The Hand, Foot, and Mouth Disease Sentinel Surveillance System in South Korea: Retrospective Evaluation Study.

Background: South Korea has implemented a hand, foot, and mouth disease (HFMD) surveillance system since 2009 to monitor incidence trends and identify disease burden. This nationwide surveillance involves a network of approximately 100 pediatric clinics that report all probable and confirmed HFMD cases. Following the COVID-19 pandemic, infectious disease surveillance systems must be evaluated to ensure the effective use of limited public health resources. Objective: This study aimed to evaluate the HFMD sentinel surveillance system in South Korea from 2017 to 2022, focusing on the transition period after the COVID-19 pandemic. Methods: We retrospectively reviewed the HFMD sentinel surveillance system from the Korea Disease Control and Prevention Agency using systematic guidelines for public health surveillance system evaluation developed by the US Centers for Disease Control and Prevention. We assessed the system's overall performance in 5 main factors: timeliness, stability, completeness, sensitivity, and representativeness (ie, the age and geographic distribution of sentinels). We rated these factors as weak, moderate, or good. Results: Our study showed that the completeness, sensitivity, and age representativeness of the HFMD surveillance performance were temporarily reduced to moderate levels from 2020 to 2021 and recovered in 2022, while the timeliness and geographic representativeness were maintained at a good level throughout the study period. The stability of the surveillance was moderate from 2017 to 2021 and weak in 2022. Conclusions: This is the first study to evaluate the HFMD surveillance system after the acute phase of the COVID-19 pandemic. We identified a temporarily reduced level of performance (ie, completeness, sensitivity, and age-specific representativeness) during the acute phase of the pandemic and good performance in 2022. Surveillance system evaluation and maintenance during public health emergencies will provide robust and reliable data to support public health policy development. Regular staff training programs and reducing staff turnover will improve HFMD surveillance system stability.

Novel Anti-Enterovirus A71 Compounds Discovered by Repositioning Antivirals from the Open-Source MMV Pandemic Response Box.

The open-source drug library, namely, MMV Pandemic Response Box, contains 153 antiviral agents, a chemically and pharmacologically diverse mixture of early-stage, emerging anti-infective scaffolds, and mature compounds currently undergoing clinical development. Hence, the Pandemic Response Box might contain compounds that bind and interfere with target molecules or cellular pathways that are conserved or shared among the closely related viruses with enterovirus A71 (EV-A71). This study aimed to screen antiviral agents included in the Pandemic Response Box for repurposing to anti-EV-A71 activity and investigate the inhibitory effects of the compounds on viral replication. The compounds' cytotoxicity and ability to rescue infected cells were determined by % cell survival using an SRB assay. The hit compounds were verified for anti-EV-A71 activity by virus reduction assays for viral RNA copy numbers, viral protein synthesis, and mature particle production using qRT-PCR, Western blot analysis, and CCID50 assay, respectively. It was found that some of the hit compounds could reduce EV-A71 genome replication and protein synthesis. D-D7 (2-pyridone-containing human rhinovirus 3C protease inhibitor) exhibited the highest anti-EV-A71 activity. Even though D-D7 has been originally indicated as a polyprotein processing inhibitor of human rhinovirus 3C protease, it could be repurposed as an anti-EV-A71 agent.

Recurrent Hand, Foot, and Mouth Disease in a Saudi Girl.

