Adenovirus

Adenovirus (member of the family Adenoviridae) is a nonenveloped, double-stranded DNA virus. Adenovirus is transmitted in a variety of ways, and it can have various presentations based on the site of entry. Presentation can include febrile pharyngitis, conjunctivitis, acute respiratory disease, atypical pneumonia, and gastroenteritis. Severe manifestations include acute hemorrhagic cystitis, hepatitis, myocarditis, and disseminated infection. The diagnosis is confirmed with PCR and antigen testing. Most infections are self-limited, so management is generally supportive. Antiviral therapy is reserved for immunocompromised patients and severe infections.

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Classification

DNA virus classification flowchart

Identification of DNA viruses:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. Viruses with a DNA genome can be further characterized as single or double stranded. “Enveloped” viruses are covered by a thin coat of cell membrane, which is usually taken from the host cell. If the coat is absent, however, the viruses are called “naked” viruses. Some enveloped viruses translate DNA into RNA before incorporating into the genome of the host cell.

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General Characteristics and Epidemiology

Basic features of adenovirus

  • Taxonomy:
    • Family: Adenoviridae
    • Genus: Mastadenovirus
  • DNA virus:
    • Double-stranded
    • Linear
  • Structure
    • Nonenveloped virus
    • Icosahedral capsid
    • Fiber-like projections from the vertices
  • Resistant to:
    • Acid
    • Detergent
    • Dry environment
  • Inactivated by:
    • Heat
    • Formaldehyde
    • Bleach

Clinically relevant species

  • 7 human adenovirus species (groups A–G)
  • > 50 serotypes

Epidemiology

  • Most common in infants and children  (cause up to 10% of febrile illnesses in this group)
  • No predilection for race
  • Increased incidence in spring and winter

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Pathogenesis

Reservoir

  • Humans
  • Mammals

Transmission

  • Contact with secretions from an infected person
  • Fomites
  • Waterborne (inadequately chlorinated swimming pools)
  • Aerosols
  • Fecal–oral

Host risk factors

The virus is most prevalent in:

  • Young children
  • Daycare centers
  • Military recruits

Viral replication cycle

  • Viral capsid fibers bind to the cell receptors or epithelial cells → endocytosis 
  • Leaves endosome → viral DNA enters the cell nucleus → transcription and replication
  • Translation and viral structural protein synthesis occurs in cytoplasm
  • Packaging → new virions released from host cell
  • During the replication process, the virus inhibits suppression of cell growth.

Pathophysiology

The site of entry generally dictates the type of infection; 2 processes can occur:

  • Lytic infection:
    • Virus replicates in host epithelial cells → cell lysis
    • Inflammatory response → clinical manifestations
  • Latent infection:
    • Mechanism not completely understood
    • Virus infects lymphoid tissue (e.g., tonsils) → asymptomatic
    • Can be reactivated (e.g., immunocompromised state) → viremia → systemic infection
Diagram pathogenesis of adenovirus infection

Diagram summarizing the pathogenesis of adenovirus infection
RB: retinoblastoma

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Clinical Presentation

Most adenovirus infections are asymptomatic. The infections with clinically apparent disease may present with the following conditions:

Table: Symptomatic adenovirus infections
DiseaseIncubationPopulation at riskClinical Presentation
Febrile pharyngitis 4–9 days Children (< 3 years)
  • Fever
  • Sore throat
  • Cough
  • Coryza
  • Mimics streptococcal infection
  • Otitis media is common.
Acute respiratory disease Military recruits
  • Fever
  • Cough
  • Sore throat
  • Rhinorrhea
  • Cervical adenitis
Conjunctivitis Older children and adults
  • Pharyngitis symptoms
  • Inflamed conjunctiva
  • Sparse mucus discharge
  • Preauricular lymphadenopathy
  • Keratitis in adults
Atypical pneumonia 10–14 days Children and adults
  • Fever
  • Nonproductive cough
  • Dyspnea
  • Diffuse patchy inflammation (interstitial pneumonia)
  • Involves ≥ 1 lobe (often diffuse)
Gastroenteritis 3–10 days Infants and young children
  • Watery diarrhea
  • Vomiting
  • May cause intussusception
Appendicitis < 10 days Children Lymphoid hyperplasia compromises blood supply → inflammation

Rare manifestations

  • Hepatitis
  • Acute hemorrhagic cystitis
  • Meningitis and encephalitis
  • Myocarditis
  • Disseminated disease (associated with ↑↑ mortality)

Diagnosis and Management

Diagnosis

The following can be used to confirm the diagnosis:

  • PCR to detect adenovirus DNA
    • Sensitive and specific
    • Can be performed on a variety of specimens
  • Antigen tests 
    • Rapid
    • Less sensitive
    • Options:
      • Direct fluorescent antigen
      • Enzyme immunoassay
  • Viral culture
  • Serology

Management

Adenovirus infections are generally self-limited, so in the majority of cases management is supportive. 

