Picornaviridae: Echovirus

Echoviruses are single-stranded positive-sense RNA viruses belonging to the genus Enterovirus. Transmission is most commonly through the fecal-oral route. The majority of patients are asymptomatic. Patients who are symptomatic can exhibit a wide range of illnesses ranging from nonspecific upper respiratory infections and exanthems to severe and life-threatening illnesses such as aseptic meningitis, encephalitis, and myocarditis. The diagnosis is usually made clinically, but laboratory confirmation using PCR and viral culture may be necessary for patients with severe disease. Most infections are self-limiting and require no specific therapy.

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Classification

RNA Viruses Flowchart Classification

RNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. RNA genome viruses can be further characterized by either a single- or double-stranded RNA. “Enveloped” viruses are covered by a thin coat of cell membrane (usually taken from the host cell). If the coat is absent, the viruses are called “naked” viruses. Viruses with single-stranded genomes are “positive-sense” viruses if the genome is directly employed as messenger RNA (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses employ RNA dependent RNA polymerase, a viral enzyme, to transcribe their genome into messenger RNA.

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General Characteristics and Epidemiology

General features of Echovirus

  • Echoviruses (enteric cytopathic human orphan viruses) represent strains of various species within:
    • Family: Picornaviridae
    • Genus: Enterovirus
  • RNA virus:
    • Linear
    • Single stranded
    • Positive sense
    • Functions as mRNA
  • Diameter: 20–30 nm
  • Icosahedral symmetry
  • Lacks a lipid envelope
  • Acid resistant
Ultrastructural morphology of echovirus Picornaviridae

Transmission electron microscopic (TEM) image showing the ultrastructural morphology exhibited by echovirus type-6 virions:
The sample was pelleted prior to microscopy, thereby concentrating the viral particles. The particles are 18–25 nm in diameter and contain a core of ssRNA, which is surrounded by a naked protein capsid that exhibits a cubic icosahedral symmetry.

Image: “Ultrastructural morphology exhibited by Echovirus type-6 virions” by CDC. License: Public Domain

Clinically relevant species

There are approximately 29 recognized Echovirus serotypes:

  • 1‒9
  • 11‒21
  • 24‒27
  • 29‒33

Epidemiology

  • Common
  • Worldwide distribution
  • Peak incidence: summer and early fall
  • Affects more children than adults
  • Sex:
    • Children: boys > girls
    • Adolescents and adults: women > men

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Pathogenesis

Reservoir

Humans are the only reservoir.

Transmission

  • Fecal-oral route (most common)
  • Respiratory aerosols

Risk factors

Outbreaks are common in:

  • Daycare centers
  • Schools
  • Hospitals

Pathophysiology

  • Oral entry of the virus → replication in the pharyngeal and GI mucosal and lymphatic tissues
  • Asymptomatic viremia → reticuloendothelial system, including:
    • Distant lymph nodes
    • Bone marrow
    • Spleen
    • Liver
  • Replication occurs → secondary spread to:
    • CNS
    • Heart
    • Lungs
    • Skin
Pathogenesis of echovirus Picornaviridae

The pathogenesis of enteroviruses:
Echoviruses initially enter and infect lymphoid tissues. Viremia occurs, allowing eventual spread to other locations, such as the central nervous system and heart.

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Clinical Presentation

Most infections are subclinical (50%‒80% are asymptomatic), and the clinical presentation can vary from mild to lethal.

Respiratory disease

Patients may have symptoms of an upper respiratory tract infection: 

  • Fever
  • Cough
  • Pharyngitis
  • Coryza

Cutaneous and mucosal disease

Herpangina:

  • Vesicular lesions of the tonsillar fossa and soft palate
  • Fever
  • Pharyngitis
  • Odynophagia
  • Headache

Exanthems may be:

  • Maculopapular
  • Morbilliform
  • Petechial
  • Papulopustular

Neurologic disease

Aseptic meningitis: 

  • Fever
  • Headache
  • Nuchal rigidity

Encephalitis:

  • Lethargy
  • Personality changes
  • Paresis
  • Seizures
  • Coma

Other rare, neurologic manifestations:

  • Muscle weakness or paralysis
  • Guillain-Barré syndrome
  • Transverse myelitis

Cardiac disease

Myopericarditis may occur in a minority of patients.