Hand, foot, and mouth disease (HFMD) is a viral illness that predominantly affects infants and children, causing blisters and sores on the hands, feet, and mouth. Recurrence is rare, but a case in a six-year-old girl in Saudi Arabia was reported. A six-year-old girl presented with a rash on her palms and soles, which was preceded by a mild sore throat and low-grade fever. She had been in contact with her two-year-old sister, who had similar symptoms but a different rash pattern.  During clinical examination, multiple erythematous deep-seated vesicles and papules were noted on the patient's palms and soles, with no involvement of mucous membranes or nails. The diagnosis of hand, foot, and mouth disease (HFMD) was made based on the characteristic clinical presentation, and the rash resolved within seven days without treatment or complications.  The patient had experienced a similar presentation six months ago, which was also diagnosed as HFMD, and the rash had resolved spontaneously within one week. In her second episode, the rash was less severe, with milder prodromal symptoms. In both episodes, the lesions were asymptomatic and had no mucosal involvement. The patient had experienced onychomadesis after her first episode, but no nail abnormalities were seen after her second episode. Although HFMD is rare to recur in children, outbreaks can lead to another episode. HFMD prevalence is underestimated in Saudi Arabia due to missed mild cases. Pediatricians and dermatologists should be aware of HFMD incidence and its complications, as early detection is vital in preventing outbreaks and transmission.

Atypical cutaneous findings of hand-foot-mouth disease in children: A systematic review.

INTRODUCTION: Hand-foot-mouth disease (HFMD) is a common childhood infectious disease. Atypical skin findings of HFMD, often associated with coxsackievirus A6 (CVA6), were first reported in 2008, with increasing reports worldwide since. Atypical lesions of HFMD often involve sites beyond the palms and soles and tend to have unusual, polymorphic morphology. METHODS: A systematic review was conducted on clinical features and outcomes of pediatric HFMD with atypical cutaneous manifestations. RESULTS: Eighty-five studies were included, representing 1359 cases with mean age 2.4 years and a male predominance of 61%. The most reported morphologies were vesicles (53%), papules (49%), and bullae (36%). Other morphologies included eczema herpeticum-like (19%), purpuric/petechial (7%), and Gianotti Crosti-like (4%). Common atypical sites included the arms and/or legs (47%), face (45%), and trunk (27%). CVA6 was identified in 63% of cases. Symptoms resolved in a mean of 10 days. Overall, 16% of cases received treatment, most commonly with acyclovir, intravenous antibiotics, or topical steroids. The most common complications were nail changes (21%) and desquamation (4%) which occurred a mean of 3 and 2 weeks after symptoms, respectively. CONCLUSION: Due to unusual morphologies resembling other conditions, HFMD with atypical cutaneous findings may be misdiagnosed, leading to inappropriate and unnecessary investigations, hospitalization, and treatment. Greater awareness of atypical presentations of HFMD is warranted to improve patient care and counseling on infection control precautions.

Down-regulated TAB1 suppresses the replication of Coxsackievirus B5 via activating the NF-κB pathways through interaction with viral 3D polymerase.

Coxsackievirus Group B type 5 (CVB5), an important pathogen of hand-foot-mouth disease, is also associated with neurological complications and poses a public health threat to young infants. Among the CVB5 proteins, the nonstructural protein 3D, known as the Enteroviral RNA-dependent RNA polymerase, is mainly involved in viral genome replication and transcription. In this study, we performed immunoprecipitation coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify host proteins that interacted with CVB5 3D polymerase. A total of 116 differentially expressed proteins were obtained. Gene Ontology analysis identified that the proteins were involved in cell development and cell adhesion, distributed in the desmosome and envelope, and participated in GTPase binding. Kyoto Encyclopedia of Genes and Genomes analysis further revealed they participated in nerve diseases, such as Parkinson disease. Among them, 35 proteins were significantly differentially expressed and the cellular protein TGF-BATA-activated kinase1 binding protein 1 (TAB1) was found to be specifically interacting with the 3D polymerase. 3D polymerase facilitated the entry of TAB1 into the nucleus and down-regulated TAB1 expression via the lysosomal pathway. In addition, TAB1 inhibited CVB5 replication via inducing inflammatory factors and activated the NF-κB pathway through IκBα phosphorylation. Moreover, the 90-96aa domain of TAB1 was an important structure for the function. Collectively, our findings demonstrate the mechanism by which cellular TAB1 inhibits the CVB5 replication via activation of the host innate immune response, providing a novel insight into the virus-host innate immunity.

Hand, Foot, and Mouth Disease in Adults.

