Enterovirus 68

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Alejandro Lemor, M.D. [2]; João André Alves Silva, M.D. [3]

Synonyms and keywords: Enterovirus D-68, EV68, EV-68, EV-D68

Enterovirus 68 (EV-D68) is a member of the enterovirus genus of the Picornaviridae family. It is a non-enveloped, positive-sense, single-stranded RNA virus. EV-D68 may be transmitted from person to person by aerosol transmission or by direct contact. It is considered a rare infection whose prevalence has recently been on the rise. Classically, it has been described as an infection of the pediatric population, but newer data is consistently suggesting an adult preponderance. Unlike other enteroviruses, EV-D68 causes respiratory disease almost exclusively. The most common signs and symptoms of EV-D68 include cough, dyspnea, and wheezing. EV-D68 infection should be considered in the differential diagnosis of similar infections due to respiratory syncytial virus, adenovirus, parainfluenza virus, seasonal influenza virus B, coronavirus, and rhinovirus. Definitive diagnosis is often made by reverse transcription polymerase chain reaction (RT-PCR) that utilizes assays from patients’ oral or nasopharyngeal swab specimens. Most patients are managed with supportive care as outpatients. Individuals at extremes of age, and those with a history of pulmonary or advanced systemic disease, are more likely to present with severe or complicated clinical disease, often necessitating hospitalizations, oxygen supplementation, and in some cases, mechanical ventilation.

EV-D68 was initially isolated in 1962 from samples of 4 hospitalized children presenting for pneumonia and bronchiolitis in California, USA. It is a rare disease that has recently become more clinically evident. The most recent outbreak occurred in USA on September 2014; it involved 10 states including Colorado, North Carolina, Georgia, Ohio, Iowa, Illinois, Missouri, Kansas, Oklahoma, and Kentucky.

Unlike other enteroviruses, EV-D68 causes respiratory disease almost exclusively. Its cellular tropism, optimal growth at lower temperatures, and acid-lability are responsible for its infection of leukocytes and cells of the respiratory mucosa. The virus has the ability to replicate inside leukocytes, which allows it to infect the parenchymal tissue, to increase its viral load that will contribute to viral dissemination, and to activate endothelial cells that attract more leukocytes to the infected site. Although viral transmission is not fully understood, the virus can be isolated in respiratory secretions and may be transmitted from person to person via aerosol or direct contact.

Enterovirus 68 (EV-D68) belongs to the genus enterovirus, serotype D. Its genome consists of a positive-sense ssRNA strand. EV-D68 is acid-labile and has an optimal growth at lower temperatures. Its genome contains one open reading frame (ORF) which encodes for a single polyprotein, that once translated and processed, yields various viral proteins. Viral serotyping is based on a gene (VP1), which encodes 1 of the 4 viral capsid proteins. The viral genome has recently undergone several rearrangements and deletions. Alterations of the untranslated regions (UTR) have led to the classification of the virus into clades. EV-D68 demonstrates tropism for the mucosal cells of the lower respiratory tract, as well as for leukocytes. The virus recognizes Decay-accelerating factor receptor (DAF) and receptors containing sialic-acid on cell surfaces.

EV-D68 infection must be differentiated from other diseases that cause fever, cough, malaise, and rhinorrhea such as respiratory syncytial virus, adenovirus, parainfluenza virus, seasonal influenza virus B, coronavirus, and rhinovirus.

EV-D68 is considered a rare disease. The true incidence and prevalence are not known, but a recent rise in reported cases has been observed. Although old data suggested predominance among children between the ages 4 to 5, new cases reveal adult preponderance. EV-D68 infection is more prevalent among males, with no variation by race or ethnicity.

Lack of hygiene etiquette, such as coughing and sneezing without covering one’s nose and mouth or washing hands inappropriately, is the most important risk factor for the development of acute EV-D68 infection. Extremes of age, pulmonary comorbidities such as asthma and cystic fibrosis, and other systemic comorbidities are considered significant risk factors for developing worse clinical disease among patients with EV-D68.

