Enterovirus d68. A focused review and clinical highlights from the 2014 U.S. Outbreak.

ANNALSATS Articles in Press. Published on 25-February-2015 as 10.1513/AnnalsATS.201412-592FR

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Enterovirus D68: A Focused Review and Clinical Highlights from the 2014 United States Outbreak

Christopher M Oermann1, Jennifer E Schuster1, Gregory P Conners1, Jason G Newland1, Rangaraj Selvarangan2, Mary Anne Jackson1

1

Department of Pediatrics, Children’s Mercy – Kansas City

2

Department of Pathology and Laboratory Medicine, Children’s Mercy – Kansas City

Corresponding Author: Christopher M Oermann Division of Pulmonary and Sleep Medicine Children’s Mercy Kansas City 2401 Gillham Road Kansas City, MO 64108 816-237-3048 [email protected]

Sources of Support: None

Disclaimers: The opinions in this article do not communicate an official position of Children’s Mercy – Kansas City

Running Head: Enterovirus D68 Outbreak 2014

Key Words: EV68, bronchiolitis, pneumonitis, epidemiology, management

Word Count: 2908

Copyright © 2015 by the American Thoracic Society


Abstract Enterovirus D68 (EV-D68), a member of the Picornaviridae family, was first identified in 1962 and is part of a group of small, nonenveloped RNA viruses. As a family these viruses are among the most common causes of disease among humans. However, outbreaks of disease attributable to EV-D68 have been rarely reported in the previous four decades. Reports from a few localized outbreaks since 2008 describe severe lower respiratory tract infection (LRTI) in children. In the late summer of 2014, EV-D68 caused a geographically widespread outbreak of respiratory disease of unprecedented magnitude in the United States. The Centers for Disease Control (CDC) was first notified of increased respiratory viral activity by Children’s Mercy Hospitals (CMH) in Kansas City, Missouri and EV-D68 was identified in 50% of nasopharyngeal specimens initially tested. Between mid-August and 18 December 2014, confirmed cases of LRTI caused by EV-D68 have been reported in 1,152 people in 49 states and The District of Columbia. A focused review of EV-D68 respiratory disease and clinical highlights from the 2014 United States outbreak are presented here.


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Enterovirus D68 Enteroviruses are members of the Picornaviridae family, a group of small, non-enveloped, positive-sense, single-stranded RNA viruses enclosed in an icosahedral capsid.1 They are among the most common viral pathogens in humans and are associated with a broad spectrum of clinical infections ranging from mild, self-limited illness to severe, life-threatening disease. Manifestations range from nonspecific febrile illnesses (the most common presentation), to respiratory, skin, neurologic, gastrointestinal, genitourinary, ophthalmic, cardiac, and musculoskeletal disease.2 Newborns are particularly susceptible to severe infections including neonatal enterovirus sepsis, meningoencephalitis, and myocarditis. Up to 15 million symptomatic enterovirus infections occur each year in the United States.3 The taxonomy of the enterovirus genus has changed from traditional groups including Polioviruses, Coxsackie A and B viruses, Echoviruses and numbered enteroviruses to now include four human species, Enterovirus A, B, C, and D, with variable numbers of serotypes within each species (Table 1). The International Committee on the Taxonomy of Viruses (ICTV) additionally recognizes five animal species (Enterovirus E, F, G, H, J) and three rhinovirus species (Rhinovirus A, B, C) within the genus. The National Enterovirus Surveillance System, in collaboration with the Centers for Disease Control (CDC), has monitored trends in circulating enteroviruses since 1961.4 Between 1970 and 2005, predominant enterovirus serotypes, the prevalence ranking of individual serotypes, and the circulation patterns of individual serotypes varied. However, serotypespecific epidemic or endemic patterns remained consistent over the surveillance period. Marked seasonal variability was detected, with a late summer to fall predominance, and a peak



incidence in August. 44.2% of reported infections occurred in children aged < 1 year, 15.0% in children aged 1-4 years, 11.6% in children aged 5-9 years, 11.9% in children aged 10-19 years, and 17.3% in adults. Enterovirus D68 (species Enterovirus D, genus Enterovirus, family Picornaviridae, order Picornavirales) was one of the most rarely reported serotypes, ranking as the 47th most common among the 58 serotypes reported during the 36 year surveillance period. Twenty-six total isolates accounted for 0.1% of all enterovirus serotypes detected.

