Enterovirus D68 (EV-D68) was originally isolated in 1962 in Berkeley, California from four children with lower respiratory tract symptoms.[15]Schieble JH, Fox VL, Lennette EH. A probable new human picornavirus associated with respiratory diseases. Am J Epidemiol. 1967 Mar;85(2):297-310.
http://www.ncbi.nlm.nih.gov/pubmed/4960233?tool=bestpractice.com
After this, EV-D68 was infrequently reported as a cause of human disease. In a large survey of enteroviruses conducted by the US Centers for Disease Control and Prevention (CDC) from 1970 to 2005, EV-D68 was isolated only 26 times.[16]Khetsuriani N, Lamonte-Fowlkes A, Oberst S, et al. Enterovirus surveillance: United States, 1970-2005. MMWR Surveill Summ. 2006 Sep 15;55(8):1-20.
http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5508a1.htm
http://www.ncbi.nlm.nih.gov/pubmed/16971890?tool=bestpractice.com
More recently, however, EV-D68 has emerged as a respiratory pathogen of significant importance worldwide.
Seasonal outbreaks have been described throughout the world, typically occurring during the late summer and autumn and causing severe lower respiratory illness, primarily in children.[17]Imamura T, Oshitani H. Global reemergence of enterovirus D68 as an important pathogen for acute respiratory infections. Rev Med Virol. 2015 Mar;25(2):102-14.
https://onlinelibrary.wiley.com/doi/10.1002/rmv.1820
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[18]Midgley CM, Watson JT, Nix WA, et al. Severe respiratory illness associated with a nationwide outbreak of enterovirus D68 in the USA (2014): a descriptive epidemiological investigation. Lancet Respir Med. 2015 Nov;3(11):879-87.
http://www.ncbi.nlm.nih.gov/pubmed/26482320?tool=bestpractice.com
[19]Landaas ET, Klundby I, Knudsen PK, et al. Emergence of enterovirus D68 in a Norwegian paediatric population 2012-2022. Front. Virol. 24 Feb 26;4.
https://www.frontiersin.org/journals/virology/articles/10.3389/fviro.2024.1358963/full
Several studies have observed a biennial outbreak pattern that aligns with spikes in acute flaccid myelitis (AFM) cases.[20]Fall A, Han L, Abdullah O, et al. An increase in enterovirus D68 circulation and viral evolution during a period of increased influenza like illness, The Johns Hopkins Health System, USA, 2022. J Clin Virol. 2023 Mar;160:105379.
https://www.sciencedirect.com/science/article/pii/S1386653223000021
http://www.ncbi.nlm.nih.gov/pubmed/36652754?tool=bestpractice.com
[21]Pons-Salort M, Lambert B, Kamau E, et al. Changes in transmission of Enterovirus D68 (EV-D68) in England inferred from seroprevalence data. Elife. 2023 Jun 9;12:e76609.
https://elifesciences.org/articles/76609
http://www.ncbi.nlm.nih.gov/pubmed/37294299?tool=bestpractice.com
Seroepidemiological studies suggest that most adults have immunity.[22]Smura T, Ylipaasto P, Klemola P, et al. Cellular tropism of human enterovirus D species serotypes EV-94,
EV-70, and EV-68 in vitro: implications for pathogenesis. J Med Virol. 2010 Nov;82(11):1940-9.
http://www.ncbi.nlm.nih.gov/pubmed/20872722?tool=bestpractice.com
A large outbreak occurred in the US Midwest starting in August 2014. The outbreak involved children primarily, many of whom required admission to hospital for severe respiratory disease.[1]Oermann CM, Schuster JE, Conners GP, et al. Enterovirus D68: a focused review and clinical highlights from the 2014 United States outbreak. Ann Am Thorac Soc. 2015 May;12(5):775-81.
http://www.ncbi.nlm.nih.gov/pubmed/25714788?tool=bestpractice.com
[2]Midgley CM, Jackson MA, Selvarangan R, et al. Severe respiratory illness associated with enterovirus d68 - missouri and illinois, 2014. MMWR Morb Mortal Wkly Rep. 2014 Sep 12;63(36):798-9.
