Enterovirus 71 related severe hand, foot and mouth disease outbreaks in South-East Asia: current situation and ongoing challenges Saraswathy Sabanathan, 1,2,3 Le Van Tan, 1,2 Louise Thwaites, 1,2,3 Bridget Wills, 1,2,3 Phan Tu Qui, 1,2 H Rogier van Doorn 1,2,3 INTRODUCTION In early 2012, doctors in Cambodia noticed high numbers of infants and young children presenting with a severe and unusual illness. The striking features of the disease were an initial encephalitic presenta- tion followed by a rapidly fatal destructive alveolar pneumonia, alarming experienced clinicians. Between April and July 2012 a total of 78 children were affected, 54 of whom died. Enterovirus 71 (EV71) was identified as the causative organism, pos- sibly aggravated by malnutrition and uncontrolled use of steroids. 1 EV71 is one of the pathogens associated with hand, foot and mouth disease (HFMD). It was respon- sible for large HFMD outbreaks in Taiwan (1.5 million cases) and Malaysia (Sarawak, 2628 cases) in the late 1990s. In 2008 and 2011 large outbreaks were also described in China (490 000 cases) and Vietnam (110 000 cases). 2 The recent Cambodian outbreak further demonstrates the emer- gence and spread of serious EV71 related disease in the South-East Asian region over the last two decades. DISEASE, PATHOGEN, EPIDEMIOLOGY The clinical syndrome of fever with oral ulcers and exanthema on the hands and feet of young children was first observed in 1957 in New Zealand. The term ‘Hand, foot and mouth disease’ was first used the following year. 3 HFMD is mostly caused by EVs belonging to the species Enterovirus A (consisting of Coxsackie viruses A 2–8, 10, 12, 14, 16 and EVs 71, 76 and 89–92). EV71 is thought to have evolved from Coxsackie virus A16 around 1940, 4 subsequently diverging into three lineages, A, B and C. Lineages B and C are further divided into five sublineages, with B4, B5, C4 and C5 the dominant sublineages identified in recent years in South-East Asia. Although genetically different, all lineages and subli- neages represent one serotype of EV71. HFMD is typically a benign self-limiting illness observed among young children and infants. Outbreaks are often associated with day care centres, nurseries and primary schools. Vesicular lesions usually occur on the palms of the hands and soles of the feet, but all parts of the limbs, including groins and buttocks may be affected. Oral ulceration is usually present, and there is clinical overlap with herpan- gina, an illness characterised by high fever, sore throat and oral ulceration that also affects young children. Herpangina is caused by a number of EV species. Prior to its association with HFMD, EV71 had already been detected in a child with encephalitis in 1969 in California. The first associations between EV71 and a more unusual form of HFMD with high numbers of complications were seen in Japan in 1973 and 1978. 5 Large outbreaks of EV71 associated encephalitis or poliomyelitis-like illness with high mortal- ity were also reported from Europe, North America and Australia during the 1970s. 6 In the 1998 HFMD Taiwan outbreak, the frequency of EV71 detection increased as the severity and lethality of complications increased. 7 Currently, EV71 associated HFMD is considered to be endemic in several South-East Asian countries and as an emerging infection in others, with serious concerns regarding the potential for spread beyond the region. In countries such as Japan and Malaysia with a long history of EV71 related disease, a cyclical pattern of outbreaks every 2–3 years is typ- ically observed. This pattern is assumed to relate to the build-up of a large population of susceptible children every few years suf- ficient to sustain transmission. In China, where outbreaks have been more recent annual peaks of HFMD are observed. 8 In addition, serological evidence sug- gests that by the age of 10 years, healthy children in North America and Vietnam have been exposed to many EVs including EV71. 9 10 Pathogenesis, clinical features and outcomes Humans are the only known hosts for HFMD associated EV infections. EVs are non-enveloped viruses and are therefore highly resistant to environmental condi- tions, and also to mild disinfectants. Transmission is thought to occur primarily through the faecal-oral route, although virus has also been detected in respiratory secretions and in skin lesions. Incubation time is reported to be between 3 days and 6 days, that is, shorter than for poliomyel- itis, which has a typical incubation period of 9–12 days. Initial viral replication is pre- sumed to occur in the lymphoid tissues of the oropharyngeal cavity (tonsils) and small bowel (Peyer’s patches), giving rise to a mild viraemia. Most infections are suc- cessfully controlled at this point and remain asymptomatic. Further dissemin- ation of EVs to the reticuloendothelial system (liver, spleen, bone marrow and lymph nodes), skin and mucous mem- branes coincides with the onset of clinical symptoms. EV71 can invade central parts of the brain, possibly by retrograde axonal transport. Patients with central nervous system involvement typically present with features of brainstem encephalitis, includ- ing myoclonus and autonomic dysregula- tion (hypertension, tachycardia). A small proportion of these patients may progress to develop cardiopulmonary failure, which may be fatal. The mechanisms underlying the cardiopulmonary failure are thought to be neurogenic in origin, with dispropor- tionate sympathetic stimulation and cat- echolamine secretion directly affecting the cardiac muscle and raising pulmonary pressures. MRI of the brain suggests typical involvement of the medulla oblon- gata, pons, midbrain and spinal cord, that resolves within 2 months in most cases. 6 A prospective study of 730 children admitted with HFMD in Sarawak found high fever, fever for more than 3 days and lethargy as risk factors for central nervous system involvement. 11 However the positive pre- dictive values for these risk factors were relatively low, resulting in high numbers of hospitalisations for relatively mild disease. Chinese surveillance data from 2008 to 2012 of over seven million children with HFMD identified the highest incidence to be in children aged 12–23 months. Children aged less than 6 months had the highest risk for severe and fatal disease, with the risk declining with increasing age. Of the 1.1% that had neurological or 1 Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Viet Nam; 2 Hospital of Tropical Diseases, Ho Chi Minh City, Viet Nam; 3 Nuffield Department of Medicine, Centre for Tropical Medicine, University of Oxford, Oxford, UK Correspondence to Dr Saraswathy Sabanathan, Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, District 5, Viet Nam; swhitehorn@oucru.org 500 Sabanathan S, et al. J Epidemiol Community Health June 2014 Vol 68 No 6 Editorial