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Epidemiological update: Fatal paediatric infections associated with Enterovirus 71 in Cambodia April-July 2012, and hand, foot and mouth disease in Asia

13 Jul 2012
Fatal Paediatric Infections Associated with Enterovirus 71 in Cambodia

From April to early July 2012 an unusual number and pattern of fatalities among young children were reported by Kantha Bopa Children’s Hospital in Cambodia’s capital Phnom Penh [1,2]. The patients presented with fever, respiratory distress and signs of encephalitis, and most of the children were under 3 years old.

Because the presentation was unusual and the cases had no immediately obvious aetiology, the Cambodian Ministry of Health issued an alert on 1 July in accordance with the International Health Regulations. Subsequently a wider joint Cambodian Ministry of Health and WHO investigation across a number of hospitals found records of 61 children attending Kantha Bopa and some other hospitals since April 2012 that met a simple case definition including fever, respiratory and neurological signs. Most of the children were under 3 years of age and they came from 14 of Cambodia’s 24 provinces. Of the 61 cases 54 had died, often soon after admission [1-3]. Laboratory investigation performed by the Pasteur Institute of Cambodia on samples from 31 cases found that the majority were positive for Enterovirus 71 (EV71). A small number were positive for other pathogens [3]. Post-mortem examinations were not undertaken and the EV71 diagnosis has not been further validated. However, the clinical presentations are consistent with published descriptions of neurological EV71 infections [4-6].

Most symptomatic EV71 infections manifest as a self-limiting hand, foot and mouth disease (HFMD) and only a very small proportion of cases develop severe and life-threatening disease[5,6]. Because Kantha Bopa Children’s Hospital serves as a tertiary centre and parents self-refer their children form large parts of Cambodia, it is not yet clear if this cluster of fatal cases represents the severe end of the spectrum of a wider epidemic of HFMD caused by EV71 in the community. However that seems a likely scenario considering that since the late 1990s, several countries in East and South-East Asia have experienced recurrent and sometimes very large outbreaks of HFMD associated with EV71 [4-8]. Human enteroviruses, which include the human polioviruses, are linear single stranded RNA viruses with a capacity to causing neurological disease. Man is the only host and direct human to human transmission plays a role in outbreaks but human enteroviruses are also excreted in the faeces and capable of surviving in water and sewage for long periods. They are prone to genetic recombination and hence genetic evolution [9].

The largest recent outbreaks of EV71 have been reported from China, Japan, Korea, Malaysia, Singapore, Taiwan, Thailand and Vietnam but cases have not previously been reported in Cambodia [4-8]. Since the large outbreaks were first reported in Asia in the 1990s, a pattern has emerged with 2-3 year epidemic cycles and peak transmission during the summer months [5,6,8]. A number of different enteroviruses can cause HFMD but EV71 and Coxsackie A16 (CV-A16) are the most common. Some genotypic subgroups of EV71 (B4, B5, C2) are more often isolated from cases with neurological infection in Asia [(4-6]. Other EV71 viruses have been found to circulate in Europe where they normally cause mild disease or asymptomatic infections [9-12]. Because of the size of the Asian HFMD outbreaks, the elevated risk of neuro-invasive infections with respiratory complications in young children and substantial numbers of fatalities, HFMD and EV71 infections have become a major public health concern in the affected countries. A regional summary of HFMD surveillance data is regularly updated by WHO’s Regional Office for the Western Pacific Region which with the Regional Emerging Diseases Intervention (REDI) Centre of Singapore has issued an extensive clinical and public health guide to management.[14]

There is as yet no vaccine to prevent EV71 infection and there is no specific pharmacological treatment for EV71 infection.[14,15] Treatment with immunoglobulins has been tried in addition to circulatory and respiratory support for severe disease. Preventive measures are the same as for other infections with respiratory or faecal – oral transmission route and focus on interrupting the chain of virus transmission through hand hygiene and social distancing [13]. Following the Cambodian cases there has been a call by clinical researchers for international collaboration for the systematic refinement and evaluation of existing treatment protocols [15].

ECDC Comment, 12 July 2012:

There is good evidence that the incidence of HFMD and severe EV71 infections in children has truly increased in parts of Asia over the last decade and that transmission has gradually extended from early outbreaks in Malaysia, Taiwan and Singapore to a more extensive distribution across parts of two WHO Regions [4-8]. In view of the ongoing HFMD epidemic in neighbouring Vietnam (> 57 000 cases already in 2012) [8], an outbreak of EV71 in Cambodia with associated fatalities is not unexpected. Indeed it is unclear why the extension of the regional epidemics to Cambodia has been delayed until now. The reasons for the scale and severity of EV71 infections in East and South-East Asia compared to other parts of the world is unclear and virological, host genetic, social and environmental factors have all been suggested [5,6].

HFMD in Europe and North America is generally considered a mild and self-limiting infection associated with a characteristic vesicular rash on the hands, soles of the feet and inside the mouth and asymptomatic enterovirus infections are common [9]. EV71 infections are thought to be uncommon in Europe though the virus has been occasionally detected at least from the 1960s to the present day [5,6]. The epidemics of infection and severe disease in Asia have stimulated revived interest among virologists in Europe and Asia and have led to efforts to develop vaccines [5,6,10-12].

