Cytomegalovirus

Background

Microbiology

• 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

Epidemiology

• 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

Pathophysiology

• 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

Children

• 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

• Most common implicated medications include cyclophosphamide, MMF, and azathioprine
• Highest-risk medications include alemtuzumab, fludarabine, and 2-chlorodeoxyadenose (CDA)
• Others include OKT3 antiserum and ATG
• Unmatched transplant, transplant rejection, GVHD, umbilical cord blood transplantation are also risk factors
• Neither prednisone nor tacrolimus appears to cause reactivation

Congenital CMV

• See congenital CMV

Complications

• 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

Investigations

• 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

Diagnosis

• 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

Management

Antivirals

• First-line: valganciclovir or ganciclovir
  • Measure baseline CBC first due to risk of cytopenias
• Second-line, if cytopenias: foscarnet
• Third-line: cidofovir, maribavir, letermovir
• New or experimental: maribavir, brincidofovir, and letermovir

Duration

• 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)

Resistance

• See antiviral resistance in CMV
• Antiviral resistance in CMV is uncommon
• Mutations in UL97 are uncommon and confer resistance to ganciclovir and valganciclovir
• Mutations in UL54 are rare and confer resistance to ganciclovir, foscarnet, and cidofovir

Prevention

Transplantation

• 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