Epidemiology Humans are the only reservoir for Enterovirus species A-D. Unlike most other enteroviruses, which are predominantly spread via the fecal-oral route, EV-D68 is spread through contact with infected respiratory secretions.2 Contaminated environmental surfaces may harbor active virus for prolonged periods, allowing wide-spread transmission. The incubation period for enteroviruses is generally 3-6 days with viral shedding for a few days prior to the development of symptoms and continued shedding in respiratory secretions for up to three weeks.2 Enterovirus D68 (EV-D68) was first reported by Schieble and colleagues in 1967 following isolation of the virus from four California children diagnosed with pneumonia and bronchiolitis in 1962.5 Only 26 cases of confirmed EV-D68 disease were reported between 1970 and 2005. The majority of cases (75%) were in children.4 Fifty percent of cases were reported in the typical summer-fall season. EV-D68 was detected in respiratory specimens in all but one case, an adult with acute flaccid paralysis, in whom the virus was detected in cerebrospinal fluid (CSF). Sporadic, small, and geographically-limited outbreaks of EV-D68 respiratory disease were reported globally between 2008 and 2010.6 These included 21 patients from the Philippines, 11


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patients from Japan, 24 patients from the Netherlands, and 39 patients from the United States (Georgia, Pennsylvania, and Arizona). Subsequent reports have documented outbreaks of respiratory disease caused by EVD68 in Great Britain, Italy, France, Thailand, China, New Zealand, and several African countries. 7-15

These cohorts further characterized the seasonality of and population susceptible to EV-

D68 infection. As in earlier surveillance reports, children represent the majority of cases. A summer-fall seasonality remains consistent though EV-D68 peaks often occur later than typical enterovirus activity. The 2014 US Outbreak represents the largest and most widespread EVD68 outbreak recognized to date and was associated with significant morbidity and mortality. This outbreak and data from other published reports suggest an increasing incidence of EV-D68 infection which may be caused by enhanced virulence and result in significantly increased severity of illness.

Pathogenesis EV-D68 is an atypical enterovirus insofar as it shares certain biological features with rhinoviruses. While most enteroviruses grow well at 37oC and under acidic conditions (pH 3.0), EV-D68 grows optimally at 33oC and does not tolerate an acidic environment.16 This likely explains the predilection of EV-D68 for the respiratory tract rather than the gastrointestinal tract with resultant respiratory infection and spread, features characteristic of rhinoviruses rather than other enteroviruses. Viruses enter the upper respiratory tract through direct inhalation of aerosolized particles or transmission of contaminated material to the upper respiratory tract via manual



transfer of infected material from environmental surfaces. Once in the upper respiratory tract, viruses attach to the epithelial cells of the mucosal surfaces and spread locally. Attachment is thought to occur through interactions between enterovirus capsid components encoded by the VP1, 2, and 3 amino acid sequences and epithelial cell surface sialic acids, specifically Nacetylneuraminic acid α2,6-galctose (NeuAc α2,6-Gal).17 Additional data suggest that similarities with rhinoviruses may explain limited systemic disease and that a predominance of NeuAcα2,3-Gal receptors in the lower respiratory tract limit spread.18,19 Recent reports have suggested possible mechanisms for the apparent increase in EVD68 prevalence and virulence. Tokarz and colleagues conducted phylogenetic analysis of EVD68 specimens obtained over two decades.20 Their analysis demonstrated that multiple distinct viral clades, genetically similar groups which share a common origin, have emerged and undergone rapid, worldwide spread. The distinct viral clades are thought to have originated from genetic rearrangement and diversification leading to the emergence of clades A and C in the mid-1990s. Clade C-type underwent additional genetic alteration leading to changes in the RNA region associated with translation efficiency, thus increasing virulence.21 Continued genetic rearrangement led to the emergence of clade B and enhanced viral persistence.15 This is supported by the demonstration of shifting antigenicity and preferential binding of EV-D68 to the α2-6-linked sialic acids found in respiratory epithelium.17 Moreover, there is speculation that these genetic mutations have led to altered antigenicity and the loss of the virus neutralizing ability of preexisting antibodies.10, 15, 22 Lastly, the detection of clades A, B, and C,


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which are genetically similar to those found worldwide, in Kenya suggests widespread transmissibility.13

