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Keywords:

  • coxsackievirus infection;
  • disease outbreak;
  • hand-foot-and-mouth disease

Abstract

  1. Top of page
  2. Abstract
  3. Key Points
  4. Outbreak Experience
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Multiple Choice Questions

Hand-foot-and-mouth disease is a common, usually mild childhood illness caused by enteroviruses. Over the last five years, coxsackievirus A6 has been identified as a causative agent in outbreaks in Europe, South-East Asia and America. It has an atypical presentation compared with other enteroviruses, with more widespread rash, larger blisters and subsequent skin peeling and/or nail shedding. We give the first description of an outbreak of coxsackievirus A6 in New Zealand and how health-care communication networks enabled detection of and dissemination of information about this emergent strain.


Key Points

  1. Top of page
  2. Abstract
  3. Key Points
  4. Outbreak Experience
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Multiple Choice Questions
  1. Hand-foot-and-mouth disease is usually a mild childhood illness, but some serotypes, such as enterovirus 71, can cause severe neurological complications and death.
  2. Coxsackievirus A6 is an emerging cause of hand-foot-and-mouth disease. It is responsible for a widespread rash that can become bullous and crusted, can affect adults and is responsible for nail shedding after resolution of the rash; rarely, it can also cause neurological and cardiac complications. More commonly it is responsible for dehydration.
  3. Management of hand-foot-and-mouth disease caused by coxsackievirus A6 is primarily supportive care, such as pain relief for mouth ulcers and ensuring adequate hydration. Careful observation for more serious effects is warranted.

Hand-foot-and-mouth disease (HFMD) is a common childhood illness caused by enteroviruses, most commonly enterovirus 71 and coxsackievirus A16. The disease is characterised by a mild febrile illness associated with the development of pink macules on the hands, feet and oral mucosa, which rapidly become small, elongated grey blisters. The rash resolves spontaneously after 7–10 days, with incidence peaks in the summer and autumn months. HFMD is very infectious and is associated with outbreaks.

Due to a mild or subclinical picture, HFMD is predominantly seen in primary care. Management includes symptomatic relief of painful mouth ulcers, which aids in the secondary management of maintaining hydration and fluid balance. Adults rarely present with HFMD, presumably due to protective immunity from other enterovirus serotypes and exposure in childhood.

Although HFMD is typically a mild clinical disease, enterovirus 71 has been associated with neurological and cardiorespiratory complications including encephalitis, myocarditis and death.[1] Outbreaks have been reported, particularly in the Asia-Pacific region, over the last 15 years, including in Australia.[2] In the summer/autumn months of 2012–2013, Sydney reported an increase of up to 30 cases of enterovirus 71 with severe neurological presentations in children.[3]

A marked increase in presentations with HFMD to the Starship Children's Emergency Department (CED), Auckland, New Zealand, occurred at the same time, leading to concern that Auckland may be seeing an outbreak of enterovirus 71 infections. The presentations were also causing diagnostic uncertainty due to atypical features of HFMD. To determine the predominant enterovirus strain causing HFMD in Auckland, surveillance serotyping was undertaken. This report outlines the outbreak experience and summarises features of the causative agent, coxsackievirus A6 (CVA6).

Outbreak Experience

  1. Top of page
  2. Abstract
  3. Key Points
  4. Outbreak Experience
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Multiple Choice Questions

Presentations to Starship Children's Emergency Department

Between December 2012 and May 2013, clinicians at CED noted an increase in presentations with an atypical clinical picture of HFMD. CED is the only dedicated paediatric emergency department in New Zealand and sees 33 000 children a year from the Auckland region (estimated catchment population aged <15 years: 80 000). Over this time period, 98 cases of presumed HFMD presented to CED or were discharged with an ICD-10 diagnosis of HFMD, in contrast to 18 cases between December 2011 and May 2012 (Fig. 1).

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Figure 1. Clinical hand-foot-and-mouth diagnoses, Children's Emergency Department, Starship Hospital, December–May, 2011–2012 and 2012–2013.

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Clinical description

The majority of children had a preceding fever with coryza, followed by a widespread rash involving hands, feet and mouth, in addition to limbs, buttocks and trunk (Figs 2 and 3). Facial blisters, painful mouth ulcers and lesions larger and more widespread than the typical HFMD lesions were seen. Referrals from primary care were due to diagnostic uncertainty and/or concern at the widespread rash. Decreased feeding, but not dehydration, was a prominent feature of the presentations. No cases of secondary infection were seen. Adult cases were also identified, affecting parents and CED staff. Nail shedding after the rash was widely reported (Fig. 4).

figure

Figure 2. Extensive rash in hand-foot-and-mouth disease caused by coxsackievirus A6.

