Enterovirus D-68 factsheet for healthcare professionals

What is Enterovirus D-68 (EV-D68)?
Enterovirus D-68 (EV-D68) is a non-polio enterovirus. EV-D68 is transmitted person to person by close contact with infected people (including cough, saliva, mucous, and fomites).

While most of the approximately 100 species of non-polio enteroviruses primarily infect the gastrointestinal tract (GIT), EV-D68 has predilection for the respiratory tract. It causes acute respiratory illness ranging from mild upper respiratory tract (URT) symptoms to severe lower respiratory tract infection (LRTI). In outpatient settings, EV-D68 disease manifests primarily in persons younger than 20 years of age and adults aged 50 to 59 years. Hospital inpatients have predominantly been children.

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

EV-D68, as with other enterovirus species, circulates seasonally in the summer, and especially in autumn months. However, infection with EV-D68 can occur all year round.

In the summer and autumn of 2014, the USA experienced a nationwide outbreak of EV-D68 infections associated with severe respiratory illness. At that time, an increased incidence of EV-D68 isolates from the nasopharyngeal secretions of inpatients with severe respiratory illness was noted. It was most commonly seen in patients with underlying asthma and a history of wheezing. It was also associated with a rare and debilitating neurological manifestation (i.e. predominantly acute flaccid paralysis (AFP)). In addition, there were likely to have been many thousands of mild EV-D68 infections for which people did not seek medical treatment and/or have confirmatory testing.

What is happening with EV-D68 currently?
No EV-D68 outbreaks have been reported to the Health Protection Surveillance Centre (HPSC) in Ireland in the past 2-3 years. Enteroviruses are ever-present in the community, and each year there is expectation of the detection of cases. The UCD National Virus Reference Laboratory (NVRL) continues to work with laboratories across the country by testing specimens to determine virus type, supporting the identification and investigation of outbreaks, and monitoring seasonal activity.

What is the pathophysiology of EV-D68 infection?
Traditionally, enteroviruses spread faeco-orally, although EV-D68 spreads via respiratory secretions.

Immunology
The immune response to enteroviruses is mainly humoral, mediated by secretory immunoglobulin A (IgA) in nasal and alimentary secretions. Serum neutralising immunoglobulin G (IgG) can be detected seven to ten days after infection and persists for life after natural enteroviral infection.

What is the incubation period for EV-D68 infection?
The incubation period is usually three to five days (although it can be as long as 10 days), once the EV-D68 invades the submucosal lining of the distal pharynx and alimentary tract.

What is the epidemiology of EV-D68 infection?
EV-D68 circulates between summer and autumn, and appears to spread by close contact with infected people (including cough, saliva, mucous, and fomites). Enteroviruses are ever-present in the community and each year we expect to detect cases.

Internationally
Global reports have confirmed similar increases in the detection of EV-D68. This rise in incidence has been partially attributed to increased awareness of EV-D68 as a respiratory pathogen, and the use of more sensitive virus identification methods such as polymerase chain reaction (PCR).

United States of America (USA)
EV-D68 was first identified in California in 1962 in isolates from four paediatric patients with bronchiolitis and pneumonia. EV-D68 was not a notifiable illness, and surveillance in the USA between 1970 and 2005 only confirmed 26 cases. In late 2009, in the context of pursuing respiratory virus surveillance during the H1N1 pandemic, a cluster of EV-D68 cases was detected.

Ireland
In Ireland, as EV-D68 does not form part of the standard laboratory respiratory screen. Therefore it is likely that cases are occurring in the community, but are not being detected. Detections are therefore biased towards those with more severe disease. It is important to note that other seasonal respiratory and enteric viruses also circulate in Ireland – in particular, other enteroviruses, respiratory syncytial virus, adenoviruses and influenza.

The NVRL in Ireland participated in a multi-centre European study in 2014, following on from the EV-D68 outbreak in the USA. Four cases of EV-D68 were identified from 1,010 screened respiratory isolates. 

What are the clinical features of EV-D68 infection?
The symptoms associated with EV-D68 infection are as follows:

• Acute onset,
• Cough,
• Fever (although a considerable percentage of cases without fever have been reported in outbreaks internationally),
• Rhinorrhoea,
• Sore throat,
• Fatigue,
• Headache,
• Myalgia,
• Dyspnoea,
• Diarrhoea, and
• Bronchiolitis.