Clinical Manifestations and Diagnostic Testing The clinical manifestations of EV-D68 have been widely reported. The respiratory tract, both upper and lower, is the primary site of disease.4-6, 9,11,14,15,20,21,23-27 Extremely rare reports of central nervous system disease exist.4,28,29 The most comprehensive descriptions of the respiratory manifestations of EV-D68 infection come from The Netherlands, two exclusively pediatric cohorts (one from the Philippines and the other from Native American children in Arizona) , and CDC surveillance data. Both reports from The Netherlands suggest a broad age range (1 month to greater than 80 years) with no sex predilection.15,26 The predominant symptoms were cough and dyspnea without systemic manifestations. Severity of illness varied greatly. The majority of patients had mild disease; however, some patients had severe disease requiring intensive care and ventilatory support. Most patients had no underlying cardiopulmonary morbidity. Imamura and colleagues provided descriptive epidemiology for 21 children in the Philippines.23 In addition to cough and dyspnea, they identified wheeze and retractions as common findings among children. The mortality rate in this population was almost 10%. During the Arizona outbreak, which ran from mid-August to mid-September, children with EV-D68 infections were afebrile and lacked systemic symptoms such as myalgia, fatigue, headache, or gastrointestinal abnormalities.25 Among the patients who presented with wheeze, 60% did not have a history of asthma or prior wheezing with respiratory illness. Lastly, abnormal blood counts (80%) with



a banded neutrophil predominance (50%) and chest radiographs demonstrating radiographic infiltrates (56%) were common. The CDC summaries report data from outbreaks between 2008 and 2010, including some of the outbreaks above, and the 2014 US outbreak. Data from these summaries are consistent with those from the reports previously discussed and indicate that EV-D68 may be a cause of severe upper and lower respiratory tract disease.6,27 EV-D68 has been recovered from the CSF of two patients with central nervous system disease (acute flaccid paralysis and fatal meningomyeloencephalitis).4,28 Additionally, EV-D68 has been identified in upper respiratory specimens, but not CSF, from clusters of children with neurologic symptoms, such as acute flaccid paralysis in California and Colorado.29,30 Because EV-D68 was not recovered from the cerebrospinal fluid of patients, a direct causal relationship cannot be assumed. Additionally, reports of an atypical neurologic illness surfaced several weeks into the 2014 US outbreak. The clinical presentation was characterized by acute onset of limb weakness with magnetic resonance imaging changes that were specific to grey matter and reminiscent of those seen with classic poliomyelitis. To date, 94 children with this presentation and with onset since August 1, 2014, have been confirmed. Extensive studies designed to detect neuroinvasive pathogens which are known to be associated with acute flaccid paralysis (West Nile virus, EV-71 and poliomyelitis) as well as EV-D68, have been negative. Based on this data, it is plausible that EV-D68 is associated with central nervous system disease, though the mechanism remains unclear. Isolation of enteroviruses through inoculation of in vitro cell culture systems or suckling mice was the primary method for detection of enteroviruses prior to 1990.31 In recent decades, the development of pan-enterovirus polymerase chain reaction (PCR) assays has replaced viral


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culture methods as the gold standard for enteroviral detection in clinical specimens.32 More recently, the introduction of rapid, multiplex, PCR-based assays for respiratory specimens allows clinical laboratories to test for multiple respiratory pathogens simultaneously. These tests are faster and more sensitive than traditional viral culture methods.33 Due to the genetic similarity between rhinoviruses and enteroviruses, the targeted region used by many multiplex PCR platforms cannot distinguish between the two species.34 Specific enterovirus serotypes are identified by sequencing the VP1 gene; the initial specimens sent to the CDC from Kansas City and Chicago during the 2014 outbreak were identified in this manner.35,27 Since the onset of the outbreak, the CDC has designed a new real-time reverse transcriptase PCR test to identify EV-D68 without sequencing. The test is specific for EV-D68 and allows for more rapid identification.