Hand, foot, and mouth disease (HFMD) is a viral infection primarily affecting children, but it can occur in individuals of all ages. In this article, we present the atypical case of a 36-year-old male with no significant medical history who recurred to the emergency department with a three-day history of fever, sore throat, and a maculopapular rash. After an extended evaluation with normal blood tests, he was discharged home with a diagnosis of HFMD. This case underscores the importance of considering HFMD when evaluating adult patients with rashes, and patients should be reassured about the self-limiting nature of the disease.

Guillain-Barré Syndrome Following Hand, Foot, and Mouth Disease in an Adult Patient.

Guillain-Barré syndrome (GBS) stands as one of the primary causes of acute flaccid paralysis. It includes acute-onset peripheral nerve lesions and typically follows a monophasic course. Its etiopathogenesis is linked to an immune-mediated response to a prior infection, often respiratory or intestinal. The main variants of GBS are acute inflammatory demyelinating polyneuropathy, which accounts for approximately 90% of cases in the USA and Europe, and acute motor axonal neuropathy, responsible for about 10% of cases in the USA and Europe. From the literature review, only one case of GBS preceded by hand, foot, and mouth disease (HFMD) has been described. The authors report a rare clinical case of typical GBS after HFMD. Recognizing this adult-onset disease as a potential preceding infection of GBS is crucial for early diagnosis and treatment. Additionally, the integration into a rehabilitation program adjusted to the deficits plays an important role in motor and functional recovery.

Severe pneumonia and pathogenic damage in human airway epithelium caused by Coxsackievirus B4.

Coxsackievirus B4 (CVB4) has one of the highest proportions of fatal outcomes of other enterovirus serotypes. However, the pathogenesis of severe respiratory disease caused by CVB4 infection remains unclear. In this study, 3 of 42 (7.2%, GZ-R6, GZ-R7 and GZ-R8) patients with severe pneumonia tested positive for CVB4 infection in southern China. Three full-length genomes of pneumonia-derived CVB4 were sequenced and annotated for the first time, showing their high nucleotide similarity and clustering within genotype V. To analyze the pathogenic damage caused by CVB4 in the lungs, a well-differentiated human airway epithelium (HAE) was established and infected with the pneumonia-derived CVB4 isolate GZ-R6. The outcome was compared with that of a severe hand-foot-mouth disease (HFMD)-derived CVB4 strain GZ-HFM01. Compared with HFMD-derived CVB4, pneumonia-derived CVB4 caused more intense and rapid disruption of HAE polarity, leading to tight-junction barrier disruption, loss of cilia, and airway epithelial cell hypertrophy. More pneumonia-derived CVB4 were released from the basolateral side of the HAE than HFMD-derived CVB4. Of the 18 cytokines tested, only IL-6 and IL-1b secretion significantly increased on bilateral sides of HAE during the early stage of pneumonia-derived CVB4 infection, while multiple cytokine secretions significantly increased in HFMD-derived CVB4-infected HAE. HFMD-derived CVB4 exhibited stronger neurovirulence in the human neuroblastoma cells SH-SY5Y than pneumonia-derived CVB4, which is consistent with the clinical manifestations of patients infected with these two viruses. This study has increased the depth of our knowledge of severe pneumonia infection caused by CVB4 and will benefit its prevention and treatment.

A Case of Hand-Foot-and-Mouth Disease in an Adult Male.

Hand-foot-and-mouth disease (HFMD) is commonly seen in infants and children; less frequently, it may be seen in adults as well. The disease is usually associated with viral infections, including many variants of enteroviruses and coxsackieviruses. We discuss the case of a 39-year-old male who presented with constitutional symptoms, fever, and lesions on his hands, feet, and mouth. His children, who had been recently diagnosed with HFMD, were likely the source of his infection. A comprehensive history and physical examination enabled us to identify the lesions, some of which were faint and difficult to visualize. Viral panel testing indicated positive results for human rhinovirus/enterovirus. Treatment and testing associated with the patient's condition were supportive, largely based on the history and physical findings which helped us narrow down our differential diagnoses. Complete resolution of the symptoms within one to two weeks is generally expected in these patients.

