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Onychomadesis after hand-foot-and-mouth disease outbreak in northern Greece: case series and brief review of the literature Zoe Apalla1, MD, Eleni Sotiriou2, PhD, Olga Pikou1, MD, Ioanna Lefaki1, PhD, MD, Aimilios Lallas3, PhD, Elizabeth Lazaridou2, PhD, and Demetris Ioannides2, PhD

1 State Clinic, Hospital of Skin and Venereal Diseases, Thessaloniki, Greece, 2First Department of Dermatology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece, and 3 Dermatology and Skin Cancer Unit, Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy

Correspondence Zoe Apalla, MD 124 Delfon Street Thessaloniki 54643 Greece E-mail: [email protected] Funding sources: None.

Abstract Background

Nail

abnormalities

in

childhood

are

generally

uncommon. Recently,

onychomadesis was described as a late complication of hand-foot-and-mouth disease (HFMD). Onychomadesis outbreaks following HFMD have been reported in many countries worldwide. Aim To present a case series of onychomadesis in children, following HFMD outbreak in Northern Greece, and review literature data. Methods Children with evident onychomadesis attending the outpatient clinic between November 2012 and January 2013 were included in the study. A questionnaire including demographic personal and family history information of the children was completed by the parents. Patients were clinically examined, and their pediatric and dermatological records were studied to confirm precedent HFMD. Direct microscopic examination and cultures for fungi were performed. Exposure of participants to coxsackievirus, based on serology testing during infection, was also recorded. Results Sixty-eight children with onychomadesis were included. The mean number of

Conflicts of interest: None.

affected nails was 8.82. Fingernails were more often involved. Previous clinical diagnosis of HFMD was confirmed in 67/68 cases. The mean time from HFMD diagnosis to onychomadesis development was 39.6 days (range: 28–56 days, STD: 7.33). Direct microscopic examination, as well as cultures for fungal species, was negative for the whole sample size. All the nail changes were transient with spontaneous regrowth after 1–4 months. Conclusion Our data indicate that onychomadesis outbreak in the region of Thessaloniki during fall–winter 2012–13 was highly related to the outbreak of HFMD. Our study reinforces existing evidence for the association between onychomadesis and HFMD.

Introduction Hand, foot, and mouth disease (HFMD) is a relatively common viral infection that predominantly affects young children, usually during the spring and fall months. It is caused by members of the human enterovirus (HEV) genus that belong to the Picornaviridae family. The most often involved serotypes are coxsackievirus A16 (CVA16) and enterovirus 71 (EV71), which both belong to the HEV-A species. However, other HEV-A serotypes, as well as some HEV-B, have also been associated with flares of the disease.1 Although in the majority of cases flares are sporadic, epidemics may also occur. In childhood, nail abnormalities are generally rare and can manifest either in the context of inherited diseases, or because of systemic illnesses, trauma, or drug uptake. Additionally, many cases are considered idiopathic. Even though nail matrix arrest had been previously related to viral infections, only recently onychomadesis ª 2015 The International Society of Dermatology

was described as a late complication of HFMD.2,3 Since then, onychomadesis outbreaks following HFMD have been reported in many countries worldwide.4–12 The aim of the current study is to present a case series of 68 children with evident nail changes following an HFMD outbreak in northern Greece and discuss our observations in correlation to the findings of other investigators. Patients and methods We present a case series of 68 children, between 2 and 13 years of age, with evident onychomadesis that attended the outpatient clinic of the Hospital of Skin and Venereal Diseases of Thessaloniki in Greece between November 2012 and January 2013. Parents of all patients provided written informed consent before any study-related procedure. They were also given a questionnaire to complete at the time of the first International Journal of Dermatology 2015, 54, 1039–1044

