Enterovirus Co-infections and Onychomadesis after Hand, Foot, and Mouth Disease, Spain, 2008

Maria A. Bracho

, Fernando González-Candelas, Ana Valero, Juan Córdoba, and Antonio Salazar

Author affiliations: Centro Superior de Investigación en Salud Pública, Valencia, Spain (M.A. Bracho); Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública, Barcelona, Spain (M.A. Bracho, F. González-Candelas); Universitat de València, Valencia (F. González-Candelas); University of Edinburgh, Edinburgh, Scotland, UK (A. Valero); Hospital Universitario La Fe, Valencia (J. Córdoba); Centre Salut Pública de València, Valencia (A. Salazar)

Abstract

Hand, foot, and mouth disease (HFMD), a common disease caused by enteroviruses (EVs), usually affects children. Clustered and sporadic HFMD cases, followed by onychomadesis (nail shedding), occurred during summer and fall 2008 in Valencia, Spain. Fecal samples from onychomadesis patients, who did or did not have previous HFMD, and from healthy children exposed to onychomadesis patients tested positive for EV. The complete viral protein 1 capsid gene sequence was obtained for typing and phylogenetic analysis. Two EV serotypes, coxsackievirus A10 and coxsackievirus B1 (CVB1), were mainly detected as a monoinfection or co-infection in a childcare center where an onychomadesis outbreak occurred. On the basis of our results, and detection of CVB1 in 2 other contemporary onychomadesis outbreaks in childcare centers in Spain, we propose that mixed infection of an EV serotype that causes HFMD, plus the serotype CVB1, could explain the emergence after HFMD of onychomadesis, a rare and late complication.

Enteroviruses (EVs) are among the most common human viruses, infecting ≈1 billion persons worldwide annually (1). On the basis of phylogenetic analysis, the genus Enterovirus (family Picornaviridae) is divided into 10 species. Members (serotypes) of human enteroviruses (HEVs) are classified into 4 species: HEV-A, HEV-B, HEV-C, and HEV-D (2). Although most EV infections are asymptomatic, they can result in a broad range of clinical manifestations, ranging from benign symptoms to notable diseases such as poliomyelitis, severe neonatal systemic disease, encephalitis, meningitis, or myocarditis (3).

Hand, foot, and mouth disease (HFMD) typically affects children <10 years of age. The main signs and symptoms are fever; sore throat; general malaise; and, often, vesicular eruptions on the palms of the hands, soles of the feet, oral mucosa, and tongue. Although HFMD is classically a mild disease, outbreaks in Asia have been associated with a high incidence of fatal cardiopulmonary and neurologic complications (4). EVs that are most frequently reported as causing HFMD outbreaks include EV71 and coxsackievirus A16 (CVA16) (5). Other HEV-A serotypes, such as CVA4, CVA5, CVA6, and CVA10, have also been reported in cases of HFMD and herpangina, a disease that shares clinical symptoms with HFMD (6–9). HFMD, followed by onychomadesis (nail shedding), was first reported in 2000 in 5 children in Chicago, Illinois, USA (10). In 2001, a similar report described it in 4 children in Europe (11). Since 2008, several onychomadesis outbreaks (HFMD outbreaks followed by onychomadesis) have been reported in various locations in Spain: Valencia (12), Valladolid (13), Saragossa (14), and A Coruña (15). A preliminary case–control study from the 2008 Valencia onychomadesis outbreak established a clear link between HFMD and onychomadesis (odds ratio 5.836, p<0.001) (12). Finally, onychomadesis cases in the context of a HFMD outbreak have also been reported in Finland in 2008 (7,16).

Molecular characterization of the etiologic agent involved in onychomadesis after HFMD, either in clustered or sporadic cases, remains controversial. Although serotypes CVA6 and CVA10 co-circulated during the 2008 HFMD outbreak in Finland (16), only CVA6 was explicitly reported in the HFMD cases in which the patients experienced onychomadesis (7). In Spain, serotype CVB1 was detected in A Coruña, and both CVB1 and CVB2 were detected in Saragossa. Noticeably, serotypes CVA10 and CVB1 were prevalent in the preliminary reports of the 2008 onychomadesis outbreak in Valencia (17). Considering all of these results together, no convincing demonstration has been made to clarify which serotype could account for the HFMD–onychomadesis epidemics.

In this study, to establish a relationship between EV infection and the onychomadesis patients in Valencia, Spain, in 2008, we analyzed fecal specimens from children who experienced onychomadesis after HFMD and from healthy children who had been in contact with onychomadesis case-patients. As a result of identifying EV serotypes and conducting phylogenetic analyses of viral protein (VP) 1 gene sequences, we propose that either co-infection or superinfection with an EV serotype that causes HFMD, along with serotype CVB1, could explain the emergence of recent HFMD–onychomadesis outbreaks. However, further research on future onychomadesis outbreaks that overcome the limitations of this study are necessary to verify this proposal.

Suggested citation for this article: Bracho MA, González-Candelas F, Valero A, Córdoba J, Salazar A. Enterovirus co-infections and onychomadesis after hand, foot, and mouth disease, Spain, 2008. Emerg Infect Dis [serial on the Internet]. 2012 Jan [date cited]. http://dx.doi.org/10.3201/eid1712.110395