Coxsackievirus A6 Polymorphic Exanthem in Israeli Children

Acta Derm Venereol 2016; 96: 546–549

CLINICAL REPORT Coxsackievirus A6 Polymorphic Exanthem in Israeli Children

Yael RENERT-YUVAL1, Eytan MARVA2, Merav WEIL3, Lester M. SHULMAN3,4, Nilsu GENCYLMAZ1, Sivan SHEFFER1, Dana G. WOLF2 and Vered MOLHO-PESSACH1 1Department of Dermatology, 2Clinical Virology Unit, Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, 3Central Virology Laboratory, Israel Ministry of Health, Sheba Medical Center, Tel Hashomer, and 4Department of Epidemiology, and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Hand foot and mouth disease (HFMD) is an acute child- is usually self-limiting and resolves within one week, hood viral exanthem usually associated with coxsackie- although severe systemic manifestations, including virus A16 or enterovirus 71. Atypical HFMD associated myocarditis, meningoencephalitis, aseptic meningitis with coxsackievirus A6 was reported recently. The aim and acute flaccid paralysis, have been reported in EV- of the current study was to describe coxsackievirus A6- 71-related HFMD (3, 4). Delayed cutaneous findings can associated atypical HFMD in a series of 8 toddlers who occur 3–8 weeks after HFMD and include acral desqua- were referred with idiopathic extensive eruptions. De- mation and nail matrix arrest (presenting as Beau’s lines mographic and clinical characteristics, Reverse trans- or nail shedding) (5). criptase-real-time PCR (RT-PCR) results for enterovi- Since 2008, CV-A6 has emerged as a cause of HFMD rus and phylogenetic analysis for the coxsackievirus A6 with an intense and widespread rash with atypical strains were recorded. Morphologically polymorphous cutaneous presentations (1). CV-A6 HFMD can easily (vesicular, erosive, papular, desquamative or purpuric) be misdiagnosed as eczema herpeticum, bullous impe- and extensive eruptions were found. One patient had de- tigo, vasculitis and primary immunobullous diseases layed nail shedding. Enterovirus was positive in all pa- of childhood (6). CV-A6 has also been shown to af- tients. Genotype analysis confirmed coxsackievirus A6 fect adults (7). Recently, 5 adults with an acute acral in 6 patients and 5 sequences underwent phylogenetic vasculitis-like rash due to CV-A6 were reported from analysis. This is the first such report in Israeli children. Israel (8); however, thus far, CV-A6 has not been re- In conclusion, coxsackievirus A6 atypical HFMD should ported as a cause of atypical HFMD in Israeli children. be regarded as a novel childhood viral exanthem. We We report here 8 Israeli toddlers with atypical HFMD. suggest the term “coxsackievirus A6 polymorphic exant- In 6 patients, sufficient quantities of RNA were avail hem” due to the extensive and variable nature of this er- able for genotyping and all were identified as CV-A6. uption. Key words: hand foot and mouth; viral exanthem; coxsackievirus A6. METHODS Accepted Oct 13, 2015; Epub ahead of print Oct 14, 2015 Patients were referred to the Hadassah Hebrew University Medical Center ER for EV detection. A swab was taken from Acta Derm Venereol 2016; 96: 546–549. the mucocutaneous lesions, and RNA was extracted by use of the automated extractor NucliSENS® easyMAG® (Biomérieux). Vered Molho-Pessach, Department of Dermatology, The purified RNA was subjected to Reverse transcriptase-real- Hadassah-Hebrew University Medical Center, Jerusalem time PCR (RT-PCR), using primers and probes derived from 91120, Israel. E-mail: [email protected] the conserved EV 5′ non-coding region, as described previously (9). A partial sequence of viral capsid protein 1 (VP1) was obtained after nested RT-PCR, as described previously (10), Enterovirus (EV)-associated hand foot and mouth disease using internal primers AN88 and AN89 for sequencing with an ABI PRISM BigDye Terminator Cycle Sequencing kit (HFMD) is an acute viral illness, ordinarily occurring (Applied Biosystems, Foster City, CA, USA). The sequences from spring to autumn, and affecting children younger were determined on an ABI 3500 Genetic Analyzer (Applied than 5 years of age. It is spread by contact with saliva, Biosystems). Six sequences were identified as CVA-6 by the faeces, respiratory secretions and vesicular fluid (1). The Enterovirus Genotyping Tool (11). The sequencer v5.0 program disease is caused by certain EV strains, with coxsackie- (Gencodes, Anne Arbor MI, USA) was used to align the sequence with equivalent regions of CVA6 prototype genotypes and virus (CV) A16 and EV-71 most commonly implicated. current isolates downloaded from the DDBJ/EMBL/GenBank Typical clinical manifestations include fever and a mu- database. After truncating 5 of the new Israeli sequences to the cocutaneous rash involving the oral cavity, hands, feet longest common sequence among isolates (214 nt) an unrooted and, occasionally, the buttocks. Oral mucosal lesions neighbor-joining tree with kimura 2-parameter correction was consist of vesicles surrounded by red areola, which often constructed using Clustal X v1.83 after bootstrapping data 1,000 times. The tree was visualized using nj polot. The Israeli ulcerate. Papulovesicles are noted on the hands and feet sequences reported here were submitted to GenBank and were and tend to run parallel to the skin lines (2). The disease assigned accession numbers KR011341 to KR011345.

