Background
Hand, foot, and mouth disease (HFMD) is a common childhood exanthema caused by species A human enteroviruses (HEVA), particularly Coxsackievirus A16 (CVA16)[
1]. In most instances, this is a mild self-limiting illness. The affected children are often given out-patient care with symptomatic treatment. However over the last decade HFMD has emerged as a growing public health problem in Asia following frequent outbreaks of death-associated HFMD caused by a more virulence member of HEVA, human enterovirus 71 (HEV71), in a number of countries in the region [
2‐
5]. This was first recognized with large outbreaks of HFMD associated with neurological disease and alarming fatalities in Sarawak, Malaysia in 1997 and in Taiwan in 1998 [
2,
3]. Fatal cases typically presented with a brief duration of febrile illness, subtle neurological signs and died dramatically of acute refractory cardiac dysfunction and fulminant pulmonary oedema within hours of developing signs of tachycardia, poor peripheral perfusion and tachypnea. Indeed, most of them died shortly after hospital admission, and some even before or on arrival at hospital [
2,
6‐
8]. Although severe neurological complications and death only occur in a small minority of children with HFMD, the fulminant disease course of the fatal cases has caused great public alarm in Asia. Experience from recent outbreaks of HEV71 associated HFMD (HEV71-HFMD) in Asia showed that primary care doctors are often overwhelmed with large number of children with HFMD seeking medical attention for the fear of neurological complications and death. Because of the risk of sudden death, coupled with tremendous parental pressure to admit children with HFMD into hospital for observation, children with HFMD are often routinely admitted into hospital for observation in Sarawak, which has imposed a huge burden on the healthcare system. Cerebrospinal fluid (CSF) pleocytosis has so far been the universal finding in fatal cases even though many have no obvious neurological signs prior to sudden onset of cardiorespiratory failure and death [
2,
6,
8]. In the absence of clear neurological sign, CSF pleocytosis (indicative of neurological involvement) has thus been considered an objective marker of complicated disease, allowing clinicians to focus their attention and provide timely intervention in these patients before they develop fatal cardiorespiratory failure. We therefore examined data collected through a prospective study of HFMD to identify and validate risk factors associated with neurological involvement in children with HFMD that may be used by clinicians managing children with HFMD.
Discussion
Early recognition of children at risk of neurological involvement and death (particularly those with encephalitis and encephalomyelitis) is critical as the disease progression from the onset of neurological involvement to fulminant cardiorespiratory failure may be remarkably rapid [
8]. However the clinical manifestations of neurological involvement may be very subtle, particularly in young children with early CNS disease [
8,
16]. While the signs of cardiorespiratory distress such as breathlessness, tachypnea, tachycardia, poor perfusion are easy to recognize, they invariably appear very late shortly before most fatal case collapsed. Our results and other published studies showed that timely diagnosis and intervention, including the use of IVIG infusion, may reduce acute mortality [
10,
17‐
19]. Hence the primary care doctors are confronted with a clinical challenge of identifying a small fraction of children who are at risk of neurological complication from an overwhelmingly large number of children who would have uncomplicated course of HFMD. For this reason it is important to find clinical predictors for neurological involvement that can guide primary care doctors perform a proper patient triage, which should be aimed to admit high risk children into hospital early for close observation and further management, while those at low risk of neurological complication may be given out-patient care after parental education and advice. Few studies have systemically examined how to identify children at risk early before they develop cardiorespiratory failure, particularly at the primary care setting where the majority of children with HFMD would first seek treatment during a community outbreak of HFMD.
In this study we identified and validated that history of lethargy, mean peak temperature ≥ 38.5°C and total duration of fever ≥ 3 days were important risk factors for neurological involvement. Our study also shows that neurological involvement occurs at early course of complicated HFMD, and may be detectable within the first 2 days of the febrile illness because CSF pleocytosis was present in 174 (30%) of 579 children seen within the first 2 days of febrile illness, where they also formed 70% (174/250) of children with HFMD-CNS in the 2006 outbreak (Figure
2). Since CSF pleocytosis may be detectable within the first 2 days of the febrile illness and fulminant cardiorespiratory failure seen in the fatal case children typically occurred on the 3
rd or later day of febrile illness, it is imperative to attempt to identify children at risk of neurological involvement before the 3
rd day of febrile illness so that they can be admitted into hospital early for close monitoring and investigation, and intervention may be instituted when necessary.