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visit. The questionnaire included information about the date of birth, gender, residency, time of onset, previous pathologic background, personal dermatological history (including psoriasis, hair disorders, dental alterations, paronychia, and onychophagia), family history, medication, trauma, as well as previous hospitalization of their child/children. Children with no underlying disease (systemic or dermatological), trauma anamnesis, or exposure to drugs associated with nail matrix arrest were considered as eligible for the study. Patients were clinically examined, and all nail alterations were digitally documented. Onychomadesis was defined as nail shedding affecting two or more nails from fingernails or toenails with no previous history of injury, systemic illness, or drug exposure. Concomitant nail disorders, if present, were also recorded. Diagnosis of related precedent HFMD was confirmed by either their pediatric or their dermatological records. Individuals with typical signs and symptoms of the disease, including fever, vesicular eruption in the oral mucosa, hands, feet, and/or diaper area, buttocks, and genitalia, as derived by the medical records of the patients, were classified as HFMD (+). Patients with medical records describing signs and symptoms similar, but not typical for HFMD (fever, atypical stomatitis, and/or macular or other eruption and/or atypical localization), were classified as HFMD (+/ ). In cases where medical records were unavailable, HFMD diagnosis was based on the history of fever and compatible eruption, as provided by the parents. However, as a definite diagnosis was not possible for the latter group they were classified as HFMD ( ).

Exposure of the individuals to coxsackievirus based on serology testing during infection was also recorded (if available). Genetic typing was not performed because of unavailability of appropriate equipment. For statistical analysis, the chi-squared test of independence was applied to compare qualitative variables; P < 0.05 was considered statistically significant.

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Results Overall, 81 patients were screened for eligibility, and 13 were excluded because of a positive history of atopic dermatitis (seven), onychophagia (two), exposure to anticonvulsants (one), alopecia areata (one), hand trauma (one), and psoriasis (one). None of the patients reported recent hospitalization (for the past 2 months) due to HFMD or other disease. Therefore, we included 68 children with onychomadesis, aged between 2 and 13 years of age, with a female/male ratio equal to 36 : 32 (Fig. 1). All patients resided in northern Greece, with 49 of them living in the area of Thessaloniki and 19 children living within a 150 km radius. Onychomadesis was clinically evident in all 68 participants. The number of affected nails varied between 2 and 19 (mean: 8.82, STD: 3.75). Fingernails (mean: 5.9) were more often involved compared to toenails (mean: 2.89), while the nail of paramesial finger was the commonest localization. Figure 2 illustrates representative cases of onychomadesis in some of our patients. Concomitant nail disorders were found in 17 of 68 (25%) of the children and included Beau’s lines

Figure 1 Number of patients with onychomadesis per age and sex. Males are shown in blue and females in red International Journal of Dermatology 2015, 54, 1039–1044

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Onychomadesis after a hand-foot-and-mouth disease outbreak

(a)

(c)

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(b)

(d)

Figure 2 Onychomadesis involving the fingers (a, b) and/or the toes (c, d), in selected cases

(12 patients), white/yellowish discoloration (four), and koilonychias (one). According to the patients’ medical records, a definite previous clinical diagnosis of HFMD (i.e., +) was available for 45 of 68 (66.17%), while a possible clinical diagnosis of previous HFMD (i.e., +/ ) was available for 22 of 68 (32.35%). One patient (1.47%) was classified as HFMD ( ) because previous medical reports were unavailable (Fig. 3).

Figure 3 History of previous clinical diagnosis of HFMD among patients with onychomadesis. Individuals with definite HFMD (HFMD+) are shown in blue, those with atypical symptoms and signs of the disease (HFMD+/ ) in green, and the case with no confirmed clinical diagnosis of the disease (HFMD ) in red. HFMD, hand, foot, and mouth disease ª 2015 The International Society of Dermatology

