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.
Enteroviruses are members of the Picornaviridae family (Table 1), a large and diverse group of small RNA viruses characterized by a positive-sense single-stranded RNA (ssRNA) associated with several humans mammalian diseases. All enteroviruses contain a genome of approximately 7,500 bases and are known to have a high mutation rate due to low-fidelity replication and frequent recombination. After infection of the host cell, the genome is translated in a cap-independent manner into a single polyprotein, which is subsequently processed by virus-encoded proteases into the structural capsid proteins and the nonstructural proteins, which are mainly involved in the replication of the virus.
Serologic studies have distinguished 71 human enterovirus serotypes based on antibody neutralization tests. Additional antigenic variants have been defined within several serotypes based on reduced or nonreciprocal cross-neutralization between variant strains.
Based on their pathogenesis in humans and animals, the enteroviruses were initially classified into four groups: Polioviruses, Coxsackie A viruses (CA), Coxsackie B viruses (CB), and Echoviruses. It was quickly realized that there were significant overlaps in the biological properties of viruses in the different groups. Enteroviruses isolated more recently are named with a system of species designation and consecutive numbers: EV-D68, EV-B69, EV-D70, EV-A71, etc.
|Group:||Group IV ((+)ssRNA)|
|Species||Enterovirus A Enterovirus B Enterovirus C Enterovirus D Enterovirus E Enterovirus F Enterovirus G Enterovirus H Enterovirus J Rhinovirus A Rhinovirus B Rhinovirus C|
The enterovirus genus includes the following twelve species (Lauinger et al., 2012):
Within these twelve species are the serotypes:
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.
|Group:||Group IV ((+)ssRNA)|
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.
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):
Progression of the disease may lead to more serious symptoms including (AAP News, 2014):
Like all enteroviruses, EV-D68 may also cause (AAP News, 2014):
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):
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:
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):
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:
|EPA Reg. No.||Product Names|
|5813-21||Clorox® Clean-Up Cleaner with Bleach Clorox® Clean-Up Cleaner + Bleach1|
|5813-40||Clorox® Disinfecting Bathroom Cleaner Tilex® Bathroom Cleaner|
|5813-40-67619||Clorox® Commercial Solutions Clorox Disinfecting Bathroom Cleaner Clorox® Commercial Solutions Tilex Soap Scum Remover & Disinfectant|
|5813-58||Clorox® Disinfecting Wipes|
|5813-79*||Clorox® Disinfecting Wipes1 Clorox® Disinfecting Wipes3 Clorox® Disinfecting Wipes4|
|5813-89||Clorox® Toilet Bowl Cleaner with Bleach Clorox® Toilet Bowl Cleaner – Clinging Bleach Gel|
|5813-100-67619||Clorox® Commercial Solutions Clorox Germicidal Bleach1|
|5813-102||Clorox® Germicidal Bleach 1|
|5813-105||Clorox® Kitchen Cleaner + Bleach1 Clorox® CareConcepts Germicidal Bleach Spray|
|56392-7||Clorox® Healthcare Bleach Germicidal Cleaner|
|56392-8||Dispatch® Hospital Cleaner Disinfectant Towels with Bleach Clorox® CareConcepts Germicidal Bleach Wipes|
|67619-9||Clorox® Commercial Solutions Clorox Disinfecting Wipes Clorox® CareConcepts Germicidal Non-Bleach Wipes|
|67619-12||Clorox® Healthcare Bleach Germicidal Wipes|
|67619-16||Clorox® Commercial Solutions Clorox Toilet Bowl Cleaner with Bleach1|
|67619-17||Clorox® Commercial Solutions Clorox Clean-Up Disinfectant Cleaner with Bleach1|
|67619-20||Clorox® Broad Spectrum Quaternary Disinfectant Cleaner Clorox® CareConcepts Germicidal Non-Bleach Spray1|
|67619-21||Clorox® Commercial Solutions Clorox Disinfecting Spray|
|67619-24||Clorox® Commercial Solutions Clorox® Hydrogen Peroxide Disinfecting Cleaner Clorox® Healthcare Hydrogen Peroxide Cleaner Disinfectant|
|67619-25||Clorox® Commercial Solutions Clorox Hydrogen Peroxide Disinfecting Wipes Clorox® Healthcare Hydrogen Peroxide Cleaner Disinfectant Wipes|
|67619-26||Clorox® CareConcepts Germicidal Bleach|
|67619-29||Clorox® Commercial Solutions Clorox 4-in-1 Disinfectant & Sanitizer Clorox® Healthcare Citrace Hospital Disinfectant & Deodorizer Clorox® CareConcepts Disinfecting & Deodorizing Spray|
|67619-29-5813||Clorox® 4 in One Disinfecting Spray|
|1839-166-67619||Clorox® Pro Quaternary All-Purpose Disinfectant Cleaner1|
Although there are no vaccines to prevent EV-D68 infections, healthcare providers should encourage all patients to follow these prevention steps (CDC, 2019):
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):
Information on cases and outbreaks of enterovirus infection is collected in the United States using two surveillance systems (CDC, 2018):
The CDC continues to (CDC, 2018):
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.