Cases involving acute neurological illness may have the following characteristics:

• Preceding febrile illness with URT symptoms or GI prodrome occurring 3 – 16 days before onset of neurological illness;
• Limb paresis or flaccid paralysis;
• Ptosis, facial droop, dysarthria, dysphagia, diplopia;
• Absence of sensory deficits; and
• Meningism in cases of meningo-encephalitis.

In addition, there were likely many hundreds or thousands of mild EV-D68 infections for which people did not seek medical treatment and/or get confirmatory testing.

Who is at risk of EV-D68 infections?
Children, especially those aged one month to 16 years, appear to be the most susceptible population based on most reports. Paediatric patients with a history of asthma, wheezing, or other underlying respiratory disease are at greater risk for more severe disease. Neurological disease has been described most commonly in males.

Adults can get infected as well, but they are more likely to have no symptoms or mild symptoms. Individuals who are immuno-compromised are also at increased risk of severe disease.

When seeing patients with respiratory illness, especially children, clinicians should be aware of EV-D68 as a potential cause. They should consider requesting laboratory testing of respiratory specimens for EV-D68 when the cause of infection in severely ill patients remains unclear. This is particularly relevant given EV-D68 outbreaks have been recently reported in Europe (i.e. Netherlands and Sweden in 2016).

What are the diagnostic test recommendations for EV-D68?
Testing of patients with mild illness is not routinely recommended. Indications include:

• Persons with acute severe respiratory illness, who have negative tests for other more common respiratory pathogen, or
• Persons with neurological symptoms (i.e. AFP or meningo-encephalitis).

These, should have raise clinical suspicion with healthcare professionals to consider EV-D68 testing. Contact the local Microbiology Department for advice and information on enterovirus testing and molecular typing before sending any specimens.

EV-D68 is detected through real-time PCR and/or viral culture from an appropriate clinical specimen (see Table 1). EV-D68 positive specimen or culture isolates should be also sent on for molecular serotyping.

Table 1: recommended specimen based on symptom pattern.
(Public Health Wellington-Dufferin-Guelph (PHWDG), 2016.)

How is EV-D68 infection treated?
There is no specific treatment for EV-D68 infections. Clinical and Public Health management is similar to that of other acute respiratory infections, or unexplained neurological illness.

• Many infections will be mild and self-limited, requiring only treatment of the symptoms;
• Some patients with severe respiratory illness and/or neurological symptoms (i.e. AFP or meningo-encephalitis) need to be hospitalised and receive intensive supportive therapy;
• No specific anti-viral therapy is currently available for treatment; and
• Follow standard contact and droplet infection control measures; liaise with local Infection Prevention and Control teams.

What is the prognosis of an EV-D68 infection?
The prognosis of EV-D68 infection varies, ranging from mild, self-limited respiratory infection to severe respiratory disease, especially in individuals with asthma.

In patients with central nervous system (CNS) involvement, which is rare, residual neurological deficits can persist. These cases may require an extended hospital stay. In contrast, some series have reported that most patients who presented with mental status changes returned to baseline.

What is the role of the clinician?
The role of the clinician is to:

• Maintain an index of suspicion;
• Discuss any suspected cases with an Infectious Diseases/Microbiology Consultant or Virology Consultant), before additional clinical specimen are requested;
• Contact NVRL, before sending any clinical specimen, for advice and information on enterovirus testing; and
• Notify the relevant Medical Officer of Health (in the local Department of Public Health) when suspected clusters or cases with neurological symptoms present.

Is EV-D68 a notifiable disease?
EV-D68 is not a disease under the Infectious Diseases (Amendment) Regulations, 2011. However, clusters of cases of severe respiratory illness caused by EV-D68 should be notified by clinicians or medical laboratories to the Medical Officer of Health (in the regional Departments of Public Health). Additionally, acute flaccid paralysis of unknown aetiology and viral meningitis or encephalitis due to enterovirus is notifiable under the Infectious Diseases (Amendment) Regulations, 2011.

What is the Public Health response?
Public Health actions focus on:

• Increasing awareness of EV-D68 infections among healthcare professionals; who are urged to remain vigilant for possible EV-D68 infections causing severe acute respiratory illness and/or with unexplained neurological symptoms (i.e. AFP or meningo-encephalitis), and report increases in cases to the Medical Officer of Health (in regional Departments of Public Health);
• Education of the general public on methods to reduce contracting respiratory illnesses; and
• Education of healthcare professionals about appropriate infection prevention and control in healthcare facilities.

Is there a vaccine available for EV-D68?
Currently, there is no specific vaccine for EV-D68 infections.

Published: 8 March 2017