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figure

Figure 3. Extensive rash in coxsackievirus A6 hand-foot-and-mouth disease, affecting trunk and limbs.

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figure

Figure 4. Onychomadesis following coxsackievirus A6 hand-foot-and-mouth disease.

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Twenty-two clinical specimens sent to the Auckland District Health Board's (ADHB's) LabPlus facility between December and May 2013 were positive for enterovirus, specifically CVA6. Ten samples were collected as ‘surveillance’ from consecutive suspected HFMD presentations at CED to determine the prevalent serotype. Clinical descriptions are summarised in Table 1. Among specimens from 10 CED presentations, median age was 13 months, and all were <24 months. A further 10 specimens were sent from primary care – 3 from adults, 7 from children <24 months (median age 14 months); 2 specimens were from hospital inpatients. One of those was from a 2-year-old in the paediatric intensive care unit with suspected encephalitis following a short history of fever and spreading rash. He had generalised febrile status epilepticus and required intubation and ventilatory support for 12 h. In the recovery phase he was ataxic for several days but had a normal neurologic examination at discharge 5 days later. CVA6 was detected by polymerase chain reaction (PCR) from perianal, rectal and throat swabs and a nasopharyngeal aspirate. It was not cultured or detected by specific PCR in cerebrospinal fluid sample.

Table 1. Clinical and management details of laboratory-confirmed coxsackievirus A6 from 2013 Auckland outbreak
  1. Data given as n (%). †Information not available/incomplete for 10 patients.

Site where swab taken 
Children's Emergency Department10 (45%)
Community10 (45%)
Hospital inpatient2 (9%)
Clinical description 
Preceding coryza and fever10/12 (83%)
Mouth ulcers, drooling or poor feeding10/13 (77%)
Vesicular or blistered description of rash10/17 (59%)
Rash on groin, trunk, limbs, face in addition to hands and feet7/12 (58%)
Community swab sent to differentiate virus from varicella virus3/10 (30%)
Commenced on antibiotics in community4/22 (18%)
Commenced on antivirals in community1/22 (5%)
Managed with analgesia and advice sheet10/12 (83%)

Laboratory detection

CVA6 is difficult to culture, and previous reports have described the use of CVA6-specific primers for real-time PCR to detect this serotype.[4] At LabPlus ADHB, laboratory specimens from clinical HFMD or atypical cases were initially cultured in human embryonic fibroblast (HEF) and human larynx epidermoid carcinoma (Hep2) cell lines. Both cell lines failed to isolate enterovirus. All samples were subsequently analysed with a generic real-time PCR enterovirus screen, which demonstrated the same samples were all positive. A CVA6 real-time PCR assay was developed that confirmed CVA6 in the 22 samples.

Public health response

The initial outbreak was identified through clinician email networks reporting increased numbers of atypical rash presenting to several Auckland emergency departments. Subsequent laboratory liaison with identification of the novel virus and description of atypical clinical features led to clinicians (the authors) contacting the Auckland Regional Public Health Service (ARPHS). By utilising general practitioner liaison networks, hospital clinicians, community laboratories, schools and child care centres, information was provided by ARPHS about the outbreak and the nature of the disease and its management. As HFMD is not a notifiable disease, information was not progressed to a national level, although key public health clinical leaders at Ministry of Health were informed. Intense media interest was utilised and helpful to distribute appropriate information to the public.[5]

Discussion

  1. Top of page
  2. Abstract
  3. Key Points
  4. Outbreak Experience
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Multiple Choice Questions

CVA6 is an emergent strain causing an atypical HFMD that is more commonly associated with nail shedding and adult infection. Our report is the first description of an outbreak of this strain in Australasia, and the national reference laboratory confirmed this as the first CVA6 outbreak in New Zealand.[6]

A comprehensive description of the variable rash of HFMD caused by CVA6 was recently published, outlining four distinct morphologies, including widespread vesiculobullous and erosive lesions, eczema coxsackium or lesions concentrated around previous areas of dermatitis, eruptions similar to Gianotti–Crosti syndrome and purpuric lesions.[7]

In our experience, the atypical HFMD clinical presentation was commonly mistaken for varicella, which remains endemic in our non-vaccinated population. Features that differentiate HFMD from varicella include that varicella lesions will cover a large skin area, have a centrifugal distribution and appear on the scalp but not the palm or sole.[7] Secondary infection is rare in HFMD, unlike varicella, where altered T-cell immunity increases susceptibility to secondary bacterial infection, particularly with Streptococcus pyogenes.[8]

Onychomadesis (nail shedding) is thought to occur due to arrest of growth at the nail matrix following inflammation at the nail bed or after systemic illness. It is uncommon in children and is a non-specific sign at the severe end of a spectrum of nail abnormalities such as nail ridges or Beau's lines. Onychomadesis is associated with CVA6[9] and was reported in our Auckland outbreak.