  • Fever
  • Chest pain
  • Dyspnea

Neonatal disease

Neonates can present with a wide range of presentations, from mild to life-threatening.

Nonspecific symptoms:

  • Fever
  • Anorexia
  • Listlessness
  • Respiratory distress

Fulminant hepatitis:

  • Jaundice
  • Hypotension
  • Coagulopathy
  • Multi-organ failure

Diagnosis and Management

Diagnosis

Most infections are diagnosed based on clinical presentation. A laboratory diagnosis may be needed in severe infections.

  • Viral culture
  • PCR
  • Serology has limited value.

Management

Most echovirus infections are self-limiting and the management is largely supportive. Unproven therapeutic options that can be considered for severe disease or immunocompromised patients may include:

  • IV immunoglobulin (IVIG)
  • Pleconaril 
    • Antiviral
    • Rarely used
    • Not FDA approved

Prevention

  • Handwashing (alcohol-based hand sanitizers may not be effective)
  • Maintaining clean living conditions
  • Minimizing contact with infected individuals

Comparison of Enteroviruses

Table: Comparison of characteristics and diseases associated with different enteroviruses
VirusCoxsackievirusPoliovirusEchovirus
Characteristics
  • ssRNA virus
  • Icosahedral
  • Nonenveloped
  • Approximately 30 nm
  • ssRNA virus
  • Icosahedral
  • Nonenveloped
  • 25–30 nm
  • ssRNA virus
  • Icosahedral
  • Nonenveloped
  • 20–30 nm
Transmission
  • Fecal-oral route
  • Respiratory aerosols
  • Fecal-oral route
  • Respiratory aerosols
  • Fecal-oral route
  • Respiratory aerosols
Clinical
  • URTI
  • Herpangina
  • HFMD
  • Aseptic meningitis
  • Myopericarditis
  • Epidemic pleurodynia
  • Neonatal infection
  • Flu-like illness
  • Aseptic meningitis
  • Asymmetric flaccid paralysis
  • Bulbar involvement
  • URTI
  • Exanthem
  • Aseptic meningitis
  • Encephalitis
  • Myopericarditis
  • Neonatal infection
Diagnosis
  • Clinical
  • PCR
  • Viral culture
  • Clinical
  • PCR
  • Serology
  • Viral culture
  • Clinical
  • PCR
  • Viral culture
ManagementSupportiveSupportiveSupportive
PreventionHandwashingVaccinationHandwashing
HFMD: hand, foot, and mouth disease
URTI: upper respiratory tract infection

