Cytomegalovirus

CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. After the primary infection, the virus becomes latent. Reactivation can occur in immunocompromised individuals, leading to conditions such as CMV esophagitis, colitis, hepatitis, retinitis, encephalitis, and pneumonia.

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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.

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

General Characteristics and Epidemiology

Basic features of CMV

  • Also known as HHV-5
  • Taxonomy:
    • Family: Herpesviridae
    • Subfamily: Betaherpesvirinae
    • Genus:  Cytomegalovirus
  • DNA virus:
    • Double-stranded
    • Linear
  • Structure:
    • DNA core
    • Icosahedral nucleocapsid
    • Tegument
    • Phospholipid envelope with glycoprotein spikes

Epidemiology

  • Approximately 60%–90% of adults have CMV antibodies (lifelong latent infection).
  • Prevalence increases with age.
  • Ethnicity: higher prevalence in non-Hispanic Black Americans and Mexican Americans
  • Higher positivity rates also associated with:
    • Female sex
    • Birthplace outside the United States
    • Low household income and education
    • Household crowding

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Pathogenesis

Reservoir

The CMV strain associated with human infection is found only in humans.

Transmission

  • Contact with infected bodily fluids 
  • Sexual contact
  • Blood transfusion
  • Organ transplantation
  • Perinatal
    • In utero (during maternal viremia)
    • During birth (from contact with vaginal secretions)
    • Breast milk 
  • Occupational exposure

Host risk factors

Immunocompromised patients are at increased risk of morbidity and mortality from CMV.

  • HIV/AIDS
  • Transplant patients

Viral replication cycle

  • Viral glycoproteins attach to host cell receptors → endocytosis or fusion with cell membrane (unclear)
  • Capsid transported to the nuclear pore → DNA released into the nucleus
  • Transcription and replication → viral assembly
  • Budding through the nuclear membrane → assembly with tegument proteins 
  • Acquires envelope → released from cell

Pathophysiology

Pathogenesis Cytomegalovirus

Pathogenesis of CMV

Image by Lecturio. License: CC BY-NC-SA 4.0
  • Virus infects oral epithelial cells → viral replication → cytomegalic cells with owl’s eye nuclear inclusions
  • Cell-mediated response ensues (most important for controlling CMV infection) → virus become latent in:
    • Myeloid progenitor cells in the bone marrow
    • Monocytes
    • Macrophages
    • Lymphocytes
  • Immunocompromised state → reactivation can occur → viremia → clinical manifestations

Pathology

Cells infected with CMV will:

  • Enlarge
  • Contain viral inclusion bodies (owl’s eye).

Diseases caused by CMV

The spectrum of clinical presentations with CMV is diverse and depends on the immune status of the host.

CMV mononucleosis

Most immunocompetent patients will be asymptomatic. In the minority who are symptomatic, the most common presentation is a syndrome similar to infectious mononucleosis (EBV).

  • Clinical presentation:
    • Fever
    • Malaise
    • Headache
    • Myalgias and arthralgias
    • Erythematous, maculopapular rash in patients exposed to beta-lactam antibiotics
    • Less common:
      • Pharyngitis
      • Lymphadenopathy
      • Hepatosplenomegaly
  • Diagnosis:
    • Lymphocytosis with atypical lymphocytes
    • Negative heterophile (monospot test)
    • Serology for CMV antibodies
    • PCR for CMV DNA
  • Management: Most cases are self-limited and do not require antiviral therapy.

Congenital CMV

Congenital CMV is one of the perinatal TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes simplex) infections.

  • Most infants with congenital CMV infection are asymptomatic at birth.
  • Symptomatic infants present with:
    • Petechial rash
    • Chorioretinitis
    • Jaundice
    • Hepatosplenomegaly
    • Intrauterine growth restriction
    • Microcephaly
    • Hypotonia
    • Sensorineural hearing loss
Cytomegalovirus infection

MRI of an infant with congenital Cytomegalovirus demonstrating periventricular calcifications, ventriculomegaly, and cerebellar hypoplasia

Image: “Axial computed tomography (CT) image” by Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD USA. License: CC BY 4.0

Opportunistic infections

The following are rare in immunocompetent hosts and are often the result of reactivation of a latent infection. Note: Infections outside the lymph nodes, spleen, and liver are considered AIDS-defining conditions. 