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6336a4.htm
http://www.ncbi.nlm.nih.gov/pubmed/25211545?tool=bestpractice.com
In that outbreak, the CDC and state public health laboratories confirmed EV-D68 infection in at least 1153 people throughout the US. Many more children with similar symptoms were hospitalised during the outbreak, but were not tested for EV-D68 because the test was not widely available. It is likely that cases of EV-D68 infection giving rise to mild symptoms, which did not require in-hospital treatment or respiratory viral testing, far exceeded confirmed or suspected cases of EV-D68-related severe respiratory illness.
Few data are available from the outbreak on the prevalence of EV-D68 in adult populations as rigorous testing was not performed in adults. The clinical impression, however, is that the EV-D68 was much more prevalent in children.
Following the 2014 outbreak in the US, surveillance in Europe, including the UK, was enhanced, and 55 sporadic cases were detected.[23]Poelman R, Schuffenecker I, Van Leer-Buter C, et al. European surveillance for enterovirus D68 during the emerging North-American outbreak in 2014. J Clin Virol. 2015 Oct;71:1-9.
http://www.journalofclinicalvirology.com/article/S1386-6532(15)00597-1/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/26364237?tool=bestpractice.com
Cases have been detected in children and adults. The majority seem to have presented with respiratory symptoms resulting in hospital admission, with two children presenting with neurological signs and symptoms. In 2018, 68 samples in England and Wales.[24]Public Health England. Enterovirus D-68: risk assessment. Oct 2018 [internet publication].
https://www.gov.uk/government/publications/enterovirus-d-68-risk-assessment
Although EV-D68 primarily causes respiratory illness, systemic disease may occur, and there is increasing evidence that EV-D68 infection can cause the serious neurological complication AFM.[9]Lu E, Sinha A, Freeman MC. Clinical progress note: enterovirus D68 and acute flaccid myelitis. J Hosp Med. 2023 May;18(5):435-8.[12]Hu Y, Musharrafieh R, Zheng M, et al. Enterovirus D68 antivirals: past, present, and future. ACS Infect Dis. 2020 Jul 10;6(7):1572-86.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8055446
http://www.ncbi.nlm.nih.gov/pubmed/32352280?tool=bestpractice.com
In 2014, an increase in AFM cases coincided with an outbreak of EV-D68-related severe respiratory illness in the US.[25]Sejvar JJ, Lopez AS, Cortese MM, et al. Acute flaccid myelitis in the United States, August-December 2014: results of nationwide surveillance. Clin Infect Dis. 2016 Sep 15;63(6):737-45.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709818
http://www.ncbi.nlm.nih.gov/pubmed/27318332?tool=bestpractice.com
[26]Centers for Disease Control and Prevention. Acute flaccid myelitis (AFM): AFM cases and outbreaks. Jun 2024 [internet publication].
https://www.cdc.gov/acute-flaccid-myelitis/cases/index.html
The US Centers for Disease Control and Prevention (CDC) verified 120 AFM case reports between August and December 2014.[25]Sejvar JJ, Lopez AS, Cortese MM, et al. Acute flaccid myelitis in the United States, August-December 2014: results of nationwide surveillance. Clin Infect Dis. 2016 Sep 15;63(6):737-45.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709818
http://www.ncbi.nlm.nih.gov/pubmed/27318332?tool=bestpractice.com
Most patients were children; the median age was 7.1 years and 59% were male. The CDC did not consistently detect EV-D68 in every confirmed AFM case.[25]Sejvar JJ, Lopez AS, Cortese MM, et al. Acute flaccid myelitis in the United States, August-December 2014: results of nationwide surveillance. Clin Infect Dis. 2016 Sep 15;63(6):737-45.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709818
http://www.ncbi.nlm.nih.gov/pubmed/27318332?tool=bestpractice.com
[26]Centers for Disease Control and Prevention. Acute flaccid myelitis (AFM): AFM cases and outbreaks. Jun 2024 [internet publication].
