Hand, Foot, and Mouth Disease Caused by Coxsackievirus A6

LETTERS

4. Shaikh N, Leonard E, Martin JM. Preva- Hand, Foot, and the exanthem. The rash resolved over lence of streptococcal pharyngitis and 7–14 days with no residual scarring. streptococcal carriage in children: a meta- Mouth Disease analysis. Pediatrics. 2010;126:e557–64. Samples from the oropharynx, rectum, http://dx.doi.org/10.1542/peds.2009-2648 Caused by and vesicles from these patients were 5. Liang Y, Shen X, Huang G, Wang C, Coxsackievirus A6 sent to the Centers for Disease Control Shen Y, Yang Y. Characteristics of Strep- and Prevention (Atlanta, GA, USA) tococcus pyogenes strains isolated from Chinese children with scarlet fever. Acta To the Editor: Coxsackievirus for analysis. Reverse transcription Paediatr. 2008;97:1681–5. http://dx.doi. A6 (CVA6) is a human enterovirus PCR and sequencing by using primers org/10.1111/j.1651-2227.2008.00983.x associated with herpangina in infants. specifi c for a portion of the viral 6. Lau MCK. Increase in scarlet fever cases In the winter of 2012, we evaluated a protein 1 coding region identifi ed in 2011. Communicable Diseases Watch. 2011; 8:48–9 [cited 2012 Jun 30]. http:// cluster of 8 patients, 4 months–3 years CVA6 (1) (Table, Appendix). www.chp.gov.hk/fi les/pdf/cdw_v8_12.pdf of age, who were brought for treatment Outbreaks of HFMD caused 7. Duncan CJ, Duncan SR, Scott S. The at Boston Children’s Hospital (Boston, by CVA6 have been described in dynamics of scarlet fever epidemics in MA, USA) with a variant of hand, Singapore, Finland, Taiwan, and England and Wales in the 19th century. Epidemiol Infect. 1996;117:493–9. http:// foot, and mouth disease (HFMD) most recently in Japan; most cases dx.doi.org/10.1017/S0950268800059161 that has now been linked to CVA6 have occurred in the warmer months 8. Köhler W, Gerlach D, Knöll H. Strepto- (Table, Appendix, wwwnc.cdc.gov/ (2–6). Cases in the cluster described coccal outbreaks and erythrogenic toxin EID/article/18/10/12-0813-T1.htm). here are likely related to an emerging type A. Zentralbl Bakteriol Mikrobiol Hyg [A]. 1987;266:104–15 10.1016/S0176- During this same period, the Boston outbreak of CVA6-associated HFMD 6724(87)80024-x. Public Health Commission’s syndromic in the United States (7). The atypical 9. Nishiura H, Chowell G. The effective surveillance system detected a 3.3-fold seasonality of the outbreak, during the reproduction number as a prelude to sta- increase in emergency department winter in Boston, could be related to tistical estimation of time-dependent epidemic trends. In: Chowell G, Hayman JM, discharge diagnoses of HFMD. In the the unusually mild temperatures in the Bettencourt LMA, editors. Mathematical United States, HFMD typically occurs winter of 2012. and statistical estimation approaches in in the summer and early autumn