The natural history of EV-D68 is poorly understood due to scarcity of data. The virus may produce a spectrum of clinical disease, ranging from an asymptomatic course to severe respiratory symptoms necessitating hospitalization. Prognosis is generally good, but few reports of fatalities have been documented. Approximately 16-21% of patients suffer from EV-D68-associated complications. Common complications, such as superimposed infections and severe pneumonia requiring mechanical ventilation, are more likely to occur among patients at extremes of age, or those with a history of pulmonary or advanced systemic disease.

EV-D68 infection presents with symptoms of an acute upper or lower respiratory tract infection. The most common symptoms of this viral infection include cough, dyspnea, and fever

On physical examination, patients with EV-D68 infection generally develop typical signs of respiratory illness. The most common findings on physical exam include fever, tachypnea, skin rash, erythematous tonsils without exudates, and wheezing.

Patients with EV-D68 infection often have leukocytosis with lymphocyte predominance. Reverse transcription polymerase chain reaction (RT-PCR) assay of an oral or nasopharyngeal swab is usually positive. Viral culture is less likely to be ordered, but will reveal positive results for the infective agent. Serology tests have a low sensitivity for the diagnosis of EV-D68 infection.

Imaging studies, such as chest x-ray, may be requested for infected patients with signs and symptoms of lower respiratory tract infection. Abnormal chest X-ray may reveal evidence of infiltration, consolidation, atelectasis, and air trapping.

There is no specific antiviral treatment indicated for EV-D68 infections. Most patients may be followed-up on an outpatient basis. Patients presenting with more severe disease may be hospitalized or even admitted to an intensive care unit for supportive management and mechanical ventilation, if needed.

Currently, there are no vaccines available for EV-D68 infections. Preventive measures such as hand washing, avoiding contact with sick people, and disinfecting touched surfaces are recommended.

Currently, there are no specific therapies targeting EV-D68. Although the management of enteroviruses in general is only supportive, the development of pharmacologic therapies has recently emerged. Immune globulin therapy has demonstrated clinical and laboratory benefit among patients with enterovirus infection. Antiviral medications against enteroviruses, such as pleconaril, are currently being studied for patients with severe infections caused by other subtypes of enteroviruses.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Human enterovirus 68 (EV-D68) was initially isolated in 1962 from samples of 4 hospitalized children presenting for pneumonia and bronchiolitis in California. It is a rare disease that has recently become more clinically evident. In September 2014 there was a nationwide outbreak of EV-D68 in the USA which involved 10 states including Colorado, North Carolina, Georgia, Ohio, Iowa, Illinois, Missouri, Kansas, Oklahoma, and Kentucky. In October 2018, the New York State Department of Health (NYSDOH) confirmed 39 cases of the enterovirus EV-D68 in children across the state.

• Human enterovirus 68 (EV-D68) was initially isolated in 1962 from samples of 4 hospitalized children presenting for pneumonia and bronchiolitis in California.^[1]
• While early descriptions of of EV-D68 identified the virus as acid resistant, newer reports refuted earlier findings and consistently confirmed the virus’s acid sensitivity.^[2][3][4]
• Between 1970 and 2005 only 26 clinical isolates of EV-D68 were reported in the USA.^[5]
• Prior to 2005, reports of EV-D68 infections were very limited. Only 26 cases of verified EV-D68 infection were documented between 1970 and 2005. EV-D68 is thus considered one of the rarest infectious enteroviruses, representing approximately 0.1% of all enterovirus isolates in that time frame.
• Over the past few years, outbreaks of EV-D68 have been documented in Japan, the Philippines, the Netherlands, and also in several clusters in the USA.^{[6][7][8][9][10]}
• In 2011, China and Phillipines was affected by the first EV-D68 sub-clade B2 strains. Sub-clade B1 contained the two strains from Ontario and three USA strains from the 2014 outbreak.^[11]
• In September 2014, there was an outbreak of EV-D68 in the US with clusters reported in 10 states including Colorado, North Carolina, Georgia, Ohio, Iowa, Illinois, Missouri, Kansas, Oklahoma, and Kentucky.
• Analysis of VP1 genes (encoding capsid proteins) of EV-D68 has helped identify three distinct clades namely A, B, and C from the prototype EV-D68 Fermon strain. Two sub-clades (B1 and B2) were identified, with most 2014 EV-D68 outbreak strains belonging to sub-cluster B2b2 (one of the two emerging clusters within sub-clade B2).^[12]
• All three clades of EV-D68 have been reported in China, Italy, Japan, Netherlands, and the USA^[13]
• In October 2018, the New York State Department of Health (NYSDOH) confirmed 39 cases of the enterovirus EV-D68 in children across the state.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Unlike other enteroviruses, EV-D68 causes respiratory disease almost exclusively. Its cellular tropism, optimal growth at lower temperatures, and acid-lability are responsible for its infection of leukocytes and cells of the respiratory mucosa. The virus has the ability to replicate inside leukocytes, which allows it to infect the parenchymal tissue, to increase its viral load that will contribute to viral dissemination, and to activate endothelial cells that attract more leukocytes to the infected site. Although viral transmission is not fully understood, the virus can be isolated in respiratory secretions and may be transmitted from person to person via aerosol or direct contact.