RESULTS 1 and 6 had purpuric or dusky papules and plaques over the limbs (Fig. 1D, E). Eight patients, 6 males and 2 females, were diagnosed Laboratory evaluation showed mild leukocytosis in between March and October 2014 (patients 1–5 were 2 patients and relative lymphocytosis of approximately referred during March and April, patients 6–8 during 60% in 3 patients. C-reactive protein was mildly elevated September and October) with an atypical presentation in 3 patients. Two patients (patients 2 and 3) had positive of HFMD. Patients’ demographics and clinical cha- skin cultures for methicillin-sensitive Staphylococcus 1 racteristics are described in Table SI . Patients’ ages aureus. RT-PCR performed on swabs obtained from ranged from 6 to 24 months. Patients were unrelated, mucocutaneous lesions was positive for EV in all 8 child- other than a pair of twins (patients 2 and 3). Past medi- ren. Seven samples (except patient 2) were subjected to cal history included atopic dermatitis (AD) in 2 patients genotypic analysis, 6 samples (patients 1, 3, 4, 5, 7 and (patients 1 and 2), food allergies (patient 1) and preterm 8) were positive for CV-A6. One sample did not yield birth and mild motor developmental delay (patients 2 results due to technical problems (patient 6). Sequences and 3). Seven patients presented with fever of up to from 5 patients (patients 3, 4, 5, 7 and 8) were used 39.4°C, other symptoms included rhinorrhoea, cervi- for phylogenetic analysis (Fig. S11). Sequences from cal and inguinal lymphadenopathy, watery diarrhoea, isolates from patients 3, 4, 5 and 7, and 2 Israeli adults, decreased appetite and cough. However, all patients KF991009 and KF991012 from 2012 and 2013, respec- were in good general condition. tively, were closely related, but different from the isolate The eruption was usually widespread (Figs 1 and 2) from patient 8. All isolates from toddlers were distinct and included the face in all patients, with a periorifi- from 3 other CV-A6s isolated from Israeli adults in 2012. cial, mainly perioral distribution (Fig. 3) in most cases Contemporary isolates that were most closely related to (patients 1, 4, 5–8). Only 3 patients (patients 4, 6 and patients 3, 4, 5 and 7 were from the UK and Japan from 8) had intraoral involvement. All patients demonstrated 2013, whereas patient 8’s isolate resembled sequences involvement of the limbs, and half of the patients had isolated in Malaysia in 2013 and China in 2012. involvement of the palms and soles (patients 1, 4, 6 and Patients 1–3, 5 and 6 were hospitalized and treated with 8). The trunk was involved in 5 patients (patients 2, 3, topical corticosteroids and oral antibiotics, as well as in- 5–7) as well as the buttock and genitalia (patients 2–4, 6 travenous acyclovir, due to an initial differential diagnosis and 8). The AD patients (patient 1 and 2) did not exhibit of eczema herpeticum. Treatment with acyclovir was dis- specific localization of the eruption to sites of eczema. continued once herpes simplex virus PCR result returned The eruption manifested with polymorphic cutaneous negative, with positive EV RT-PCR. During admission, features, but was usually monomorphic in each patient all patients were stable and showed gradual resolution of (Figs 1 and 2). The most common morphological pattern their rash. Patients 4, 7 and 8 were not admitted, due to was erythematous erosive or crusted papules (Fig. 1B, their good general condition and the clinical diagnosis C). Intact vesicles were noted in patient 4. Patients 2 of atypical HFMD upon presentation. They were treated and 3 presented with diffuse erythematous and crusted with topical corticosteroids with disappearance of the rash papules and plaques with marked desquamation (Fig. within several days. One month after admission, patient 4 2). Parents reported a preceding vesiculobullous phase. was the only patient to develop nail shedding of several Patient 6 was also noted to have desquamation. Patients fingernails. Patient 5 developed widespread hyperpigmen- ted macules, which resolved slowly and were consistent clinically with post-inflammatory hyperpigmentation. 1http://www.medicaljournals.se/acta/content/?doi=10.2340/00015555-2261