and Recent CVA6 outbreaks have epidemiology. New York: Springer; 2009. is characterized by a febrile enanthem been characterized by a febrile illness p. 103–21. of oral ulcers and macular or vesicular associated with an oral enanthem Address for correspondence: Eric H.Y. Lau, lesions on the palms and soles; the and lesions on the palms, soles, and School of Public Health, The University of etiologic agents are most often CVA16 buttocks. CVA6 infections in Taiwan Hong Kong, Pokfulam, Hong Kong Special and enterovirus 71. during 2004–2009 were associated Administrative Region, People’s Republic of In contrast to the typical mani- with HFMD in 13% of cases, with China; email: [email protected] festation, the patients in the Boston disease defi ned as oral ulcers on the cluster exhibited symptoms in tongue or buccal mucosa and vesicular late winter (Table, Appendix) and rashes on the palms, soles, knees, or Letters had perioral (Figure, panel A) and buttocks (2). In Singapore, where Letters commenting on recent articles perirectal (Figure, panel B) papules CVA6 accounted for 24% of HFMD as well as letters reporting cases, and vesicles on the dorsal aspects cases, patients had oral lesions and <5 outbreaks, or original research are of the hands and feet (Figure, panel peripheral papules, placing them on welcome. Letters commenting on ar- C). Patients experienced a prodrome a spectrum closer to the herpangina ticles should contain no more than lasting 1–3 days, consisting of fever more typically observed in CVA6 300 words and 5 references; they are (8 patients), upper respiratory tract infection (8). more likely to be published if submitted symptoms (4 patients), and irritability The patients we report in this within 4 weeks of the original article’s (7 patients). This prodrome was cluster most typically had perioral publication. Letters reporting cases, followed by the development of a and perirectal papules in addition to outbreaks, or original research should perioral papular rash (8 patients), vesicles on the dorsum of their hands. contain no more than 800 words and which was often impetiginized with Two reports of CVA6-associated 10 references. They may have 1 secondary crusting; a prominent HFMD outbreaks describe cases Figure or Table and should not be di- papulovesicular rash on the dorsum that more closely resemble patients vided into sections. All letters should of the hands and feet (6 patients); in the Boston outbreak. In a series contain material not previously pub- and a perirectal eruption (7 patients). from Finland in 2008, representative lished and include a word count. Half of the patients had intraoral patients had both perioral lesions and lesions. Fever abated in most of the vesicles on the dorsum of their hands patients within a day after onset of (6). In a large series of patients with

