Atypical Hand, Foot, And Mouth Disease Research Articles

Emerging concerns of atypical hand foot and mouth disease caused by recombinant Coxsackievirus A6 variants in Henan, China.

An increasing number of studies have reported that atypical hand, foot, and mouth disease (HFMD) is becoming a new concern for children's health. At present, there is no official definition for atypical HFMD, but some studies have defined that it occurs at anatomic sites not listed in the definition of HFMD issued by the World Health Organization. Several pathogens have been reported to cause atypical HFMD, such as Coxsackievirus (CV)A6. As one of the most prevalent enteroviruses in the world, CVA6 seems to affect a wider range of children and causes more severe and prolonged illness than other enteroviruses. The early lesions of atypical HFMD are very similar to the clinical presentations of other diseases, such as eczema, which poses a challenge for clinicians aiming to identify and diagnose HFMD in a timely manner. Here, we report on six atypical HFMD patients caused by recombinant CVA6 variants, and the atypical manifestations include eczema coxsackium, large herpes, rice-like red papules and herpes, purpuric rash, and onychomadesis, as well as and large red herpes on scalp, perianal, testicles, shoulders and neck, and other atypical eruption sites, hoping to draw the attention of other pediatricians. This study will provide scientific guidance for timely diagnosis of HFMD to prevent serious complications.

Coxsackievirus A6 2C protein antagonizes IFN-β production through MDA5 and RIG-I depletion.

Coxsackievirus A6 (CV-A6) is a major emerging pathogen associated with atypical hand, foot, and mouth disease and can cause serious complications such as encephalitis, acute flaccid paralysis, and neurorespiratory syndrome. Therefore, revealing the associated pathogenic mechanisms could benefit the control of CV-A6 infections. In this study, we demonstrate that the nonstructural 2CCV-A6 suppresses IFN-β production, which supports CV-A6 infection. This is achieved by depleting RNA sensors such as melanoma differentiation-associated gene 5 and retinoic acid-inducible gene I (RIG-I) through the lysosomal pathway. Such a function is shared by 2CEV-A71 and 2CCV-B3 but not 2CCV-A16, suggesting the latter might have an alternative way to promote viral replication. This study broadens our understanding of enterovirus 2C protein regulation of the RIG-I-like receptor signaling pathway and reveals a novel mechanism by which CV-A6 and other enteroviruses evade the host innate immune response. These findings on 2C may provide new therapeutic targets for the development of effective inhibitors against CV-A6 and other enterovirus infections.

Arising Concerns of Atypical Manifestations in Patients with Hand, Foot, and Mouth Disease.

Hand, foot, and mouth disease (HFMD) is a mild exanthematous, febrile disease, but it also remains a threat to global public health. HFMD is characterized by a brief febrile illness in children and with a typical skin rash of the hand and foot, with or without mouth ulcers. However, the morphology and distribution of vesicles, as well as accompanying symptoms, are varied among atypical HFMD. An upsurge in atypical presentations of HFMD caused by Coxsackievirus A6 (CVA6), including Gianotti-Crosti-like eruptions, eczema coxsackium, petechial/purpuric eruption, and vesiculobullous exanthema, can be difficult to diagnose clinically as it may mimic other severe skin diseases, such as eczema herpeticum, varicella, disseminated zoster, and erythema multiforme major. The recognition of the distinguishing features of atypical HFMD is vital for an accurate and timely diagnosis, as is initiating appropriate laboratory evaluation and supportive care. Clinicians must identify the wide range of cutaneous and mucosal alterations caused by atypical HFMD. A systemic, high-quality overview of atypical HFMD is needed for advances in better strategies for clinical diagnosis and treatment. Hence, this review is aimed at summarizing the available data on clinical investigations and differential diagnostics to provide a scientific guide for the timely diagnosis of HFMD for preventing serious complications.

Clinical characteristics of 68 children with atypical hand, foot, and mouth disease caused by coxsackievirus A6: a single-center retrospective analysis.