EV-68 belongs to the Human Enterovirus D species (HEV-D), along with EV-70 and EV-94. Unlike the remaining enteroviruses in its class, EV-68 is acid-labile, which reduces its ability to colonize the gastrointestinal mucosa. It has been implicated in respiratory infections and in very rare occasions in CNS disease. This property of EV-68 sets it apart from other enteroviruses.^[1]

• The virus shows optimal growth at lower temperatures, making the respiratory tract an adequate host for viral replication. Besides the cells of the respiratory mucosa, EV-68 also shows tropism for leukocytes. The virus binds receptors on the lymphocyte surface containing sialic-acid in order to access the cytoplasm.^[2] Since leukocytes are capable of migrating to other tissues, by infecting these cells, the virus gains access to secondary sites.^[1] Viral replication inside leukocytes limits their function, thereby facilitating viral replication and spread.^[3]

• EV-68 also replicates inside endothelial cells that provide the required increase in viral load for the virus to infect parenchymal tissue, and gain access to secondary sites.^[3] The virus also promotes the activation of endothelial cells leading to chemoattraction of further leukocytes.

• However, EV-68 shows less tropism for endothelial cells than EV-70 or EV-94, which makes infection of secondary sites less common.^[1]

Non-polio enteroviruses can be found in an infected person’s:^{[4] [5]}

• Feces (stool)
• Eye, nose, and mouth secretions (such as saliva, nasal mucus, or sputum)
• Blister fluid

Transmission occurs via the following routes:

• Close contact, such as touching or shaking hands, with an infected person
• Touching objects or surfaces that have the virus on them, then touching eyes, nose, or mouth before washing hands
• Changing diapers of an infected person, then touching the eyes, nose, or mouth before washing hands
• Drinking water that has the virus in it

• Pregnant women who are infected with a non-polio enterovirus shortly before delivery can pass the virus to their babies.

Viral shedding from the respiratory tract, such as through coughing or sneezing, for 1 to 3 weeks or less. Infected people can shed the virus even if they do not have symptoms.

The immune response towards EV-68 is not fully understood. Viral clearance is achieved by an adequate T and B-cell response that contain and eliminate the virus. B lymphocytes, along with tissue macrophages contain the pathogen, while T lymphocytes penetrate the areas of infection, causing tissue damage. Tissue damage may lead to cell death of the affected areas.^[6]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Enterovirus 68 (EV-D68) belongs to the genus enterovirus, serotype D. Its genome consists of a positive-sense ssRNA strand. EV-D68 is acid-labile and has an optimal growth at lower temperatures. Its genome contains one open reading frame (ORF) which encodes for a single polyprotein, that once translated and processed, yields various viral proteins. Viral serotyping is based on a gene (VP1), which encodes 1 of the 4 viral capsid proteins. The viral genome has recently undergone several rearrangements and deletions. Alterations of the untranslated regions (UTR) have led to the classification of the virus into clades. EV-D68 demonstrates tropism for the mucosal cells of the lower respiratory tract, as well as for leukocytes. The virus recognizes Decay-accelerating factor receptor (DAF) and receptors containing sialic-acid on cell surfaces.

