Enterovirus D68 (EV-D68): Unraveling the Mystery

Enteroviruses alone, excluding the poliovirus, cause about 10 to 15 million infections in the United States each year. Tens of thousands of individuals are hospitalized each year for illnesses caused by enteroviruses. Enterovirus D68 (EV-D68, EV68, HEV68) is a member of the Picornaviridae family, an enterovirus. First isolated in California in 1962 and once considered rare, EV-D68 has been on a worldwide upswing in the 21st century (CDC, 2018).

In 2014, the United States experienced a nationwide outbreak of EV-D68 associated with severe respiratory illness. From mid-August 2014 to January 15, 2015, the CDC or state public health laboratories confirmed 1,153 total cases of respiratory illness caused by EV-D68 in 49 states and the District of Columbia (CDC, 2018). Almost all of the confirmed cases were among children, many of whom had asthma or a history of wheezing.

Additionally, there were likely millions of mild EV-D68 infections for which individuals did not seek medical treatment and get tested (TMA, 2014).

The CDC received about 2,600 specimens for enterovirus laboratory testing during 2014, substantially more than usual. About 36% of those tested positive for EV-D68. About 33% tested positive for an enterovirus or rhinovirus other than EV-D68. EV-D68 was detected in specimens from 14 patients who died and had samples submitted for testing. State and local officials have the authority to determine and release information about the cause of these deaths (CDC, 2018).

The pain and suffering caused by the enteroviruses and the upsurge specifically in EV-D68 infections have caused the world to pause, back up, and investigate retrospectively why there has been an upsurge in activity and how better can we as healthcare providers prevent EV-D68 infections in the future before EV-D68 raises its ugly head again.

Enteroviruses affect millions of people worldwide each year. They are often found in the respiratory secretions (e.g., saliva, sputum, or nasal mucus) and stool of an infected individual. Historically, poliomyelitis was the most significant disease caused by an enterovirus, i.e., the poliovirus.

There are 64 non-polio enteroviruses that can cause disease in humans: 23 Coxsackie A viruses, Coxsackie B viruses, 28 echoviruses, and five other enteroviruses (CDC, 2019). Poliovirus and coxsackie, and echovirus are spread through the fecal-oral route. Infection can result in various symptoms ranging from mild respiratory illness, i.e., the common cold, hand, foot, and mouth disease, acute hemorrhagic conjunctivitis, aseptic meningitis, myocarditis, severe neonatal sepsis-like disease, and acute flaccid myelitis.

EV-D68 (Table 2) is one of more than one hundred types of enteroviruses (Table 1), as discussed previously. It is unenveloped. Unlike all other enteroviruses, EV-D68 displays acid lability and lower optimum growth temperature, both characteristic features of the human rhinoviruses. It was previously called human rhinovirus 87 by some researchers.

In the United States, people are more likely to get infected with enteroviruses in the summer and fall. EV-D68 cases have been described to occur late in the enterovirus season, which is typical during the warm months, from summer to autumn (August and September in the Northern hemisphere).

EV-D68 can shed from an infected person's respiratory secretions, such as saliva, nasal mucus, or sputum, for 1 to 3 weeks or less. Infected people can shed the virus even if they are asymptomatic.

The virus likely spreads from person to person when an infected person coughs, sneezes, or touches objects or surfaces that have the virus on them and then touches their own eyes, mouth, or nose.

• Age
  • Infants, children (especially less than five years old), and teenagers are more likely to become infected and become sick. They simply have not yet acquired immunity from previous exposures to the enteroviruses. This is also believed to be true for EV-D68.
  • Adults can also become infected with enteroviruses, but they are more likely to have no symptoms or mild symptoms. EV-D68, similar to other enteroviruses, is known to cause infections primarily in children but has been known to infect adults. According to the CDC, approximately a quarter of all EV-D68 cases before 2005 were adults.
• Children/adults suffering from reactive airway disease
• Children/adults with asthma or a history of wheezing
• Children/adults who have weakened immune systems or who are immunosuppressed

EV-D68 almost exclusively causes respiratory illness, which may vary from mild to severe. Respiratory symptoms are more acute among children than adults. Infants, children, and teenagers, especially if they have a history of asthma or reactive airway disease, can require a trip to the emergency department for treatment and possible admission.

