Prevalence study uncovers rising threat: enterovirus D68 and acute flaccid myelitis link

A recent study published in the eLife Journal evaluated the changes in the transmission of enterovirus (EV)-D68 in England inferred from seroprevalence data.

Study: Changes in transmission of Enterovirus D68 (EV-D68) in England inferred from seroprevalence data. Image Credit: KaterynaKon/Shutterstock.com

Background

Interest in the epidemiology and impact of EVs, especially EV-D68, has increased in recent years. Unlike most human EVs, EV-D68 can cause severe respiratory illness and transmit via the respiratory route.

From 2009-10 onwards, numerous outbreaks of severe respiratory disease associated with EV-D68 have occurred worldwide. A major outbreak of EV-D68-related respiratory disease occurred in the United States in 2014.

In parallel, unusual increases in acute flaccid myelitis (AFM), cases were also reported. Subsequently, similar AFM outbreaks occurred in different regions. A growing body of evidence implicates EV-D68 as the main cause of AFM outbreaks, although other EV serotypes have not been ruled out.

No effective vaccine or therapy exists for EV-D68 infection; the neurologic sequelae and residual paralysis after AFM are common and persist lifelong.

The mechanisms underlying the resurgence of EV-D68 outbreaks are not clear, and several hypotheses have been proposed, such as increased pathogenicity, evolutionary selection for higher replication fitness, or acquisition of immune-evasive mutations.

EV surveillance is passive in many countries, and therefore, determining the exact incidence of infection remains difficult.

The study and findings

In the present study, researchers measured the seroprevalence of neutralizing antibodies against EV-D68 in England. They used serologic data from three cross-sectional retrospective studies representative of the population in 2006, 2011, and 2017. These studies used neutralization assays to measure antibodies against EV-D68.

The researchers estimated the annual force of infection (FOI), the rate at which susceptible seronegative individuals become seropositive.

They used a serocatalytic mathematical model in which individuals were either seropositive or seronegative at birth based on the presence of maternal antibodies. Maternal antibodies, when present, were assumed to wane at a constant rate.

The analysis assumed no seroreversion, i.e., seropositive individuals do not become seronegative later. Two models were evaluated based on FOI changes. One model assumed a constant FOI over time, and the other assumed a varying FOI. The researchers used two seropositivity cut-offs – 1:16 and 1:64.

A slight decline in seroprevalence was observed from 0 to 1-4 years that sharply increased until 20-29 years and plateaued after that, regardless of the seropositivity cut-off. Seropositivity for the 1-4 age group with the weak cut-off (1:16) ranged from 0.65 in 2006 to 0.92 in 2017. With a more stringent cut-off (1:64), these estimates were 0.29 in 2006 and 0.51 in 2017 for the same age group.

Age-stratified seroprevalence was lower in 2006 than in 2011 or 2017, suggesting that individuals were first infected at a younger age.

Minimum seroprevalence was observed at eight and four months of age for 1:16 and 1:64 cut-offs, respectively. The second model that assumed a varying FOI was deemed the best and had a better fit to the data than the other.

Accordingly, transmission increased throughout the study period for either cut-off. Increases in FOI continued until 2017 for the 1:16 cut-off. Contrastingly, FOI reached a plateau by 2011 for the 1:64 cut-off. The best model also estimated a more rapid decline in maternal antibody levels for the 1:64 cut-off.

The median duration of seropositivity through maternal antibodies was 17.6 and 4.9 months for the 1:16 and 1:64 cut-offs, respectively.

Further, the researchers used estimates from the second model and data on population age structure to reconstruct the annual seroprevalence of EV-D68 in the population between 2006 and 2017.

Overall, the annual seroprevalence, which was already substantially high in 2006, increased progressively and reached 97% for the 1:16 cut-off and 87% for the 1:64 cut-off in 2017. Similarly, the researchers reconstructed the annual incidence of infections and observed the highest yearly infections in the two-year age group.

Conclusions

In summary, the findings suggest increased EV-D68 transmission over time in England. The estimated probabilities of infection and the decline in maternal antibodies appeared more realistic with the 1:64 cut-off.

However, analysis with the stringent cut-off indicated no substantial changes in FOI since 2011. Contrastingly, FOI increased until 2017 with the weak cut-off, raising questions regarding a relevant seropositivity cut-off.

The reconstructed estimates indicate that the increase in transmission was mainly in children aged 1-5. Despite increased transmission, the results suggest that EV-D68 was already spreading before the observed AFM outbreaks, implying that higher EV-D68 infections alone cannot explain increases in AFM incidence.

Therefore, an increase in or acquisition of neuropathogenicity is additionally required to explain the emergence of AFM outbreaks.

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.