Viruses; ssRNA viruses; ssRNA positive-strand viruses, no DNA stage; Picornavirales; Picornaviridae; Enterovirus; Enterovirus D^[1]

Enterovirus D68 is a non-enveloped, positive-sense ssRNA enterovirus that belongs to the family Picornaviridae.^[2] Enteroviruses may be classified according to their antigenic, molecular and biological properties into 4 serotypes of Human Enterovirus (HEV): A, B, C, and D.^[3] EV-68 belongs to serotype D, along with EV-D70, EV-D94 and EV-D111. Contrarily to other viruses of the same genus, EV-68 is acid-labile, its replication is optimal at lower temperatures, being more related to rhinoviruses. It commonly causes respiratory disease and has recently been implicated in several outbreaks in Japan, Netherlands, Philippines and in the USA.^{[3][2][4][5][6]} Lower pHs and higher temperatures reduce infectivity titres and viral replication, respectively.^[7][8] This ability to survive at lower temperatures is the reason why EV-68 is frequently isolated from respiratory specimens.^[9]

The common genome of an enterovirus is contained within an RNA strand of approximately 7500 nucleotides. It contains one open reading frame (ORF) which encodes for a single polyprotein. Once translated, the polyprotein is processed, yielding different individual viral proteins. Two UTRs flank the ORF polyprotein on both sides, one of which contains an Internal Ribosome Entry Site (IRES).^[10]

A gene (VP1), which encodes 1 of the 4 viral capsid proteins, is used to distinguish the different serotypes of enterovirus. Accordingly, the different enteroviruses may be organized in the following serotypes:^[11]

• HEV-A
• HEV-B
• HEV-C
• HEV-D

Serotype specific rabbit antisera are used for typing of EV-68 isolates. Partial sequencing of VP1 capsid gene, using primer 292 (5′-MIGCIGYIGARACNGG-3′) and 222 (5′-CICCIGGIGGIAYRWACAT-3′) is another method used for sequencing. The serotype is determined by comparing partial sequences of isolates with a database containing partial sequences of all known enterovirus serotypes.^[7]

Since 1960, the genome of enterovirus 68 has underwent several rearrangements and deletions, particularly of the UTR, which have led to the classification of the virus into clades. Genomic variations within the IRES region may lead to different effects on virulence, however, in the particular case of EV-68 spacer region, little is known about this impact.^[2]

The spacer regions of rhinoviruses are small. It is important to notice that besides sharing cellular tropism for the respiratory epithelium, enterovirus 68 spacer region has been experiencing deletions throughout the years towards the size of the spacer region seen in rhinoviruses. The genome deletions seen in EV-68 may also be responsible for changes in the virulence of the virus, justifying recent outbreaks seen worldwide.^[2]

Human rhinovirus 87 was isolated at the same time as EV-68. Corn is a prototype of HRV-87 and is very unique in its receptor quality. Cross neutralization and partial capsid sequence studies revealed that HRV-87 Corn belongs to the same group as EV-68.^[12]

Unlike other enteroviruses, EV-68 shows tropism for the mucosal cells of the lower respiratory tract, justifying respiratory manifestations that arise from infection.^[13] The virus also shows tropism for different leukocyte cell lines, such as: granulocytes; monocytes; B and T lymphocytes.^[14] Occasionally, EV-68 may infect the CNS, causing severe complications.^[14]

The cellular receptors responsible for the tropism of EV-68 are:^[14][15][16]

• Decay-accelerating factor (DAF)
• Receptors containing sialic-acid

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Enterovirus 68 infection must be differentiated from other diseases that cause fever, cough, malaise, and rhinorrhea such as respiratory syncytial virus, adenovirus, parainfluenza virus, seasonal influenza virus B, coronavirus, and rhinovirus.