Summer – Fall 2014 Outbreak A clinical concern from a Pediatric Emergency Medicine physician on August 15, 2014 alerted pediatric infectious disease specialists at Children’s Mercy Hospitals (CMH) to an unusual increase in the number of patients presenting to the Emergency Department with respiratory distress and severe bronchospasm. Many of these children needed hospital admission. Most admitted children required significant levels of respiratory support, including continuous nebulized albuterol, parenteral therapy for bronchospasm (magnesium and aminophylline), and noninvasive ventilation. A minority of patients required intensive care. Review of reports monitoring viral activity confirmed an unexpectedly high number of multiplex respiratory panel PCR (Biofire™) detections of rhinovirus/enterovirus during this same



time frame. The level of activity was nearly four times higher than the detections from similar periods in the prior 2 years. EV-D68 infection was suspected and consultation with CDC was obtained. A case definition was developed to facilitate specific testing in collaboration with CDC and implementation of appropriate isolation precautions. Criteria included any patient admitted to CMH with cough, respiratory distress with or without fever, or wheezing, and requiring supplemental oxygen or continuous albuterol. Because the multiplex PCR utilized does not discriminate between the many different types of rhinoviruses and enteroviruses, nasopharyngeal specimens from 20 patients who presented with severe bronchospasm plus specimens from 2 other patients, all of whom were hospitalized in the intensive care unit at CMH, were sent to the CDC for specific viral identification. Sequencing identified EV-D68 in 19/22 (86%) specimens, including 18/19 (95%) children with severe bronchospasm. The CDC also confirmed that a physician from a geographically distinct location, Comer Children’s Hospital in Chicago, Illinois, had noted similar disease during the same time period. Eleven out of fourteen (79%) specimens sent from those patients were identified as enterovirus D-68. Subsequent complete genomic sequencing of one specimen and partial sequencing of six additional specimens obtained during the 2014 outbreak were confirmed by the CDC to represent the three known strains of EV-D68, clades A, B, and C. They appear to be genetically related to strains detected in prior years in the US, Europe and Asia. During the peak of the outbreak, Emergency Department and Urgent Care Center (EDUC) activity at CMH increased 15-20%, hospital inpatient census rose by 25% (300 versus 250), and ICU admissions due to respiratory infection increased significantly. At CMH, the


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outbreak peaked approximately 4 weeks after the putative onset in mid-August. By week 6, inpatient admissions had returned to near-normal levels though EDUC activity remained elevated. Subsequent CDC serotyping identified EV-D68 in 48/74 (65%) admitted patients. The full extent of the disease burden is still under investigation but from August 15 through September 16, almost 700 children, ranging in age from 1 week to 18 years, had positive testing for rhinovirus/ enterovirus at CMH (Figure 1). A retrospective chart review protocol was approved by the CMH Institutional Review Board to allow more comprehensive characterization of the clinical manifestations of infection and therapeutic interventions provided. Data extraction including all patients identified as being infected with rhinovirus/enterovirus during the outbreak has begun. The initial experience with the EV-D68 outbreak in Kansas City and Chicago has been recently reported.27 Children with confirmed EV-D68 during the original testing period, ranged in age from 6 weeks to 16 years. Most were school aged. Many had a history of asthma, but one-third had no prior history of wheeze. In both Kansas City and Chicago, disease was recognized in outpatient and inpatient settings, there were high rates of hospital admission, and intensive care was necessary for many children. Clinical manifestations of disease included marked tachypnea, increased work of breathing, hypoxemia, wheeze, and chest pain. Fever was present in a minority of patients. In the initial cohort of 19 Kansas City children identified by the CDC to have EV-D68, only 26% were febrile.27 68% of children had a history of asthma or prior wheezy illness. Chest radiographs were largely normal though some demonstrated hyperinflation or perihilar infiltrates.



Therapies used included supplemental oxygen, inhaled bronchodilators, systemic corticosteroids, and intravenous magnesium. Parenteral aminophylline and injected epinephrine were used less commonly. Unlike most children with viral LRTIs, patients treated for respiratory infection during this outbreak appeared to respond to the combination of inhaled bronchodilators and systemic corticosteroids, albeit more slowly than is typically expected with asthma triggered by LRTI. Supportive care included high-flow nasal canula oxygen, Bi-level Positive Airway Pressure, and rarely, intubation with mechanical ventilation; one patient in Chicago required ECMO. While no patient deaths directly attributed to EV-D68 were confirmed at CMH, nationally, there have been reports of 12 deaths in children confirmed to have EV-D68 infection during the 2014 US Outbreak. Investigation as to the role of EV-D68 in these deaths is ongoing. As of 18 December, 2014, CDC reports that 1152 patients from 49 states and The District of Columbia have been confirmed to be EV-D68 positive. Testing has occurred at the national, state, and hospital level. Nationally, CDC has tested more than 2,000 specimens with approximately 40% positive for EV-D68. This is undoubtedly an underestimate of the true burden of disease as many children with mild respiratory disease were not tested.

