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EV-D68

After consultation with public health practitioners, including provincial and territorial chief medical officers of health and staff of the Public Health Agency of Canada, it was decided that a rapid review of the current enterovirus outbreak would be useful for Canadian public health practitioners.

To prepare this debrief, information has been gathered from a number of sources, including the Public Health Agency of Canada, provincial health organizations, USA Centers for Disease Prevention and Control and other American public health organizations, MMWR, ProMED, media reports, and previous literature (although not a formal literature review).

Because there appear to have been relatively few observations and analyses of cases and outbreaks specifically associated with EV-D68, much of the information in this Disease Debrief is based on incomplete information from current and previous reports of outbreaks or has been extrapolated from what has been known about similar viruses. Questions, comments or suggestions would be most appreciated.

What are Disease Debriefs? To find out more about how information is collected, see our page dedicated to the Disease Debriefs.

What do we know about the current and previous outbreaks of Enterovirus D68 (EV-D68)?

Recent outbreak

Canada

  • As of December 9, 2014, confirmed cases have been reported in British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Quebec, New Brunswick, Nova Scotia and Prince Edward Island.
  • As of November 4, 2014, a total of 214 specimens, collected from across Canada between August and October 2014, had tested positive for EV-D68 at the NML. This does not represent all reported EV-D68 cases in Canada as some provinces perform their own testing for EV-D68.
  • Since September 2014, the BCCDC has been conducting enhanced surveillance on laboratory-confirmed cases of EV-D68 in collaboration with the Public Health Agency of Canada. During the autumn enhanced surveillance period, from September 1 to December 31, 2014, a total of 221 EV-D68 cases were detected in BC, of which at least 140 required hospitalization. As of December 31, 2014, enhanced surveillance has ended in BC.
  • On October 16, 2014, the first recorded death in Canada associated with a positive EV-D68 lab specimen was confirmed by the BCCDC. The patient had a history of severe asthma and was in the hospital when he developed respiratory failure. In total, since mid-August, three deaths (one child, one adult, and one elderly) associated with EV-D68 have been reported in BC. However, it remains unclear to what extent EV-D68 infection caused or contributed to these severe manifestations.
  • Public Health Ontario Laboratories has not detected EV-D68 since late October 2014 and stopped testing for the virus on December 1. They mention that testing will resume on August 3, 2015. Alberta documented 111 lab-confirmed cases between July 1, 2014 and November 7, 2014, but their case count remained unchanged as of December 4.
  • PHAC is currently collaborating with participating provinces and territories to collect additional clinical and epidemiological information on hospitalized cases of EV-D68 through a time-limited severe outcomes surveillance pilot. In addition, PHAC is collaborating with the Sentinel Physician Surveillance Network to determine whether some of the mild influenza-like-illnesses observed in the community during the 2013-2014 influenza season were due to EV-D68.
  • The current outbreak in Canada began on September 15, 2014, when Alberta Health Services reported 18 cases of EV-D68 among hospitalized patients under the age of 18. Nine cases were among children admitted to a Calgary children’s hospital, with a diagnosis of asthma or bronchiolitis between September 1 and September 11, 2014.

Relevant Links and References

U.S.A.

