 7-10 day duration.
- phase: Resolution
notes: >-
Spontaneous resolution of lesions without scarring. Onychomadesis
may occur 4-8 weeks after acute illness.
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "These symptoms typically resolve spontaneously within a few days without complications."
explanation: Confirms self-limiting nature of typical HFMD.
epidemiology:
- name: Global incidence and pathogen shift
description: >-
Common worldwide with millions of cases annually, especially in the
Asia-Pacific region. EV-A71 vaccine rollout has shifted the dominant
pathogen from EV-A71 to CV-A6/CV-A10 in many settings.
evidence:
- reference: DOI:10.1186/s12985-023-02169-x
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A total of 29,861 laboratory-confirmed cases of HFMD-related enterovirus infection were reported from 2013 to 2022."
explanation: Demonstrates large-scale HFMD burden in a single Chinese city over 10 years.
- name: Age distribution
description: >-
Predominantly affects children under 5 years, with highest incidence
in children aged 1-3 years.
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "HFMD is a viral illness commonly seen in young children under 5 years of age"
explanation: Confirms predominant age group affected by HFMD.
- name: Seasonality
description: >-
Peaks in summer and early autumn in temperate climates; year-round
in tropical regions.
evidence:
- reference: DOI:10.2196/59604
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The 2021-2023 epidemic seasons for HFMD in Henan usually lasted from June to August, with peaks around June and July."
explanation: Confirms summer seasonality of HFMD in temperate settings.
prevalence:
- population: China (Chengdu)
notes: >-
29,861 laboratory-confirmed cases over 10 years (2013-2022) in a single
Chinese city, demonstrating high endemic burden in the Asia-Pacific region.
evidence:
- reference: DOI:10.1186/s12985-023-02169-x
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A total of 29,861 laboratory-confirmed cases of HFMD-related enterovirus infection were reported from 2013 to 2022."
explanation: Quantifies the large case burden of HFMD in a Chinese surveillance setting.
- population: India
notes: >-
403 cases at a single centre over 10 years (2009-2019), with 84% under 5
years old and male:female ratio of 1.6:1.
evidence:
- reference: PMID:36226004
reference_title: "Hand, Foot and Mouth Disease: A Single Centre Retrospective Study of 403 New Cases and Brief Review of Relevant Indian Literature to Understand Clinical, Epidemiological, and Virological Attributes of a Long-Lasting Indian Epidemic."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There were 96.8% children and adolescents (M:F 1.6:1) aged 2 months to 18 years and 84% were aged <5 years."
explanation: Demonstrates HFMD demographic pattern in an Indian cohort.
diagnosis:
- name: Clinical diagnosis
description: >-
HFMD is usually diagnosed clinically from the characteristic combination of
low-grade fever, oral ulcerations, and acral papulovesicular rash on the
hands and feet.
diagnosis_term:
preferred_term: physical examination
term:
id: MAXO:0000527
label: physical examination
evidence:
- reference: PMID:31573162
reference_title: "Hand-Foot-and-Mouth Disease: Rapid Evidence Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Patients present with a low-grade fever, a maculopapular or papulovesicular rash on the hands and soles of the feet, and painful oral ulcerations."
explanation: Supports bedside clinical recognition of HFMD based on its characteristic symptom constellation.
- name: Enterovirus RT-PCR and sequencing confirmation
description: >-
Molecular confirmation with RT-PCR, with or without sequencing, can confirm
EV-A71 infection from clinical specimens in severe or atypical cases.
diagnosis_term:
preferred_term: nucleic acid amplification testing
term:
id: MAXO:0000589
label: nucleic acid amplification testing
evidence:
- reference: PMID:39599865
reference_title: "Identification of the Emerging C1-like Lineage of Enterovirus A71 in Two Uruguayan Children with Hand-Foot-and-Mouth Disease and Neurological Complications."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "EV-A71 was identified through RT-PCR and next-generation sequencing of stool and skin lesion samples."
explanation: Directly supports molecular confirmation of EV-A71-associated HFMD from patient specimens.
differential_diagnoses:
- name: Herpangina
description: >-
Also caused by enteroviruses (especially Coxsackievirus A), herpangina
presents with posterior oropharyngeal vesicles and ulcers but without the
characteristic hand and foot exanthem of HFMD.
distinguishing_features:
- Vesicles limited to posterior oropharynx (soft palate, tonsillar pillars)
- Absence of hand and foot skin lesions
- More prominent fever, often higher than in HFMD
disease_term:
preferred_term: herpangina
term:
id: MONDO:0005791
label: herpangina
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand, foot, and mouth disease is characterized by a painful oral enanthem and asymptomatic exanthem on the palms and soles."
explanation: The distinguishing feature of HFMD from herpangina is the presence of exanthem on palms and soles, which is absent in herpangina.
