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  • A dsDNA virus and the largest member of the Herpesviridae family
  • DNA in the nucleoprotein core is embedded in matrix proteins and pp65 antigen, which is surrounded by lipid envelope
  • UL54 encodes DNA polymerase and is highly conserved
  • UL97 encodes a tyrosine kinase required to phosphorylate (and therefore activate) ganciclovir
  • May have four genotypes

Antiviral Resistance

  • See antiviral resistance in CMV
  • Inherent acyclovir resistance
  • Tyrosine kinase mutation UL97 confers resistance to (val)ganciclovir
  • Polymerase mutation UL54 confers resistance to (val)ganciclovir and to foscarnet


  • Transferred by droplets and blood transfusions (though less now that we leukoreduce donor blood)
  • 50 to 80% of people are CMV-IgG seropositive
    • Increases with age
    • Higher in poor countries1 and First Nations2


  • Persists in CD34-positive cells, including monocytes and other tissues
  • Immunomodulatory
    • Downregulates HLA in T cells, which predisposes to bacterial and fungal infections
    • Increased risk of transplant rejection
    • Increased risk of atherosclerosis

Risk Factors

  • Crowding
  • Immunosuppression; refer to specific scenarios below

Clinical Manifestations


  • Often asymptomatic when young

Infectious Mononucleosis

  • CMV causes 21% of IM
  • Fever, lymphadenopathy, and lymphocytosis
  • Often mild liver abnormalities
  • Occasionally cold agglutinin disease, RF positivity, cryoglobulinemia, and ANA positivity
  • Symptoms can persist or relapse over months (average 2 months, but up to 8)

Asymptomatic Viremia

  • May have asymptomatic viremia with any intercurrent illness, of no significance

Immunodeficient Patients

Stem Cell Transplantation

  • See also CMV after hematopoietic stem cell transplantation
  • Low risk until day 21 post-transplantation, when cell lines begin to return, up to about 120 days
  • May present as asymptomatic viremia
  • Most common symptomatic presentation is pneumonitis (an interstitial pneumonia), which has high mortality
    • Onset over less than 2 weeks, with fever, non-productive cough, and dyspnea
    • More common with GVHD
  • Can also present with GI involvement

Solid Organ Transplantation

  • See also CMV after solid organ transplantation
  • Tends to reactivate within the transplanted organ (lungs, liver, kidney)
  • However, all can have colitis
  • The CMV syndrome is another non-specific manifestation that requires viremia plus two of:
    • Fever >38ºC for >2 days
    • New or worsened fatigue or malaise
    • Leukopenia or neutropenia
    • >5% reactive lymphocytes
    • Thrombocytopenia <100,000 (or <20% of initial platelet count if it was <115,000)
    • Elevated transaminases

Advanced HIV

  • Coinfection is common, with 90% CMV seropositivity in HIV-positive men
  • Advanced HIV disease carries increased risk of severe CMV disease
  • CMV retinitis is the most common form in AIDS
    • Classic white fluffy retinal infiltrate with areas of hemorrhage
  • Can cause polyradiculopathy and myopathy, with back pain and subacute flaccid paralysis
    • CSF will be abnormal
  • Can cause esophagitis and colitis
  • Rarely, pancreatitis and cholecystitis

Other Immunosuppression

Congenital CMV


  • Pneumonitis, most common in HSCT and lung transplant
    • Can cause an interstitial pneumonia
    • Severe in SCT patients, mild in mononucleosis patients
  • Hepatitis, most common in liver transplant
    • Usually mild
    • Can include granulomatous hepatitis in the context of mononucleosis
  • Guillain-Barré syndrome
    • Sensory and motor palsies in the extremities and cranial nerves
    • Resolves over months
  • Meningoencephalitis
    • Headache, photophobia, lethargy, and pyramidal tract dysfunction
    • May have concurrent motor and sensory palsies
  • Myocarditis
    • Rare
  • Thrombocytopenia and hemolytic anemia
    • Common in congenital infection, and occasionally seen in adults
  • Rashes
    • Can cause maculopapular or rubelliform rashes following treatment with amipicillin
  • Colitis, in anyone, including older age
    • Symptoms include diarrhea, often fever, and occasionally hematochezia
    • On sigmoidoscopy, has plaque-like pseudomembranes, serpiginous ulcers, and erosions
    • Can occasionally present with a mass lesion that can cause partial obstruction


  • CBC showing leukopenia or pancytopenia
  • Mild elevation in liver enzymes
  • CMV-IgG positive
  • Detectable CMV DNA in peripheral blood, though it can rise during intercurrent illness


  • Serology
    • IgG
      • Useful for prior exposure (suggesting latent infection)
      • IgG avidity can confirm recent infection (avidity increases with time since primary infection)
    • IgM
      • >300 U/mL can help diagnose acute infection
      • Usually positive by 6 weeks after primary infection, but can remain positive for as long as 12 months
      • False positives, including from rheumatoid factor, EBV infection, lupus
IgG IgM Avidity Interpretation
+ N/A past infection, low risk for congenital infection
+ + high past infection, low risk for congenital infection
+ + low primary maternal infection within the past 3 months
N/A either no infection, or repeat in 4 weeks

  • Quantitative PCR is most useful for diagnosis and monitoring response to treatment
    • Can be done on blood, BAL, urine, saliva, etc.
    • Standards for reporting are defined by WHO, but results are still lab-specific
    • Can be undetectable, less than lab cutoff, or quantified in IU/mL
    • However, can shed CMV asymptomatically during an acute illness, so must be taken within the clinical context
    • Sensitivity/specificity for CMV disease depends on the laboratory methods and cutoff used
  • Microscopy of tissue biopsy or cytology may demonstrate large nuclear inclusions, and can use immunofluorescence to pp65 antigen to confirm diagnosis
  • Viral culture can be done with human fibroblast cells, but is slow




  • Depends on the clinical site of infection, which usually resolves over several weeks
  • In transplant patients, viremia is treated until negative viral load (not just undetectable)




  • See also CMV after solid organ transplantation and CMV after hematopoietic stem cell transplantation
  • Risk of reactivation is determined by the specific transplantation and the donor/recipient serostatus
  • Asymptomatic viremia precedes CMV disease by about a week
  • Solid organ transplant
    • Donor+/Recipient– high risk, with the the donor organ infecting the recipient
    • Donor–/Recipient+ intermediate risk
    • Donor+/Recipient+ intermediate risk
    • Donor–/Recipient– lowest risk
    • High and intermediate risk patients get prophylaxis with valganciclovir 900 mg po bid for about 6 months
  • Hematologic stem cell transplant
    • Donor±/Recipient+ high risk
    • Donor+/Recipient– intermediate risk
    • Donor–/Recipient– lowest risk
    • Preemptive monitoring with weekly CMV DNA PCR starting week 2 or 3
      • Treat if greater than threshold (1451 at McMaster) or if rising titre with symptoms
      • Expect 1-log drop within 2 weeks (lab-dependent)
      • Continue treatment until PCR is negative


  1. ^  Michael J. Cannon, D. Scott Schmid, Terri B. Hyde. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Reviews in Medical Virology. 2010;20(4):202-213. doi:10.1002/rmv.655.
  2. ^  Jutta K. Preiksaitis, R. P. Bryce Larke, Glory J. Froese. Comparative seroepidemiology of cytomegalovirus infection in the Canadian Arctic and an Urban center. Journal of Medical Virology. 1988;24(3):299-307. doi:10.1002/jmv.1890240307.