Cytomegalovirus
From IDWiki
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
- 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
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
Clinical Manifestations
Children
- Often asymptomatic when young
Infectious mononucleosis syndrome
- 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 >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
- 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
- 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 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 urually resolves over several weeks
- In transplant patients, viremia is treated until negative viral load (not just undetectable)
Resistance
- Consider resistance if CMV DNA titres not decreasing despite appropriate treatment
- Resistance genotyping available to help distinguish resistance from refractory
- UL97: resistance to ganciclovir, but not cidofovir or foscarnet
- UL54: resistance to ganciclovir ± foscarnet ± cidofovir
- UL56: resistance to letermovir
Prevention of disease in transplant patients
- 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
Complications
- Even when dormant, can cause mild immunosuppression that predisposes to fungal infections
- Asymptomatic shedding in lungs during intercurrent illness
- Viremia with influenza-like illness
- End-orgam damage
- CMV colitis
- Retinitis in AIDS patient (CD4 < 50-100)
- Organ inflammation of solid-organ transplants
- Pneumonitis in stem cell transplants
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.