BackgroundHand, foot, and mouth disease (HFMD) caused by coxsackievirus A6 (CV-A6) has become prevalent in many parts of the world. It is commonly referred to as atypical HFMD which more likely to present as bullous lesions. Compared with traditional HFMD, its misdiagnosis rate is relatively high, which brings difficulties to clinical diagnosis. We retrospectively analyze the clinical characteristics of children with HFMD with bullous lesions caused by CV-A6.MethodsThe study included 68 children with atypical HFMD caused by CV-A6 who were hospitalized from 2018 to 2020. Data of the children including age, sex, month of HFMD onset, the morphologies and distribution of rashes, the details of fever, the presence or absence of onychomadesis, and laboratory test results were analyzed and compared between an infant group (<1 year), a toddler group (1–<3 years), and a preschool group (3–<6 years).ResultsOf the 68 children, 67 were younger than 5 years old, with a male to female ratio of 1.62:1. The disease peaked in the period from June to September. With 75.0% of the infant group had more than three kinds of rashes; 95.0% of the preschool group had rashes in more than five locations. These differences were statistically significant (P<0.05). All children had fever. The peak fever in the toddler group was lower (P=0.033). No critical cases were observed in any of the groups. Of the 61 children who were successfully followed up, 68.9% developed onychomadesis within 2–3 weeks. The proportion of cases with abnormal liver function was 83.3%, 41.7%, and 10.0% in the infant, toddler, and preschool groups (P<0.001). The proportion of cases with increased serum creatine kinase MB isoenzyme (CK-MB) were significantly higher in the toddler group (P<0.05).ConclusionsAtypical HFMD caused by CV-A6 infection usually occurred in children under 5 years old. The morphologies of the rashes in the infant group changed more, while the rashes in the preschool group was more widely distributed. The incidence of critical cases was low. More than half of the cases can develop onychomadesis in the recovery period. Organ damage was relatively mild in the preschool group.

Coxsackievirus A6 Recombinant Subclades D3/A and D3/H Were Predominant in Hand-Foot-And-Mouth Disease Outbreaks in the Paediatric Population, France, 2010-2018.

Coxsackievirus A6 (CVA6) emerged as the most common enterovirus of seasonal outbreaks of hand-foot-and-mouth disease (HFMD). We investigated CVA6 genetic diversity among the clinical phenotypes reported in the paediatric population during sentinel surveillance in France between 2010 and 2018. CVA6 infection was confirmed in 981 children (mean age 1.52 years [IQR 1.17–2.72]) of whom 564 (58%) were males. Atypical HFMD was reported in 705 (72%) children, followed by typical HFMD in 214 (22%) and herpangina in 57 (6%) children. Throat specimens of 245 children were processed with a target-enrichment new-generation sequencing approach, which generated 213 complete CVA6 genomes. The genomes grouped within the D1 and D3 clades (phylogeny inferred with the P1 genomic region). In total, 201 genomes were classified among the recombinant forms (RFs) A, B, F, G, H, and N, and 12 genomes were assigned to 5 previously unreported RFs (R–V). The most frequent RFs were A (58%), H (19%), G (6.1%), and F (5.2%). The yearly number of RFs ranged between 1 (in 2012 and 2013) and 6 (2018). The worldwide CVA6 epidemic transmission began between 2005 and 2007, which coincided with the global spread of the recombinant subclade D3/RF-A.

A large-scale outbreak of hand, foot and mouth disease, France, as at 28 September 2021.

We report a large-scale outbreak of hand, foot and mouth disease (HFMD) in France. As at 28 September 2021, 3,403 cases have been reported (47% higher than in 2018–19). We prospectively analysed 210 clinical samples; 190 (90.5%) were enterovirus-positive. Most children presented with atypical HFMD. Coxsackievirus (CV)A6 (49.5%; 94/190) was predominant; no enterovirus A71 was detected. Dermatological and neurological complications of HFMD justify prospective syndromic and virological surveillance for early detection of HFMD outbreaks and identification of associated types.

