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Enterovirus D68 Infection in Appropriate Clinical Scenarios CREDIT CHARLES B

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Enterovirus D68 Infection in Appropriate Clinical Scenarios CREDIT CHARLES B REVIEW CME EDUCATIONAL OBJECTIVE: Readers will suspect enterovirus D68 infection in appropriate clinical scenarios CREDIT CHARLES B. FOSTER, MD NEIL FRIEDMAN, MD JOHN CARL, MD GIOVANNI PIEDIMONTE, MD Center for Pediatric Infectious Diseases, Director, Center for Pediatric Neurology, Center for Pediatric Pulmonary Medicine, Professor and Chair, Cleveland Clinic Pediatric Pediatric Institute, and Children’s Hospital, Pediatric Institute, and Children’s Pediatric Institute, and Children’s Hospital, Institute; Physician in Chief, Cleveland Clinic Cleveland Clinic; Associate Professor of Hospital, Cleveland Clinic Cleveland Clinic; Associate Professor of Children’s Hospital; President, Cleveland Clinic Pediatrics, Cleveland Clinic Lerner College of Pediatrics, Cleveland Clinic Lerner College Children’s Hospital for Rehabilitation Medicine of Case Western Reserve of Medicine of Case Western Reserve University, Cleveland, OH University, Cleveland, OH Enterovirus D68: A clinically important respiratory enterovirus ABSTRACT n the fall of 2014, the United States ex- I perienced an outbreak of severe respiratory Seasonal peaks of viral respiratory illnesses are common illness due to a virus of emerging importance, during late summer and early fall and have often been enterovirus D68 (EV-D68). Here, we review attributed to human rhinovirus. In the fall of 2014, the the features of this virus and related viruses, number of children hospitalized with severe lower respira- the clinical syndromes this virus causes, the tory symptoms and asthma suddenly increased, and the epidemiology of the recent outbreak, and its children tested positive by sequencing for enterovirus D68 diagnosis and treatment. (EV-D68). As the outbreak unfolded, a possible association was also observed between EV-D68 infection, polio-like ■ THE ENTEROVIRUSES: AN OVERVIEW acute flaccid paralysis, and cranial neuropathy in children. Originally identified in 1962 from the throat swab of a child with pneumonia, human EV- KEY POINTS D68 has unique genetic and clinical features EV-D68 is a respiratory virus that has genetic and biologic that blur the typical division between human enteroviruses and rhinoviruses.1–4 Enterovirus- features that blur the distinction between the rhinovi- es and rhinoviruses are closely related species ruses and enteroviruses. within the Picornaviridae family that are now classified together within the genus Enterovi- Recognition of EV-D68 as an important cause of viral rus.5 Picornaviruses are small, nonenveloped, lower respiratory tract illness in children underscores the positive-stranded RNA viruses of medical sig- role of specific strain typing in advancing our understand- nificance. ing of the epidemiology of respiratory virus infections. Poliovirus: The first enterovirus discovered Given the inability of commonly used clinical tests The first human enterovirus to be discovered for rhinovirus to distinguish EV-D68 in the absence of was poliovirus.6 Although sporadic cases of strain-specific sequence data, caution needs to be used “infantile paralysis” occurred before the late in attributing severe or acute lower respiratory illness to 19th century, epidemic poliomyelitis abruptly rhinovirus and in interpreting epidemiologic associations appeared in Europe and the United States be- between asthma and rhinovirus. ginning around 1880. Before the introduction in 1955 of the inactivated poliovirus vaccine and then the oral poliovirus vaccine, polio was Emerging data suggest that, in addition to its important one of the most feared illnesses in the devel- role in pediatric respiratory illness, EV-D68 may cause oped world. Outbreaks occurred primarily in systemic disease, especially acute neurologic disease. cities during summer months. At its peak, epi- demic polio killed or paralyzed more than half doi:10.3949/ccjm.82a.14166 a million people a year. 26 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 82 • NUMBER 1 JANUARY 2015 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. FOSTER AND COLLEAGUES One hypothesis to explain the sudden onstrating the breadth of illness associated emergence of epidemic polio is that improved with particular strains.10 personal hygiene and public sanitation de- layed the age at which children acquired this ■ ENTEROVIRUS D68: enteric infection.7 Infections acquired after AN EMERGING PATHOGEN infancy occurred in the absence of maternal EV-D68 was first isolated in the United States antibodies that may have protected against from four children in Berkeley, California, the virus’s propensity to invade the nervous who had lower respiratory tract symptoms