  • According to CDC, 1153 cases of EV-D68 have been lab-confirmed in 49 states from mid-August to January 15, 2015. EV-D68 was detected in specimens from 14 patients who died in the United States. The role of EV-D68 in these deaths is being investigated.
  • The current outbreak in the U.S.A. began in the month of August 2014, when two pediatric hospitals in the American Mid-West (Children’s Mercy Hospital in Kansas City and the University of Chicago Medicine Comer Children’s Hospital) reported increased rates of hospitalization and ICU admission for severe respiratory illness, along with increased detections of rhinovirus/enterovirus by PCR-assay of nasopharyngeal specimens. On September 8, 2014, the CDC announced that it had confirmed 30 cases of EV-D68 in these two hospitals and was investigating suspected outbreaks in jurisdictions across the United States (USA).
  • CDC has 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. CDC has submitted the sequences to GenBank to make them available to the scientific community for further testing and analysis.
  • Of the more than 2600 specimens tested by the CDC lab, about 36 per cent have tested positive for EV-D68 and one-third have tested positive for a rhinovirus or an enterovirus other than EV-D68.
  • On October 14, 2014 the CDC published a Press Release stating that they had developed and started using a new, faster lab test for detecting EV-D68 in specimens from people in the United States with respiratory illness.
  • This new lab test allowed the CDC to rapidly process the more than 1,000 specimens received since mid-September.
  • CDC’s new lab test is a “real-time” reverse transcription polymerase chain reaction, or rRT-PCR;it is expected to identify all strains of EV-D68 that have been documented in the USA this summer and fall.
  • With falling counts of EV-D68 and rising counts of other viruses such as influenza and respiratory syncytial virus, the CDC discontinued its weekly reporting of EV-D68-like illness. In its last report, for the week of October 26 to November 1, 2014, 47 states and the District of Columbia had submitted assessments to CDC of activity of EV-D68-like illness. While 37 states and the District of Columbia reported low or declining activity, 7 states had reported elevated activity, and 3 states increasing activity.

For further information on USA cases, please refer to the CDC Enterovirus-D68 website.

  • The actual or estimated rates of suspect or probable cases have not been described in Canada or the USA on a population-based or other systematic surveillance method.
  • In most EV-D68 cases, recovery has occurred within a few days of supportive care, including a significant proportion requiring intensive care and assisted ventilation.

Acute Flaccid Paralysis

  • Since September, 2014, the CDC and various health departments in Canada and the USA have been investigating reports of children and young adults with acute muscle weakness or paralysis who have had EV-D68 found in respiratory specimens.
  • On September 30, the BC Centre for Disease Control issued a notice through ProMED mail providing details on two confirmed EV-D68 cases in BC with paralytic manifestations. Paralysis cases are also being investigated in Alberta and Ontario for association with EV-D68. In total since mid-August, five cases of neurologic illness (three paediatric, two adult) associated with EV-D68 have been reported in BC. However, it remains unclear to what extent EV-D68 infection caused or contributed to these severe manifestations.Paralysis cases are also being investigated in Alberta and Ontario for association with EV-D68.
  • On September 26, 2014 the CDC released a health advisory (http://emergency.cdc.gov/han/han00370.asp) [page no longer found] about an investigation into a cluster of nine (now ten) pediatric patients hospitalized with acute neurologic illness of undetermined etiology at Children’s Hospital Colorado between August 9 and September 17, 2014. The CDC has been looking into possible linkages of this cluster of neurological disease to the fall 2014 EV-D68 outbreak.
  • The National Center for Immunization and Respiratory Diseases (NCIRD) of the CDC is now referring to this illness as acute flaccid myelitis (due to consistent observations of grey matter inflammation in the spinal cord). They post regular updates (http://www.cdc.gov/ncird/investigation/viral/sep2014.html) [page no longer found] on the CDC investigation.
  • From August 2 to January 14, 2015  the CDC has verified reports of 107 cases in 34 states that have met their case definition. To be considered a case in this investigation, a patient must meet ALL FOUR of the following criteria:
  1. Patient ≤21 years of age
  2. Acute onset of focal limb weakness
  3. On or after August 1, 2014
    AND
  4. An MRI showing a spinal cord lesion largely restricted to gray matter.

