Risk, burden and control of non-polio enterovirus infections
Keywords: Mixed-method study
Clinical research
Non-polio enterovirus

Non-polio enteroviruses are a large and diverse group of viruses that cause a wide spectrum of disease syndromes, ranging from mild, self-limiting cutaneous infections (hand-foot-mouth disease or herpangina), through to serious neurological complications such as encephalitis and life-threatening pulmonary haemorrhage or fulminant myocarditis. The international health risk posed by these viruses is demonstrated by the ongoing burden of enterovirus A71 in southeast and east Asia since its re-emergence in 1997, and the more recent re-emergence of enterovirus D68 in Europe and North America associated with severe respiratory disease and acute flaccid paralysis.
This thesis sets out to (i) improve preparedness for emerging non-polio enteroviruses by better characterising the public health risk they pose, and (ii) to improve the management of patients with moderate to severe disease by better describing the clinical epidemiology and by evaluating the performance of existing clinical case classification systems.
The thesis contains four results chapters. Chapter 2 presents a summary of newly emerged enteroviruses and their geographic distribution. This shows that whilst new enterovirus genotypes are regularly reported, the public health importance of these new genotypes appears limited, with greater morbidity and concern arising from the re-emergence of NPEVs that have been recognised for some time. This has implications for surveillance and pathogen characterisation activities. Chapter 3 reports the development, implementation and results of a novel tool to assess the public health risk of non-polio enteroviruses. The 'Enterovirus Risk Assessment Tool (ERAT) provides a robust and transparent ranking of the public health risk of non-polio enteroviruses and also provides new insights into critical research and knowledge gap. Chapter 4 reports the clinical features, disease progression, management and outcome of 6139 paediatric patients admitted to Zhengzhou Children's Hospital, China between Jan 1, 2015 and Dec 31, 2016. In particular, this chapter shows that although overall case fatality is very low (0.05%) many patients are classified as having complications and receive treatments, such as steroids, mannitol and intravenous immunoglobulin, whose value in these patients is as yet unproven. Chapter 5 identifies clinical case classification systems for hand-foot-mouth disease and explores their performance when applied to the clinical cohort described in chapter 4. This chapter identifies significant problems with the existing case classification systems and makes recommendations for their improvement.
Overall, this thesis has generated and validated a new tool for prioritising non-polio enterovirus for research and development (the ERAT) and has generated new knowledge about the specific priorities for non-polio enterovirus research and development. The thesis also presents one of the largest and most complete analysis of patients hospitalised with hand, foot and mouth disease, identifying important questions about the optimal clinical management of these patients, which should be assessed in future clinical studies. Finally, the thesis provides the first critical appraisal of existing clinical case classification systems for hand, foot and mouth disease, identifying areas for improvement and further development.