Atypical hand-foot-mouth disease in children: a hospital-based prospective cohort study

In children with infectious diseases, cutaneous lesions usually provide clues for early diagnoses [1, 2]. Hand-foot-mouth disease (HFMD), a common and potentially fatal infectious disease in children, largely relies on clinical manifestations for early diagnosis, including maculopapular or vesicular rashes on soles, palms and buttocks, and oral ulcers in the pharynx [3]. Enteroviruses, particularly enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), are known to cause HFMD. Most oral-dermatological phenotypes are self-limited; however, in certain patients, EV 71 infection may lead to severe neurological complications, especially in young children [4]. For example, during an outbreak in 1998 in Taiwan, EV71 caused 78 deaths out of more than 129,000 patients who had presented with HFMD or herpangina initially [5]. Since then, the Centers for Disease Control in Taiwan (CDC-Taiwan) have been closely monitoring the trends of enterovirus infections by cooperating with the Sentinel Physicians Surveillance and Virology Reference Laboratories Network. The surveillance database is published weekly and provides information regarding the circulating trends of enteroviruses [6].

Since spring 2010, we have observed an unusual type of skin lesion presenting on children in Taiwan, including large vesicles or bullae over the limbs, trunks or buttocks and papules on faces, accompanied by fevers, stomatitis, and sore throats. Moreover, a few children developed onychomadesis, desquamation and skin pigmentation over the areas previously presenting with large vesicles or bullae. These presentations shared several of the traits of HFMD, including vesicular regions on limbs and oral ulcers, yet with distinct vesiculobullous lesions from the typical maculopapular rashes. Over the past decade, the association between onychomadesis and enterovirus infection has been reported in coxsackievirus A5 (CVA5), coxsackievirus A6 (CVA6) and coxsackievirus A10 [7, 8]. However, whether the morphology and distribution of vesicles and accompanying symptoms varied among enterovirus infections of different serotypes remained unknown. Therefore, we aimed to evaluate the etiology of the atypical presentations of HFMD during the epidemic period.

Our data showed most of the CVA6 infections are a common cause of atypical HFMD in children with relatively benign courses. Among the lesions of atypical HFMD, distinct bullae or large vesicles were more likely to occur on CVA6-positive children. Also, children with CVA6 infections had higher chances developing bullous vesicles.

Before the epidemic in 2010, CVA6 circulation had been observed in 2007 and 2009 in Northern Taiwan. In the study by Lo et al. [9], most children infected with CVA6 were < 7 years of age. Although 2% of the children (3/141) had meningitis or encephalitis, none had sequelae. The frequencies of myoclonic jerks (21.3%) and febrile convulsions (3.5%) reported in Lo et al’s study were similar to ours. However, less than 13% of children presented with HFMD. Herpangina was the predominant phenotype, which might be accompanied by fever, decreased oral intake and upper respiratory symptoms (e.g. cough and rhinorrhea). The epidemic CVA6 strain in the current study in 2010 shared a great deal of genetic commonality with the CVA6 strain in 2009 in Taiwan as determined by VP1 sequencing. Chen et al. sequenced complete genomes of circulating CVA6 strains between 2009 and 2010 in Taiwan, and revealed little difference in VP1 sequences. However, several changes in amino acids were noted in structure proteins (VP2 and VP3) and non-structure proteins (2A, 3C and 3D) [10]. Whether the variations in amino acids contribute to the discerning clinical presentations in 2010 still needs further investigation.

In our study, CVA6 was the major strain of enterovirus that caused atypical HFMD. In the same epidemic period, CDC-Taiwan retrospectively analyzed 130 patients with laboratory-confirmed CVA6 infections. Their findings showed that CVA6 patients had higher chances of experiencing desquamation (51%) and onychomadesis (37%) [11]. This study did not analyze early presentations of the infection as in ours. Thus, the two studies are in some part complementary, showing that in CVA6 infection, vesiculobullous lesions might develop early, followed by marked desquamation and pigmentation on palms and soles as the bullae crusted. Nail deformities could also be observed after the resolution of infection. These uncommon manifestations may provide valuable information to detect enterovirus infections in endemic countries. Early diagnosis is beneficial to pediatric patients in order to limit invasive examinations, such as skin biopsies, when determining the pathogenesis.

We examined the bullous fluid collected from the skin lesions. The viral loads of CVA6 were higher in the bullous fluid than in the throat swabs. Similar observations have not been reported among the other HFMD patients. Vesicular or bullous fluid may be considered a specimen for a more sensitive but also more specific source to determine the infectious etiology of HFMD, since issues may be raised that bystander viruses and true pathogens are indistinguishable in samples from throats and feces. In murine models, viral titers of EV71 were much higher in muscle and skin compared to those in the intestines or brain [12], suggesting enteroviruses also propagate in other organs. It once again addresses the importance of hand hygiene in the prevention of HFMD. The transmission of enterovirus is not limited to the oral-fecal route. Rather, it may pass on to other hosts through fluid from ruptured skin lesions.

In the summer of 2008, a CVA6 outbreak was reported in Finland and Spain, and the circulating strains in these two countries shared high levels of similarity based on partial VP1 sequences [7, 8]. In the following years, outbreaks of vesicular-bullous eruptions and onychomadesis occurred in Taiwan (2010), Japan (2011) and the United States (2012), and CVA6 was the viral stain responsible for the events [11, 13‐15]. According to these reports and ours, the majority of the infected patients had uncomplicated symptoms. The clinical presentations of CVA6 infections were quite different from those of EV71-infected children, who usually presented small papules or vesicles on distal limbs. Also, young children with EV71 infections had much higher chances of developing severe neurological complications, sequalae or mortalities [16]. Moreover, CVA6 has become one of the endemic strains of enterovirus in Singapore, China and Thailand in recent years [17‐19]. It is not known whether CVA6 may transform into a more virulent stain as it circulates in broader regions. Further research is needed to understand the mechanisms that cause atypical HFMD and in monitoring CVA6 epidemiology.

Several limitations of this study are summarized: (1) children with maculopapular rashes over the uncommon sites in addition to the bullous vesicles might be considered as having viral exanthems, leading to underrepresentation among the small rashes group. (2) Children who developed skin lesions in the later phase of infection might be under-represented if they were not hospitalized, or if they were discharged early. (3) The number of patients was relatively small due to the short epidemic period. More investigations with expanded cohort sizes are required to explore the relationship between skin phenotypes and enterovirus species, to provide evidence in clinical diagnosis.

xCoxsackievirus A6 infections may cause atypical presentation of HFMD, including small vesicles on faces or vesiculobullous lesions on trunks. The majority of patients were self-limited. The pathogenesis of CVA6-induced bullae should be further investigated.