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35 Cards in this Set
- Front
- Back
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What is Cytomegalovirus (CMV)?
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* Member of the family Herpesviridae
* Large, double-stranded DNA virus - Largest virus known to infect humans * Virus consists of: - Capsid containing genetic material - “Tegument” or matrix (slime layer) between capsule and envelope, consisting of an amorphous mass of various virus-encoded proteins - Envelope containing viral glycoproteins and lipids originally derived from the host cellular membrane |
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How is CMV spread?
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Human to human
No animal reservoir |
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What is the prevalence of CMV?
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* Primary infection eventually occurs in nearly all adults
- 35 to 40% seropositive by age 25-30 - 80 to 100% seropositive by age 60 * Worldwide distribution, affects all ethnic and socioeconomic groups |
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How does the primary infection usually occur?
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Primary infection usually occurs:
* NEWBORN: through vertical transmission from mother * CHILDREN & TODDLERS, or in YOUNG ADULTS: from kissing or sexual contact |
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How does CMV enter the body?
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* Virus enters body through epithelial lining of respiratory, GI, or GU tracts
- Hematogenous infection may occur through blood & blood products - Transplantation of infected bone marrow or solid organs from seropositive donors especially important |
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Where does CMV establish latency?
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* myeloid progenitor cells
* epithelial cells of solid organs * circulating monocytes |
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T or F
Immunocompetant patients do not normally experience reactivation of CMV? |
FALSE
Reactivation common in immunocompetent persons - Shedding of CMV in saliva, urine, cervical secretions, semen, breast milk |
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Where is severe disease usually seen clinically?
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More severe clinical syndromes (“disease”) usually seen in immunocompromised hosts
* May be associated with either primary infection or reactivation * Premature infants: fever, pneumonia, GI disease, hepatitis * Cancer patients, organ transplant recipients, AIDS: viremia, pneumonia, retinitis, colitis, esophagitis, hepatitis, encephalitis, leukopenia, adrenalitis, severe oral ulcers |
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How does CMV infection present in immunocompetent patients?
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* Primary infection in immunocompetent children or adults usually results in subclinical or very mild, nonspecific clinical infection
* More severe clinical manifestations in older adults * Second most common cause of mononucleosis (after EBV) |
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CMV Retinitis
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* Retinal involvement is a severe complication seen almost exclusively in AIDS patients
* Progressive, irreversible disease characterized by severe retinal inflammation, retinal hemorrhage & necrosis, visual defects, retinal detachment, partial or total blindness |
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Prior to the advent of _______, 21 - 44% of patients with AIDS developed CMV disease
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HAART therapy
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What is the most common manifestation of CMV in ADIS patients?
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85% = CMV retinitis
* Especially common with CD4+ lymphocyte counts <50 cells/L * Introduction of HAART reduced incidence of retinitis by 50% to 90% |
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Risk of CMV Disease in Organ Transplant Patients
D-, R- |
LOW
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Risk of CMV Disease in Organ Transplant Patients
D-, R+ |
Moderate-High risk of reactivation of the recipients own CMV
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Risk of CMV Disease in Organ Transplant Patients
D+, R- |
Moderate-High risk of the recipient developing a primary CMV infection
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Risk of CMV Disease in Organ Transplant Patients
D+, R+ |
Very High risk of both reactivation and primary infection with different strain
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Direct Consequences of CMV Infection in Organ Transplant Recipients
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Viral syndromes
Involvement of grafted organ Invasive complications |
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Indirect Consequences of CMV Infection in Organ Transplant Recipients
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Further immunosuppression
Increased incidence of bacterial, fungal other opportunistic infections Risk factor for acute rejection and chronic graft dysfunction Increased atherosclerotic complications in heart recipients Decreased graft survival rates Increased morbidity and mortality Increased healthcare expenses |
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How is CMV Infection/Disease diagnosed?
