Abstract
BackgroundEnterovirus D68 (EV-D68) has historically been a sporadic disease, causing occasional small outbreaks of generally mild infection. In recent years, there has been evidence of an increase in EV-D68 infections globally. Large outbreaks of EV-D68, with thousands of cases, occurred in the United States, Canada and Europe in 2014. The outbreaks were associated temporally and geographically with an increase in clusters of acute flaccid myelitis (AFM). Aims: We aimed to evaluate a causal association between EV-D68 and AFM. Methods: Using data from the published and grey literature, we applied the Bradford Hill criteria, a set of nine principles applied to examine causality, to evaluate the relationship between EV-D68 and AFM. Based on available evidence, we defined the Bradford Hill Criteria as being not met, or met minimally, partially or fully. Results: Available evidence applied to EV-D68 and AFM showed that six of the Bradford Hill criteria were fully met and two were partially met. The criterion of biological gradient was minimally met. The incidence of EV-D68 infections is increasing world-wide. Phylogenetic epidemiology showed diversification from the original Fermon and Rhyne strains since the year 2000, with evolution of a genetically distinct outbreak strain, clade B1. Clade B1, but not older strains, is associated with AFM and is neuropathic in animal models. Conclusion: While more research is needed on dose–response relationship, application of the Bradford Hill criteria supported a causal relationship between EV-D68 and AFM.
Highlights
Enterovirus D68 (EV-D68) has historically been a sporadic disease, causing occasional small outbreaks of generally mild infection
The second study was conducted in Colorado and California in patients with acute flaccid myelitis (AFM) between January 2012 and October 2014 as well as cases identified from a state-wide surveillance system in the same period [12]
None of the total 25 AFM patients tested positive for the virus in cerebrospinal fluid (CSF)
Summary
Enterovirus D68 (EV-D68) has historically been a sporadic disease, causing occasional small outbreaks of generally mild infection. An increase in clusters of acute flaccid myelitis (AFM) occurred in the same geographical areas, with the highest number of cases (n = 120) in the US [1,2,3]. Smaller numbers of AFM cases (at least six) associated with EV-D68 infection were reported from Denmark, France, the Netherlands, Spain, Sweden and the United Kingdom (UK) [1,2,3]. This raised the question of causal association between EV-D68 and AFM [1,2,3]. Following the 2014 epidemic, EV-D68 has emerged as another possible cause of AFM [12]
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