  • GI manifestations:
    • Esophagitis
    • Colitis
    • Hepatitis
    • Pancreatitis
  • Neurologic manifestations:
    • Encephalitis
    • Guillain-Barré syndrome
  • Ocular manifestations: 
    • Retinitis
  • Cardiopulmonary manifestations:
    • Pneumonia
    • Pericarditis
    • Myocarditis
CMV retinitis

Fundoscopic image of CMV retinitis

Image: “Fundus photograph-CMV retinitis” by National Eye Institute. License: Public Domain

Comparison of Herpesviruses

The following table compares the 9 herpesviruses considered endemic in humans; there are 115 known species of herpesviruses, grouped into 3 families: 

  • Alpha (infect epithelial cells and produce latent infection in postmitotic neurons)
  • Beta (infect and produce latent infection in a variety of cell types)
  • Gamma (produce latent infection mainly in lymphoid cells)
Table: Comparison of the 9 herpesviruses considered endemic in humans
HHVCommon namePrimary target cellsLatency siteClinical presentation*
1
(alpha group)
HSV-1 Mucoepithelial cells Dorsal root ganglia
  • Gingivostomatitis
  • Keratitis
  • Herpetic whitlow
  • Encephalitis
  • Hepatitis
  • Esophagitis
  • Pneumonitis
2
(alpha group)
HSV-2
  • Genital herpes
  • Meningitis
  • Proctitis
3
(alpha group)
VZV
  • Chickenpox
  • Herpes zoster
4
(gamma group)
EBV Epithelial cells B cells Memory B cells
  • Infectious mononucleosis
  • Hodgkin lymphoma
  • Burkitt lymphoma
  • Oral hairy leukoplakia
  • EBV-associated gastric cancer
5
(beta group)
CMV
  • Monocytes
  • Lymphocytes
  • Epithelial cells
Hematopoietic progenitor cells in bone marrow
  • CMV mononucleosis
  • CMV retinitis
  • CMV colitis
  • CMV encephalitis
6A, 6B
(beta group)
HHV-6 T cells Monocytes Roseola
7
(beta group)
HHV-7 T cells
8
(gamma group)
Kaposi’s sarcoma–associated herpesvirus
  • Lymphocytes
  • Epithelial cells
B cellsKaposi’s sarcoma
* Bold in “clinical presentation” column: AIDS-defining illness
VZV: varicella-zoster virus

References

  1. Friel, T.J. (2021).  Epidemiology, clinical manifestations, and treatment of cytomegalovirus infections in immunocompetent adults. UpToDate. Retrieved May 26, 2021, from https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-treatment-of-cytomegalovirus-infection-in-immunocompetent-adults
  2. Caliendo, A.M. (2020).  Overview of diagnostic tests for cytomegalovirus infection. UpToDate. Retrieved May 26, 2021, from https://www.uptodate.com/contents/overview-of-diagnostic-tests-for-cytomegalovirus-infection
  3. Demmler-Harrison, G.J.  (2021). Congenital cytomegalovirus infection: clinical features and diagnosis. UpToDate. Retrieved May 26, 2021, from https://www.uptodate.com/contents/congenital-cytomegalovirus-infection-clinical-features-and-diagnosis
  4. Kaye, K.M. (2019). Cytomegalovirus (CMV) infection. MSD Manual Professional Version. Retrieved May 30, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/herpesviruses/cytomegalovirus-cmv-infection
  5. Gupta, M., Shorman, M. (2020). Cytomegalovirus. StatPearls. Retrieved May 30, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK459185/
  6. Akhter, K., Wills, T.S. (2018). Cytomegalovirus. In Bronze, M.S. (Ed.), Medscape. Retrieved May 30, 2021, from https://emedicine.medscape.com/article/215702-overview
  7. Jean Beltram, P.M., Cristea, I.M. (2014). The life cycle and pathogenesis of human cytomegalovirus infection: lessons and proteomics. Expert Rev Proteomics 11:697–711. https://www.tandfonline.com/doi/full/10.1586/14789450.2014.971116

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