A Case of Atypical Hand-Foot-And-Mouth Disease Caused by Coxsackievirus A6: Differential Diagnosis from Varicella in a Pediatric Intensive Care Unit

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Jpn. J. Infect. Dis., 66, 564-566, 2013 Laboratory and Epidemiology Communications A Case of Atypical Hand-Foot-and-Mouth Disease Caused by Coxsackievirus A6: Differential Diagnosis from Varicella in a Pediatric Intensive Care Unit

Yoshinori Yasui1, Tomohiko Makino2, Nozomu Hanaoka2,KenjiOwa1, Atsuko Horikoshi1, Atsuo Tanaka1, Yutaka Suehiro1, Hiroyuki Shimizu3, Kazuhiko Kanou2, Masaaki Kobayashi4, Masami Konagaya2, and Tsuguto Fujimoto2* 1Saiseikai Nakatsu Hospital, Osaka 530-0012; 2Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo 162-8640; 3Department of Virology II, National Institute of Infectious Diseases, Tokyo 208-0011; and 4Kobayashi Pediatric Clinic, Fujieda 426-0067, Japan Communicated by Takaji Wakita (Accepted August 26, 2013)

In 2011, a large outbreak of hand-foot-and-mouth transmitted from person to person via direct contact disease (HFMD) caused by coxsackievirus A6 (CV-A6) with the virus shed from the gastrointestinal or upper occurred in Japan and other countries. The cutaneous respiratory tract. To prevent enteroviral transmission, manifestations of CV-A6-associated HFMD (CV-A6- hand hygiene is particularly important (4). Although HFMD) are more extensive and variable than those of there was no other case of suspected chickenpox in classic HFMD (1–3). Differential diagnosis of HFMD PICU, the Department of Pediatrics was concerned from chickenpox is occasionally challenging because of about the high transmissibility of varicella, which is air- its unusual clinical characteristics. For example, the borne. ICT in collaboration with the pediatric staff im- spread of rashes in CV-A6-HFMD is more toward the mediately initiated varicella infection control in the extremities and body trunk, a manner different from pediatric ward and performed laboratory diagnosis for that in typical HFMD in which the rashes are mostly lo- treatment of the present case. ICT decided to implement calized to the hands and soles of the feet (1,2). the following responses: (i) immediate isolation of the A 24-month-old girl was hospitalized in the pediatric infected patient from other children in PICU from June intensive care unit (PICU) on May 16, 2013 (23 days be- 10, 2013; (ii) immediate restriction on PICU use from fore day 0) due to hypoxemia. The patient had an un- June 10, 2013; and (iii) drafting a plan of broad derlying diagnosis of Down syndrome with a ventricular prophylactic administration of antivirals against VZV septal defect and pulmonary hypertension but no histo- for children who were housed in the same room depend- ry of varicella infection or vaccination against varicella. ing on the laboratory result for VZV. Before discharge on June 8, 2013 (day 0), she devel- In addition to a specific laboratory examination for oped a reddish papular rash with some vesicles on her VZV, specimens of pharyngeal swabs, vesicular fluid, hip, which rapidly spread throughout her entire body and feces were collected during the course of medical and face; she was afebrile. care, and laboratory tests were performed for diagnosis On June 10, 2013 (day 2), the Infection Control Team and treatment. Informed consent for this study was ob- (ICT) of the Saiseikai Nakatsu Hospital (Osaka, Japan) tained from the patient’s guardian, and the clinical was notified of this patient as a suspected case of chick- samples were tested to device a treatment plan and in- enpox in PICU. Assessment of this case was complicat- fection control measures. ed because the rash spread to her upper and lower ex- On June 12, 2013 (day 4), the results of VZV tests in- tremities; however, it was also observed to a lesser cluding analysis of IgM, IgG, and specific viral antigen, extent on her body trunk but not on the head. Although were negative. On the same day, specimens (vesicle the papules were comparable to varicella in terms of fluid, nasopharyngeal swabs, and feces) were collected, their size (approximately 5 mm), HFMD was considered and reverse transcription (RT)-hyper PCR (5) was per- to be more likely because there were fewer vesicles than formed to screen for enterovirus in all samples (day 4). that expected for varicella, and the rash was neither RT-hyper PCR was employed because it is faster than crusted nor pigmented. previously available PCR methods (5,6). Infection control policies and measures for varicella- Based on the results obtained by RT-hyper PCR, ICT zoster virus (VZV) and enterovirus are different. VZV is immediately terminated varicella surveillance and dis- transmitted via droplet nuclei, whereas enterovirus is continued the restriction on PICU use and antiviral therapy to the patient. The team also withdrew the broader prophylactic antiviral administration through- *Corresponding author: Mailing address: Infectious Dis- out the unit and instead endorsed precautions against ease Surveillance Center, National Institute of Infectious contact infections. Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, On June 14, 2013 (day 6), RT-PCR was performed to Japan. Tel: ＋81-3-5285-1111, Fax: ＋81-3-5285-1129, determine the partial nucleotide sequence of the capsid E-mail: fujimo-t＠nih.go.jp protein VP1 cording region. Primer pairs were designed