https://www.cdc.gov/acute-flaccid-myelitis/cases/index.html
There have been 756 confirmed cases of AFM reported to the CDC between August 2014 and July 2024.[26]Centers for Disease Control and Prevention. Acute flaccid myelitis (AFM): AFM cases and outbreaks. Jun 2024 [internet publication].
https://www.cdc.gov/acute-flaccid-myelitis/cases/index.html
Most patients develop AFM between August and November, and there have been peaks in case numbers in 2014, 2016 and 2018.[26]Centers for Disease Control and Prevention. Acute flaccid myelitis (AFM): AFM cases and outbreaks. Jun 2024 [internet publication].
https://www.cdc.gov/acute-flaccid-myelitis/cases/index.html
In 2022, several US health systems reported increases in severe respiratory illness in children who tested positive for rhinovirus or enterovirus, with a higher proportion of EV-D68 positivity than in previous years. The CDC published an advisory urging healthcare providers to consider EV-D68 as a possible cause of acute severe respiratory illness, with or without fever in children, and to advise of the potential for an increase in AFM cases.[27]Centers for Disease Control and Prevention. Severe respiratory illnesses associated with rhinoviruses and/or enteroviruses Including EV-D68 – Multistate, 2022. Sep 2022 [internet publication].
https://archive.cdc.gov/#/details?url=https://www.cdc.gov/han/2022/han00474.html
Sporadic cases of AFM associated with EV-D68 infection have also been reported in Australia, Canada, Norway, Sweden, France, Spain, Scotland, and the UK.[10]Knoester M, Helfferich J, Poelman R, et al. Twenty-nine cases of enterovirus-D68-associated acute flaccid myelitis in Europe 2016: a case series and epidemiologic overview. Pediatr Infect Dis J. 2019 Jan;38(1):16-21.
https://journals.lww.com/pidj/fulltext/2019/01000/twenty_nine_cases_of_enterovirus_d68_associated.4.aspx
http://www.ncbi.nlm.nih.gov/pubmed/30234793?tool=bestpractice.com
[28]Levy A, Roberts J, Lang J, et al. Enterovirus D68 disease and molecular epidemiology in Australia. J Clin Virol. 2015 Aug;69:117-21
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[29]Skowronski DM, Chambers C, Sabaiduc S, et al. Systematic community- and hospital-based surveillance for enterovirus-D68 in three Canadian provinces, August to December 2014. Euro Surveill. 2015;20(43).
http://www.ncbi.nlm.nih.gov/pubmed/26804195?tool=bestpractice.com
[30]Pfeiffer HC, Bragstad K, Skram MK, et al. Two cases of acute severe flaccid myelitis associated with enterovirus D68 infection in children, Norway, autumn 2014. Euro Surveill. 2015 Mar 12;20(10):21062.
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=21062
http://www.ncbi.nlm.nih.gov/pubmed/25788251?tool=bestpractice.com
[31]Lang M, Mirand A, Savy N, et al. Acute flaccid paralysis following enterovirus D68 associated pneumonia, France, 2014. Euro Surveill. 2014 Nov 6;19(44).
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20952
http://www.ncbi.nlm.nih.gov/pubmed/25394254?tool=bestpractice.com
[32]Williams CJ1, Thomas RH, Pickersgill TP, et al. Cluster of atypical adult Guillain-Barré syndrome temporally associated with neurological illness due to EV-D68 in children, South Wales, United Kingdom, October 2015 to January 2016. Euro Surveill. 2016;21(4).
http://www.ncbi.nlm.nih.gov/pubmed/26848143?tool=bestpractice.com
[33]Holm-Hansen CC, Midgley SE, Fischer TK. Global emergence of enterovirus D68: a systematic review. Lancet Infect Dis. 2016 Feb 24;16(5):e64-e75.
http://www.ncbi.nlm.nih.gov/pubmed/26929196?tool=bestpractice.com