In adults, the symptoms may not be as severe, but in the confirmed cases of EV-D68 from 2008 to 2010, the median length of time adults were hospitalized ranged from 1.5 to five days.

Healthcare providers should consider EV-D68 as a possible cause of acute, unexplained severe respiratory illness.

Initial symptoms resemble those of the common cold including (AAP News, 2014):

• a runny nose
• sore throat
• cough
• sneezing
• fever (some but not all)
• body and muscle aches

Progression of the disease may lead to more serious symptoms including (AAP News, 2014):

• difficulty breathing as in pneumonia
• wheezing
• hypoxemia
• reduced alertness
• reduction in urine production
• dehydration
• respiratory failure

Like all enteroviruses, EV-D68 may also cause (AAP News, 2014):

• variable skin rashes
• abdominal pain
• soft stools
• muscle weakness or paralysis of one or more limbs

When seeing patients, especially children with respiratory illness, healthcare providers should be aware of EV-D68 as a potential cause. They should consider laboratory testing of respiratory specimens for enteroviruses when the cause of infection in severely ill patients is unclear.

Many hospitals and clinics can test suspected patients for enteroviruses, but most are not able to do the testing needed to determine the type of enterovirus. Healthcare providers can approach their state health department for such testing. Healthcare providers should report clusters of severe respiratory illness to state and local health departments.

The CDC recommends that healthcare providers (Modlin, 2018):

• Consider EV-D68 as a possible cause of acute, unexplained severe respiratory illness, even if the patient does not have a fever. For these patients, they should:
  • Consider laboratory testing of respiratory specimens for enteroviruses.
  • Consider EV-D68 testing of specimens that test positive for enterovirus or rhinovirus. State health departments can be approached for diagnostic and molecular typing for enteroviruses. However, state or local health departments should be contacted before sending the specimens.
• Report suspected clusters of severe respiratory illness to local and state health departments. EV-D68 is not nationally notifiable, but state and local health departments may have additional guidance on reporting.

EV-D68 can only be diagnosed by doing specific laboratory tests on specimens from a patient's nose and throat.

Many hospitals and some physicians' offices can test ill patients to see if they have enterovirus infection. However, most cannot do specific testing to determine the type of enterovirus, like EV-D68. The CDC and some state health departments can do this sort of testing.

On October 14, 2014, the CDC started using a new, faster laboratory test for detecting EV-D68, allowing the CDC to test and report results within a few days of receiving specimens. The CDC's new laboratory test is a "real-time" reverse transcription-polymerase chain reaction or rRT-PCR, and it identifies all strains of EV-D68 that were seen this past summer and fall. The new test has fewer and shorter steps than the test that the CDC and some states were using for the EV-D68 2014 outbreak. Also, the new test allows more specimens to be tested simultaneously (Modlin, 2018).

Since the outbreak of EV-D68 began in August, the CDC has tested 1163 specimens submitted from around the country. About half of the specimens tested by the CDC laboratory from August 1 to October 10 have tested positive for EV-D68. About one-third have tested positive for a rhinovirus or an enterovirus other than EV-D68. The new laboratory test will allow the CDC to process the approximately one-thousand remaining specimens faster.

The CDC Picornavirus Laboratory from mid-September to mid-October 2014 developed and evaluated the EV-D68-specific rRT-PCR assay. The assay and protocol primarily focus on evaluating respiratory disease due to EV-D68.

Before sending specimens for diagnostic and molecular typing:

• Contact your state or local health department.
• Submit specimens (nasopharyngeal and oropharyngeal swabs are preferred or any other type of respiratory specimens) using:
  • www.cdc.gov/non-polio-enterovirus/lab-testing/specimen-collection.html
  • and complete specimen submission form 50.34
• Complete a patient summary form for each patient for whom specimens are being submitted. Please send a printed copy of the form at the same time as the specimen submission.
  • www.cdc.gov/non-polio-enterovirus/downloads/ev68-patientsummaryform.pdf

There is no specific treatment and vaccine, so EV-D68 has to run its course. There are no antiviral medications currently available for people who become infected with EV-D68. The antiviral drugs pleconaril, pocapavir, and vapendavir have significant activity against enteroviruses and rhinoviruses. The CDC has tested these drugs for activity against currently circulating strains of EV-D68, and none of them has activity against EV-D68 at clinically relevant concentrations. A 2015 study suggested that the antiviral drug pleconaril may be useful for the treatment of EV-D68 (Modlin, 2018).