Enterovirus 68 infection must be differentiated from other diseases that produce symptoms such as fever, runny nose, sneezing, cough, malaise, chest pain, and diarrhea. Any viral upper respiratory infection must be included in the differential diagnosis of enterovirus 68 infection, and a definitive diagnosis is commonly achieved by PCR assay of a nasopharingeal or oral swab specimen^[1][2]

The following table differentiates acute flaccid myelitis due to EV-D68 from other diseases that cause muscle weakness, hypotonia, and flaccid paralysis:

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]; Alejandro Lemor, M.D. [3] Syed Hassan A. Kazmi BSc, MD [4]

The disease caused by EV-D68 infection is considered a rare entity. The true incidence and prevalence are not known, but a recent rise in reported cases has been observed. Although old data suggested predominance among children between the ages 4 to 5 years, new cases reveal adult preponderance. EV-D68 infection is more prevalent among males, with no variation by race or ethnicity. People with respiratory infections such as asthma, chronic obstructive pulmonary disease and atopy are also more prone to develop severe infection with EV-D68.

EV-D68 infection is considered extremely rare. The true prevalence and incidence are not known. Recent data suggests that increased awareness and earlier diagnosis of the disease might be attributed to a rising trend in prevalence of EV-D68.

• Less than one in a million people in the United States get acute flaccid myelitis (AFM) from EV-D68 each year.
• The Center for Disease Control (CDC) reports a total of 26 cases in USA between 1987 to 2005, 11 of which occurred in 2003 alone.^[1] EV-D68 was reported in San Diego among military personnel in 2004-2005 and in New York City in 2009.
• From August 2014 through October 2018, CDC has received information on a total of 396 confirmed cases of acute flaccid myelitis (AFM) from EV-D68 across the US; most of the cases have occurred in children
• Even with an increase in cases since 2014, AFM remains a very rare condition.

• In summer and fall 2014, the United States experienced a nationwide outbreak of EV-D68 associated with severe respiratory illness.
• From mid-August 2014 to January 15, 2015, CDC or state public health laboratories confirmed a total of 1,153 people in 49 states and the District of Columbia with respiratory illness caused by EV-D68.
• Almost all of the confirmed cases were among children, many whom had asthma or a history of wheezing. Additionally, there were likely many thousands of mild EV-D68 infections for which people did not seek medical treatment and/or get tested. This was the first documented nationwide outbreak of EV-D68. EV-D68 cases in years since 2014 have been reported more sporadically, which is considered typical.
• CDC received about 2,600 specimens for enterovirus testing during 2014, which was 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.

• In October 2018, the New York State Department of Health (NYSDOH) confirmed 39 cases of the enterovirus EV-D68 in children across the state.

• During the period between October 2008 and March 2009, an outbreak of EV-D68 was detected in the Eastern Visayas region of the Philippines among pediatric patients hospitalized with pneumonia.^[2]

• In Japan, the first cases of EV-D68 were reported in 2005. From 2005 to 2010, less than 10 cases were discovered annually. However, almost 120 new cases occurred in 2010 alone. Most of the patients presented with an acute respiratory illness characterized by cough, dyspnea, and/or wheezing.^[3]

• In 2010, all patients with pneumonia and pneumonia-like symptoms were prospectively studied and their samples were sequenced. A total of 24 cases were attributed to EV-D68, 50% of which were less than 20 years of age.

• Between 2008 and 2009, 12 cases of enterovirus 68 were reported in Italy among patients with viral respiratory infections.^[4]

• Approximately 80% of reported cases of EV-D68 infection occurred among children.
• The age at presentation ranges between 1 month to 78 years.
• Based on older data, the median age at infection is 4-5 years; but new reports are consistently revealing adult preponderance^[5][6][7]

• EV-D68 infection is more prevalent in males
• The male to female ratio of EV-D68 infection is approximately 1.2-1.5^{[8][9][4][10][11]}

• The prevalence of EV-D68 does not vary by race.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]; Alejandro Lemor, M.D. [3]

Lack of hygiene etiquette, such as coughing and sneezing without covering one’s nose and mouth or washing hands inappropriately, is the most important risk factor for the development of acute EV-D68 infection. Extremes of age, pulmonary comorbidities such as asthma and cystic fibrosis, and other systemic comorbidities are considered significant risk factors for developing worse clinical disease among patients with EV-D68.