- name: Herpes simplex gingivostomatitis
description: >-
Primary herpes simplex virus (HSV) infection in young children presents
with painful oral vesicles and ulcers resembling HFMD oral enanthema.
distinguishing_features:
- Vesicles typically involve gingiva and anterior mouth
- No hand or foot exanthem
- Lesions often more extensive and hemorrhagic
- Responds to acyclovir therapy
disease_term:
preferred_term: herpes simplex gingivostomatitis
term:
id: MONDO:0005792
label: herpes simplex virus gingivostomatitis
evidence:
- reference: PMID:36284392
reference_title: "Hand, Foot, and Mouth Disease: A Narrative Review."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hand, foot, and mouth disease is characterized by a painful oral enanthem and asymptomatic exanthem on the palms and soles."
explanation: HFMD is distinguished from HSV gingivostomatitis by the characteristic exanthem on palms and soles, which is absent in HSV infection.
- name: Chickenpox
description: >-
Varicella-zoster virus infection causes a generalized vesicular rash
that can overlap with atypical HFMD presentations.
distinguishing_features:
- Centripetal rash distribution (trunk-predominant)
- Lesions in different stages (macules, papules, vesicles, crusts)
- Pruritic rather than painful
- Does not preferentially involve palms and soles
disease_term:
preferred_term: chickenpox
term:
id: MONDO:0005700
label: chickenpox
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "characterized by typical manifestations such as oral herpes and rashes on the hands and feet"
explanation: HFMD is distinguished from chickenpox by its acral distribution (hands and feet) versus the centripetal trunk-predominant distribution of varicella.
- name: Erythema multiforme
description: >-
Immune-mediated mucocutaneous reaction that can present with target
lesions and oral erosions mimicking HFMD.
distinguishing_features:
- Classic target or iris-shaped lesions
- Often triggered by HSV or medications
- Lesions are non-vesicular targets rather than true vesicles
disease_term:
preferred_term: erythema multiforme
term:
id: MONDO:0006545
label: erythema multiforme
evidence:
- reference: DOI:10.1186/s12929-023-00908-4
supports: SUPPORT
evidence_source: OTHER
snippet: "characterized by typical manifestations such as oral herpes and rashes on the hands and feet"
explanation: HFMD vesicular lesions on hands and feet are distinguished from the target/iris-shaped lesions of erythema multiforme.
clinical_trials:
- name: NCT03281174
phase: PHASE_IV
status: COMPLETED
description: >-
A five-year immune persistence study evaluating the durability of
antibody responses following inactivated EV-A71 vaccination
(Sinovac Biotech).
evidence:
- reference: clinicaltrials:NCT03281174
supports: SUPPORT
snippet: "The purpose of this study is to evaluate the 5-year Immune Persistence of Inactivated Enterovirus Type 71 (EV71) Vaccine manufactured by Sinovac (Beijing) Biotech Co., Ltd."
explanation: Evaluates long-term immune persistence of the approved EV-A71 vaccine.
- name: NCT01376479
phase: PHASE_I
status: COMPLETED
description: >-
A Phase I, double-blind, randomized, placebo-controlled dose escalation
study to assess safety and immunogenicity of a prophylactic EV-A71
vaccine in healthy adults.
evidence:
- reference: clinicaltrials:NCT01376479
supports: SUPPORT
snippet: "The purpose of this study is to evaluate the safety and immune response of an inactivated vaccine to prevent hand, foot and mouth disease (HFMD) caused by Enterovirus 71 (EV71)."
explanation: Documents early-phase EV-A71 vaccine development.