Other atypical features reported with CVA6 include infection in adult patients and, rarely, neurological complications.[10, 11] The low reported incidence of neurological complications supports the view that CVA6 may be less neurotropic when compared with other enteroviral serotypes. In our review, only one case had neurologic symptoms but also had a negative enterovirus PCR in cerebrospinal fluid. No increased paediatric neurologic presentations or positive enterovirus CSF detections were reported during our outbreak, despite active communication networks with paediatric neurology and the laboratory for case finding.

Emergency department surveillance for disease outbreaks is increasingly attracting interest. A recent study in Canada showed that Google search terms and presentations to emergency departments were able to predict an influenza outbreak 2 weeks earlier than conventional laboratory public health alerts.[12] In this report, liaison between clinicians and the laboratory, in addition to recognition of altered primary care referrals triggered identification, then confirmation, of the novel outbreak of CVA6.

Conclusion

  1. Top of page
  2. Abstract
  3. Key Points
  4. Outbreak Experience
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Multiple Choice Questions

CVA6 is an emergent cause of HFMD outbreaks, and our report identifies CVA6 as the cause of increased presentations to a tertiary children's emergency department in New Zealand. We report one case with neurologic symptoms and describe the atypical features previously reported in other regions, such as more extensive vesiculobullous rash with propensity to subsequent crusting, skin peeling, increased adult infections and nail shedding weeks after resolution of the rash.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Key Points
  4. Outbreak Experience
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Multiple Choice Questions

We thank Dr Margaret Croxson, Head of Department, Virology, LabPlus ADHB, and Dr Dhanya Jayaraj, Section Leader, Viral Culture, LabPlus ADHB. We also thank the children and their parents who consented to allow us to use their images.

References

  1. Top of page
  2. Abstract
  3. Key Points
  4. Outbreak Experience
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Multiple Choice Questions

Multiple Choice Questions

  1. Top of page
  2. Abstract
  3. Key Points
  4. Outbreak Experience
  5. Discussion
  6. Conclusion
  7. Acknowledgements
  8. References
  9. Multiple Choice Questions
  • 1.
    Hand-foot-and-mouth disease is a common childhood illness characterised by the following:
    1. Febrile illness for 1–3 days followed by the development of painful blisters on the hands, feet and mouth.
    2. Febrile illness for 1–3 days followed by the development of itchy macules on the hands, feet and mouth.
    3. Febrile illness for 1–3 days with flu-like symptoms, followed by the development of itchy macules that become blisters, initially on the trunk but spreading to the hands, feet and mouth.
    4. Febrile illness occurring at the same time as weeping and crusting of erythematous itchy lesions located around the mouth, hands and feet.

Answer

  1. True. HFMD is commonly associated with a mild febrile illness followed by macules on the palms of the hands, on the soles of the feet and in the mouth, which rapidly blister and are painful.
  2. False. HFMD tends to have painful blisters rather than itchy macules.
  3. False. Chicken pox or varicella typically presents with a flu-like prodrome followed by itchy macules, which blister. The rash of varicella typically starts on the trunk and will crop; that is, lesions will be seen at different stages of progress on the same patient.
  4. False. HFMD does not tend to crust or be itchy. This would be more likely with infected eczema.
  • 2.
    Coxsackievirus A6 is generally responsible for which atypical features of HFMD disease?
    1. Seizures, pulmonary oedema and myocarditis
    2. High fever, vomiting, lethargy
    3. Widespread vesiculobullous rash, infection in adults and nail shedding
    4. Erythematous papules and blisters in webs of hands and feet that are itchy

Answer

  1. False. Enterovirus 71 can cause these symptoms.
  2. False. Consider meningitis or other serious infection.
  3. True. Coxsackievirus A6 is associated with all these presentations.
  4. False. Consistent with scabies infection.
  • 3.
    The management of hand-foot-and-mouth disease due to coxsackievirus A6 includes:
    1. Prompt treatment with acyclovir.
    2. Treatment with antibiotics to prevent secondary infection.
    3. Analgesia to treat mouth pain.
    4. Admission to hospital for 48 h of neurological observations.

Answers

  1. False. Acyclovir is tailored to inactivate thymidine kinase, an enzyme in herpesviruses, not enteroviruses. Although there have been reports of improvement in symptoms and use of acyclovir in immunocompromised patients, it is not currently accepted as first-line treatment.
  2. False. Secondary infection is rare in hand-foot-and-mouth disease compared with other viral infections, such as varicella, that alter T-cell immunity.
  3. True. The mainstay of treatment is ensuring oral hydration, and this is facilitated by treating painful mouth ulcers with appropriate analgesia.
  4. False. Coxsackievirus A6 very rarely has neurological complications, and patients generally can be managed at home.