  • Hydration
  • Rest
  • Antiviral therapy (varying efficacy)
    • Indicated for:
      • Immunocompromised patients
      • Severe infection
    • Options:
      • Cidofovir
      • Ribavirin

Prevention

  • Avoid infected individuals.
  • Handwashing
  • Clean surfaces.
  • Chlorination of swimming pools
  • A live oral vaccine:
    • Targets adenovirus types 4 and 7
    • Only for military personnel

Comparisons of Clinically Similar Viruses

The following table compares and contrasts viruses with similar clinical presentations:

Table: Comparison of adenovirus, rhinovirus, and respiratory syncytial virus
VirusAdenovirusRhinovirusRespiratory syncytial virus
Family Adenoviridae Picornaviridae Paramyxoviridae
Characteristics
  • Double-stranded
  • DNA virus
  • Nonenveloped
  • Icosahedral capsid
  • Single-stranded, positive-sense
  • RNA virus
  • Nonenveloped
  • Icosahedral capsid
  • Single-stranded
  • Negative-sense
  • RNA virus
  • Enveloped
  • Helical capsid
Transmission
  • Aerosols
  • Direct contact
  • Fomites
  • Aerosols
  • Direct contact
  • Fomites
  • Aerosols
  • Direct contact
Clinical
  • Upper and lower respiratory infections
  • Otitis media
  • Conjunctivitis
  • Gastroenteritis
  • Upper and lower respiratory infections
  • Otitis media
  • Upper and lower respiratory tract infections
  • Otitis media
Diagnosis
  • Clinical
  • PCR
  • Antigen testing
  • Clinical
  • PCR
  • Clinical
  • PCR
  • Antigen testing
Management Supportive
Prevention
  • Avoid affected individuals.
  • Handwashing
  • Oral live vaccine
  • Avoid affected individuals.
  • Handwashing
  • Avoid infected individuals.
  • Handwashing
  • Palivizumab for high-risk infants

Differential Diagnosis

  • Bacterial pharyngitis: infection of the pharynx. Patients typically experience a sore throat and fever. Diagnosis can include rapid streptococcal screening to detect group A Streptococcus and bacterial cultures. Treatment includes penicillin or amoxicillin.  
  • Bacterial pneumonia: infection of the lung parenchyma. Patients present with fever, dyspnea, and a productive cough. Chest X-ray findings usually show lobar consolidation; however, multifocal infiltrates can be seen in some cases. Management usually involves empiric antibiotics, which can be tailored if the causative organism is identified.  
  • Pertussis: infectious disease caused by Bordetella pertussis. Patients initially have mild cough, fever, coryza, sneezing, and conjunctivitis. This progresses to the characteristic, intense cough followed by a whooping sound on inspiration. Diagnosis is confirmed by PCR or culture. Macrolides are used for treatment.

References

  1. Vora GJ, Lin B, Gratwick K, et al. (2006). Co-infections of adenovirus species in previously vaccinated patients. Emerg Infect Dis 12:921–930.
  2. Echavarría M. (2008). Adenoviruses in immunocompromised hosts. Clin Microbiol Rev 21:704–715. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570151/
  3. Ghebremedhin B. (2014). Human adenovirus: viral pathogen with increasing importance. Eur J Microbiol Immunol (Bp), 4(1):26–33. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955829/
  4. Zhao S, Wan C, Ke C, et al. (2014). Re-emergent human adenovirus genome type 7d caused an acute respiratory disease outbreak in Southern China after a twenty-one-year absence. Sci Rep 4(4):7365. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258649/
  5. Kajon AE, Lu X, Erdman DD, et al. (2010). Molecular epidemiology and a brief history of emerging adenovirus 14-associated respiratory disease in the United States. J Infect Dis 202(1):93–103. https://pubmed.ncbi.nlm.nih.gov/20500088/
  6. Flomenberg, P., Kojaoghlanian, T. (2021). Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection. UpToDate. Retrieved May 27, 2021, from https://www.uptodate.com/contents/pathogenesis-epidemiology-and-clinical-manifestations-of-adenovirus-infection
  7. Munoz, F.M., and Flomenberg, P. (2020). Diagnosis, treatment, and prevention of adenovirus infection. UpToDate. Retrieved May 27, 2021, from https://www.uptodate.com/contents/diagnosis-treatment-and-prevention-of-adenovirus-infection
  8. Tesini, B.L. (2021). Adenovirus infection. MSD Manual Professional Version. Retrieved May 27, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/respiratory-viruses/adenovirus-infections
  9. Doerfler, W. (1996). Adenoviruses. Chapter 67 of Baron, S. (Ed.), Medical Microbiology, 4th ed. University of Texas Medical Branch at Galveston. https://www.ncbi.nlm.nih.gov/books/NBK8503/
  10. Gompf, S.G., Cornelius, T. (2021). Adenovirus. Medscape. Retrieved May 27, 2021, from https://emedicine.medscape.com/article/211738-overview

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