Surveillance for Enteroviruses Associated with Hand, Foot, and Mouth Disease, and Other Mucocutaneous Symptoms in Spain, 2006–2020

Hand, foot, and mouth disease (HFMD) is a mild illness caused by enteroviruses (EV), although in some Asian countries, large outbreaks have been reported in the last 25 years, with a considerable incidence of neurological complications. This study describes epidemiological and clinical characteristics of EV infections involved in HFMD and other mucocutaneous symptoms from 2006 to 2020 in Spain. EV-positive samples from 368 patients were included. EV species A were identified in 85.1% of those typed EV. Coxsackievirus (CV) A6 was the prevalent serotype (60.9%), followed by EV-A71 (9.9%) and CVA16 (7.7%). Infections affected children (1–6 years old) mainly, and show seasonality with peaks in spring–summer and autumn. Clinical data indicated few cases of atypical HFMD as well as those with neurological complications (associated with the 2016 EV-A71 outbreak). Phylogenetic analysis of CVA6 VP1 sequences showed different sub-clusters circulating from 2010 to present. In conclusion, HFMD or exanthemas case reporting has increased in Spain in recent years, probably associated with an increase in circulation of CVA6, although they did not seem to show greater severity. However, EV surveillance in mucocutaneous manifestations should be improved to identify the emergence of new types or variants causing outbreaks and more severe pathologies.

An atypical manifestation of hand-foot and mouth disease involving the genitalia

Hand-foot and mouth disease (HFMD), an acute viral illness, is caused by the Coxsackievirus (CV) that commonly affects young children. We report a case of a 15-month-old female child with painful erosions over the genitalia, following which she developed erythematous macules over the palms and soles. Viral polymerase chain reaction was positive for CV. She was diagnosed to have atypical HFMD. HFMD with atypical manifestations involving the genitalia as initial presentation is a quite unusual or under-reported entity. Prompt recognition of atypical features of HFMD aids in early diagnosis and defers detailed evaluation.

Atypical hand-foot-mouth disease in Belém, Amazon region, northern Brazil, with detection of coxsackievirus A6

BackgroundEnterovirus (EV) A71 and coxsackievirus (CV) A16 were the most frequent serotypes involved in hand, foot, and mouth disease (HFMD) outbreaks throughout Asia. In the past 5 years, however, CV-A6 has emerged as a new important pathogen worldwide, and more severe and extensive dermatologic presentations has been reported. ObjectivesIdentify the clinical spectrum for atypical HFMD and enterovirus serotypes in Belém, Pará, Amazon region of northern Brazil. Study designA prospective ambulatory clinic–based surveillance conducted from January to June 2019, involving patients under 15 years with symptoms of HFMD. Stool, serum, oropharyngeal, and skin swab samples were analyzed. Real-time RT-PCR was performed to detect the viral genome of enteroviruses. Positive specimens were submitted to semi-nested PCR. Physical examinations and demographic data were recorded on a standardized form. Results48 patients with symptoms of HFMD were included in the study and collected all samples according to protocol. Enteroviruses were detected in 83 % of patients. An atypical form of HFMD with vesiculobullous exanthema was present in 70 % (28/40); desquamation of the palms and soles detected in 90 % (36/40) and onychomadesis in 30 % (12/40) of patients. The serotype was identified in 22 patients, CV- A6 occurred in 81.8 % of them. ConclusionThis is the first ambulatory surveillance and virologic investigation involving HFMD performed in outpatients from Amazon region, Brazil. The detection of CV-A6 was related to atypical forms HFMD. Desquamation of the palms and soles and nail changes occurred with frequency, such as a late sequel in the HFMD disease.

Coxsackievirus A6 Induces Necroptosis for Viral Production.