SHFL inhibits enterovirus A71 infection by triggering degradation of viral 3Dpol protein via the ubiquitin-proteasome pathway.

Enterovirus A71 (EV-A71) is a highly contagious virus that poses a major threat to global health, representing the primary etiological agent for hand-foot and mouth disease (HFMD) and neurological complications. It has been established that interferon signaling is critical to establishing a robust antiviral state in host cells, mainly mediated through the antiviral effects of numerous interferon-stimulated genes (ISGs). The host restriction factor SHFL is a novel ISG with broad antiviral activity against various viruses through diverse underlying molecular mechanisms. Although SHFL is widely acknowledged for its broad-spectrum antiviral activity, it remains elusive whether SHFL inhibits EV-A71. In this work, we validated that EV-A71 triggers the upregulation of SHFL both in cell lines and in a mouse model. Knockdown and overexpression of SHFL in EVA71-infected cells suggested that this factor could markedly suppress EV-A71 replication. Our findings further revealed an intriguing mechanism of SHFL that it could interact with the nonstructural proteins 3Dpol of EV-A71 and promoted the degradation of 3Dpol through the ubiquitin-proteasome pathway. Furthermore, the zinc-finger domain and the 36 amino acids (164-199) of SHFL were crucial to the interaction between SHFL and EV-A71 3Dpol . Overall, these findings broadened our understanding of the pivotal roles of SHFL in the interaction between the host and EV-A71.

Triaging cases of fever with vesicular rash relevant to the monkeypox epidemic.

Fever with a vesicular rash is a common clinical scenario and monkeypox (MPX) characteristically presents as a fever with a vesiculopustular rash. The clinical morphology of MPX mimics many infectious and non-infectious disorders, and narrowing down the differentials of vesiculopustular rash necessitates thorough history taking and physical examination. The clinical evaluation involves the assessment of the primary skin lesions, sites of involvement, distribution, number and size of lesions, and pattern of progression of the rash, along with the onset of the rash relative to the occurrence of fever and other systemic signs. Common disorders which are close differentials include Varicella, Erythema Multiforme, enteroviral exanthems, and disseminated herpes simplex. Distinct clinical indicators of MPX include the presence of deep-seated umbilicated vesiculopustules, lymphadenopathy, involvement of the palms and soles, centrifugal spread, and genital involvement. We delineate and enlist features of common disorders presenting as vesiculopustular rash, which can help the clinician differentiate them from MPX.

Isolation and Characterization of scFv Antibody against Internal Ribosomal Entry Site of Enterovirus A71.

Enterovirus A71 (EV-A71) is one of the causative agents of hand-foot-mouth disease, which can be associated with neurocomplications of the central nervous system. A limited understanding of the virus's biology and pathogenesis has led to the unavailability of effective anti-viral treatments. The EV-A71 RNA genome carries type I internal ribosomal entry site (IRES) at 5' UTR that plays an essential role in the viral genomic translation. However, the detailed mechanism of IRES-mediated translation has not been elucidated. In this study, sequence analysis revealed that the domains IV, V, and VI of EV-A71 IRES contained the structurally conserved regions. The selected region was transcribed in vitro and labeled with biotin to use as an antigen for selecting the single-chain variable fragment (scFv) antibody from the naïve phage display library. The so-obtained scFv, namely, scFv #16-3, binds specifically to EV-A71 IRES. The molecular docking showed that the interaction between scFv #16-3 and EV-A71 IRES was mediated by the preferences of amino acid residues, including serine, tyrosine, glycine, lysine, and arginine on the antigen-binding sites contacted the nucleotides on the IRES domains IV and V. The so-produced scFv has the potential to develop as a structural biology tool to study the biology of the EV-A71 RNA genome.

Hand, Foot, and Mouth Disease Outbreak What You Need to Know.