Serologic testing was available in 51 of 68 cases, and the antibody titer was positive in all of the 51 serum samples for coxsackievirus. Exposure to coxsackievirus based on serology was established in 29 of 45 HFMD (+) cases, in 21 of 22 HFMD (+/ ), and in the one HFMD ( ) case. The mean age of participants was 6 years (range: 2–13, SD: 2.47). In females the mean age was 6.4 years, while for males it was 5.6 years. Of 68 children, 43 (63.23%) were ≤6 years and 25 (36.76%) older than 6 years. In younger ages (≤6 years old), the mean number of affected nails was nine, while in older children (>6) it was 8.4. We also observed a higher rate of typical symptoms of HFMD (+) in younger children (32 of 42, 76.19%) compared to ages over 6 (10 of 25, 40%; P < 0.05). The mean time from HFMD diagnosis to onychomadesis development was 39.6 days (range: 28–56 d, SD: 7.33). In children ≤6 years of age the mean time from HFMD to onychomadesis was 37 days (range: 22–55 d), while in older children this was found to be 44.16 days (range: 29–56 d). Signs and symptoms of HFMD were less likely to be typical as the time of onychomadesis onset increased. Analytically, 76.31% of patients with early-onset onychomadesis (≤40 d from onset of symptoms) had experienced typical HFMD symptoms (HFMD+). On the contrary, as time from infection increased (>40 d), the percentage of HFMD (+) patients dropped to 53.33%. Additionally, we observed that when the latency period was ≤40 days, the mean number of affected nails was 9.5 per case (fingernails: 6.3, toenails: 3.2) while in latency period >40 days the corresponding number was 7.9 International Journal of Dermatology 2015, 54, 1039–1044

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(a)

(b)

Figure 4 Spontaneous normal regrowth of the nail plate (a) 3.5 months from diagnosis (b)

(fingernails: 5.5, toenails: 2.4), indicating that increasing the time interval from infection, less nails per case were found to be affected. All the nail changes in all of our patients were temporary with spontaneous normal re-growth 1–4 months from diagnosis (Fig. 4). Discussion In the current study, we describe an onychomadesis outbreak following HFMD in northern Greece. In 66.17% of our patients with onychomadesis, clinical diagnosis of HFMD was previously established, highly indicating its causative role in onychomadesis. This finding is in line with pre-existing data, reporting similar percentages of patients with typical clinical signs of HFMD in the outbreaks of Valencia9 and Vallalolid,6 while in La Coruna the reported rate was even higher, reaching 92%.8 In the same period, in the outbreak in Saragossa, Guimbao et al.7 reported that 75% of HFMD cases experienced onychomadesis and additionally pointed out that the rate of onychomadesis attack changed with age, affecting mainly younger children. Compared to previous studies, we found a higher mean age of patients (6 years). This can be partially explained by the setting of our study. Specifically, we pooled patients from a general dermatology outpatient clinic and not from a pediatric or a pediatric dermatology department. Subsequently, the age range of our studied population was broader (2–13 years), compared to the majority of previous reports conducted in pediatric settings. In our studied population, there were no ages below 2 years, as these age groups more frequently attend pediatric than dermatology outpatient clinics. Regarding the time interval between HFMD and the development of onychomadesis, our observations are in agreement (39.6 d average, range 4–8 weeks) with those of other investigators,1–12 who in general report a latency period of 1–2 months. In all of the available studies, including the current, there is a drawback concerning preInternational Journal of Dermatology 2015, 54, 1039–1044

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cise evaluation of the time interval between infection and onychomadesis initiation. Specifically, taking into account that complete replacement of the nail plate takes 4–6 months in fingernails and 8–12 in toenails, the optimal way to record the time interval from HFMD and onychomadesis would be to measure the length of the new rising nail. However, the aforementioned measurement was not performed. In the current study, the average number of affected nails (including both fingernails and toenails) was approximately nine. There are only two case series7,10 commenting on the mean number of affected nails, in which it was found lower than in ours (four and six nails, respectively). In addition, we observed that the most commonly affected nail was that of the paramesial finger. Only Wei et al,10 in the outbreak of Taiwan, recorded a similar observation, but in their study the right thumb was the digit most often involved. Concerning concomitant nail alterations, Beau’s lines, white/yellowish discoloration, and koilonychia were observed in 12, four, and one of our patients, respectively. Apart from onychomadesis and Beau’s lines, no other nail changes in association to HFMD have been reported in the literature. In agreement with previous publications,1–17 our analysis suggested a strong correlation between onychomadesis and HFMD. Notably, our records indicate that this association is more evident in younger ages. The latter has also been reported in the literature.7 A possible explanation of this observation was introduced by Blomqvist et al.1 who suggested the hypothesis of low herd immunity against new strains of coxsackievirus resulting in a higher incidence of infection among a younger population. The latter hypothesis is reinforced by the most recent publication of Oza in the outbreak caused by a newer strain of CV A6 in the United States in 2012. In particular, Oza noticed that even if the spectrum of ages was broad, the newer strain of CV A6 attacked mainly younger children, provoking more atypical signs, including onychomadesis, and supposed the absence of acquired immunity within the community.17 Table 1 summarizes previously published studies reporting onychomadesis outbreaks correlated to specific strains of coxsackievirus in Europe and other continents. In our study, unfortunately, due to lack of equipment, virus isolation and subtyping were not available. Furthermore, we identified coxsackievirus as a causal agent of HFMD in all of the 51 individuals that had performed serology testing. Serologic enterovirus positivity was confirmed in 67% of the studied population in the Finnish outbreak of HFMD1 and in 47% of HFMD cases in the outbreak in La Coruna.8 The rate of enterovirus positivity among onychomadesis cases in the outbreaks of ª 2015 The International Society of Dermatology