Clinical care is directed against symptoms (symptomatic treatment): bronchodilators, oxygen therapy up to and including mechanical ventilation, antibiotics for coinfections where appropriate, pain control if necessary, fever control if needed. Most people recover completely. However, some need to be hospitalized, and some have died due to the virus.

Five EV-D68 paralysis cases were unsuccessfully treated with steroids, intravenous immunoglobulin, and plasma exchange. The treatments had no apparent benefit as no recovery of motor function was seen.

Healthcare providers in healthcare settings should strive to prevent the spread of EV-D68 (CDC, 2019):

• Infection control precautions should include Standard, Contact, and Droplet Precautions.
• Although non-enveloped viruses such as EV-D68 may be less susceptible to alcohol than enveloped viruses or vegetative bacteria, alcohol-based hand rub (ABHR) offers skin tolerance, compliance, and, especially when combined with glove use, overall effectiveness for a wide variety of healthcare pathogens. Therefore, upon removal and before donning gloves, perform hand hygiene using either ABHR or soap and water.
• As EV-D68 is a non-enveloped virus, environmental disinfection of surfaces in healthcare settings should be performed using a hospital-grade disinfectant with an EPA label claim for any non-enveloped viruses (e.g., norovirus, poliovirus, rhinovirus). Disinfectant products should be used in accordance with the manufacturer's instructions for the specific label claim and in a manner consistent with environmental infection control recommendations.

Other than health care settings such as home, office, schools, etc., infection control recommendations include Clorox products. Clorox has a broad portfolio of EPA-registered surface disinfectants that can be used to clean and disinfect frequently touched surfaces. Although currently, Clorox does not have any products that have been tested against EV-D68, the following products meet the criteria established by the CDC (CDC, 2019). (Table 3)

Criteria established by the CDC: Must be an EPA-registered disinfectant with claims against:

• Pseudomonas aeruginosa
• At least one non-enveloped virus (Norovirus, Adenovirus, Rotavirus, Rhinovirus, Poliovirus, Hepatitis A Virus

Although there are no vaccines to prevent EV-D68 infections, healthcare providers should encourage all patients to follow these prevention steps (CDC, 2019):

• Avoid those who are sick.
• Wash hands often with soap and water for 20 seconds.
• Cover the nose and mouth when sneezing or coughing.
• Avoid touching eyes, nose, and mouth with unwashed hands.
• Avoid kissing, hugging, and sharing cups or eating utensils with people who are sick.
• Disinfect frequently touched surfaces, such as toys and doorknobs, especially if someone is sick.
• Stay home when you are sick.

Children/adults with asthma or from reactive airway disease are at greater risk for severe symptoms from EV-D68 and other respiratory illnesses. The CDC recommends that healthcare providers (UpToDate, 2019):

• Discuss and update the patient's asthma action plan.
• Encourage the patient to take their prescribed asthma medications, especially long-term control medication(s).
• Encourage the patient to keep their reliever medication with them.
• Encourage the patient to get the influenza vaccine when available. The CDC recommends that everyone age six months and older get an annual influenza vaccination.
• Stress that if the patient develops new or worsening symptoms, they should be encouraged to follow the steps of their asthma action plan. If their symptoms do not resolve, they should call their primary care provider as soon as possible or go to their nearest emergency department.
• Encourage parents to educate their child's caregiver and teacher about their child's condition. Parents should make sure that they know how to help if the child experiences any symptoms related to asthma.

Information on cases and outbreaks of enterovirus infection is collected in the United States using two surveillance systems (CDC, 2018):

• National Respiratory and Enteric Virus Surveillance System (NREVSS) is a voluntary, laboratory-based surveillance system that has included enterovirus reporting since July 2007. This system is used to track the number of enterovirus tests done and the positive proportion by specimen type, location, and when they were collected. Serotyping, demographic data, and clinical data are not reported.
• National Enterovirus Surveillance System (NESS) is a passive, voluntary, laboratory-based system that collects basic data on positive specimens for enterovirus, including serotype.