A summary of the condition was issued by the United States Centers for Disease Control as part of a September 26, 2014 health advisory:
August 9 – September 17, 2014
October 13, 2014
October 21, 2014
October 23, 2014
Of 64 patients meeting the CDC criteria before October 29, 2014, 80% had had a preceding respiratory illness, and 75% reported fever in the days leading up to limb weakness, which was generally abrupt. By November 20, 2014, the number of confirmed cases stood at 88 from 29 states.
The suspected cause of the 2014 cases is a strain of enterovirus D. Most enteroviruses and rhinoviruses cause only common cold symptoms. On September 26, 2014, the CDC health advisory that described the cases continued with the identification of EV-D68, a member of the enterovirus D species, as a suspected cause (Migita, 2019).
Cerebral spinal fluid (CSF) testing had been negative for West Nile virus and other enteroviruses, including poliovirus. Nasopharyngeal specimens were positive for rhinovirus/enterovirus in six out of eight tested patients. Of the six positive specimens, four were typed as EV-D68, and the other two were pending typing results. Testing of other specimens continued. Eight out of nine children had been confirmed to be up to date on polio vaccinations. Epidemiologic and laboratory investigations of these cases are ongoing (Migita, 2019).
The Morbidity and Mortality Weekly Report (MMWR) noted the difficulty of establishing causation by EV-D68:
"This cluster of acute neurologic illnesses occurred against a backdrop of detection of EV-D68, causing severe respiratory disease in many parts of the United States, including Colorado. There are two case reports in the literature of EV-D68, causing neurologic illness (acute flaccid paralysis and encephalomyelitis), as evidenced by the detection of EV-D68 in the CSF. However, given the current suspected widespread circulation of EV-D68 respiratory infections in Colorado and the antecedent respiratory illness in most of these children, the detection of EV-D68 in nonsterile upper respiratory tract specimens in those with neurologic illness might be coincidental. Epidemiologic and laboratory investigations of these cases are ongoing".
Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke and president of the International Society for NeuroVirology, compared the situation to the prolonged investigations that led to the confirmation of HIV as the cause of AIDS. In response to the suggestion that the enterovirus might be taking over the role of polio, Nath said that enterovirus 68 was far less virulent and spread much more slowly than polio and that, unlike in polio, only a few cases of paralysis were seen per thousand children infected. He also suggested that adults with respiratory diseases should also be evaluated for neurologic deficits and that infectious disease should be considered a cause when patients presented with neurologic symptoms.
There is no known treatment for acute flaccid myelitis. It has not been established whether steroids are helpful or harmful. Plasmapheresis, intravenous immunoglobulin, and experimental antiviral drugs have been attempted on a trial basis but have not been reported to be effective.
On November 7, 2014, the CDC issued "Interim Considerations for Clinical Management of Patients with Acute Flaccid Myelitis," based on "consensus guidance drawn from experts in infectious diseases, neurology, pediatrics, critical care medicine, public health epidemiology, and virology." Mark Sawyer of the American Academy of Pediatrics, who contributed to the guidance, was quoted by the organization's newsletter:
"The most important issue summarized in the document is that there is no clear evidence that therapies intended to modify the immune system (e.g., corticosteroids, immune globulin, plasmapheresis) have a beneficial effect in this condition. Plasmapheresis is specifically not recommended because the potential for harm is significant in the absence of any evidence of benefit."
Six of ten children in Denver were sent home for outpatient treatment. Some with mild symptoms have recovered from temporary limb weakness, while the fate of those more severely affected remains unclear. Intensive physical therapy and occupational therapy may be beneficial for recovery.
The Enterovirus genus includes twelve species within which are the serotypes for each species. The serotypes are astounding in number. EV-D68 is only one of the total known serotypes, and during the 2014 EV-D68 outbreak, at least three strains of EV-D68 were discovered. Years of research and development will ensue before a vaccine will be discovered to stop the enteroviruses in their tracts. Until then, treatment for EV-D68 infection will remain symptomatic.
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