The results of his study suggest that the onychomadesis epidemic which occurred in Taiwan was significantly associated with the HFMD caused by the CA6 infection. In addition to onychomadesis, our study found that HFMD patients with CA6 infection presented with more widespread skin lesions and more profound tissue destruction. The CA6 strains circulating in 2010 differed from those circulating before 2010, not only in terms of clinical manifestations, but also in the genetic sequences of the VP1 genes.
The fact that HFMD patients with CA6 infection had more widespread skin lesions also explains the difference in the percentage of nail abnormalities in CA6 and non-CA6 HFMD cases. Expanded skin site involvement in our study indicated a broad spectrum of direct cell infection by the CA6 virus. Onychomadesis is a painless, non-inflammatory nail change that is idiopathic or results from a wide range of systemic diseases or drug exposures . The mechanism of onychomadesis in our study remains unclear. It has been speculated that onychomadesis occurs secondary to inflammation of the nail matrix or maceration associated finger blisters . In the outbreak of hand, foot, and mouth disease (HFMD) which occurred in Finland in 2008, in which onychomadesis was a common symptom, Osterback et al. detected CA6 in shed nail fragments of a patient who had onychomadesis following a HFMD episode by using RT-PCR and suggested that CA6 virus replication damaged the nail matrix, resulting in onychomadesis . Although direct evidence of a viral infection in the nail matrix was not obtained, our study adds to the mounting evidence of a causal relationship between CA6 HFMD and nail abnormalities.
In addition to CA6 infection, we found that some patients with echovirus 30, EV71, and CA16 infection also experienced nail abnormalities. In an onychomadesis outbreak in Spain, Davia et al. found that several serotypes of enteroviruses, such as coxsackieviruses A5, A6, A16, B1, B3, echoviruses 3, 4, and 9, and enterovirus 71, may cause onychomadesis, in addition to the major enterovirus serotype, coxsackievirus A10, and concluded that more than one enterovirus serotype was implicated in the nail matrix arrest outbreak . Our study supports this observation. However, there were no reports of nail abnormalities associated with the aforementioned enterovirus serotypes in Taiwan. Whether or not another enterovirus serotype, other than CA6, is associated with nail changes warrants further investigation.
The validity of virus isolation results was crucial to the study. Specimens obtained from skin blisters were the most appropriate for microbiological studies for HFMD. The majority of the specimens were obtained from pharyngeal swabs and we took the specimens within 3 days of HFMD onset. Although the results of the pharyngeal swabs did not provide direct evidence of a causal relationship, we believe that there is a high degree of association between CA6 and HFMD.
There are several limitations to this study. Recall bias of enrolled patients may exist because of the telephone interview. The gap period between the telephone interview, which was carried out in early 2011, and the HFMD episode may have been as long as 8 months, and the enrolled patients may not have been able to accurately describe the details of onychomadesis or the skin sites involved. In addition, the prevalence of the nail changes may have been underestimated due to patients' unawareness of them. Since the nail changes associated with HFMD are generally painless, the presence of nail changes may not have drawn the attention of the patients.