1702 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 18, No. 10, October 2012 LETTERS

Figure. Manifestations of hand, foot, and mouth disease in patients, Boston, Massachusetts, USA, 2012. Discrete superﬁ cial crusted erosions and vesicles symmetrically distributed in the perioral region (A), in the perianal region (B), and on the dorsum of the hands (C). A color version of this ﬁ gure is available online (wwwnc.cdc.gov/EID/article/18/10/12-0813-F1.htm).

HFMD in Taiwan in 2010, patients Because of the atypical presentation DOI: http://dx.doi.org/10.3201/eid1810.120813 with CVA6 had perioral lesions in of CVA6-associated HFMD, clinical References addition to an enanthem (3). vigilance is needed to recognize Outbreaks of CVA6-associated emerging regional outbreaks. More 1. Nix WA, Oberste MS, Pallansch MA. HFMD in Finland, Taiwan, and Japan detailed epidemiologic and genetic Sensitive, seminested PCR amplifi cation of VP1 sequences for direct identifi cation were associated with onychomadesis, analyses will be required to of all enterovirus serotypes from original with the loss of nails occurring 1–2 characterize the role of CVA6 in US clinical specimens. J Clin Microbiol. months after initial symptoms (3,4,6). outbreaks of HFMD. 2006;44:2698–704. http://dx.doi.org/10. The association between more typical 1128/JCM.00542-06 2. Lo SH, Huang YC, Huang CG, Tsao KC, HFMD and onychomadesis has Acknowledgments Li WC, Hsieh YC, et al. Clinical and additionally been described in the We thank Richard Rossi and Renee epidemiologic features of coxsackievirus United States and Europe but without Roy for clinical sample preparation and A6 infection in children in northern Taiwan between 2004 and 2009. J Microbiol a link to specifi c serotype or with a processing and Kenneth McIntosh for Immunol Infect. 2011;44:252–7. http:// small percentage of CVA6-associated critical review of this manuscript. dx.doi.org/10.1016/j.jmii.2011.01.031 cases (9). Cases from the Boston 3. Wei SH, Huang YP, Liu MC, Tsou TP, epidemic may fi t into an emerging A.A.A. is supported by National Lin HC, Lin TL, et al. An outbreak clinical phenotype of CVA6, and it Institutes of Health grant no. 5 K08 of coxsackievirus A6 hand, foot, AI093676-02. and mouth disease associated with will be interesting to see whether nail onychomadesis in Taiwan, 2010. BMC loss develops in those patients. Kelly Flett,1 Ilan Youngster,1 Infect Dis. 2011;11:346. http://dx.doi. Given the numerous CVA6 org/10.1186/1471-2334-11-346 Jennifer Huang, outbreaks in multiple countries in 4. Fujimoto T, Iizuka S, Enomoto M, Alexander McAdam, Abe K, Yamashita K, Hanaoka N, et al. 2008 and a US population that may be Thomas J. Sandora, Hand, foot, and mouth disease caused by relatively naïve to this serotype, CVA6 Marcus Rennick, coxsackievirus A6, Japan, 2011. Emerg is likely to spread throughout North Infect Dis. 2012;18:337–9. http://dx.doi. Sandra Smole, America. Clinicians should be aware org/10.3201/eid1802.111147 Shannon L. Rogers, 5. Blomqvist S, Klemola P, Kaijalainen S, that, although standard precautions W. Allan Nix, M. Steven Oberste, Paananen A, Simonen ML, Vuorinen T, are routinely recommended for Stephen Gellis, and Asim A. Ahmed et al. Co-circulation of coxsackieviruses managing enteroviral infections A6 and A10 in hand, foot and mouth Author affi liations: Children’s Hospital in health care settings, contact disease outbreak in Finland. J Clin Boston, Boston, Massachusetts, USA (K. Virol. 2010;48:49–54. http://dx.doi. precautions are indicated for children Flett, I. Youngster, J. Huang, A. McAdam, org/10.1016/j.jcv.2010.02.002 in diapers to control institutional 6. Osterback R, Vuorinen T, Linna M, Susi T.J. Sandora, S. Gellis, A.A. Ahmed); outbreaks (10). In addition, the P, Hyypia T, Waris M. Coxsackievirus A6 Boston Public Health Commission, presence of perioral lesions and and hand, foot, and mouth disease, Finland. Boston (M. Rennick); Massachusetts Emerg Infect Dis. 2009;15:1485–8. http:// peripheral vesicles on the dorsum Department of Public Health, Jamaica dx.doi.org/10.3201/eid1509.090438 rather than palmar/plantar surface of Plain, Massachusetts, USA (S. Smole); the hands and feet represents a unique and Centers for Disease Control and phenotype of HFMD that could be Prevention, Atlanta, Georgia, USA (S.L. confused with herpes simplex or Rogers, W.A. Nix, M.S. Oberste) 1These authors contributed equally to this varicella-zoster virus infections. article.

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 18, No. 10, October 2012 1703 LETTERS