HFMD is an obvious disease in children mostly below the age of five constituting a public health challenge to Asian-Pacific and developing countries majorly. This disease is often caused by enterovirus 71 (EV71) and Coxsackievirus A16. HFMD is a mild degree fever and general illness which manifests for about 10 days. Young age, male gender, poor hygiene, and high social contacts are some risk factors. HFMD can be diagnosed clinically by isolating the virus from stool and pharynx and identifying it on Light microscopic examination. Polymerase Chain Reaction Assay is a gold standard for confirming the virus from swabbed lesions. Late confirmation could lead to severe complications. There are no specific treatments and vaccines licensed for general use in the treatment of various serotypes of HFMD. The major strategy to prevent and control this disease is to strictly follow the WHO 8 guidelines to curb the spread of the disease.

Hand-Foot-Mouth Disease in an Adult.

Hand-foot-mouth syndrome is a common childhood illness. Although occurrence in adults is rare, its incidence has been increasing. In such cases, it usually presents with atypical symptoms. The authors present the case of a 33-year-old male patient who presented with constitutional symptoms, feverish sensation, and macular palmoplantar rash associated with oral and oropharynx ulcers. The epidemiological history revealed exposure to two cohabitants (children) with a recent diagnosis of hand-foot-mouth disease (HFMD).

Establishment of the 1st Chinese national standard for CA6 neutralizing antibody.

Coxsackievirus A6 (CA6) is one of the major causative agents of herpangina and hand-foot-mouth disease (HFMD). Since 2008, CA6 has circulated widely around the world. Especially in Asia-Pacific region CA6 had even replaced enterovirus A71 (EV71) and coxsackievirus A16 (CA16) as the main prevalent strain of HFMD. In the recent 10 years, monovalent and multivalent vaccines against CA6 have been researched and developed by manufacturers from China, Korea, and the USA. The neutralizing antibody titer is a key indicator for accurately evaluating immunogenicity of vaccine. However, so far, the World Health Organization international standard for CA6 neutralizing antibody has not been available. In order to meet the needs of evaluating the immunogenicity of vaccines against CA6, the first Chinese national standard for CA6 neutralizing antibody was established, which was conducted to ensure that methods used to measure the neutralizing antibody titers against CA6 are accurate, reliable, and comparable. Three lyophilized candidate standards (29#, 39# and 44#) were produced with 0.40 ml/vial from plasma samples donated by healthy individuals. The collaborative study showed that the 29# candidate standard could effectively minimize the variability in neutralization titers between labs and across challenging viruses of different genotypes (A, D1, and D3). Therefore, the 29# candidate sample was established as the first Chinese national standard for CA6 neutralizing antibody test. This standard has good long-term stability and was assigned a potency of 150 units per milliliter (U/ml) of CA6 neutralizing antibody. It will contribute to ensure uniformity of potency or activity of vaccines and potentially therapeutic antibody preparations.

Epidemiological characteristics and etiological changes of hand-foot-mouth disease in Shijiazhuang City in 2009-2021 / 公共卫生与预防医学

Objective To understand the epidemiological and etiological characteristics of hand-foot-mouth disease (HFMD) in Shijiazhuang City from 2009 to 2021, and to provide scientific evidence for the prevention and control of HFMD. Methods The epidemic data and etiological data of HFMD in Shijiazhuang City from 2009 to 2021 were collected, and descriptive epidemiological methods were used for data analysis. Results The reported incidence of HFMD in Shijiazhuang showed a fluctuating downward trend from 2009 to 2021, with a high incidence every other year in most years. The proportion of severe cases and the mortality rate showed a decreasing trend (χ2severe cases=282.09, P2mortality=51.33, P2=4 507.84，Pr=-2.85，P22 =521.86，P2proportion of severe cases=93.71，P=0.000，χ2mortality rate=26.62，P=0.000，χ2proportion of EV71=1060.86，P=0.000). Conclusion The incidence of HFMD in Shijiazhuang presented a declining trend, and the dominant etiological changes of different cases were different. It is necessary to continue to strengthen the etiological monitoring, health education and EV71 vaccination for the prevention and control of HFMD.