animal_models:
- species: Mouse
genotype: suckling mouse infection model
description: >-
Neonatal mouse model of CV-A16 infection used to study IP-10/TNF-alpha-driven
blood-brain barrier injury, brain pathology, and mortality in severe HFMD.
associated_phenotypes:
- Brain pathology
- Increased mortality
- Neuroinflammation
evidence:
- reference: DOI:10.3389/fimmu.2024.1374447
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "in a suckling mouse model, IP-10 and TNF-α treatments exacerbated clinical symptoms, mortality and pathological changes in the brain of CV-A16-infected mice, but Anti-IP-10 and Anti-TNF-α treatments alleviated these changes."
explanation: Supports a neonatal mouse model that recapitulates key CNS manifestations of severe HFMD and is experimentally tractable for mechanistic studies.
- species: Mouse
genotype: EV71 microvesicle-mediated neuroinvasion model
description: >-
Mouse model used to study EV71 transport across the blood-brain barrier and
the resulting brain injury after systemic infection.
associated_phenotypes:
- Cerebral hemorrhage
- Brain inflammatory infiltration
- Blood-brain barrier disruption
evidence:
- reference: PMID:40229831
reference_title: "Microvesicles carrying EV71 virions cross BBB through endocytic pathway to induce brain injury."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Also, our investigation unveiled that MVsEV71 infection of animals induced cerebral hemorrhage and more severe inflammatory infiltration in the brain compared to animals infected by EV71 in vivo."
explanation: Supports a mouse EV71 neuroinvasion model that reproduces BBB crossing and inflammatory brain injury relevant to severe HFMD.
datasets:
- accession: geo:GSE269965
title: Effects of Monocyte/Macrophages on the Severity of Hand, Foot, and Mouth Disease Patients due to Enterovirus
description: >-
Transcriptomic analysis of monocyte/macrophage populations from HFMD patients
investigating immune cell contributions to disease severity.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: SINGLE_CELL_RNA_SEQ
evidence:
- reference: PMID:40918094
reference_title: "Integrative scRNA-seq and transcriptomic analysis initially reveals monocyte/macrophage activation drives EV-A71-induced immune dysregulation and neural injury in severe HFMD."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Single-cell sequencing technology was used to sequence obtained PBMCs from a severe HFMD patient due to EV-A71 and a healthy control."
explanation: Supports this dataset as a severe-HFMD single-cell PBMC resource focused on monocyte/macrophage activation.
- accession: geo:GSE261751
title: "Enterovirus-A71 Preferentially Infects and Replicates in Human Motor Neurons, Inducing Neurodegeneration by Ferroptosis"
description: >-
Gene expression profiling of human motor neurons infected with EV-A71,
investigating viral neurotropism and motor neuron vulnerability.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: SINGLE_CELL_RNA_SEQ
evidence:
- reference: PMID:39017655
reference_title: "Enterovirus-A71 preferentially infects and replicates in human motor neurons, inducing neurodegeneration by ferroptosis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Single cell transcriptomics of a mixed neuronal population reveal higher viral RNA load in motor neurons, suggesting higher infectivity and replication of EV-A71 in motor neurons."
explanation: Supports this dataset as a human motor-neuron single-cell transcriptomic resource relevant to EV-A71 neurotropism.
- accession: geo:GSE212105
title: Coxsackievirus A10 impairs nail regeneration and induces onychomadesis by mimicking DKK1 to attenuate Wnt signaling
description: >-
Transcriptomic study of CV-A10-induced nail matrix damage in a mouse model,
elucidating the mechanism of post-HFMD onychomadesis.
organism:
preferred_term: mouse
term:
id: NCBITaxon:10090
label: Mus musculus
data_type: BULK_RNA_SEQ
evidence:
- reference: PMID:38836810
reference_title: "Coxsackievirus A10 impairs nail regeneration and induces onychomadesis by mimicking DKK1 to attenuate Wnt signaling."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Here, we found that CV-A10 infection in mice could suppress Wnt/β-catenin signaling by restraining LDL receptor-related protein 6 (LRP6) phosphorylation and β-catenin accumulation and lead to onychomadesis."
explanation: Supports this dataset as a mouse transcriptomic/modeling resource for CV-A10-associated onychomadesis after HFMD.