Managing the Illness At the time of the outbreak, there was a paucity of data regarding the medical management of patients with respiratory infection caused by EV D-68. Jacobson and colleagues provided information on the treatment of the children involved in an Arizona outbreak.25 Among their patients, 83% required supplemental oxygen, 83% were treated with albuterol, 61% received


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antibiotics, and 56% received systemic corticosteroids. The median length of hospitalization was 1.5 days. Similarly, care at CMH was supportive and followed basic guidelines for treating asthmatic children with severe bronchospasm; no investigational treatments were undertaken. In contrast to the Arizona experience, few patients received antibiotics at our hospital and all children with severe bronchospasm who were over 12 months of age received systemic corticosteroids. We found that a key component of disease management related to infection prevention and control. As there are no vaccines available for EV-D68 prophylaxis, conventional infection control measures in both community and healthcare settings were utilized. For hospitalized patients, precautions included observation of appropriate infection control policies (Standard, Contact, and Droplet). We recommended community practices including meticulous hand hygiene, proper cough and sneeze etiquette, avoidance of sick contacts, and environmental decontamination of potentially infected surfaces and objects, particularly in settings with large congregations of children. Additionally, we recommended that patients with underlying cardio-respiratory morbidity keep in close contact with their healthcare providers and adhere to existing care plans including Asthma Action Plans. No specific antiviral therapy is available to treat EV-D68 infection. Drugs such as pleconaril, pocapavir, and vapendavir demonstrate variable activity against some enteroviruses and are under development but are not commercially available. Pleconaril prevents viral uncoating and attachment to host epithelial cells.36 Pocapavir works in a similar way, preventing viral uncoating and RNA release, and has been developed primarily as a potential therapy for polio but shows broad spectrum anti-enterovirus activity.37 Another capsid



inhibitor, vapendavir, has been developed primarily as a potential treatment for rhinovirus but has shown activity against other enteroviruses.38 “CDC has tested these drugs for activity against currently circulating strains of enterovirus D68 (EV-D68), and none of them has activity against EV-D68 at clinically relevant concentrations.”39

Lessons Learned EV-D68 appears to be increasing in prevalence and virulence. The reasons for this are not well understood but may relate to viral diversification and genetic rearrangement. Current PCR platforms are not specific and will identify EV-D68 as rhinovirus/enterovirus. Specific identification requires referral to CDC. EV-D68 infection can be associated with severe upper and lower respiratory tract disease. In addition to supportive care, and unlike most viral lower respiratory tract infections, patients with EV-D68 infection benefited from the use of bronchodilators and systemic steroids. Prolonged therapy was often necessary. Routine community and healthcare facility infection control practices were essential in preventing the spread of disease.

Future Directions The clinical significance of EV-D68 and its capacity for geographically widespread outbreaks involving very large numbers of patients is only now being appreciated. CDC reports confirm a total of 1,152 people in 49 states and the District of Columbia with infection caused by enterovirus D-68 between August and mid-December, 2014. Because only the most severely ill children were tested, the full burden of disease remains unknown and it is likely that milder


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disease occurred in a substantial number of children who went undiagnosed. It will be critical to continue to monitor the epidemiology of EV-D68 and understand key elements leading to its recent increased incidence and global spread. Considerable research will be needed to characterize the pathophysiologic processes involved in viral adhesion, local and systemic spread, and increased virulence. Lastly, comprehensive analysis of existing data sets will be necessary to determine optimal prevention and treatment strategies and to define strategies to evaluate the role of EV-D68 in future late summer/fall seasonal outbreaks of respiratory infection.