The CDC continues to (CDC, 2018):

• Collect information from states to assess the situation to understand better:
  • EV-D68 and the illness caused by the virus
  • how widespread EV-D68 infections may be within each state and the populations affected
• Help states with diagnostic and molecular typing for EV-D68
• Work with state and local health departments and clinical and state laboratories to:
  • enhance their capacity to identify outbreaks
  • perform diagnostic and molecular typing tests to improve detection of enteroviruses and enhance surveillance
• Provide information to healthcare professionals, policymakers, the general public, and partners in numerous formats, including Morbidity and Mortality Weekly Reports (MMWRs), health alerts, websites, social media, podcasts, infographics, and presentations

The CDC obtained one complete genomic sequence and six nearly complete genomic sequences from viruses representing the three known strains of EV-D68 that are causing infection at this time. Comparison of these sequences to sequences from previous years shows they are genetically related to strains of EV-D68 that were detected in previous years in the United States, Europe, and Asia. The CDC has submitted the sequences to GenBank to make them available to the scientific community for further testing and analysis.

On October 14, 2014, the CDC started using a new, faster laboratory test for detecting EV-D68, allowing the CDC to test and report results within a few days of receiving specimens. The CDC's laboratory test is a "real-time" reverse transcription-polymerase chain reaction or rRT-PCR, and it identifies all strains of EV-D68 that circulated during summer and fall 2014. It has fewer and shorter steps than the test that the CDC and some states used previously during this EV-D68 outbreak.

The CDC has made the protocols publicly available on its EV-D68 for Health Care Professionals web page and is exploring options for providing test kits to state public health labs.

Acute flaccid myelitis has been formerly described as "acute flaccid paralysis with anterior myelitis" or "polio-like syndrome." It is an acute neurologic illness with focal limb weakness in children. Its etiology is unknown.

EV-D68 has been suspected as the leading candidate for the cause of this rare polio-like syndrome since two California children who tested positive for the virus had muscle weakness or paralysis of one or more limbs reaching peak severity within 48 hours of onset. "Recovery of motor function was poor at 6-month follow-up (Migita, 2019).

As of October 2014, the CDC was investigating 10 cases of paralysis and cranial dysfunction in Colorado and other reports around the country, coinciding with the increase in EV-D68 activity. As of October 23, 2014, it was believed that the actual number of cases might be 100 or more.

• AAP News (The American Academy of Pediatrics). CDC continues investigation of neurologic illness; will issue guidelines. Published October 3, 2014. Retrieved October 6, 2014. Visit Source.
• CDC, Center for Disease Control and Prevention. Enterovirus D68. Updated November 14, 2018, Retrieved November 16, 2019. Visit Source.
• CDC. "Guidelines for Environmental Infection Control in Health-Care Facilities." 10/2/19. Retrieved 11/16/19. Visit Source.
• Lauinger, I. L.; Bible, J. M.; Halligan, E. P.; Aarons, E. J.; MacMahon, E.; Tong, C. Y. W. (2012). "Lineages, Sub-Lineages, and Variants of Enterovirus 68 in Recent Outbreaks". PLoS ONE 7 (4): e36005.
• The transverse myelitis association. An update on Outbreak of Paralysis in US: Acute Flaccid Myelitis. Published 2014-10-16. Accessed 2019-11-14. Visit Source.
• Migita, R. Etiology, and evaluation of the child with weakness. UpToDate.com. Update: 10/8/19. Accessed 11/16/19. Visit Source.
• Modlin, J. Enterovirus and parechoviruse infections: Clinical features, laboratory diagnosis, treatment, and prevention. UpToDate. Published. 10/25/18. Accessed 11/16/19.
• The transverse myelitis association. An update on Outbreak of Paralysis in US: Acute Flaccid Myelitis. Accessed 2019-11-14. Visit Source.
• UpToDate. Patient education: Enterovirus D68 (The Basics). UpToDate.com. Updated 11/8/19. Retrieved 11/16/19. Visit Source.