Hand, foot, and mouth disease (HFMD) is a febrile exanthematous disease with typical or atypical symptoms. Typical HFMD is usually caused by enterovirus 71 (EV71) or coxsackievirus A16, while atypical HFMD is usually caused by coxsackievirus A6 (CA6). In recent years, worldwide outbreaks of CA6-associated HFMD have dramatically increased, although the pathogenic mechanism of CA6 is still unclear. EV71 has been established to induce caspase-dependent apoptosis, but in this study, we demonstrate that CA6 infection promotes a distinct pathway of cell death that involves loss of cell membrane integrity. Necrostatin-1, an inhibitor of necroptosis, blocks the cell death induced by CA6 infection, but Z-DEVD-FMK, an inhibitor of caspase-3, has no effect on CA6-induced cell death. Furthermore, CA6 infection up-regulates the expression of the necroptosis signaling molecule RIPK3. Importantly, necrostatin-1 inhibits CA6 viral production, as assessed by its ability to inhibit levels of VP1 protein and genomic RNA and infectious particles. CA6-induced necroptosis is not dependent on the generation of reactive oxygen species; however, viral 3D protein can directly bind RIPK3, which is suggestive of a direct mechanism of necroptosis induction. Therefore, these results indicate that CA6 induces a mechanism of RIPK3-dependent necroptosis for viral production that is distinct from the mechanism of apoptosis induced by typical HFMD viruses.

The clinical manifestations and treatment of hand, foot and mouth disease caused by Coxsackievirus A6

Hand-foot-and-mouth disease (HFMD) is a common infectious disease caused by human enterovirus (EVs). It is more common in children under 5 years of age.The clinical symptoms are mainly rash and herpes in the hands, feet, mouth and other parts.Some serious cases may suffer from serious complications in nervous system, respiratory system or circulatory system.Since 1998, HFMD has been mainly caused by enterovirus 71 and coxsackievirus A16 (CV-A16). In the past 10 years, coxsackievirus A6(CV-A6) has gradually replaced EV-71 and CV-A16, and become a main pathogen of HFMD.Many literatures have shown that CV-A6 often causes atypical HFMD, which is mainly characterized by a wider and more serious rash and desquamation, and even onychomadesis.At present, there are some reports on the prevalence and detection methods of HFMD caused by CV-A6.The paper reviewed on CV-A6 related etiology, epidemiology, clinical manifestations and treatment of HFMD. Key words: Hand, foot and mouth disease; Coxsackie A6; Pathogen; Epidemiology; Clinical manifestations; Treatment

Recombinant CV-A6 strains related to hand-foot-mouth disease and herpangina at primary care centers (Barcelona, Spain).

Aim: To describe the genetic diversity of enteroviruses (EV) causing hand, foot and mouth disease (HFMD) and herpangina, especially of coxsackievirus (CV)-A6, from patients attended at pediatric primary care centers during the 2017-2018 season. Methods: Phylogenetic analysis of partial VP1 region was performed for genetic characterization. The complete VP1 and 3Dpol proteins were sequenced for lineage determination and detection of recombination events. Results: An 80% of samples were EV laboratory-confirmed. CV-A6 was the most detected (70%) and associated with atypical HFMD (78%). The comparison of VP1 and 3Dpol phylogenies showed evidence of recombination in three strains, in which two shifted to CV-A16 3Dpol. Conclusion: The study provides recent information regarding the nonrecombinant and recombinant EVs related to HFMD at primary care centers.

Severe atypical hand-foot-and-mouth disease in adults due to coxsackievirus A6: Clinical presentation and phylogenesis of CV-A6 strains

BackgroundTypically, hand-foot-and-mouth disease (HFMD) is a mild childhood illness associated with coxsackievirus (CV)-A16, CV-A6, enterovirus (EV)-A71. ObjectivesTo identify the viral agents associated with severe cases of atypical HFMD in Italy. Study designEpidemiologically unrelated cases of severe atypical HFMD admitted to the Emergency Room (ER) of IRCCS San Martino IST (Genoa, Italy) in 2014–2016 were investigated. Serologic screening for viral positivity was performed against exanthem-inducing agents. Ten cases with serology indicative of recent EV infection were selected. Molecular assays were used to detect viral genomes in blood [EVs, Parvovirus B19 (PVB19), herpesviruses (CMV; EBV, HHV-6, -7, -8)]. ResultsCV-A6 was detected in 10 cases of severe atypical HFMD. Two cases were also infected with PVB19. Herpesviruses were not detected. Phylogenetic analysis mapped the CV-A6 strains into a single cluster related to two recent isolates from a German and an Asian child. Fever, systemic symptoms, severe vasculitis-like rash, and enanthem were predominant at presentation. Spontaneous recovery occurred in 1–3 weeks. ConclusionsCV-A6 is emerging as a frequent cause of severe atypical HFMD in Italian adults. This viral agent is disseminating worldwide. Dermatologists must identify the manifold alterations caused by EVs and understand the diagnostic power of current virology methods.