system. (bronchiolitis and pneumonia) in 1962. The Nonpolio human enteroviruses finding was published in the medical litera- 1 In the decades since poliovirus was discov- ture in 1967. Since its initial identification, ered, more than 100 nonpolio human entero- EV-D68 was infrequently reported as a cause viruses have been recognized.8 This group in- of human disease, with the US Centers for cludes the coxsackieviruses, echoviruses, and Disease Control and Prevention (CDC) list- ing only 26 cases in the 36 years from 1970 the newer numbered nonpolio human entero- 11 viruses classified into four species, designated through 2005. Human enterovirus A, B, C, and D. The last However, the past decade has seen EV-D68 of these, Human enterovirus D, includes three emerge as a significant respiratory pathogen, serotypes known to cause disease in humans: with more reports of acute respiratory illness 9 associated with it in North America, Europe, EV-D68, EV-D70, and EV-D94. 12–17 As with poliovirus infection, most people and Asia, especially in children. A sea- infected with a nonpolio human enterovi- sonal pattern may exist; a longitudinal survey of samples collected from New York City de- rus have a mild illness without distinctive 18 features.5 In temperate climates, enteroviral tected a focal outbreak in the fall of 2009. infections are most common during the sum- The observation that recent EV-D68 out- mer and fall and are an important cause of breaks have primarily been in children sug- gests that most adults have immunity to it. the “summer cold.” In tropical climates, the The genus seasonal pattern is absent, and infections may In this regard, seroepidemiologic studies from Finland demonstrated that most adults have occur throughout the year. Enterovirus neutralizing antibodies from previous infec- The clinical syndromes associated with includes the tion.9 a nonpolio human enterovirus can include polioviruses; nonspecific febrile illness; upper respiratory The blurred line between enteroviruses tract infection; pharyngitis; herpangina; hand, and rhinoviruses nonpolio foot, and mouth syndrome; various skin exan- Enteroviruses and rhinoviruses are typically enteroviruses thems; bronchiolitis; asthma exacerbation; distinguished on the basis of the temperature A, B, C, and D; gastrointestinal manifestations such as diar- at which they grow best (rhinoviruses grow rhea and vomiting (which are especially com- better at lower temperatures, allowing them and rhinovi- mon); more serious clinical syndromes such as to replicate in the nose) and their sensitivity ruses hepatitis, pancreatitis, and cardiomyopathy; to acidity (enteroviruses are more resistant, and neurologic illness, including aseptic men- enabling them to survive in the stomach). ingitis, encephalitis, and polio-like paralytic The original (“Fermon”) strain of EV-D68 disease. isolated in 1962 was first classified as an en- Outbreaks caused by nonpolio human en- terovirus because it was resistant to low pH.1 teroviruses occur on a regular basis, may vary However, when molecular sequencing became by strain from year to year, and often occur available, EV-D68 was found to be identical to within a geographic region; multiple strains human rhinovirus 87 (HRV87), a phylogenet- may circulate simultaneously. Occasionally, as ic outlier among the rhinoviruses that binds with EV-D68 in August 2014 in the United to cells at a receptor site distinct from that of States, epidemics can emerge suddenly and other human rhinoviruses.19 spread rapidly across the world, causing dis- Thereafter, further testing showed that ease in hundreds or thousands of people, dem- both EV-D68 and HRV87 isolates were sensi- CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 82 • NUMBER 1 JANUARY 2015 27 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. ENTEROVIRUS D68 tive to acid treatment by two different meth- Viremia in systemic disease ods.4 Moreover, unlike most enteroviruses, Like other enteroviruses, EV-D68 has the abil- EV-D68 behaves like a rhinovirus and grows ity to infect lymphocytes.9 This may provide a preferentially at 33°C, the temperature of the mechanism by which the virus is transported nose.2 during the viremic phase to secondary target organs. Indeed, EV-D68 was detected in the How enterovirus D68 enters cells serum of 12 (43%) of 28 pediatric patients Viral surface proteins, including hemaggluti- with pneumonia and positive nasopharyngeal nin, from certain respiratory viruses have the swabs.24 ability to bind sugars on cells in the nose and Interestingly, whether EV-D68 was detect- lungs, which facilitates viral entry and repli- ed in the serum varied with age. Viremia was cation. EV-D68 binds specifically to alpha 2-6 not detected in the serum of children younger sialic acid, the predominant sialic acid found 19,20 than 1 year,
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