To the Editor: Coxsackievirus A6 (CVA6) is a human enterovirus associated with herpangina in infants. In the winter of 2012, we evaluated a cluster of 8 patients, 4 months–3 years of age, who were brought for treatment at Boston Children’s Hospital (Boston, MA, USA) with a variant of hand, foot, and mouth disease (HFMD) that has now been linked to CVA6 (Table). During this same period, the Boston Public Health Commission’s syndromic surveillance system detected a 3.3-fold increase in emergency department discharge diagnoses of HFMD. In the United States, HFMD typically occurs in the summer and early autumn and is characterized by a febrile enanthem of oral ulcers and macular or vesicular lesions on the palms and soles; the etiologic agents are most often CVA16 and enterovirus 71.



Table

Demographic and clinical characteristics of patients with CVA6-associated HFMD, Boston, Massachusetts, USA, 2012*



In contrast to the typical manifestation, the patients in the Boston cluster exhibited symptoms in late winter (Table) and had perioral (Figure, panel A) and perirectal (Figure, panel B) papules and vesicles on the dorsal aspects of the hands and feet (Figure, panel C). Patients experienced a prodrome lasting 1–3 days, consisting of fever (8 patients), upper respiratory tract symptoms (4 patients), and irritability (7 patients). This prodrome was followed by the development of a perioral papular rash (8 patients), which was often impetiginized with secondary crusting; a prominent papulovesicular rash on the dorsum of the hands and feet (6 patients); and a perirectal eruption (7 patients). Half of the patients had intraoral lesions. Fever abated in most of the patients within a day after onset of the exanthem. The rash resolved over 7–14 days with no residual scarring. Samples from the oropharynx, rectum, and vesicles from these patients were sent to the Centers for Disease Control and Prevention (Atlanta, GA, USA) for analysis. Reverse transcription PCR and sequencing by using primers specific for a portion of the viral protein 1 coding region identified CVA6 (1) (Table).



Figure

Manifestations of hand, foot, and mouth disease in patients, Boston, Massachusetts, USA, 2012. Discrete superficial crusted erosions and vesicles symmetrically distributed in the perioral region (A), in the perianal region (B), and on the dorsum of the ...



Outbreaks of HFMD caused by CVA6 have been described in Singapore, Finland, Taiwan, and most recently in Japan; most cases have occurred in the warmer months (2–6). Cases in the cluster described here are likely related to an emerging outbreak of CVA6-associated HFMD in the United States (7). The atypical seasonality of the outbreak, during the winter in Boston, could be related to the unusually mild temperatures in the winter of 2012.

Recent CVA6 outbreaks have been characterized by a febrile illness associated with an oral enanthem and lesions on the palms, soles, and buttocks. CVA6 infections in Taiwan during 2004–2009 were associated with HFMD in 13% of cases, with disease defined as oral ulcers on the tongue or buccal mucosa and vesicular rashes on the palms, soles, knees, or buttocks (2). In Singapore, where CVA6 accounted for 24% of HFMD cases, patients had oral lesions and <5 peripheral papules, placing them on a spectrum closer to the herpangina more typically observed in CVA6 infection (8).

The patients we report in this cluster most typically had perioral and perirectal papules in addition to vesicles on the dorsum of their hands. Two reports of CVA6-associated HFMD outbreaks describe cases that more closely resemble patients in the Boston outbreak. In a series from Finland in 2008, representative patients had both perioral lesions and vesicles on the dorsum of their hands (6). In a large series of patients with HFMD in Taiwan in 2010, patients with CVA6 had perioral lesions in addition to an enanthem (3).

Outbreaks of CVA6-associated HFMD in Finland, Taiwan, and Japan were associated with onychomadesis, with the loss of nails occurring 1–2 months after initial symptoms (3,4,6). The association between more typical HFMD and onychomadesis has additionally been described in the United States and Europe but without a link to specific serotype or with a small percentage of CVA6-associated cases (9). Cases from the Boston epidemic may fit into an emerging clinical phenotype of CVA6, and it will be interesting to see whether nail loss develops in those patients.