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severe respiratory tract infections. J Clin Virol. 2011; 52:103-6. doi: 10.1016/j.jcv.2011.06.019. 27. Midgley CM, Jackson MA, Selvarangan R, Turabelidze G, Obringer E, Johnson D, Giles BL, Patel A, Echols F, Oberste MS, Nix WA, Watson JT, Gerber SI. Severe respiratory illness associated with enterovirus D68 - missouri and illinois,2014. MMWR Morb Mortal Wkly Rep. 2014 Sep 12;63(36):798-9. 28. Kreuter JD, Barnes A, McCarthy JE, et al. A fatal central nervous system Enterovirus 68 infection. Archiv Pathol Lab Med 2011;135:793–6. 29. Ayscue P, Haren KV, Sheriff H, Waubant E, Waldron P, Yagi S, Yen C, Clayton A, Padilla T, Pan C, Reichel J, Harriman K, Watt J, Sejvar J, Nix WA, Feikin D, Glaser C, Ek M. Acute flaccid paralysis with anterior myelitis - California, June 2012-june 2014. MMWR Morb Mortal Wkly Rep. 2014; 63:903-6. 30. Pastula DM, Aliabadi N, Haynes AK, Messacar K, Schreiner T, Maloney J, Dominguez SR, Davizon ES, Leshem E, Fischer M, Nix WA, Oberste MS, Seward J, Feikin D, Miller L. Acute neurologic illness of unknown etiology in children - Colorado, August-September 2014. MMWR Morb Mortal Wkly Rep. 2014; 63:901-2. 31. Pallansch MA, Roos RP. Enteroviruses: polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses. In: Knippe DM, Howley PM, eds. Fields Virology. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001:723–75. 32. Rotbart HA. Diagnosis of enteroviral meningitis with the polymerase chain reaction. J Pediatr 1990;117:85–9. 33. Mahony JB, Petrich A, Smieja M. Molecular diagnosis of respiratory virus infections. Crit Rev Clin Lab Sci. 2011; 48:217-49. doi:10.3109/10408363.2011.640976. 34. Poritz MA, Blaschke AJ, Byington CL, Meyers L, Nilsson K, et al. (2011) FilmArray, an Automated Nested Multiplex PCR System for Multi-Pathogen Detection: Development and Application to Respiratory Tract Infection. PLoS ONE 6(10): e26047. doi:10.1371/journal.pone.0026047 35. Oberste MS, Maher K, Kilpatrick DR, Flemister MR, Brown BA, Pallansch MA. Typing of human enteroviruses by partial sequencing of VP1. J Clin Microbiol. 1999; 37:1288-93. 36. Florea N, Maglio D, Nicolau D. Pleconaril, a novel antipicornaviral agent. Pharmacotherapy 2003; 23:339–48. 37. Buontempo P, Cox S, Wright-Minogue J, DeMartino J, et al. SCH 48973: a potent, broadspectrum, antienterovirus compound. Antimicrobial agents and chemotherapy 1997; 41:1220-25. 38. Tijsma A, Franco D, Tucker S, Hilgenfeld R, Froeyen M, Leyssen P, Neyts J. The Capsid Binder Vapendavir and the Novel Protease Inhibitor SG85 Inhibit Enterovirus 71 Replication. Antimicrob Agents Chemother. 2014;58:6990-2. 39. CDC Recommendations: http://www.cdc.gov/non-polio-enterovirus/hcp/EV-D68-hcp.html


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Table 1: Taxonomy for Enterovirus genus Traditional Taxonomy Polioviruses PV1-3

Coxsackie A viruses CAV 1-22, 24

Coxsackie B viruses CBV 1-6

Echoviruses E1-7, 9, 11-21, 24-27, 29-33

Current Taxonomy Species: Enterovirus A (EV-A) Serotypes: Coxsackieviruses: CV-A2, CV-A3, CV-A4, CV-A5, CV-A6, CV-A7, CV-A8, CV-A10, CV-A12, CVA14, CV-A16 Enteroviruses: EV-A71, EV-A76, EV-A89, EV-A90, EV-A91, EV-A92, EV-A114, EV-A119 Species: Enterovirus B (EV-B) Serotypes: Coxsackieviruses: CV-B1, CV-B2, CV-B3, CV-B4, CV-B5, CV-B6, CV-A9 Echoviruses: E-1, E-2, E-3, E-4, E-5, E-6, E-7, E-9, E-11, E-12, E-13, E-14, E-15, E-16, E-17, E-18, E-19, E-20, E-21, E-24, E-25, E-26, E-27, E-29, E-30, E-31, E-32, E-33 Enteroviruses: EV-B69, EV-B73, EV-B74, EV-B75, EV-B77, EV-B78, EV-B79, EV-B80, EV-B81, EV-B82, EV-B83, EV-B84, EV-B85, EV-B86, EV-B87, EV-B88, EV-B93, EV-B97, EV-B98, EVB100, EV-B101, EV-B106, EV-B107, EV-B110 Species: Enterovirus C (EV-C) Serotypes: Polioviruses: PV-1, PV-2, PV-3 Coxsackieviruses: CV-A1, CV-A11, CV-A13, CV-A17, CV-A19, CV-A20, CV-A21, CV-A22, CVA24 Enteroviruses: EV-C95, EV-C96, EV-C99, EV-C102, EV-C104, EV-C105, EV-C109, EV-C113, EV-C116, EV-C117 & EV-C118 Species: Enterovirus D (EV-D) Serotypes: Enteroviruses: EV-D68, EV-D70, EV-D94, EV-D111 & EV-D120

