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See also Commentary, p. 303 CLINICAL REPORT ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica
Atypical Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6 in Denmark: A Diagnostic Mimicker
Hans-Henrik HORSTEN 1, Michael KEMP 2, Thea K. FISCHER 3, Kim H. LINDAHL 4 and Anette BYGUM 1
1
Department of Dermatology and Allergy Centre, Odense University Hospital, 2 Department of Clinical Microbiology, Odense University Hospital, University of Southern Denmark, 3 Virology Surveillance and Research Section, Department of Microbiological Diagnostics and Virology, Statens Serum Institut, Copenhagen, Denmark and University of Southern Denmark, Clinical Institute, and Center for Global Health, and
4
Department of Clinical Pathology, Odense University Hospital, Odense, Denmark
Since 2008, outbreaks of atypical hand, foot, and mouth disease( HFMD) in children and adults have been reported worldwide. The majority of these outbreaks are caused by a new lineage of Coxsackie virus A6( CV-A6) presenting a more severe clinical phenotype than the classical childhood HFMD caused by CV- A16. Between June 2014 and January 2016, 23 cases of atypical HFMD disease presented at a Dermatology Department at a regional University Hospital in Denmark. Patients were referred by general practitioners and dermatologists with a variety of clinical diagnoses, including eczema herpeticum, vasculitis, syphilis, dermatophytid, erythema multiforme and Stevens-Johnson syndrome. Three adults and 3 children required hospitalization due to extensive skin involvement and fever. All reported patients had laboratory-confirmed enterovirus infection. This study demonstrated an upsurge in atypical HFMD caused by CV-A6 in the Region of Southern Denmark and that atypical HFMD can be difficult to diagnose clinically as it may mimic other severe skin diseases.
Key words: atypical hand, foot, and mouth disease; Coxsackievirus A6; diagnostic mimicker.
Accepted Nov 24, 2017; Epub ahead of print Nov 28, 2017 Acta Derm Venereol 2018; 98: 350 – 354.
Corr: Hans-Henrik Horsten, Department of Dermatology and Allergy Centre, Odense University Hospital, DK-5000 Odense C, Denmark. E-mail: hans-henrik. horsten @ rsyd. dk
Hand, foot, and mouth disease( HFMD) is a common viral illness generally affecting children under 7 years of age( 1). Classical HFMD is a self-limiting condition presenting with oropharyngeal blisters, papular vesicles on the palms and soles, and sometimes fever. Patients will rarely be referred to the hospital, as symptoms are mild and complications, such as encephalitis and myocarditis, are rare in Europe( 2 – 4). Seasonal outbreaks occur, with incident peaks during the summer and early autumn. The major causative agents have been Coxsackievirus A16( CV-A16) and enterovirus( EV)-A71 within the species EV-A, members of the virus family Picornaviridae in the genus Enterovirus( 5).
Since 2008 outbreaks of atypical HFMD caused by CV-A6 have been reported worldwide, mostly during the winter in temperate climates( 6, 7). An increasing number of reports indicate that this new lineage of CV-A6 is more virulent, causing a widespread vesicular skin eruption in children as well as adults( 8, 9). In atopic children, a clinical presentation resembling eczema herpeticum has been described and termed eczema coxsackium( 10, 11).
The histopathological findings are mainly in the epithelium and consist of widespread keratinocyte necrosis and spongiosis, often with formation of vesicles. Neutrophilic exocytosis and reticular degeneration of the basal cell layer also occur. In the papillary dermis there is often massive oedema and a variable inflammatory infiltrate dominated by lymphocytes. As opposed to common findings in other viral diseases, there are no multinucleate cells, inclusion bodies or koilocytes( 12, 13).
The aim of this study is to present the clinical and paraclinical features of atypical HFMD, in order to inform physicians about the new phenotype. Intrafamilial cases are also reported.
METHODS
The Department of Dermatology and Allergy Centre, Odense University Hospital see patients referred from primary care physicians, practicing dermatologists and other hospital departments in the Region of Southern Denmark, which covers a population of ~ 1.2 million people. Based on a clinical picture suspicious of atypical HFMD, specimens were taken as vesicle fluid swabs, oropharyngeal swabs, and / or stool samples. The initial testing for EV was performed at the local Department of Microbiology using an in-house real-time PCR method. EV-positive samples were sent to the National World Health Organization( WHO) Reference Center for Polio at Statens Serum Institut for further characterization. Here, EV-RNA was subjected to a multiplex 1-step real-time assay with semi-nested PCR, and subsequently sequenced using Sanger technique targeting the region encoding the VP1 and VP2 genes, whose sequence corresponds with antigenic serotype( 14). In addition, all EV-RNA positive samples were routinely cultivated in 3 cell lines established as part of the poliovirus surveillance programme. For samples that might not have been characterized successfully during the first attempts, the typing procedure was repeated on cultivated material.
RESULTS
From June 2014 until January 2016, a total of 26 patients with a clinical presentation suggesting possible atypical HFMD were tested for EV infection. Of these patients, 23( 88 %) tested EV-positive, including 15 adults and 8 doi: 10.2340 / 00015555-2853 Acta Derm Venereol 2018; 98: 350 – 354
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2018 Acta Dermato-Venereologica.