The association between acute flaccid myelitis (AFM) and Enterovirus D68 (EV-D68) – what is the evidence for causation?

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.

Detection of multiple viral sequences in the respiratory tract samples of suspected Middle East respiratory syndrome coronavirus patients in Jakarta, Indonesia 2015–2016

“…In 2014, a large outbreak of enterovirus D68 was confirmed in 49 states in the USA involving at least 1153 cases and 14 deaths. Recent reports have shown a possible association between enterovirus D68 and acute flaccid paralysis (Messacar et al, 2016;Dyda et al, 2018). However, no sign of neurological disorder was observed in this patient.…”

Acute Flaccid Myelitis: Characteristics and Outcomes of 2014 and 2016 Cases at a Single Center

“…11,12 There is increasing evidence of an association between AFM and EV infection, but whether this association is related to direct viral invasion of the spinal cord, para-infectious autoimmune response to infection, or a combination of the two, remains unclear. 3,13,14 We did not find EV by PCR testing in cerebrospinal fluid from the 13 children that underwent lumbar puncture. We did, however, find evidence of EV infection in multiple other sites.…”

“…1 AFM can be associated with a variety of viruses, including enteroviruses (eg, poliovirus, enterovirus [EV] D68, and EV A71). 2,3 Weakness typically begins in the setting of a recent or current respiratory and/or febrile illness and may be rapidly progressive. 2,4 Despite increased cases in the US in 2014 and 2016, the diagnosis is often delayed, optimal treatment regimens are not defined, and outcomes are poorly understood.…”

Outbreaks of acute flaccid myelitis in the US

“…However, enterovirus is not always found in cerebrospinal fluid,7 and other evidence suggests that the current outbreak is caused by enterovirus D68 13…”

“…Many scientists believe this regular cycling is due to the seroprevalance of enterovirus antibodies waning in the population every two years, as new children are born without immunity 15. Secondly, there is a temporal association between previous outbreaks of enterovirus D68 and acute flaccid myelitis,13 for example, in the US in 2014 8. Thirdly, enterovirus D68 infects human neurones—a recent study shows that enterovirus D68 strains, including 2014 strains, can enter and replicate in neuronal cells 16.…”