7. Centers for Disease Control and the presence of the parasite in these gorillas (i.e., Democratic Republic Prevention. Notes from the fi eld: severe regions, the most convincing of of the Congo [3], Uganda [4], and hand, foot, and mouth disease associated with coxsackievirus A6—Alabama, which were the steady and consistent Equatorial Guinea [5]). During our Connecticut, California, and Nevada, numbers of non-African travelers who seroepidemiologic study from the November 2011–February 2012. MMWR returned to their countries of origin Democratic Republic of the Congo, Morb Mortal Wkly Rep. 2012;61:213–4. infected with malarial parasites that in which P. vivax sporozoite–specifi c 8. Wu Y, Yeo A, Phoon MC, Tan EL, Poh CL, Quak SH, et al. The largest outbreak of were subsequently identifi ed as P. antibodies were detected in ≈10% of hand; foot and mouth disease in Singapore vivax (2). the population, we found that women in 2008: the role of enterovirus 71 and More recently, evidence has were signifi cantly more likely than coxsackievirus A strains. Int J Infect emerged regarding the transmission men to have been exposed to P. vivax Dis. 2010;14:e1076–81. http://dx.doi. org/10.1016/j.ijid.2010.07.006 of P. vivax in regions of Africa sporozoites (3). Women in this region 9. Bracho MA, Gonzalez-Candelas F, Valero where the local human population is typically spend more time than men A, Cordoba J, Salazar A. Enterovirus co- predominantly Duffy negative (3–6). near the forest fringe, where they work infections and onychomadesis after hand, In 4 (3.5%) of 155 patients from in crop fi elds. This forest is within the foot, and mouth disease, Spain, 2008. Emerg Infect Dis. 2011;17:2223–31. western Kenya (6), 7 (0.8%) of 898 known habitat range of the chimpanzee http://dx.doi.org/10.3201/eid1712.110395 persons from Angola (4), and 8 (8.2%) Pan troglodytes and the gorilla, Gorilla 10. Siegel JD, Rhinehart E, Jackson M, of 97 persons from Equatorial Guinea gorilla gorilla, both of which have Chiarello L. 2007 Guideline for isolation (4), P. vivax parasites were detected been reported to be natural hosts of the precautions: preventing transmission of infectious agents in health care settings. in the blood of apparently Duffy- malaria parasite P. schwetzi, which is a Am J Infect Control. 2007;35(Suppl negative persons, suggesting that the P. vivax–like or P. ovale–like parasite 2):S65–164. http://dx.doi.org/10.1016/j. parasite might not be as absolutely that might also be unable to invade ajic.2007.10.007 dependent on the Duffy receptor for the erythrocytes of persons who are erythrocyte invasion as previously Duffy negative (8). These animals have Address for correspondence: Asim A. Ahmed, thought. These fi ndings are supported recently been shown to be infected Children’s Hospital Boston–Infectious by a report from Madagascar (where occasionally with parasites that have Diseases, 300 Longwood Ave, Boston, MA the human population is composed mitochondrial genomes closely 02115, USA; email: asim.ahmed@childrens. of a mixture of Duffy-positive and resembling those of P. vivax (9,10). harvard.edu Duffy-negative persons), in which 42 We have argued that, given the (8.8%) of 476 Duffy-negative persons high malaria transmission rates in sub- who had symptoms of malaria were Saharan Africa, it is plausible that the reported to be positive for P. vivax 1%–5% of the human population who by both microscopy and PCR (7). are Duffy positive might maintain The prevalence of P. vivax in Duffy- the transmission of the parasite (2). negative persons was signifi cantly The discovery of P. vivax parasites Duffy Phenotype lower than its prevalence in Duffy- (or P. vivax–like parasites) in the positive persons residing in the same blood of African great apes leads to and Plasmodium area, suggesting that Duffy negativity a question: could nonhuman primates vivax infections in is a barrier to the parasite to some in Africa be acting as Duffy-positive Humans and Apes, degree. Given the extremely high rates reservoirs of P. vivax in regions of malaria transmission in western and where the human population is almost Africa central Africa, a P. vivax parasite that entirely insusceptible? This possibility To the Editor: Benign tertian could effi ciently invade Duffy-negative warrants further investigation. Given malaria, caused by Plasmodium vivax, erythrocytes would, presumably, the increasing rarity of the great has long been considered absent, or become highly prevalent very rapidly. apes, however, their capacity to act as at least extremely rare, in western With the exception of the cases zoonotic reservoirs could be limited. and central Africa. In these regions, reported from Angola and Kenya, It would be informative, in any case, 95%–99% of humans are of the Duffy which lie outside the area where to determine how the regions that P. negative phenotype, a condition that is the proportion of the population vivax–positive travelers visit during thought to confer complete protection with Duffy negativity is highest, their stay in Africa correspond with the against the parasite during the blood the reports of the transmission of P. ranges of chimpanzees and gorillas. stages of its life cycle (1,2). Sporadic vivax within predominantly Duffy- If African great apes do, indeed, reports throughout the latter half of the negative populations all come from constitute a zoonotic reservoir of 20th century, however, have hinted at regions inhabited by chimpanzees and P. vivax parasites, what are the

1704 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 18, No. 10, October 2012