Relevant Links and References

Previous outbreaks

(see Table 1)

  • Although it is not unusual for late summer and early autumn seasonal spikes of viral respiratory infections associated with rhinoviruses, enteroviruses, and other pathogens, previously reported outbreaks of EV-D68 in Asia, Europe and the USA have had similar characteristics but do not appear to have been as large or widespread as the current outbreak. Reported deaths have been rare.
  • Six outbreaks have been reported in the previous five years (Philippines, 2008, 21 confirmed cases; Japan, 2010, ≥120 confirmed cases; Netherlands, 2009, 24 confirmed cases; Georgia, USA, 2009, 6 confirmed cases; Pennsylvania, USA, 2009, 28 confirmed cases; Arizona, USA, 2010, 5 confirmed cases).
  • Typically, enteroviruses have circulated with summer-fall seasonality in temperate climates.
  • Outbreaks of enterovirus diseases have usually occurred in several-year cycles. EV-D68 outbreaks have usually occurred within or later than the typical enterovirus season.
  • Sporadic cases of EV-D68 have been identified in Canada, but outbreaks of public health significance have not been previously reported. This could reflect testing frequency as well as biological occurrence.
Table 1: Previously Reported EV-D68 Outbreaks, 2008–2010

RELEVANT LINKS AND REFERENCES

What do we know about the science and epidemiology of EV-D68?

Taxonomy

Enterovirus D68 (EV- D68) shares biologic and epidemiologic features with human rhinoviruses (HRV). They are a species within the Enterovirus genus of the Picornaviridae family.

Approximately 100 serotypes of nonpolio enteroviruses have been recognized; EV-D68 (identified in 1962) has been one of the less commonly identified and reported.

Serotypes of human enteroviruses have traditionally been classified into echoviruses, coxsackieviruses group A and B, and polioviruses. Current taxonomy takes into account molecular and biologic characteristics which resulted originally in the division of human enteroviruses into four species: human enterovirus [HEV] A, B, C, and D. (There are more now.)

Enterovirus and rhinovirus species names were revised recently to remove the (human) host name and to append the type number to the species designation; hence, human enterovirus 68 (HEV-68, also previously called EV68) is now called EV-D68.

Relevant Links and References

Burden of illness

  • Since it was first identified in 1962 amongst four cases in California, there have been at least six reported outbreaks associated with EV-D68, all occurring after 2008.
  • It is possible, if not likely, that a large number of sporadic cases and outbreaks of EV-D68 (as well as other enterovirus-associated illness) have occurred which have not undergone specific testing.
  • It is likely that testing for and reporting of EV-D68 cases have occurred among the most severe cases or outbreaks, resulting in detection bias of the observed severity of illness.

Relevant Links and References

High Risk Groups

Children and adults can be affected, but children have been in the predominant age groups in reported cases and outbreaks.

A history of previous respiratory disease (asthma, wheezing, bronchiolitis) has been associated with cases in children, especially those that have had more severe illness.

Predominance of severe cases in children (compared with adults) is likely the result of 1) higher exposure 2) lower prior immunity and 3) smaller airways.

The most common age group has been children aged 0-4 years, but approximately one fourth of previous reports was in adults aged >20 years.

Immunocompromise has been associated with adult cases.

Previous outbreaks: High Risk Groups

  • Among the 95 cases described in the six reported outbreaks, fifty-four (57%) were 0-4 yrs, eleven (12%) were 5-9 yrs, twelve (13%) were 10-19 yrs, and eighteen (19%) were over 20 yrs.
  • In Netherlands (24 cases), chronic underlying illness was present in about 80% of patients (half were over 20 yrs old). In Georgia (6 cases), 2 cases were immunocompromised (over 50 yrs old)

Current outbreak: High Risk Groups

(See Table 2)

As of November 4, 2014, two thirds of the 150 lab-confirmed cases in BC are in children ≤ 10 years of age (range <1 to=””>80 years) and 57% of cases with known gender are male.

  • Among the Kansas City cases (19 cases): 10 (53%) were male, with a median age of 4 years and an age range of 6 weeks to 16 years. Among the Chicago cases (11 cases): 9 (82%) were female, with a median age of 5 years and an age range of 20 months to 15 years.
  • In Kansas City, 13 cases (68%) had a previous history of asthma or wheezing and only 5 cases (26%) were febrile. In Chicago, 8 cases (73%) had a previous history of asthma or wheezing and only 2 cases (18%) were febrile.