Given the numerous CVA6 outbreaks in multiple countries in 2008 and a US population that may be relatively naive to this serotype, CVA6 is likely to spread throughout North America. Clinicians should be aware that, although standard precautions are routinely recommended for managing enteroviral infections in health care settings, contact precautions are indicated for children in diapers to control institutional outbreaks (10). In addition, the presence of perioral lesions and peripheral vesicles on the dorsum rather than palmar/plantar surface of the hands and feet represents a unique phenotype of HFMD that could be confused with herpes simplex or varicella-zoster virus infections. Because of the atypical presentation of CVA6-associated HFMD, clinical vigilance is needed to recognize emerging regional outbreaks. More detailed epidemiologic and genetic analyses will be required to characterize the role of CVA6 in US outbreaks of HFMD.

/pdf/hand-foot-and-mouth-disease-caused-by-coxsackievirus-a6-483f3v2ckl.pdf

Hand, foot, and mouth disease caused by coxsackievirus a6.

OBJECTIVE: To characterize the atypical cutaneous presentations in the coxsackievirus A6 (CVA6)–associated North American enterovirus outbreak of 2011–2012. METHODS: We performed a retrospective case series of pediatric patients who presented with atypical cases of hand, foot, and mouth disease (HFMD) from July 2011 to June 2012 at 7 academic pediatric dermatology centers. Patients were included if they tested positive for CVA6 or if they met clinical criteria for atypical HFMD (an enanthem or exanthem characteristic of HFMD with unusual morphology or extent of cutaneous findings). We collected demographic, epidemiologic, and clinical data including history of skin conditions, morphology and extent of exanthem, systemic symptoms, and diagnostic test results. RESULTS: Eighty patients were included in this study (median age 1.5 years, range 4 months–16 years). Seventeen patients were CVA6-positive, and 63 met clinical inclusion criteria. Ninety-nine percent of patients exhibited a vesiculobullous and erosive eruption; 61% of patients had rash involving >10% body surface area. The exanthem had a perioral, extremity, and truncal distribution in addition to involving classic HFMD areas such as palms, soles, and buttocks. In 55% of patients, the eruption was accentuated in areas of eczematous dermatitis, termed “eczema coxsackium.” Other morphologies included Gianotti-Crosti–like (37%), petechial/purpuric (17%) eruptions, and delayed onychomadesis and palm and sole desquamation. There were no patients with serious systemic complications. CONCLUSIONS: The CVA6-associated enterovirus outbreak was responsible for an exanthem potentially more widespread, severe, and varied than classic HFMD that could be confused with bullous impetigo, eczema herpeticum, vasculitis, and primary immunobullous disease.

/pdf/eczema-coxsackium-and-unusual-cutaneous-findings-in-an-3ndgkur2eh.pdf

"Eczema coxsackium" and unusual cutaneous findings in an enterovirus outbreak.

Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the predominant pathogens causing outbreaks of hand, foot and mouth disease (HFMD) worldwide. Other human enterovirus A (HEV-A) serotypes tend to cause only sporadic HFMD cases. However, since a HFMD caused by coxsackievirus A6 broke out in Finland in 2008, CA6 has been identified as the responsible pathogen for a series of HFMD outbreaks in Europe, North America and Asia. Because of the severity of the clinical manifestations and the underestimated public health burden, the epidemic of CA6-associated HFMD presents a new challenge to the control of HFMD. This article reviewed the epidemic characteristics, molecular epidemiology, clinical features and laboratory diagnosis of CA6 infection. The genetic evolution of CA6 strains associated with HFMD was also analyzed. It indicated that the development of a multivalent vaccine combining EV71, CA16 and CA6 is an urgent necessity to control HFMD.

Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide

Hand, foot, and mouth disease (HFMD) is a contagious viral disease and mainly affects infants and young children. The main manifestations are fever, vesicular rashes on hand, feet and buttocks and ulcers in the oral mucosa. Usually, HFMD is self-limiting, but a small proportion of children may experience severe complications such as meningitis, encephalitis, acute flaccid paralysis and neurorespiratory syndrome. Historically, outbreaks of HFMD were mainly caused by two enteroviruses: the coxsackievirus A16 (CV-A16) and the enterovirus 71 (EV-A71). In the recent years, coxsackievirus A6 and coxsackievirus A10 have been widely associated with both sporadic cases and outbreaks of HFMD worldwide, particularly in India, South East Asia and Europe with an increased frequency of neurological complications as well as mortality. Currently, there is no pharmacological intervention or vaccine available for HFMD. A formalin-inactivated EV-A71 vaccine has completed clinical trial in several Asian countries. However, this vaccine cannot protect against other major emerging etiologies of HFMD such as CV-A16, CV-A6 and CV-A10. Therefore, the development of a globally representative multivalent HFMD vaccine could be the best strategy.

/pdf/hand-foot-and-mouth-disease-hfmd-emerging-epidemiology-and-h7iqujdubv.pdf

Hand, foot and mouth disease (HFMD): emerging epidemiology and the need for a vaccine strategy

Over the last decade, major outbreaks of hand, foot, and mouth disease (HFMD) have been reported in Asian countries, resulting in thousands of deaths among children. However, less is known regarding the effect of meteorological variables on the incidence of HFMD in children. This study aims at quantifying the relationship between meteorological variables and the incidence of HFMD among children in Guangzhou, China. The association between weekly HFMD cases in children aged <15 years and meteorological variables in Guangzhou from 2008 to 2011 were analyzed using the generalized additive model (GAM) and time-series method, after controlling for long-term trend and seasonality, holiday effects, influenza period and delayed effects. Temperature and relative humidity with one week lag were significantly associated with HFMD infection among children. We found that a 1°C increase in temperature led to an increase of 1.86% (95% CI: 0.92, 2.81%) in the weekly number of cases in the 0–14 years age group. A one percent increase in relative humidity may lead to an increase of 1.42% (95% CI: 0.97, 1.87%) in the weekly number of cases in the 0–14 years age group. This study provides quantitative evidence that the incidence of HFMD in children was associated with high average temperature and high relative humidity. The one-week delay in the effects of temperature and relative humidity on HFMD is consistent with the enterovirus incubation period and the potential time lag between onset of children’s sickness and parental awareness and response.

https://link.springer.com/content/pdf/10.1186%2F1471-2334-13-134.pdf

Effect of meteorological variables on the incidence of hand, foot, and mouth disease in children: a time-series analysis in Guangzhou, China

To the Editor: Coxsackievirus A6 (CVA6) belongs to human enterovirus species A of the genus Enterovirus. According to a Japanese Infectious Agents Surveillance Report, this virus is one of the major causes of herpangina, an acute febrile disease characterized by vesicles, ulcers, and redness around the uvula, which occurs mainly in young children and infants (1).

In June 2011, a sudden increase in cases of hand, foot, and mouth disease (HFMD) at pediatric sentinel sites (≈3,000 pediatric hospitals and clinics) was reported to the National Epidemiologic Surveillance of Infectious Diseases System in Japan. Compared with past numbers of cases over 30 years of surveillance, the number of cases of HFMD per sentinel site peaked in week 28 (July) of 2011 (10.97 cases per sentinel), particularly in western Japan (2). According to the Infectious Agents Surveillance Report (as of September, 18, 2011), CVA6 was detected in 709 HFMD cases and 156 herpangina cases throughout Japan (1).