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Table 1 Published studies reporting onychomadesis outbreaks correlated to specific serotypes of coxsackievirus in Europe and other continents Authors

Year

Location

Responsible serotypes

Clementz et al.2 Bernier et al.3 € Osterback et al.5 Guimbao et al.7 Davia et al.9 Redondo et al.6 Cabrerizo et al.8 Wei et al.10

2000 2001 2008 2008 2008 2009 2009 2010

Chicago, IL, USA France, Belgium Finland Saragossa, Spain Valencia, Spain Valladolid, Spain La Coruna, Spain Taiwan

Fujimoto et al.11 McIntyre et al.12 Oza et al.17

2011 2012 2012

Japan USA USA

Not identified Not identified CVA6 CVB1, CVB2, non-polio enterovirus CVA10, CVA6, CVB1 Not identified CVB1 CVA6, CVA16, CVA5, CVA4, EV71, CVA2, CVB5, echovirus 4, echovirus 30 CVA6 CVA6 CVA6

Saragossa7 and Valencia9 were 61% and 66%, respectively. Interestingly, we found a high percentage of patients with atypical signs of the HFMD and serologic positivity to coxsackievirus, while in the only case of onychomadesis without a definite diagnosis of HFMD (HFMD ), the serum sample confirmed exposure to coxsackievirus. Similarly, cases of onychomadesis following clinically atypical HFMD were previously reported in the USA epidemic.17 These observations, provide an indication that onychomadesis is rather related to the coxsackievirus infection itself than to clinical symptoms of HFMD. Literature data suggest that CVA6, CVA10, and CVB1 are considered as the main responsible pathogens of HFMD-associated onychomadesis. However, it remains unclear whether onychomadesis is associated with a single or with multiple viral strains. As genetic virus typing was not performed in the present study, our results cannot contribute in addressing this issue. The underlying pathogenetic mechanism of onychomadesis following HFMD remains unclear. In the first reported outbreak, the authors postulated that onychomadesis may be explained by the neuropathogenic poten€ tial of EV71.2 However, Osterback et al. after detecting CVA6 in one piece of a shed nail, suggested that the virus replication specifically leads to temporary nail dystrophy.5 Although failing to isolate the virus in the nail matrix, Wei et al.10 outbid the previous hypothesis, adding that CVA6 attacks a broader spectrum of skin sites and causes deeper tissue damage. On the other hand, other investigators even though verified multiple strains, they attributed onychomadesis primarily to CVA10 and did not correlate the severity of the preceding HFMD to onychomadesis.9 Another potential explanation for the relationship between the two conditions could be intensive hygienic

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measures during HFMD outbreaks leading to extreme maceration and a local environment favoring Candida infection and allergic contact dermatitis, both of which can cause onychomadesis.13 In one case report, the authors observed that onychomadesis appeared only in digits with more severe cutaneous involvement around nails, suggesting that nail alterations are due to direct inflammation spreading from skin eruption.15 In 2012, Bettoli et al.16 speculated that onychomadesis might be caused not only by direct inflammation due to the virus but also by distal embolism due to virus-specific immunocomplexes. Future studies focusing on the pathogenesis are needed to clarify the underlying mechanism of this phenomenon. All being well, in HFMD-induced onychomadesis the nail basement remains intact, so nail changes are reversible and the regrowth of the nail is not affected. The latter is confirmed by the clinical observation of spontaneous regression and replacement of the nail bed with a normal one within the next 1–4 months.2,3,5–7,9–11,15,16 In conclusion, according to our data, the onychomadesis outbreak in the region of Thessaloniki during fall– winter 2012–13 was highly related to the outbreak of HFMD caused by coxsackievirus. Our study reinforces existing evidence for the association between onychomadesis and HFMD.

