Molecular and Clinical Comparison of Enterovirus D68 Outbreaks Among Hospitalized Children, Ohio, USA, 2014 and 2018

Huanyu Wang; Alejandro Diaz; Katherine Moyer; Maria Mele-Casas; Maria Fatima Ara-Montojo; Isabel Torrus; Karen McCoy; Asuncion Mejias; Amy L. Leber


Emerging Infectious Diseases. 2019;25(11):2055-2063. 

In This Article


The recent emergence of EV-D68 as a cause of severe respiratory disease, coupled with its association with AFM, suggests that a deeper understanding of this virus is needed.[12–14] In this study, we examined >1,000 patient specimens from 2 outbreaks and from 1 period with low EV-D68 activity and conducted both molecular and clinical analyses to compare these periods. Although the 2018 EV-D68 outbreak appeared to be milder, as shown by the lower number of hospital admissions for asthma and lower rates of PICU admissions, we observed severe neurologic manifestations only in 2018.

The comparative clinical analyses between outbreaks showed that hospitalized children during 2018 were younger, but the proportion with underling medical conditions, including asthma, was comparable between periods. Symptoms also were similar in the 2 outbreaks, with the notable exceptions of greater gastrointestinal manifestations in 2018, as well as 3 children with severe neurologic manifestations (2 with AFM and 1 with OMS), which we did not observe during 2014 or 2016.

Since 2014, concurrent with the surge of EV-D68 respiratory-associated illness, children with severe neurologic manifestations have been reported in the United States and elsewhere; episodic increases were identified in 2016 and 2018.[5,12,14–21] The cause of AFM has not been established in most cases, despite extensive pathogen-specific or metagenomic sequencing tests. Although a direct link between AFM and EV-D68 has not been established, observational and animal studies suggest a strong association. On the one hand, EV-D68 causes paralytic myelitis in mice; AFM cases have been shown to cluster during periods of EV-D68 circulation, and EV-D68 has been the most common virus detected in respiratory specimens from children with AFM, albeit rarely in cerebrospinal fluid.[22–25] Other neurologic conditions associated with EV-D68 have been described, but to our knowledge, no other cases of OMS have been reported in the literature.[26,27] Further studies are ongoing, but our findings agree with others and highlight the importance of comprehensive surveillance and research to further characterize the role of EV-D68 in AFM that will enable pursuit of effective therapies and prevention strategies.

Although the EV-D68 rRT-PCR testing in this study was not designed to determine true incidence, it did help to monitor EV-D68 activity and showed a marked increase in EV-D68 circulation during the summers of 2014 and 2018 and little or no activity during the same period in 2016. The increase in EV-D68 activity during 2014 and 2018 mirrored an increase in the number of admissions for asthma during those periods, and although the 2014 outbreak had a sharper increase at the end of August, the duration of the 2018 outbreak was longer. Nonetheless, in both periods admissions for asthma were significantly higher than during 2016. Although reported to have a biennial seasonality,[20,24,28–31] the peaks of EV-D68 in 2014 and 2018 were related to an increase in summertime hospitalizations for asthma, which agrees with a recent study conducted in Japan.[32] During the same period in 2016, admissions for asthma were low and no peak was observed, nor was there evidence of high EV-D68 circulation based on surveillance testing in our laboratory, which differs from data reported from other states.[28,33] The magnitude of the increase in asthma hospitalizations was higher in 2014 than in 2018 (peak of 128 admissions during the peak week in 2014 vs. 61 during 2018). Whether these decreases in EV-D68 activity and severity are continued in subsequent EV-D68 outbreaks in the population studied here needs be determined. Nevertheless, EV-D68 should be suspected when summertime admissions related to asthma increase above baseline.

Phylogenetic analyses showed that EV-D68 isolates from 2014 and 2018 clustered differently within clade B.[10,29,34,35] The relationship of these changes in sequence and the pathogenicity of the virus are unclear.[36] Nevertheless, at NCH, no AFM cases were identified in 2014, but 2 AFM cases and 1 OMS case occurred in 2018. The pathogenicity and virulence of this new clade needs to be monitored and confirmed by active surveillance, which was implemented at NCH after the 2014 outbreak. Based on our experience, we have made the EV-D68 rRT-PCR test available for respiratory specimens in real time. This test will be used on the basis of clinician orders particularly as it relates to unexplained acute paralysis/muscle weakness.

This study has limitations. We did not test every specimen that was RV/EV-positive for EV-D68; we did, however, test >40% of all samples that tested positive for RV/EV during these 2 outbreaks and a low-activity period, which provides a good representation of EV-D68 circulation during those periods. The clinical analysis was limited to inpatients, thus possibly biasing the apparent severity of the EV-D68 infections; however, data were comparable between the 3 periods, which was the main study objective. Unfortunately, the samples associated with the 2 AFM cases were not available for sequencing, and thus we cannot make any definitive conclusions about different or more pathogenic viral strains.

In summary, EV-D68 circulation was associated with a significant medical burden. By more consistent and specific testing for EV-D68, a better understanding of the epidemiology of this emerging virus will help inform clinical care.[37]