Atypical hand, foot, and mouth disease caused by Coxsackievirus A6 in Argentina in 2015

We present two groups of cases of atypical hand, foot, and mouth disease (HFMD) caused by Coxsackievirus A6 (CV-A6) detected in Argentina in 2015. The first group involved 14 patients from Chubut province and the second group affected 12 patients from San Luis province. Molecular analysis of the complete VP1 protein gene revealed the circulation of E2 sublineage, the most predominant worldwide. To our knowledge, this is the first report of CV-A6 infections associated with atypical HFMD in Argentina and South America.

Coxsackievirus A6 Induces Cell Cycle Arrest in G0/G1 Phase for Viral Production.

Recent epidemiological data indicate that outbreaks of hand, foot, and mouth disease (HFMD), which can be categorized according to its clinical symptoms as typical or atypical, have markedly increased worldwide. A primary causative agent for typical HFMD outbreaks, enterovirus 71 (EV71), has been shown to manipulate the cell cycle in S phase for own replication; however, it is not clear whether coxsackievirus (CVA6), the main agent for atypical HFMD, also regulates the host cell cycle. In this study, we demonstrate for the first time that CVA6 infection arrests the host cell cycle in G0/G1-phase. Furthermore, synchronization in G0/G1 phase, but not S phase or G2/M phase, promotes viral production. To investigate the mechanism of cell cycle arrest induced by CVA6 infection, we analyzed cell cycle progression after cell cycle synchronization at G0/G1 or G2/M. Our results demonstrate that CVA6 infection promotes G0/G1 phase entry from G2/M phase, and inhibits G0/G1 exit into S phase. In line with its role to arrest cells in G0/G1 phase, the expression of cyclinD1, CDK4, cyclinE1, CDK2, cyclinB1, CDK1, P53, P21, and P16 is regulated by CVA6. Finally, the non-structural proteins of CVA6, RNA-dependent RNA polymerase 3D and protease 3C , are demonstrated to be responsible for the G0/G1-phase arrest. These findings suggest that CVA6 infection arrested cell cycle in G0/G1-phase via non-structural proteins 3D and 3C, which may provide favorable environments for virus production.

Hand-Foot-and-Mouth Disease, Aseptic Meningitis, and Encephalitis Caused by Enterovirus

Enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16), and CV-A6 are the major causative agents of Hand-foot-and-mouth disease (HFMD). These viruses belong to the species Enterovirus A of the genus Enterovirus of the family Picornaviridae. These viruses can also cause aseptic meningitis (AM), encephalitis and/or paralysis. EV-A71 is one of the main infectious agents related to severe encephalitis. Between 1997 and 2013, East and Southeast Asia experienced large encephalitis outbreaks caused by EV-A71 infections, which ranged from severe to lethal. In Japan, national surveillance for HFMD has been conducted since 1982 by monitoring both the notifications of HFMD patients and the causative agents. Even though EV-A71 and CV-A16 are the two major causative agents of HFMD, CV-A6 has been reported to cause atypical HFMD in Japan, since 2011. Both CV-A6 and CV-A16 also cause encephalitis: however, the reported numbers of encephalitis caused by CV-A6 and CV-A16 have been far fewer than those caused by EV-A71. Vaccines against EV-A71 have become available in some Asian countries, such as in China, but as of 2017 they remain unavailable in Japan, likely due to the sparsity of fatal cases. This article summarizes the complications of HFMD on the central nervous system, as well as its epidemiology, clinical manifestations, and treatment. Moreover, the article reviews the history of HFMD and discusses the experimental results of research aimed at the prevention, grading, sample collection, diagnosis, and treatment of severe EV-A71 infections.

Atypical Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6 in Denmark: A Diagnostic Mimicker.