564 Fig. 1. (Color online) The vesicles on the trunk (A) and shoulder with a red halo (A?) similar to the early stage of varicella. Rashes in the early stage of the illness (B, B?) could be seen with CV-A6-HFMD, which could be useful for distinguishing CV-A6-HFMD from varicella. to amplify the VP1 (partial) to VP2 (partial) coding HFMD as of June 2013. Considering that CV-A6 strains region of CV-A6 (AB678778) and used for sensitive de- have caused a larger number of atypical HFMD cases tection of the viral genome. We used specific primers since 2011, our experience should provide useful infor- for CV-A6 because the clinical picture was similar to the mation regarding infection control in PICUs. Early unique clinical characteristics of the CV-A6-HFMD PCRtestingwasusefulinthiscase.Fortheclinical outbreak in 2011 (2). The primers used were Ca6seq1_5 differentiation of CV-A6-HFMD from varicella, CV- (5?-AAATGCAGTGGAAAGTGCTGTGAGC-3?)and A6 cases show eruption more frequently on the limbs, Ca6seq1_3(5?-TTTACCACTCTAAAGTTACCCAC- buttocks, and peristome than those found in varicella 3?). The size of the PCR product was 957 bp, and the se- cases. In several cases, the eruptions can spread to the quence was determined by the Sanger method. All three trunk (2), similar to the eruptions associated with samples (vesicle, nasopharyngeal swab, and feces) had varicella infections (Fig. 1). Differential diagnosis by the same sequence length of 909 bp, which had 95z PCR should be particularly useful to differentiate CV- similarity to AB678778 and was subsequently identified A6-HFMD from varicella. as CV-A6 (deposited to the DDBJ under the accession no. AB827357). Thus, the case was finally diagnosed as Parts of this article appeared in the Infectious Agents CV-A6-HFMD. Surveillance Report (IASR), vol. 34, p. 204, 2013 in Several types of enteroviruses may cause HFMD. Japanese. Although the dominant pathogens of HFMD are considered to be CV-A16 and enterovirus 71, a growing Acknowledgments This work was partly supported by KAKENHI number of HFMD cases due to CV-A6 have been (Grant-in-Aid for Scientific Research (C), 24592662) and a Grant-in- reported in Japan since 2009, followed by the largest Aid for Research on Emerging and Re-emerging Infectious Diseases nationwide outbreak in 2011. CV-A6 causes atypical from the Ministry of Health, Labour and Welfare of Japan. HFMD, which is a characterized by a large rash that Conflict of interest None to declare spreads over the entire body trunk, as occurred in the present case. However, ICT planned measures against varicella control that included ruling out varicella, REFERENCES which has potential to severely impact on the patients 1. Mathes, E.F., Oza, V., Frieden, I.J., et al. (2013): ``Eczema cox- housed together (7). Therefore, because of a rapid sackium'' and unusual cutaneous findings in an enterovirus outbreak. Pediatrics, 132, e149–157. laboratory diagnosis, unnecessary prophylactic ad- 2. Kobayashi, M., Makino, T., Hanaoka, N., et al. (2013): Clinical ministration was avoided and PICU was reopened as manifestations of coxsackievirus A6 infection associated with a soon as possible. The patient was carefully followed-up major outbreak of hand, foot, and mouth disease in Japan. Jpn. J. for onychomadesis, which typically results after CV-A6- Infect. Dis., 66, 260–261. HFMD (2,3). 3. Fujimoto, T., Iizuka, S., Enomoto, M., et al. (2012): Hand, foot, and mouth disease caused by coxsackievirus A6, Japan, 2011. CV-A6-HFMD was the most common cause of

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