Coxsackievirus

Coxsackievirus is a member of a family of viruses called Picornaviridae and the genus Enterovirus. Coxsackieviruses are single-stranded, positive-sense RNA viruses, and are divided into coxsackie group A and B viruses. Both groups of viruses cause upper respiratory infections, rashes, aseptic meningitis, or encephalitis. Group A viruses cause herpangina; hand, foot, and mouth disease; and acute hemorrhagic conjunctivitis. Group B viruses cause myopericarditis, epidemic pleurodynia, and systemic neonatal disease. The diagnoses are usually made clinically. Viral culture and PCR can be performed for confirmation if the diagnosis is uncertain. Coxsackievirus infections are self-limiting and the management is supportive.

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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.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics and Epidemiology

General features of Coxsackievirus

  • Family: Picornaviridae
  • Genus: Enterovirus
  • RNA virus:
    • Linear
    • Single stranded
    • Positive sense
    • Functions as mRNA
  • Diameter: approximately 30 nm
  • Icosahedral symmetry
  • Lacks a lipid envelope
  • Acid-stable viruses
Coxsackie b4 virus

A transmission electron microscopy (TEM) image depicting numerous round Coxsackie B4 virus virions

Image: “5630” by CDC. License: Public Domain

Clinically relevant species

Coxsackie group A virus (23 serotypes):

  • Herpangina
  • Hand, foot, and mouth disease (HFMD)
  • Acute hemorrhagic conjunctivitis

Coxsackie group B virus (6 serotypes):

  • Myopericarditis
  • Pleurodynia
  • Hepatitis
  • Neonatal disease

Both groups can cause:

  • Upper respiratory tract infection
  • Aseptic meningitis
  • Encephalitis
  • Exanthems

Epidemiology

  • Common
  • Worldwide distribution
  • More common in summer
  • Affects men and women equally
  • Occurs in all age groups, but more common in infants and young children

Pathogenesis

Reservoir

Humans are the only reservoir.

Transmission

  • Fecal-oral route
  • Respiratory aerosols

Pathophysiology

  • Oral entry of the virus → replication in the submucosal lymphatic tissue of the pharynx and intestine
  • Spread to regional lymph nodes → replication
  • Asymptomatic viremia → reticuloendothelial system and organs:
    • CNS
    • Lungs and pleura
    • Heart
    • Pancreas
    • Liver
    • Skin and mucous membranes
  • Replication at these locations → cell death and inflammation → clinical manifestations
Pathogenesis of enteroviruses

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

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Clinical Presentation

Herpangina

Coxsackie group A viruses are the principal cause of this self-limiting disease.

Symptoms:

  • Fever
  • Pharyngitis
  • Dysphagia
  • Headache
  • Odynophagia

Exam findings:

  • Vesicular lesions with surrounding erythema of the: 
    • Tonsils
    • Soft palate
    • Uvula
    • Tongue
  • Lesions evolve into shallow ulcers before healing.

Hand, foot, and mouth disease

Hand, foot, and mouth disease is a mild, self-limiting disease caused by the coxsackie group A virus.

Symptoms:

  • Fever
  • Mouth pain
  • Pharyngitis
  • Anorexia 
  • Malaise

Exam findings:

  • Oral enanthem:
    • Initially erythematous macules
    • Progresses to vesicles with surrounding erythema
    • Eventual rupture → superficial ulcers with grey-yellow base
    • Most commonly involve the tongue and buccal mucosa
  • Exanthem:
    • Appearance may be: 
      • Macular
      • Papular
      • Vesicular
    • Not painful or pruritic
    • Locations:
      • Hands (palms)
      • Feet (soles)
      • Buttocks 
      • Legs
      • Arms
Hand foot and mouth disease presentation

An adult patient presenting with hand, foot, and mouth disease:
A: Oral enanthem
B and C: Exanthem on the hands and feet

Image: “A typical adult HFMD patient” by Department of Infectious Diseases, Centre for Gastroenterology and Hepatology, The First Affiliated Hospital of Jiaxing College, 1882 Central-South Road, Jiaxing 314001, Zhejiang Province, People’s Republic of China. License: CC BY 4.0

Other manifestations

Table: Additional presentations of coxsackievirus infections
Condition Coxsackie group Signs and symptoms
Acute hemorrhagic conjunctivitis A
  • Lid edema
  • Pain
  • Photophobia
  • Subconjunctival hemorrhage
Epidemic pleurodynia (Bornholm disease) B
  • Sudden, sharp, paroxysmal chest pain
  • Truncal muscle tenderness
  • Fever
  • Headache
  • Fatigue
Myocarditis B
  • Flu-like symptoms
  • Dyspnea
  • Chest pain
  • Fatigue
Neonatal disease B
  • Fever
  • Lethargy
  • Respiratory distress
  • Encephalitis
  • Hepatitis
  • Myocarditis (heart failure)
Exanthem A and B
  • Maculopapular
  • Morbilliform
  • Petechiae
  • Purpura
  • Urticarial appearance
Aseptic meningitis A and B
  • Fever
  • Headache
  • Nuchal rigidity
  • Rash
Encephalitis A and B
  • Lethargy
  • Personality changes
  • Paresis
  • Seizures
  • Coma
Flu-like symptoms A and B
  • Fever
  • Malaise
  • Cough
  • Headache
  • Pharyngitis
  • Congestion

Diagnosis and Management

Diagnosis

The diagnosis is usually made clinically. The following may be performed if the diagnosis is uncertain or in the case of severe disease:

  • Viral culture
  • PCR
  • Serology has limited value.