There are two principal risks to consider for European citizens; first, the acute risk from severe HFMD and neurological EV71 infections for young children visiting high transmission countries in Asia. As of yet, ECDC is unaware of any travel associated HFMD or EV71 infections reported in Europe. The outbreak of EV71 in Cambodia further increases the geographical distribution of documented outbreaks of severe EV71 infection and therefore the area where EU travellers may be exposed to the virus. Because only a small proportion of all infected normally develop severe disease it is likely that EV71 transmission is widespread in Cambodia. EV71 is prone to outbreaks and year to year changes in the transmission of EV71 are large in the affected areas [5,6,8]. Though impossible to quantify, the outbreak in Cambodia is unlikely to substantially increase the overall risk for visitors from the EU to become infected in Asia. Young age is an important risk factor for severe disease and the proportion of young children visiting Cambodia is low compared to those travelling with families to more popular tourist destinations such as Vietnam, Thailand and Malaysia.

The second longer term risk assessment is whether or not the strains of EV71 associated with severe disease with neurological and respiratory manifestations will emerge or be imported to Europe and spread with the intensity and severity reported from Asia. What determines if an infection with EV71 will be asymptomatic, cause self-limiting HFMD or develop into severe disease with neurological and systemic manifestations is unclear [5,6] Young age is an important risk factor but does not explain the extension and spread of large outbreaks in Asia. Historically there have been occasional outbreaks of EV71 infection with fatalities in Europe. The two largest outbreaks were in Bulgaria in 1975 (44 deaths) and in Hungary in 1978 (47 deaths) [7]. The potential for the Asian EV71 genotypes to cause large outbreaks and severe disease in Europe remains to be established. A successful response to an extension of EV71 outbreaks to Europe will depend on early detection of clusters of disease and determining the most effective preventive measures to limit transmission as well as optimal treatment.[15] The capacity in individual European Member States for diagnosing human enteroviruses and genotyping EV71 subgroups will be crucial.

References:

  1. Ministry of Health Kingdom of Cambodia and World Health Organization Joint news release. Update on investigation of unknown disease in Cambodia – 6 July 2012
  2. Ministry of Health Kingdom of Cambodia and World Health Organization Joint news release. Update on investigation of unknown disease in Cambodia – 9 July 9th 2012
  3. Ministry of Health Kingdom of Cambodia and World Health Organization Outbreak news Severe form of Hand, Foot and Mouth disease caused illnesses and deaths in majority of the children under recent investigation, Ministry of Health Cambodia concluded - 12 July 2012
  4. Chan KP, Goh KT, Chong CY, Teo ES, G, Ling AE Epidemic Hand, Foot and Mouth Disease Caused by Human Enterovirus 71, Singapore. Emerg Infect Dis. 2003 January; 9(1): 78–85. doi: 10.3201/eid1301.020112
  5. Wong SSY, Yip CCY, Lau SKP Yuen KY. Human enterovirus and hand foot and mouth disease (Review). Epidemiol Infection 2010; 138 1071-1089.
  6. Solomon T, Lewthwaite P, Perera D, Cardosa, M.J.; McMinn, P.; Ooi, M.H. Virology, epidemiology, pathogenesis, and control of enterovirus 71 (Review) Lancet Infectious Diseases 2010; 10: 778–790.
  7. ECDC threat assessment: Hand, foot and mouth disease (HFMD) in Asia, May 2010
  8. WHO Western Pacific Region Hand, Foot and Mouth Disease (HFMD) Situation Update June 2012
  9. Melnick JL Enteroviruses: polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses. In: Fields BN, Knipe DM, Howley PM, Chanlock RM, Melnick JL, Monath TP, et al., editors. Field’s virology. 3rd ed. Philadelphia: Lippincott-Raven Publishers; 1996. p. 655–712.
  10. Van der Sanden S, Van Eek J, Martin DP , Van der Avoort H, Vennema H, Koopmans M. Detection of recombination breakpoints in the genomes of human enterovirus 71 strains isolated in the Netherlands in epidemic and non-epidemic years, 1963–2010 Infection, Genetics and Evolution 11 (2011) 886–894.
  11. Schuffenecker I, Mirand A, Antona D, Henquell C, Chomel JJ, Archimbaud C et al Epidemiology of human enterovirus 71 infections in France, 2000–2009. Journal of Clinical Virology 50 (2011) 50–56.
  12. Mirand A, Schuffenecker I,Henquell C, Billaud G, Jugie G, Falcon D et al Phylogenetic evidence for a recent spread of two populations of human enterovirus 71 in European countries. Journal of General Virology (2010), 91, 2263–2277 DOI 10.1099/vir.0.021741-0
  13. WHO Regional Office for the Western Pacific with the REDI Centre A Guide to Clinical Management and Public Health Response for Hand, Foot and Mouth Disease (HFMD) WHO 2011
  14. Xu J, Qian Y, Wang S, Serrano JM, Li W, Huang Z, Lu S. EV71: an emerging infectious disease vaccine target in the Far East? Vaccine. 2010 Apr 30;28(20):3516-21. Epub 2010 Mar 19
  15. Van Doorn R and others. Undiagnosed illness, fatal, child - Cambodia (05): EV71 treatment options in the outbreak of fatal illness in Cambodian children. ProMed 2012-7-11 Archive Number: 20120711.1197882
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