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* Serologic assays
+ IgG indicates past infection + IgM in previously seronegative individual indicates recent infection * Culture from blood, urine, BAL fluid * Immunoassay = monoclonal antibody against pp65 matrix protein * Quantitative PCR of DNA or RNA - Highly sensitive and specific, has become diagnostic method of choice * Tissue pathology * Clinical signs/symptoms |
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Antiviral Agents for CMV Infections
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* Ganciclovir (Cytovene)
* Valganciclovir * Ganciclovir Intraocular Implants(Vitrasert) * Foscarnet (Foscavir) * Cidofovir (Vistide) * CMV Immune Globulin (CMVIG) |
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Pharmacology of Ganciclovir (Cytovene)
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* Guanine nucleoside analogue, closely related to acyclovir
* Converted to ganciclovir monophosphate by viral protein kinase enzyme (similar in function to thymidine kinase) coded by CMV-specific UL97 gene - Further phosphorylated to active drug by cellular guanosine monophosphate synthetase * Potent inhibitor of viral DNA polymerase * Resistance usually mediated by mutations in UL97 gene coding for protein kinase enzyme - Resistance rarely caused by point mutation in DNA polymerase - Resistance may occur in up to 10% of strains in some studies * Ganciclovir has excellent in vitro activity against CMV and other herpesviruses (e.g., HSV, VZV, EBV) |
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Pharmacokinetics Ganciclovir
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* Poor oral absorption (F = 3-6%)
* Valganciclovir increases oral bioavailability to 60-70% - Produces serum AUC similar to IV ganciclovir - Should be given with high-fat meal to maximize absorption * Good penetration into CNS, eyes, other tissues * Primarily excreted in urine as unchanged drug (>90%) through both filtration and active secretion * Plasma half-life = 2-4 hours - 28-40 hours in severe renal impairment - Intracellular half-life in CMV-infected cells is 16-18 hours * Sometimes administered by intravitreal injection, implants for treatment/suppression of CMV retinitis |
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Ganciclovir Intraocular Implants
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Delivers constant 1 g/hour for 6 months
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Ganciclovir Adverse Effects
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*Bone marrow suppression
-Leukopenia in ~40% of patients - Severe neutropenia (<500 cells/cc3) in ~20%, requires drug discontinuation - Thrombocytopenia in approximately 15% of patients - Anemia also common - Usually reversible upon drug discontinuation - May be prevented or reversed with use of G-CSF * Cutaneous: rash (5%) * GI (25-40%) = nausea, diarrhea * CNS = neuropathy, paresthesias in <10% of patients * Increased serum creatinine in 20% of patients, often transient, not usually considered true toxicity * Phlebitis * Carcinogenic and teratogenic * Intraocular implants: retinal detachment, hemorrhage, bacterial infection * Close monitoring of renal function and CBC is required during use of ganciclovir - Monitor all cell lines, although leukopenia most significant * Avoid use of other myelosuppressive drugs - Chemotherapy, high-dose TMP/SMX, AZT, etc. *Also interaction with probenecid (AUC ↑ >50%) |
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Pharmacology of Foscarnet (Foscavir)
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* Inorganic pyrophosphate compound
* Inhibits viral DNA polymerase through reversible competitive binding to pyrophosphate binding site of the enzyme - Does not require phosphorylation to active moiety - Retains activity against ganciclovir-resistant strains of CMV - Resistance occurs through point mutations in DNA polymerase |
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Pharmacokinetics of Foscarnet (Foscavir)
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Oral bioavailability 12% to 22%
80-90% elimination in urine as unchanged drug |
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Adverse effects of Foscarnet (Foscavir)
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- Nephrotoxicity (10-40%)
- Nephrogenic diabetes insipidus - Electrolyte abnormalities (esp. Ca2+) - Rash |
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Pharmacology of Cidofovir (Vistide)
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* Nucleotide cytosine analogue
* Does not require initial phosphorylation by viral kinases, but does require conversion to active diphosphate form - Cross-resistance to ganciclovir through polymerase mutations, not by UL97 mutations * Inhibits viral DNA polymerase |
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Pharmacokinetics of Cidofovir (Vistide)
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* Poor oral bioavailability, must be administered IV
* Very short plasma half-life with extraordinary renal tubular secretion * Administered with probenecid to reduce tubular secretion and increase half-life - 2 gms 3 hours prior, 1 gm at 2 and 8 hours after end of cidofovir infusion * Also sometimes administered by intravitreal injection for retinitis |
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Adverse effects of Cidofovir (Vistide)
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* Nephrotoxicity:
- Proteinuria, increased SCr, decreased CrCL in 30% to 60% of patients - Prior foscarnet exposure increases toxicity - Renal toxicities may be reduced by probenecid, saline loading prior to drug infusion * Neutropenia in ~25% of patients - G-CSF often used to prevent or manage occurrence * Ocular effects: - Uveitis, iritis (10%); may be treated with topical steroids - Decreased intraocular pressure (24%) * Headache (30%), peripheral neuropathy * Rash (25-30%), alopecia *Bicarbonate wasting through urine - Probably related to other renal toxicities |
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How are CMV disease manifestations treated?