Management

Most coxsackievirus infections are self-limiting, and management is largely supportive. 

  • Analgesics for pain:
    • NSAIDs
    • Acetaminophen
  • Unproven therapeutic options for severe disease or immunocompromised patients:
    • IV immunoglobulin (IVIG)
    • Pleconaril: 
      • Antiviral
      • Rarely used
      • Not FDA approved

Prevention

  • Minimize contact with infected individuals.
  • Handwashing

Comparison of Enteroviruses

The following table summarizes the characteristics and diseases associated with different enteroviruses:

Table: Comparison of enteroviruses
Virus Coxsackievirus Poliovirus Echovirus
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
  • URI
  • Herpangina
  • HFMD
  • Aseptic meningitis
  • Myopericarditis
  • Epidemic pleurodynia
  • Neonatal infection
  • Flu-like illness
  • Aseptic meningitis
  • Asymmetric flaccid paralysis
  • Bulbar involvement
  • URI
  • Exanthem
  • Aseptic meningitis
  • Encephalitis
  • Myopericarditis
  • Neonatal infection
Diagnosis
  • Clinical
  • PCR
  • Viral culture
  • Clinical
  • PCR
  • Serology
  • Viral culture
  • Clinical
  • PCR
  • Viral culture
Management Supportive Supportive Supportive
Prevention Handwashing Vaccination Handwashing
HFMD: hand, foot, and mouth disease
URI: upper respiratory tract infection

Differential Diagnosis

  • Respiratory syncytial virus infection: an infection of the lower respiratory tract caused by an enveloped ssRNA virus. The 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 the rhinovirus is inactivated by gastric acid, it can only affect the nasal mucosa and conjunctiva and cause edema of 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, which is characterized by fever, fatigue, lymphadenopathy, and pharyngitis. Complications can include viral meningitis 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 of aseptic meningitis, CSF analysis will show a turbid fluid having low glucose levels and a high WBC count with neutrophil predominance. Gram stain and culture are used to identify the causative bacteria. Treatment includes antibiotics and corticosteroids.
  • Adenovirus infection: an infection caused by a non-enveloped double-stranded DNA virus, which typically causes mild respiratory infections, though conjunctivitis, atypical pneumonia, gastroenteritis, meningoencephalitis, and myocarditis can also occur. The diagnosis is typically clinical, but PCR testing may be performed for severe disease. Management is supportive.
  • West Nile virus infection: an infection caused by Flavivirus. The majority of patients will be asymptomatic or have headaches, myalgias and arthralgias, vomiting, diarrhea, or a rash. Some patients develop encephalitis, meningitis, or flaccid paralysis. The diagnosis can be made with serology, PCR, and viral cultures. 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. 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. Diagnosis is made using PCR. Treatment of both diseases is with doxycycline.

References

  1. Woodland, D.L. (2019). Hand, foot, and mouth disease. Viral Immunol. 32(4):159. https://www.ncbi.nlm.nih.gov/pubmed/31038400
  2. Zhu, L., Yin, H., Sun, H., Qian, T., Zhu, J., Qi, G., Wang, Y., Qi, B. (2019). The clinical value of aquaporin-4 in children with hand, foot, and mouth disease and the effect of magnesium sulfate on its expression: A prospective randomized clinical trial. Eur J Clin Microbiol Infect Dis. 38(7):1343–1349. https://www.ncbi.nlm.nih.gov/pubmed/31028503
  3. Wu, C.Y., Lin, F.L. (2019). Hand-foot-and-mouth-disease-induced Koebner phenomenon in psoriasis. J Dtsch Dermatol Ges. 17(5):549–551. https://www.ncbi.nlm.nih.gov/pubmed/30994243
  4. Muzumdar, S., Rothe, M.J., Grant-Kels, J.M. (2019). The rash with maculopapules and fever in children. Clin Dermatol. Mar-Apr 37(2):119–128. https://www.ncbi.nlm.nih.gov/pubmed/30981292
  5. Schiff, G.M., Sherwood, J.R. (2000). Clinical activity of pleconaril in an experimentally induced coxsackievirus A21 respiratory infection. J Infect Dis. 181(1):20–26. http://reference.medscape.com/medline/abstract/10608746
  6. Muehlenbachs, A., Bhatnagar, J., Zaki, S.R. (2015). Tissue tropism, pathology and pathogenesis of enterovirus infection. J Pathol. 11. http://reference.medscape.com/medline/abstract/25211036
  7. Romero, J.R. (2020). Hand, foot, and mouth disease and herpangina. In Torchia, M.M. (Ed.), UpToDate. Retrieved April 27, 2021, from https://www.uptodate.com/contents/hand-foot-and-mouth-disease-and-herpangina
  8. 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
  9.  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
  10. Tesinin, B.L. (2019). Epidemic pleurodynia. [online] MSD Manual Professional Version. Retrieved April 27, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/enteroviruses/epidemic-pleurodynia
  11. Muller, M.L. (2019). Coxsackieviruses. In Bronze, M.S. (Ed.), Medscape. Retrieved April 27, 2021, from https://emedicine.medscape.com/article/215241-overview
  12. Guerra, A.M., Orille, E., Waseem, M. (2021). Hand foot and mouth disease. [online] StatPearls. Retrieved April 27, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK431082/
  13. Tariq, N., Kyriakopoulos, C. (2020). Group B coxsackie virus. [online] StatPearls. Retrieved April 27, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK560783/

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