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

# Overview
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.

# Historical Perspective
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.

# Pathophysiology
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.

# Causes
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.

# Differentiating Enterovirus 68 from other Diseases
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.

# Epidemiology and Demographics
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.

# Risk Factors
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.

# Natural History, Complications and Prognosis
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.

# History and Symptoms
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

# Physical Examination
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.

# Laboratory Findings
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.

# Chest X Ray
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.

# Medical Therapy
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.

# Primary Prevention
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.

# Future or Investigational Therapies
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.