Relevant Links and References

Severity

Because testing for viruses and special testing for species sub-typing is more likely to occur with severe cases, it would be expected that a high proportion of cases of EV-D68 would be identified among intensive care patients and those requiring mechanical ventilation. Despite this, there have been few reports of fatalities in the current outbreaks.

Previous outbreaks: Severity

  • The six previous outbreaks (95 cases) of respiratory illness associated with HEV-68 described in this report were associated with respiratory illness ranging from relatively mild illness that did not require hospitalization to severe illness requiring intensive care (≥ 20/95) and mechanical ventilation. In the Philippines, all 21 cases were pediatric patients hospitalized with pneumonia. Three cases were fatal.

Current outbreak: Severity

(See Table 2)

  • In Kansas City, 100% of the 19 EV-D68 cases (and 15% of all cases of respiratory illness) were admitted to the pediatric ICU. Four required bi-level positive airway pressure ventilation. In Chicago, 10 cases (91%) were admitted to the pediatric ICU for respiratory distress; two required mechanical ventilation (one of whom also received extracorporeal membrane oxygenation), and two required bi-level positive airway pressure ventilation.

Relevant Links and References

Clinical features

  • EV-D68 has been reported to cause mild to severe respiratory illness. However, the full spectrum of EV-D68 illness has not been well-defined.
  • Most enterovirus infections are probably asymptomatic (editorial note in CDC MMW report, Sept. 30, 2011). Clinical manifestations vary widely and include upper and lower respiratory manifestations (cold-like or influenza-like illness, atelectasis, pneumonia, airway obstruction), fever, rash, and neurologic illness, such as aseptic meningitis and encephalitis. In contrast, EV-D68 has been most significantly associated with lower respiratory manifestations.

Previous outbreaks: Clinical features

  • Clinical features described in 6 previous outbreaks include: Philipines (21 cases) – cough, difficulty breathing, wheezing, and retractions; Japan (11 cases) – asthmatic bronchitis or pneumonia (10/11), febrile convulsions (1/11); Netherlands (24 cases) – acute respiratory illness, including pneumonia, asthma, exacerbation and wheezing; Georgia (6 cases) – fever (5/6), cough (4/6); Arizona (5 cases) – couch and tachypnea or hypoxemia, abnormal lung examination result, new-onset wheezing; (Pennsylvania (28 cases) – features not described).

Current outbreak: Clinical features

(See Table 2)

  • Clinical manifestations described for the recent patients from Kansas (19 cases) and Chicago (11 cases) include: difficulty breathing and hypoxemia (19/19); wheezing (4/19); febrile illness (5/19 and 2/11); chest radiographs showing perihilar infiltrates(~19/19) with atelectasis (often); respiratory distress (10/11)
  • A minority of cases have presented with acute neurological illness characterized by extremity weakness, cranial nerve dysfunction (e.g. diplopia, facial droop, dysphagia, or dysarthria), or both.
Table 2: Characteristics of EV-D68 Cases in Three Pediatric Hospitals, August 2014
Table 2: Characteristics of EV-D68 Cases in Three Pediatric Hospitals, August 2014

Relevant Links and References

Laboratory testing and surveillance

  • The Public Health Agency performs testing for EV-D68 at the National Microbiology Laboratory in Winnipeg upon requests from provincial health authorities. Since 1999, and prior to the current outbreak, it has identified 82 cases of EV-D68 infections in Canada.
  • Since the original isolation of EV-D68 from four children in California in 1962, EV-D68 has been reported infrequently in Canada and the United States. The National Enterovirus Surveillance System (NESS) in the United States received 79 EV-D68 reports during 2009-2013 and only 26 during 1970-2005. Small outbreaks of EV-D68 associated with respiratory illness were reported in the United States, Netherlands, Japan and the Philippines during 2008–2010.
  • Laboratory methods used for enterovirus identification have changed substantially. The molecular method for enterovirus typing, based on sequence of the VP 1 gene, was developed in the late 1990s and is being used by increasing numbers of laboratories.
  • Antigenic typing reagents however, are still not widely available for EV-D68, so it is likely that there are EV-D68 strains among the many untyped enteroviruses isolated in laboratories.