Since 2008, outbreaks of atypical hand, foot, and mouth disease (HFMD) in children and adults have been reported worldwide. The majority of these outbreaks are caused by a new lineage of Coxsackie virus A6 (CV-A6) presenting a more severe clinical phenotype than the classical childhood HFMD caused by CV-A16. Between June 2014 and January 2016, 23 cases of atypical HFMD disease presented at a Dermatology Department at a regional University Hospital in Denmark. Patients were referred by general practitioners and dermatologists with a variety of clinical diagnoses, including eczema herpeticum, vasculitis, syphilis, dermatophytid, erythema multiforme and Stevens-Johnson syndrome. Three adults and 3 children required hospitalization due to extensive skin involvement and fever. All reported patients had laboratory-confirmed enterovirus infection. This study demonstrated an upsurge in atypical HFMD caused by CV-A6 in the Region of Southern Denmark and that atypical HFMD can be difficult to diagnose clinically as it may mimic other severe skin diseases.

Ambulatory Pediatric Surveillance of Hand, Foot and Mouth Disease as Signal of an Outbreak of Coxsackievirus A6 Infections, France, 2014-2015.

The clinical impact of enteroviruses associated with hand, foot and mouth disease (HFMD) is unknown outside Asia, and the prevalence of enterovirus A71 (EV-A71) in particular might be underestimated. To investigate the prevalence of enterovirus serotypes and the clinical presentations associated with HFMD in France, we conducted prospective ambulatory clinic-based surveillance of children during April 2014-March 2015. Throat or buccal swabs were collected from children with HFMD and tested for the enterovirus genome. Physical examinations were recorded on a standardized form. An enterovirus infection was detected in 523 (79.3%) of 659 children tested. Two epidemic waves occurred, dominated by coxsackievirus (CV) A6, which was detected in 53.9% of enterovirus-infected children. CV-A6 was more frequently related to atypical HFMD manifestations (eruptions extended to limbs and face). Early awareness and documentation of HFMD outbreaks can be achieved by syndromic surveillance of HFMD by ambulatory pediatricians and rapid enterovirus testing and genotyping.

Incontinentia Pigmenti Coxsackium

Late recurrences of first-stage inflammatory vesiculobullous lesions of incontinentia pigmenti (IP) are uncommon but have been reported to occur in the setting of infections, fevers, and vaccinations. This phenomenon has not been described in the setting of atypical hand, foot, and mouth disease (HFMD). In addition, atypical HFMD often has a predilection for areas of previous inflammation or trauma, such as areas of atopic dermatitis (eczema coxsackium). We present a case of incontinentia pigmenti coxsackium in which a coxsackievirus infection triggered reactivation of IP and cutaneous viral lesions were concentrated in areas of IP.

Atypical Forms of Hand, Foot, and Mouth Disease: A Prospective Study of 47 Italian Children.

Atypical forms of hand, foot, and mouth disease (HFMD) caused by coxsackievirus A6 have been reported in recent years. High fever and severe cutaneous lesions are common, whereas neurologic complications are rare. Eczematous areas of patients with atopic dermatitis show more lesions. The goal of the current study was to describe the clinical characteristics of children with atypical HFMD and to investigate the involvement of the different enterovirus serotypes associated. All patients referred to our service for atypical HFMD from January 2012 to February 2014 were enrolled and classified as having the diffuse form (lesions extended to the trunk), the acral form (lesions with a mainly acral distribution), or eczema coxsackium (lesions on preexisting eczematous areas). Data from 47 patients were analyzed (median age 22 months [range 4-84 mos]); viral genotyping was performed in 11 cases. Sixty-two percent of the subjects developed the acral form, 23% eczema coxsackium, and 15% the diffuse form. Most patients had a nonclassical vesicular eruption and moderate to severe extent of cutaneous involvement. Approximately 80% of patients had palmoplantar purpuric macules. Most children younger than 2 years old had the acral form, most patients with eczema coxsackium were age 2 years and older, and the diffuse form was similarly distributed between the two age groups. Coxsackievirus A6 was detected in 9 of 11 genotyped cases. Our prospective study allowed the identification of three HFMD phenotypes differing from the classical form. Clinical care of these patients should include symptomatic treatment of extracutaneous features and, if necessary, hospitalization for complications.