Clinical Manifestations of Coxsackievirus A6 Infection Associated with a Major Outbreak of Hand, Foot, and Mouth Disease in Japan

Kawasaki City Institute for Public Health, Kanagawa 210-0821, JapanCommunicated by Takaji Wakita(Accepted April 24, 2013)A serious outbreak of hand, foot, and mouth disease(HFMD) occurred in Japan in the summer of 2011 (1,2).A major cause of this epidemic was coxsackievirus A6(CA6), and the clinical manifestations of the diseasediffered from those of typical HFMD. The InfectiousDiseases Control Law mandates medical doctors inJapan to officially report cases exhibiting the followingsymptoms immediately after diagnosis: fever with sorethroat and appetite loss, followed by the appearance ofreddish vesicles on the hands and feet approximately 2days after the onset of fever. The vesicles usually disap-pear within 7 to 10 days without specific treatment.Reported cases should satisfy both of the following clin-ical criteria: (i) vesicles measuring 2–5 mm with blisterson the palm of the hand and sole or dorsum of the footand oral mucosa and (ii) vesicles that heal without crustformation.During the 2011 outbreak, it was challenging forpediatricians to judge whether the majority of HFMDcases should be diagnosed as a subtype of conventionalHFMD or a new type caused by CA6 infection. Werecommend that pediatricians should be alert whilemaking diagnosis because the rashes caused by CA6 aresimilar to those caused by chickenpox. Establishingdifferential diagnoses is necessary in order to preventmisdiagnosis and inappropriate treatment. The criticalpoint in differentiating CA6 from other infections is thespecific clinical course and spread of eruptions withscabbing. For this purpose, in 2011, we summarized thedetailed clinical features of HFMD caused by CA6infection (CA6-associated HFMD).On the basis of laboratory confirmation (1), we re-viewed28 cases of CA6-associated HFMD thatoccurredin Japan between June 2011 and July 2011. CA6 strainswere detected in samples of feces and/or pharyngealswabs and tested using reverse transcription (RT)-PCRand sequencing of the VP1 region (AB649286–AB649291).Clinical samples were collected during the course ofmedical care in hospitals and laboratory tests were per-formed for the purpose of diagnosis and treatment.Informed consent for this study was obtained from allthe patients' guardians, and the clinical samples werediagnosed for national surveillance.Patient age ranged from 9 months to 9 years (mean,29.1 months), and 75z of patients were aged under 3years. There was no statistically significant genderdifference. All HFMD cases were associated with afever (38.0–40.29C; mean, 39.09C) that lasted for 1.5days on an average. The appearance of rashes on theoral mucosa was noted from the second day of onset offever, similar to that observed in cases of herpanginawith less oral pain and reluctance to eat. The appear-ance of reddish vesicles on the extremities and buttockswas noted on the third day of onset; these vesicles weremostly found on the upper arms, thighs, lips, neck, andbuttocks, while they were found less frequently on thehands and soles of the feet. The vesicles were flat andumbilicated. Some lesions grew to be more than 10 mmin diameter, and scabbing was observed within severaldays (Fig. 1).As described above, the criteria for notification inJapan require that the vesicles associated with HFMDheal without crust formation. However, in this study,crust formation was observed within several days of dis-ease onset in all 28 cases. The notification criteria forHFMD include vesicles that heal without crust forma-tion. Our results showed that CA6-associated HFMDdid not fulfill the notification criteria for HFMD.However, it was impossible to find crust formation inthe early stage of the illness. In some cases, a carefuldifferential diagnosis from chickenpox, impetigo con-tagiosa, herpes simplex disease, and varicella-zosterdisease was required. The critical features of CA6-asso-ciated HFMD were the successive appearance of her-pangina-like oral mucosal lesions, widely spread rashes,and crust formation during the healing process.We followed 16 recovered cases for 2–8 weeks andfound that 6 (37.5z) experienced onychomadesis,whichwasa significant finding. All cases healed withoutsevere sequelae, except for the 6 cases that developedonychomadesis. The incidence of CA6-associatedHFMD with crust formation is thought to be high(almost 100z), with the rate of onychomadesis esti-matedtobeover30z. Further studies are therefore