Differential Diagnosis

  • Respiratory syncytial virus infection: an infection of the lower respiratory tract caused by an enveloped ssRNA virus. Respiratory syncytial virus infection presents with fever, cough, wheezing, tachypnea, and crackles. The diagnosis is made clinically. Management is supportive.
  • Rhinovirus infection: an infection caused by an acid-labile, positive-sense RNA virus of the Picornaviridae family. As rhinoviruses are inactivated by gastric acid, they can only affect the nasal mucosa and conjunctiva, causing edema of the subepithelial tissues. A rhinovirus infection presents as a “common cold” with mild upper respiratory symptoms. Diagnosis is clinical, and the disease is typically minor and self-limiting. Management is supportive.
  • Infectious mononucleosis: a disease caused by the EBV that is characterized by fever, fatigue, lymphadenopathy, and pharyngitis. Complications can include peripheral neuropathy, viral meningitis, Guillain-Barré syndrome, and myocarditis. The diagnosis is based on clinical features and testing, such as a positive heterophile antibody test or serology. Management is supportive. 
  • Bacterial meningitis: an acute infection of the meninges. Patients present with headache, fever, nuchal rigidity, and rapid clinical deterioration. A lumbar puncture is performed to make the diagnosis. Unlike the findings in aseptic meningitis, CSF studies show turbid fluid, low glucose levels, and high WBC count with neutrophil predominance. Gram stain and culture are used to determine the causative bacteria. Treatment includes antibiotics and corticosteroids.
  • Adenovirus infection: a non-enveloped double-stranded DNA virus that typically causes mild respiratory infections; conjunctivitis, atypical pneumonia, gastroenteritis, meningoencephalitis, and myocarditis can also occur. The diagnosis is typically clinical, but a PCR test may be performed to confirm the diagnosis of severe disease. Management is supportive.
  • West Nile virus infection: an infection by a flavivirus. The majority of patients will be asymptomatic or have a headache, myalgias and arthralgias, vomiting, diarrhea, or a rash. A small proportion of patients develop encephalitis, meningitis, or flaccid paralysis. The diagnosis can be made using serology, PCR, and viral cultures, which can differentiate a West Nile virus infection from an echovirus infection. Management is supportive.
  • Lyme disease: a tick-borne infection caused by the gram-negative spirochete, Borrelia burgdorferi. The presentation of Lyme disease can vary depending on the stage of the disease and may include the characteristic erythema migrans rash (not present in an echovirus infection). Neurological, cardiac, ocular, and joint manifestations are also common in later stages. Diagnosis of Lyme disease relies on clinical findings and tick exposure, and is supported by serological testing. Antibiotics are used for treatment. 
  • Ehrlichiosis and anaplasmosis: tick-borne infections caused by Ehrlichia chaffeensis and Anaplasmosis phagocytophilum, respectively. Symptoms of ehrlichiosis and anaplasmosis include fever, headache, and malaise. Disseminated intravascular coagulation, multiorgan failure, and coma can also occur with severe disease. The diagnosis is made using PCR. Treatment of both diseases is with doxycycline.

References

  1. Modlin, J.F. (2019). Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention. In Bloom, A. (Ed.), UpToDate. Retrieved April 27, 2021, from https://www.uptodate.com/contents/enterovirus-and-parechovirus-infections-clinical-features-laboratory-diagnosis-treatment-and-prevention
  2. Modlin, J.F. (2021). Enterovirus and parechovirus infections: Epidemiology and pathogenesis. In Bloom, A. (Ed.), UpToDate. Retrieved April 27, 2021, from https://www.uptodate.com/contents/enterovirus-and-parechovirus-infections-epidemiology-and-pathogenesis
  3. Choudhary, M.C. (2019). Echovirus infection. In Bronze, M.S. (Ed.), Medscape. Retrieved April 27, 2021, from https://emedicine.medscape.com/article/216564-overview
  4. Sinclair, W., and Omar, M. (2021). Enterovirus. [online] StatPearls. Retrieved April 27, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK562330/
  5. Tesini, B.L. (2019). Overview of enterovirus infections. [online] MSD Manual Professional Version. Retrieved April 27, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/enteroviruses/overview-of-enterovirus-infections
  6. Khetsuriani, N., Lamonte-Fowlkes, A., Oberst, S., Pallansch, M.A. (2006). Enterovirus surveillance–United States, 1970-2005. MMWR Surveill Summ. http://reference.medscape.com/medline/abstract/16971890
  7. Yarmolskaya, M.S., Shumilina, E.Y., Ivanova, O.E., Drexler, J.F., Lukashev, A.N. (2015). Molecular epidemiology of echoviruses 11 and 30 in Russia: Different properties of genotypes within an enterovirus serotype. Infect Genet Evol. 30:244-248. http://reference.medscape.com/medline/abstract/25562123
  8. Oberste, M.S., Maher, K., Flemister, M.R., Marchetti, G., Kilpatrick, D.R., Pallansch, M.A. (2000). Comparison of classic and molecular approaches for the identification of untypeable enteroviruses. J Clin Microbiol. 38(3):1170-1174. http://reference.medscape.com/medline/abstract/10699015

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