References 1 Blomqvist S, Klemola P, Kaijalainen S, et al. Cocirculation of coxsackieviruses A6 and A10 in hand, foot and mouth disease outbreak in Finland. J Clin Virol 2010; 48: 49–54. 2 Clementz GC, Mancini AJ. Nail matrix arrest following hand-foot-mouth disease: a report of five children. Pediatr Dermatol 2000; 17: 7–11.

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3 Bernier V, Labreze C, Bury F, et al. Nail matrix arrest in the course of hand, foot and mouth disease. Eur J Pediatr 2001; 160: 649–651. 4 Salazar A, Febrer I, Guiral S, et al. Onychomadesis outbreak in Valencia, Spain, June 2008. Euro Surveill 2008; 13: ii, 18917. € 5 Osterback R, Vuorinen T, Linna M, et al. Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis 2009; 15: 1485–1488. 6 Redondo Granado MJ, Torres Hinojal MC, Izquierdo0020L opez B. Post viral onychomadesis outbreak in Valladolid. An Pediatr (Barc) 2009; 71: 436–439. 7 Guimbao J, Rodrigo P, Alberto MJ, et al. Onychomadesis outbreak linked to hand, foot, and mouth disease, Spain, July 2008. Euro Surveill 2010; 37: 1–5. 8 Cabrerizo M, De Miguel T, Armada A, et al. Onychomadesis after a hand, foot, and mouth disease outbreak in Spain, 2009. Epidemiol Infect 2010; 138: 1775–1778. 9 Davia JL, Bel PH, Ninet VZ, et al. Onychomadesis outbreak in Valencia, Spain associated with hand, foot, and mouth disease caused by enteroviruses. Pediatr Dermatol 2011; 28: 1–5. 10 Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis 2011; 11: 346. 11 Fujimoto T, Iizuka S, Enomoto M, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Japan, 2011. Emerg Infect Dis 2012; 18: 337–339.

12 Centers for Disease Control and Prevention Notes from the field: severe hand, foot, and mouth disease associated with coxsackievirus A6 – Alabama, Connecticut, California, and Nevada, November 2011–February 2012. MMWR Morb Mortal Wkly Rep 2012; 61: 213– 214. 13 Haneke E. Onychomadesis and hand, foot and mouth disease—is there a connection? Euro Surveill 2010; 37: pii19664. 14 Bracho MA, Gonz alez-Candelas F, Valero A, et al. Enterovirus co-infections and onychomadesis after hand, foot, and mouth disease, Spain, 2008. Emerg Infect Dis 2011; 17: 2223–2231. 15 Shikuma E, Endo Y, Fujisawa A, et al. Onychomadesis developed only on the nails having cutaneous lesions of severe hand-foot-mouth disease. Case Rep Dermatol Med 2011; 2011: 324193. 16 Bettoli V, Zauli S, Toni G, et al. Onychomadesis following hand, foot, and mouth disease: a case report from Italy and review of the literature. Int J Dermatol 2013; 52: 728–730. 17 Oza V. S018 – Late-breaking Research: Eczema Coxsackiuma and Other Unusual Cutaneous Findings in an Enterovirus Outbreak. Presented at: American Academy of Dermatology 2013 Annual Meeting; March 1–5, Miami Beach, Fla.

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International Journal of Dermatology 2015, 54, 1039–1044

ª 2015 The International Society of Dermatology

Onychomadesis after hand-foot-and-mouth disease outbreak in northern Greece: case series and brief review of the literature.

Nail abnormalities in childhood are generally uncommon. Recently, onychomadesis was described as a late complication of hand-foot-and-mouth disease (H...
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