Relevant Links and References

Transmission

EV-D68 has not been identified frequently, so it has been studied less than other enteroviruses. The virus has been found in saliva, nasal mucus, and sputum. The virus likely spreads from person to person by droplets when an infected person coughs or sneezes. In addition, like other enteroviruses, it is likely that the virus is also spread by the fecal-oral route and indirectly via unwashed hands and contaminated surfaces and other materials and objects.

Reservoir

Humans are the only known reservoirs.

Incubation period

Incubation period is likely similar to rhinoviruses and other enteroviruses, namely, between one and five days.

Period of communicability

This is likely similar to rhinoviruses and other enteroviruses, namely, from one day prior to onset until about five days after onset of symptoms.

Prevention

There is no vaccine or other prophylactic pharmaceutical to prevent infections.

  • Hygiene methods include:
    • Use hand sanitizer or wash hands regularly and thoroughly with soap and water, especially after changing diapers, using the toilet, as well as before and after touching one’s eyes, nose or mouth;
    • 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.
    • Avoid work or school when ill.

Treatment

  • There is no specific treatment (e.g., anti-virals) for EV-D68 infections.
  • Mild cases are self-limited, and require no treatment.
  • Severe cases with lower respiratory infection often require hospitalization and supportive care (oxygen, intravenous hydration, bronchodilators). The need for intensive care (including mechanical ventilation) has been more common in children. With few exceptions, the case-fatality rate of treated patients has been extremely low (usually zero)

Relevant Links and References

  • CDC: Enterovirus D68: Question and Answer
  • Heymann DL., Control of Communicable Diseases Manual. 19th ed. Washington, DC: American Public Health Association; 2008. p. 516.
    • http://www.unboundmedicine.com/ccdm (page no longer found)

What public health interventions can be considered at this time?

  • PHAC has been in close contact with U.S. public health officials and is closely monitoring the situation. They have, in collaboration with the Canadian Paediatric Society, already reminded paediatricians to remain vigilant and to be on the watch for any possible EV-D68 cases in February, 2014 when initial serious cases were first reported in the United States.
  • In the absence of a vaccine or other preventive intervention, public health actions include the following:
    • Public education (see #4 below)
    • Health care provider education (see #5 below)
    • Sentinel clinical and laboratory surveillance to identify the occurrence of EV-D68
    • Enhanced surveillance of cases of severe acute respiratory illnesses

What do we know that can be used to inform the general public about EV-D68?

  • As expected, cases of EV-D68 have been detected among hospitalized patients with acute respiratory infections. Increased cases of viral acute respiratory illness are common at this time of year, after school has resumed, and when enteroviruses tend to increase their circulation.
  • Regardless of the magnitude of increased risk at this time, Canadians can be reminded and encouraged to take usual measures to protect themselves through hand-washing, cough etiquette, avoiding self-contact of mucous membranes, and staying home when sick.
  • In the absence of symptoms other than those of a typical upper respiratory infection, there is usually no need for professional health care, unless there are specific risk factors such as a history of asthma or immune compromise; however, the presence of lower respiratory symptoms such as wheezing, cough, shortness of breath are all indications for prompt or urgent assessment by a health care provider.
  • PHAC has created a webpage on Non-polio enterovirus where individuals can find a Public Health Update on Enterovirus-D68 and a Message from the Chief Public Health Officer of Canada on Enterovirus-D68.

Relevant Links and References

What do we know that can be used to inform health care practitioners?