Clinical samples (throat swab specimens and feces) obtained from sentinel sites in Shimane, Hyogo, Hiroshima, and Shizuoka, Japan, were screened for enteroviruses by using an enterovirus-specific reverse transcription PCR and sequence analysis of the partial viral protein (VP)4/VP2 or VP1 region (3). Among 93 clinical samples from 108 HFMD case-patients, we identified 74 case-patients as CVA6 positive by sequence analysis.

On the basis of sequence analysis of the entire VP1 region (GenBank accession nos. {"type":"entrez-nucleotide-range","attrs":{"text":"AB649286-AB649291","start_term":"AB649286","end_term":"AB649291","start_term_id":"342166534","end_term_id":"342166544"}}AB649286-AB649291), the consensus sequence had 82.3%–82.5% nt identity (94.8%–95.4% aa identity) with the prototype CVA6 Gdula strain (GenBank accession no. {"type":"entrez-nucleotide","attrs":{"text":"AY421764","term_id":"40068436"}}AY421764). CVA6 was not isolated from clinical samples in a cell culture system. Therefore, most CVA6 strains were identified by molecular detection directly from clinical samples and sequence analysis. Some CVA6 strains were grown and isolated in suckling mice; these strains were antigenically identified as CVA6 by a neutralization test with specific antiserum against CVA6 (4).

In Japan, HFMD and herpangina are classified as category V infectious diseases. On the basis of clinical diagnosis, suspected infections were reported by pediatric sentinel sites on a weekly basis to the Infectious Disease Surveillance Center of the National Institute of Infectious Diseases (Tokyo, Japan). Typical clinical signs and symptoms of HFMD cases caused by CVA6 were fever, mild vesicles in oral mucosa, and skin blisters on hands, arms, feet, legs, buttocks, and nail matrixes (Figure). Some patients with HFMD had onychomadesis (periodic shedding of the nails) 1–2 months after onset of HFMD. Most cases of HFMD were self-limited. However, additional follow-up may be necessary for patients with onychomadesis who are treated at dermatology clinics.



Figure

Typical clinical manifestations of hand, foot, and mouth disease associated with coxsackievirus CVA6 in Shizuoka, Japan, June–July, 2011. A) Hand and arm of a 2.5-year-old boy; B) foot and C) buttocks of a 6-year-old boy; D) nail matrix of a 20-month ...



As in other countries in the Asia–Pacific region, major causes of HFMD in Japan were CVA16 and enterovirus 71. In 2010, enterovirus 71 was identified as a major cause of HFMD (2). In contrast, CVA6 was consistently associated with herpangina, as were CVA2, CVA4, CVA5, and CVA10, but CVA6 was occasionally detected in HFMD case-patients. CVA6 was the major cause of herpangina in 2007, but an increase in the detection rate of CVA6 in HFMD case-patients was reported in Japan in 2009 (2).

HFMD outbreaks caused by CVA6 were reported in Singapore, Finland, and Taiwan in 2007–2009 (5–8). Recent HFMD outbreaks in Finland and Spain were associated with cases of onychomadesis 1–2 months after onset of HFMD (6,8,9). In Japan, cases of onychomadesis after onset of HFMD were reported in 2009 (10). Therefore, changes in clinical outcomes of CVA6-associated diseases should be investigated.

Although most HFMD cases caused by CVA6 in Japan were mild, CVA6 was also detected in other clinical samples, including cerebrospinal fluid from a patient with acute encephalitis in Hiroshima, which reaffirmed possible additional clinical manifestations during an HFMD outbreak caused by CVA6. Careful surveillance of disease and infectious agent activities are crucial in monitoring CVA6-associated HFMD, onychomadesis, and neurologic diseases. Nucleotide identity between CVA6 strains in Finland (2008) (7) and Japan (2011) was ≈95% in the partial VP1 region. More detailed genetic, phenotypic, and epidemiologic analyses of CVA6 are needed to determine the role of CVA6 in HFMD outbreaks with or without onychomadesis.

Katsuhiko Abe

Papers

Hand, foot, and mouth disease caused by coxsackievirus A6, Japan, 2011.