Fig. 1. (A) Papular eruption over the lower limbs in patient 7. (B) Erosive papular eruption in patient 4. (C) Erosive papules in patient 8. (D, E) Purpuric/ dusky papules and plaques in patients 6 and 4.

Acta Derm Venereol 96 548 Y. Renert-Yuval et al.

Fig. 2. (A, B) Widespread erythematous and crusted papules and plaques with marked desquamation in patient 2. (C) Crusted plaques with desquamation in patient 3.

DISCUSSION Atypical HFMD had not been previously reported in Israeli children, although CV-A6 was recently shown In an outbreak of HFMD in Finland in 2008, CV-A6, to cause HFMD in Israeli adults (8). We report here which had been previously associated with herpangina 8 toddlers, seen between March and October 2014 in and only sporadically related to HFMD, was first found Jerusalem, with acute extensive polymorphic (papular, to be an eminent cause of HFMD (12, 13). Since then, vesicular, erosive, purpuric and desquamative) rash, yet reports of outbreaks from North America, Europe, Asia monomorphic in each patient. RT-PCR confirmed the and New Zealand have revealed that CV-A6 HFMD is diagnosis of EV infection and genotyping was positive becoming more prevalent (1, 6, 7, 14–17). In 2012, the for CV-A6 in 6 patients. The partial VP1 sequences of 4 US Centers for Disease Control and Prevention repor- of the CV-A6 strains were similar to those observed for ted a growing number of “severe and extensive” cases 2 Israeli adults and distinct from the sequence of a fifth of HFMD associated with CV-A6. The appearance isolate. The Israeli strains isolated from the children of CV-A6 as a novel cause of HFMD and its’ unique mapped into branches that included isolates from the presentation have both been attributed to mutations in UK (2013), Japan (2013), China (2012) and Malaysia various regions of the viral genome (18). (2013); although no evidence has directly linked any Several different morphological patterns of the CV- of these or previous Israeli cases to importation (8). A6 atypical HFMD were described (6): (i) a widespread The eruption in the toddlers was always extensive and vesiculobullous and erosive eruption – seen most fre- tended to involve facial periorifical pattern, most often quently (19); (ii) an eczema herpeticum-like eruption perioral. Although 2 patients had a history of AD, we (“eczema coxsackicum”), described as grouped vesicles did not observe specific distribution of the eruption to or erosions, mainly affecting areas involved by eczema eczema-affected areas. Only 3 toddlers had involvement in children with AD (7, 20); (iii) a Gianotti-Crosti like of the oral mucosa. In accordance with our finding, in- eruption – a papulovesicular eruption with prominent traoral erosions are less commonly reported in atypical involvement of the cheeks, extensor surfaces of the ex- HFMD, as opposed to classic HFMD where oral lesions tremities, and buttocks, sparing the torso; (iv) petechial are present in up to 90% of cases (2, 6). The majority or purpuric eruption – often seen in children older than of patients had complete resolution of their symptoms 5 years of age, most frequently on acral sites; and (v) within 7–10 days, with post-inflammatory hyperpig- a bullous palmoplantar eruption (21). mentation and nail shedding noted during follow-up in Delayed nail changes were seen in up to 37% of one patient each. Secondary staphylococcal cutaneous patients (6, 22). infection was the only complication observed. Despite increasing reports worldwide of CV-A6 atypical HFMD, clinicians are still unaware of this novel, yet common, childhood viral exanthem. All the patients reported herein were referred to the ER with various misdiagnoses, leading to futile admission, investigations, and occasional treatments. The phenotypic heterogeneity and the extensive distribution of the eruptions in our patients as well as in previous reports, argue that the term HFMD may be Fig. 3. (A) Perioral vesicles in patient 4. (B) Erosive erythematous papules in patient 8. a misnomer for this viral exanthem. We sug-

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