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* All types of invasive CMV disease are largely treated the same
* Treatment of active infections are initially treated with “induction” doses to: - Rapidly achieve high tissue levels - Rapidly suppress viral replication - Produce complete healing of lesions * Long-term suppressive or “maintenance” regimens often used in patients at continued high risk, i.e. AIDS patients with very low CD4+ counts |
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Induction regimens for treatment of CMV
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* DOC: Ganciclovir 5 mg/kg IV Q12H x 14-21 days
* Alternative regimens: - Foscarnet 90 mg/kg IV Q12H x 14-21 days - Valganciclovir 900 mg PO BID x 21 days - Cidofovir 5 mg/kg IV (+ probenecid) once weekly x 2 consecutive weeks * Alternate regimens for retinitis: - Ganciclovir 400 g intravitreal injection 3x/week x 3 weeks - Ganciclovir ocular implant PLUS ganciclovir 5 mg/kg IV QD or valganciclovir 900 mg PO QD x 14-21 days * Induction regimens for colitis may be extended to 4-6 weeks * IV ganciclovir + IV foscarnet may be used in patients failing monotherapy, i.e. continued disease progression |
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Maintenance regimens for treatment of CMV
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* DOC: Valganciclovir 900 mg PO QD
* Alternative regimens: - Ganciclovir 5 mg/kg IV QD 5x/week - Foscarnet 90-120 mg/kg IV Q12H 5x/week - Ganciclovir ocular implant Q 6 months + valganciclovir 900 mg PO QD - Ganciclovir 400 g by intravitreal injection Q week - Cidofovir 5 mg/kg IV (+ probenecid) Q 2 weeks * Duration of maintenance regimen depends on level of immunosuppression (e.g. CD4+ count in AIDS patient, intensity of immunosupressive drug therapy in transplant patients) |
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CMV Immune Globulin (CMVIG)
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* CMVIG pooled from serum of CMV-seropositive donors contains high levels of IgG
- May provide passive immune protection from CMV, adjunctive immunotherapy of active disease * Overall benefits of CMVIG in treatment of active disease controversial * CMVIG not universally recommended, but may be beneficial in certain populations when given in combination with antiviral drugs - CMV pneumonia in BMT & solid organ transplant patients associated with 40-70% mortality - CMVIG + ganciclovir may provide survival benefits but data not consistent - May be considered for treatment of other severe CMV disease |
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Pre-emptive Therapy for CMV
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* Prophylactic therapy commonly used in patients at high risk of CMV disease
* “Pre-emptive” therapy often initiated at first sign of active CMV infection or change/increase in CMV antibody titers - Goal is to prevent development of severe invasive disease through aggressive early treatment - Studies indicate survival benefit in BMT & solid organ transplant recipients * Both prophylaxis and pre-emptive therapy usually based on ganciclovir or valganciclovir +/- CMVIG - Optimal regimens not known - Exact regimens depend on risk category of patient, specific institutional practices |