Progress in research on Coxsackievirus A6 / 中国生物制品学杂志

@#Hand-foot-mouth disease(HFMD) is an infectious disease that seriously affects the health of infants and young children and has become a major public health problem worldwide,especially in the Asia-Pacific region.HFMD can be caused by a variety of enteroviruses,the most common being enterovirus 71(EV71) and Coxsackievirus A16(CVA16).In recent years,with the significant increase of HFMD caused by Coxsackievirus A6(CVA6) infection,CVA6 has gradually become the main pathogen of HFMD in many countries and regions around the world.CVA6 is not only susceptible to children,but also infects adults with normal immune function.The paper reviewed the CVA6 related etiology,epidemiology,clinical symptoms,laboratory diagnosis and development of vaccine.

Distribution and type characteristics of HPV infection of women in Shiyan , Hubei Region / 公共卫生与预防医学

Objective To analyze the distribution and type characteristics of human papillomavirus (HPV) infection in women in Shiyan, Hubei region, so as to provide a basis for the prevention and treatment of HPV infection. Methods From January 2019 to December 2020, a sample of 3,180 women in XX region who had sexual intercourse experience were randomly selected, and their HPV genotypes were tested using flow-through hybridization, then the distribution characteristics and types of HPV infection in women of different ages were observed. Results Among of 3 180 patients, HPV infection was predominant in women aged 31-50 years , with 25.85% (822/3 180) aged 31-40 years and 22.08% (702/3,180) aged 41-50 years. HPV infection was the least prevalent in the ≤25 and >60 years age groups, with 428 cases and 289 cases respectively. HPV infection occurred in 1 310 out of 3 180 women , with a positive infection rate of 41.19% (1 310/3 180). HPV infection was most prevalent in the ≤25 years and ≥60 years age groups, accounting for 56.78% and 67.13% respectively. Single infection was the main infection type in all age groups, accounting for 76.03%. Twenty-one HPV genetic subtypes were detected in the subjects, out of a total of 1 918 strains of the virus. The main high-risk subtypes for single infection were HPV16, HPV52 and HPV58, accounting for 13.92%, 13.87% and 12.57% respectively, followed by HPV53 and HPV33, accounting for 7.61% and 5.58% respectively. The predominant low-risk subtypes for single infection were HPV11, HPV8 and HPV6, with accounting for 7.51%, 5.47% and 5.01% respectively. Conclusion HPV infection in women in Shiyan, Hubei region is predominantly in the ≤25 and ≥60 years age groups, and early clinical screening and preventive measures such as vaccination for high-risk HPV typing are of vital importance.

The Bottlenecks of Preparing Virus Particles by Size Exclusion for Antibody Generation.

Enterovirus 71 (EV71) is the major etiological agent contributing to the development of hand-foot-mouth disease (HFMD). There are not any global available vaccines or antibody drugs against EV71 released yet. In this study, we perform the virus immunization in a cost-effective and convenient approach by preparing virus particles from size exclusion and immunization of chicken. Polyclonal yolk-immunoglobulin (IgY) was simply purified from egg yolk and monoclonal single-chain variable fragments (scFv) were selected via phage display technology with two scFv libraries containing 6.0 × 106 and 1.3 × 107 transformants. Specific clones were enriched after 5 rounds of bio-panning and four identical genes were classified after the sequence analysis. Moreover, the higher mutation rates were revealed in the CDR regions, especially in the CDR3. IgY showed specific binding activities to both EV71-infected and Coxsackievirus 16-infected cell lysates and high infectivity inhibitory activity of EV71. However, while IgY detected a 37 kDa protein, the selected scFv seemingly detected higher size proteins which could be cell protein instead of EV71 proteins. Despite the highly effective chicken antibody generation, the purity of virus particles prepared by size exclusion is the limitation of this study, and further characterization should be carried out rigorously.