Background Microbiology A dsDNA virus and the largest member of the human herpesvirus 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 2 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 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 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 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 >38ÂșC 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
Can cause esophagitis and colitis
Rarely, pancreatitis and cholecystitis Other Immunosuppression 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
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
IgM >300 U/mL can help diagnose acute infection 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 diagnosisViral culture can be done with human fibroblast cells, but is slowManagement Antivirals Duration Depends on the clinical site of infection, which urually resolves over several weeks
In transplant patients, viremia is treated until negative viral load (not just undetectable) Resistance 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+/Recipientâ high risk, with the the donor organ infecting the recipient
Donorâ/Recipient+ intermediate risk
Donor+/Recipient+ intermediate risk
Donorâ/Recipientâ 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+/Recipientâ intermediate risk
Donorâ/Recipientâ 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 References
^ 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 . ^ 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 .