Examination of body temperature and careful enquiry into history of lethargy, duration of fever and home record of body temperature should form an integral part of HFMD patient triage at the primary care level. The three risk factors are readily elicited, and can also be used after minimal training by paramedics, who are the key primary care providers in many developing countries including in Sarawak (Malaysia) in Asia. The parents of children with HFMD can also play an important role in early diagnosis of neurological complication in children with HFMD. They should be educated about the 3 risk factors, and be encouraged to monitor the children's body temperature regularly and observe the children's physical activity closely. Body temperature ≥ 38.5°C and history of lethargy may be particularly useful clinical clues for neurological involvement during the first 2 days of febrile illness since at this time the presentation of complicated HFMD is typically undifferentiated and subtle, even to the experienced clinicians [
8]. Indeed both history of lethargy and temperature ≥ 38.5°C were observed for 24–48 hours in all the 9 fatal case children before they succumbed to unexpected fulminant cardiorespiratory failure (Table
4). Primary care doctors should have high index of suspicions of neurological complication when they are presented with children with HFMD who have been febrile ≥ 3 days. The children should be admitted into hospital for close observation and investigated for CNS involvement, if necessary. Our study showed that 92 (31%) of 293 children with total duration of fever ≥ 3 days in the 2000/3 outbreak, and 183 (61%) of 300 children in the 2006 outbreak had neurological involvement (Table
2). CSF pleocytosis was present in 25% (19/74) of children with a single risk factor of being febrile ≥ 3 days on hospital admission (Figure
2). The risk of CNS complication is increased significantly when there are added risk factors of having history of lethargy and temperature ≥ 38.5°C. In contrast children who have a brief duration of low grade fever (≥ 38.5°C) and no history of lethargy are of low risk of neurological disease, and may be provided with out-patient care and parental reassurance.
Our results are in keeping with findings reported by Chang and co-authors where fever ≥ 39°C, fever duration ≥ 3 days and lethargy were more frequently observed in children with CNS involvement and in children with HEV71-HFMD than in those with CVA16-HFMD [
8,
20]. Although several other clinical features and laboratory abnormalities have been associated with fatal HEV71-HFMD, they have yet been validated, and been shown useful in detecting neurological disease or disease progression [
8,
21,
22]. For example, Chong and co-authors reported that absence of mouth ulcers predicted a more complicated or fatal HFMD, and have recommended that children without mouth ulcers should be monitored closely [
22]. However, in our study we did not find that children without mouth ulcers were more likely than children with mouth ulcers to have features of more severe HFMD or develop neurological complication. Not all the risk factors identified in these published studies can readily be translated into clinical practice, particularly at primary care settings. Hyperglycemia and leucocytosis have been shown as risk factors for fatal HEV71 disease [
8]. However, in our experience hyperglycemia and leucocytosis are late laboratory changes in children with fulminant cardiorespiratory failure (unpublished observations), and thus are not helpful clinically in identifying children at high risk of complication and death. Elevated cardiac Troponin I, a sensitive cardiac-specific biomarker for myocardial injury, has been noted in children who subsequently developed left ventricular failure, and may be useful in identifying patients at risk of left ventricular failure and pulmonary oedema [
21]. Although cardiac Troponin I has been used widely in developed countries for early diagnosis of acute coronary syndrome, it is expensive and not widely available in many developing countries, including in Sarawak. Screening for heart rate variability abnormalities, an index of autonomic nervous system, through non-invasive continuous ECG monitoring may provide early warning of impending cardiorespiratory failure about 7 hours before its onset [
16]. The labour-intensive approach is most suited in a critical care setting for children already diagnosed of CNS involvement because it requires the use of expensive and sophisticated device, and close monitoring for the heart rate abnormalities.
A limitation of our study is that the clinical predictors developed for use at primary care setting were identified and tested using data collected through a hospital-based study. Clinical characteristics of children treated at primary care settings may differ from hospitalized children. However, as a large number of children with mild HFMD were admitted into our study, we had the opportunity to systemically examine the clinical feature of HFMD of varying severity, including children with mild disease that would normally be treated at primary care clinics, where we have shown history of lethargy, peak temperature 38.5C and total duration of fever 3 days were reported infrequently in children with mild HFMD.
Acknowledgements
We would like to thank the State Health Director Dr Andrew Kiyu for his support and the Former State Health Directors of Sarawak, Tan Sri Datu Dr Taha Mohamad Arif, Dr Sik Chi Yao and Dr Sik King Yao for their approval and support for this work during their tenure as Director of Sarawak Health Department. We are grateful to Sibu Hospital Director Dr Abdul Rahim Abdullah, the doctors and nurses of paediatric wards and clinics, Peng Chin Pek, Guloi Selingau and medical records officers of Sibu Hospital for administrative, clinical and laboratory assistance.
Financial support
This work was funded by grant 06-02-09-002 BTK/ER/003 from the Ministry of Science, Technology and Innovation, Government of Malaysia and the Wellcome Trust of Great Britain awarded to MJC. MHO is a Wellcome Trust Clinical Training Fellow, and TS is a United Kingdom Medical Research Council Senior Clinical Fellow.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
MHO, SCW, MJC and TS conceived of the study; they were assisted by AM, CHC, DC and SS in the planning, design, and execution of the clinical aspects and by PHT, YP and DP in the analysis and interpretation of the clinical samples; all authors contributed to writing the manuscript.