Numbered enteroviruses EV68-71



Taxonomy for the Enterovirus genus has recently changed. The human versus animal-specific designations have been eliminated. Current International Committee on Taxonomy of Viruses convention recognizes the following species within the genus: four human enteroviruses (Enterovirus A, B, C, D), five animal enteroviruses (Enterovirus E, F,G, H, J) and three rhinoviruses (Rhinovirus A, B, C). Within each species, specific serotypes are identified. http://ictvonline.org/index.asp


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Table 2: EV-D68 Implications for Clinical Care Epidemiology Diagnosis Medical Management Infection Prevention and Control

EV-D68 appears to be increasing in prevalence and virulence EV-D68 is identified on standard PCR platforms as rhinovirus/enterovirus; specific testing for EV-D68 requires referral to CDC EV-D68 infection can be associated with severe lower respiratory tract disease; therapy may include supplemental oxygen, bronchodilators, systemic corticosteroids, and ventilatory support Standard community and healthcare facility infection control precautions will be essential in preventing spread



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Figure 1: Rates of Rapid Viral Panel Testing and Rhino/Entero Virus Positivity at CMH (all patients)

60

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30 RP tested

20 RhinEnt pos

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Enterovirus D68 nosocomial outbreak in elderly people, France, 2014.

Molecular Evolution and Intraclade Recombination of Enterovirus D68 during the 2014 Outbreak in the United States.

Enterovirus D68 infection, Chile, Spring 2014.

Enterovirus D68-associated severe pneumonia, China, 2014.

Respiratory Presentation of Pediatric Patients in the 2014 Enterovirus D68 Outbreak.

Clinical Characterization of Children Presenting to the Hospital with Enterovirus D68 Infection During the 2014 Outbreak in St. Louis.

Global Distribution and Evolutionary History of Enterovirus D68, with Emphasis on the 2014 Outbreak in Ontario, Canada.

Evaluation of a Real-Time Reverse Transcription-PCR Assay for Detection of Enterovirus D68 in Clinical Samples from an Outbreak in New York State in 2014.

Enterovirus D68: the unexpected guest.

Enterovirus D68 Subclade B3 Strain Circulating and Causing an Outbreak in the United States in 2016.

Enterovirus D68 Infection.

Genome sequence of enterovirus D68 and clinical disease, Thailand.

Molecular epidemiology of enterovirus D68 from 2013 to 2014 in Philippines.

First Enterovirus D68 (EV-D68) cases detected in hospitalised patients in a tertiary care university hospital in Spain, October 2014.

Antiviral Activity of Broad-Spectrum and Enterovirus-Specific Inhibitors against Clinical Isolates of Enterovirus D68.

Upsurge of Enterovirus D68, the Netherlands, 2016.

Epidemic 2014 enterovirus D68 cross-reacts with human rhinovirus on a respiratory molecular diagnostic platform.

Clinical severity of pediatric respiratory illness with enterovirus D68 compared with rhinovirus or other enterovirus genotypes.

Whole-Genome Sequence Analysis Reveals the Enterovirus D68 Isolates during the United States 2014 Outbreak Mainly Belong to a Novel Clade.

Genome sequence of enterovirus D68 from St. Louis, Missouri, USA.

Highlights from the 2014 National Kidney Foundation Clinical Meetings.

Severe respiratory illness associated with enterovirus D68 - Missouri and Illinois, 2014.

Epidemiology of Enterovirus D68 in Ontario.

Highlights from easl 2014.