  • At this time, the clinical approach to patients with upper respiratory infections should be as usual, with the exception, perhaps, of closer observation of children with a history of asthma or immune compromised adults, especially for those who have had known contact within five days with an ill person.
  • Because EV-D68 has biological characteristics that are similar to rhinoviruses and other enteroviruses, it is likely spread by droplets as well as direct and indirect contact, especially in children. In addition to routine precautions, contact and droplet precautions should be considered for suspected cases, especially children. There do not appear to be any recommendations at this time for the need for respirator masks for aerosol generating medical procedures.
  • The antiviral drugs pleconaril, pocapavir, and vapendavir have significant activity against a wide range of enteroviruses and rhinoviruses. 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.
  • 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 of several non-enveloped viruses (e.g. norovirus, poliovirus, rhinovirus).
  • Clinicians should perform hand hygiene using either alcohol based hand rub (ABHR) or soap and water upon removal and prior to donning gloves.
  • While rectal swabs and faecal specimens are typical for molecular detection and typing in most cases of enterovirus, respiratory nasopharyngeal/oropharyngeal swabs appear to be most common and appropriate for collecting EV-D68 specimens
  • A positive laboratory test for non-polio enteroviruses from certain specimens, such as a rectal or respiratory swab, does not necessarily mean the virus is the cause of infection. Non-polio enteroviruses can be shed for an extended period of time after the symptoms have resolved.
  • Some diagnostic tests might not detect EV-D68 or might misidentify it as an HRV. The gold standard test for EV-D68 detection is partial sequencing of the structural protein genes, VP4-VP2 or VP1.
  • Healthcare professionals should:
    • Be aware of EV-D68 as a potential cause of outbreaks of severe respiratory illness and possibly neurologic symptoms, particularly in young children.
    • Consider laboratory testing of respiratory and CSF specimens for enteroviruses in cases of severe respiratory illness and/or acute neurological abnormalities.
    • Report cases and outbreaks of severe acute respiratory illnesses and/or acute neurological abnormalities.

Relevant Links and References

  • CDC: Enterovirus D68: Question and Answer
  • PHAC: Routine Practices and Additional Precautions for Preventing the Transmission of Infection in Healthcare Settings
    • http://www.ipac-canada.org/pdf/2013_PHAC_RPAP-EN.pdf (page no longer found)
  • British Columbia Centre for Disease Control (BCCDC): Emerging Respiratory Virus Updates
    • http://www.bccdc.ca/dis-cond/DiseaseStatsReports/EmergingRespiratoryVirusUpdates.htm (page no longer found)

Diagnostic Testing and Surveillance in Canada

  • Non-polio enteroviruses, including EV-D68, are not nationally notifiable, but individual jurisdictions may have specific enterovirus reporting protocols for healthcare professionals to follow. Providers should refer to the communicable disease protocols specific to their jurisdiction.
  • The Polio and Enterovirus Section at the Public Health Agency of Canada (Enteroviruses and Enteric Viruses Laboratory of the Viral Diseases Division) provides reference diagnostics, molecular typing and surveillance of clinically relevant human polio virus and non-polio enterovirus infections in Canada. This section types isolates of non-polio enterovirus to carry out surveillance on emerging enterovirus infections of concern.
  • PHAC’s protocol for investigation of cases of severe acute respiratory illness (especially for patients with recent travel) includes viral testing and sub-typing to identify specific species of enterovirus cultures.
  • According to the NML, the best specimens are virus cultures or nasal swabs.

Relevant Links and References

  • CDC: Enterovirus D68 for Health Care Professionals
  • PHAC: Enteroviruses and Enteric Viruses Laboratory Section Contact Information
    • https://www.nml-lnm.gc.ca/guide2/labsview.php?labID=16 (page no longer found)
  • PHAC: Non-polio Enterovirus (NPEV) and Human Parechovirus (HPeV) Molecular Detection and Typing Reference Page
    • https://www.nml-lnm.gc.ca/guide2/tests_engview.php?refdiagID=301 (page no longer found)