Since EV-D68 may be transmitted via aerosol or direct contact, proper hygiene and etiquette via regular hand washes for at least 20 seconds and covering the nose and mouth during coughing and sneezing are highly recommended lifestyle practices to prevent transmission of EV-D68.

• All patient populations are susceptible to EV-D68 infection. However, extremes of age is considered an important risk factor for worse clinical disease.
• Younger children, who lack previous immunity against the virus, and elderly patients, who have a decreased immune response, are more likely to develop worse disease manifestations ^[1]
• Immunocompromised patients have an increased risk of developing disease manifestations when exposed to EV-D68.

Patients with pulmonary comorbidities are susceptible to severe lower respiratory tract disease when infected with EV-D68. Presence of pulmonary co-morbidities is associated with more admissions to the intensive care unit, need for mechanical ventilation, and death due to the infection. The most common pulmonary co-morbidities desribed in the literature include the following^[2]:

• Asthma
• Cystic fibrosis
• Chronic pulmonary disease requiring home oxygen supplementation
• Lung transplantation

Advanced systemic diseases not related to the respiratory system, such as hepatic cirrhosis, are also considered a risk factor for worse outcome in EV-D68 infections.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2] Alejandro Lemor, M.D. [3]

The natural history of Enterovirus 68 is poorly understood due to scarcity of data. The virus may produce a spectrum of clinical disease, ranging from an asymptomatic course to severe respiratory and neurological illness necessitating hospitalization. Prognosis is generally good, but few reports of fatalities have been documented. Approximately 16-21% of patients suffer from enterovirus 68-associated complications. Common complications, such as superimposed infections and severe pneumonia requiring mechanical ventilation, are more likely to occur among patients with a history of pulmonary disease.

• Enterovirus 68 colonizes the respiratory mucosa. It is believed to be transmitted through respiratory droplets and is often detected by nasopharyngeal swabs of patients presenting with respiratory illness. Nonetheless, the incubation period of the virus is unknown.
• The virus has been isolated among patients of all age groups, ranging from 1 month to 72 years. Although 4 to 5-year-old children are believed to be the most susceptible hosts, accounting for approximately 80% of all reported cases, newer reports are currently noting more adult infections.^[1][2][3]
• The clinical features of the virus are characterized by non-specific signs and symptoms including cough, dyspnea, wheezing, and other symptoms of bronchitis.^[3][4][5][6]
• Without treatment, symptoms generally self-resolve within 4-6 days of symptom onset.
• The disease may progress in the minority of untreated cases to pneumonia, asthma exacerbations, and severe respiratory distress. Patients may require hospitalization, oxygen supplementation, or less commonly mechanical ventilation. The majority of patients requiring intensive care hospitalization are those with a history of pulmonary disease, such as asthma, cystic fibrosis, or lung transplantation.^[3][4][5][6]

Complications are observed among 16-21% of patients diagnosed with enterovirus 68. The majority of patients with complications have a history of pulmonary or systemic co-morbidities.^[7] Complications that can develop as a result of infection with enterovirus 68 are:

• Lower respiratory infections^[1]

• • Pneumonia is considered the most common complication of enterovirus 68
  • Bacterial super-infection is reported with organisms that are commonly associated with lower respiratory infections, such as Streptococcus pneumoniae, Hemophilus influenzae, Mycoplasma pnuemoniae, and Chlamydia pneumniae
  • Viral co-infection with RSV and CMV has been described
• Respiratory failure^[8]

• Asthma exacerbation^[8]

• Febrile convulsions^[8]

• CNS sequelae^[9]

• • Lymphocytic meningomyelitis and encephalitis were both reported in only 1 case of a previously healthy 5-year-old boy
• Death^[10]

• • Death due to enterovirus 68-associated complications is documented among both children and adults, but is considered a very rare event

• Most patients recover uneventfully.
• Asthmatic patient shave an increased risk of developing severe disease.^[11]
• One case report describes a fatal case of enterovirus 68 infection associated with pneumonia, flaccid paralysis and neurologic impairment. ^[12]