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

Abstract

Background: In 2010, we observed children with atypical presentations of hand-foot-mouth disease (HFMD), such as rashes on earlobes and faces, or bullae on trunks and bilateral limbs. Hyperpigmentation later developed as the bullous lesions crusted. Thus, we intended to study the etiology of the illness and the phylogeny of the pathogens.

Method: Patients were prospectively enrolled in a tertiary medical center in Taipei, Taiwan. The definition of atypical HFMD includes symptoms of acute viral infection with either of the following presentations: (1) maculopapular rashes presenting on the trunks, buttocks or facial areas, or (2) large vesicles or bullae on any sites of the body. Patients were classified into two groups according to vesicle sizes by two pediatricians at different points in time. The large vesicle group was defined as having vesciculobullous lesions ≥ 1 cm in diameter; the small rashes group had maculopapular rashes < 1cm in diameter. Two throat swabs were collected from each patient for virus isolation and reverse transcription polymerase chain reactions.

Results: We enrolled 101 patients between March and December 2010. The mean age of the participants was 3.3 ± 3.0 years (median age: 2.5 years, range: 21 days-13.5 years). The ratio of males to females was 1.8 to 1. All samples were enterovirus-positive, including coxsackievirus A6 (80%), coxsackievirus A16 (6%), enterovirus 71 (1%), coxsackievirus A5 (1%) and 12 non-typable enterovirus (12%). Bullous fluid aspirated from 2 patients also grew coxsackievirus A6. Among the patients infected with coxsackievirus A6, 54% (45/81) had bullae, compared to 25% (5/20) of those having non-coxsackievirus A6 infections (P=0.02). Fourteen cases had myoclonic jerks and one boy was diagnosed with febrile convulsions. None had complications or sequelae. Phylogenetic analysis showed the strains in Taiwan in 2010 shared more commonality with strains from Finland in 2009 (GenBank: FJ870502-FJ870508), and were close to those circulating in Japan in 2011 (GenBank: AB649286-AB649291).

Conclusions: Coxsackievirus A6 infections may cause atypical manifestations of HFMD, including vesicles or papules on faces or bullae on trunks. These features could provide valuable information to distinguish this versatile enterovirus infection from other virus-induced vesiculobullous diseases.

Figure 1

Monthly and age distribution of atypical HFMD. (A) This epidemic of CVA6 started in early spring of 2010. The enrollment of patients peaked in between July and October. (B) Most of the children in the small rash group were younger than 6 year-old. In the bullae group, 78% were children under 5 year of age and 10% were teens.

Figure 2

Dermatologic presentations of atypical HFMD. Erythema was frequently observed at the base of large vesicles. These lesions were distributed on limbs, trunks or perioral areas. (Top, left) Bullae were formed on a 5 year-old boy’s sole, which caused mild pruritus and prickling sensations. (Top, right) Atypical rashes of CVA6 spread on a 4 year-old child’s forehead and temporal area of the face. The lesions did not involve the cornea or conjunctiva. (Bottom, left) Late presentation of atypical HFMD, severe desquamation was presented on bilateral palms and soles of a 12 year-old boy. Ten days earlier, he had marked blisters on his bilateral limbs and scattered vesicles on his buttock, yet without fever or other systemic symptoms. (Bottom, right) Onychomadesis occurred on the 2 weeks post CVA6 infection.

Figure 3

The analysis of phylogeny is based on partial VP1 gene sequence (264–377 nucleotides). Clade I, is CVA6 strain HN421 (JQ964234), isolated from Henan, China in 2012. Clade II are the two circulating strains of CVA6 in Taiwan between 2004 and 2005 (EU908166, EU908170). Clade III includes the prototype CVA6 strain from the USA (AY421764), Japanese circulating strains in 2011 (AB649286- AB649291), 2009 Finland strains (FJ870502- FJ870508) and Taiwanese circulating strains in 2009–2010 (JN896786, JN896796, JQ390220, JQ390221) and the strains of the current study in 2010 (KC297130-KC297135).