Table 1. Mechanisms of CMV Disease after Solid Organ Transplantation. Table 2. Risk Factors for CMV Infection after Solid Organ Transplantation

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1 Table 1. Mechanisms of CMV Disease after Solid Organ Transplantation Primary CMV infection (seronegative recipient) CMV re-activation (seropositive recipient) CMV super-infection (seropositive recipient) 1. CMV D+/R- mismatch 2. CMV D-/R-. Blood transfusion from seropositive donor or exposure to infected body fluids CMV R+. Reactivation of latent virus in the recipient. Milder disease. CMV D+/R+. The recipient is infected from an exogenous CMV strain. This leads to reactivation of the donor-derived or, less commonly, the recipient-derived virus. Table 2. Risk Factors for CMV Infection after Solid Organ Transplantation CMV D+/R- mismatch Immunosuppressive medications: Lymphocyte depleting agents (muromonab-cd3 [OKT3], anti-thymocyte globulins, anti-lymphocyte globulin, alemtuzumab) Mycophenolate mofetil, high-dose steroids Allograft rejection Invasive bacterial and fungal infection Critical illness Surgical procedure

2 Table 3. Laboratory Methods for Diagnosis of CMV Infection and Disease. Viral culture I. Conventional culture. II. Shell vial assay Method Clinical Use Comments Diagnosis of CMV infection and disease With the conventional assay, cytopathic effects in human fibroblasts are seen within 1 to 6 weeks. With the shell vial assay, results are available within 24 to 48 hours. Nucleic acid detection and amplification Antigenemia assay (pp65 matrix protein antigen detection) Serology (ELISA) Rapid diagnosis of CMV infection and disease Guide for preemptive therapy Guide for duration of antiviral therapy Rapid diagnosis of CMV infection and disease Guide for preemptive therapy Guide for duration of antiviral therapy Pre-transplant evaluation of donor and recipient. The culture technique is less sensitive compared to nucleic acid detection and antigenemia. Sensitive assay with rapid turnaround time. Viral load threshold can serve as prognostic indicator of risk of disease and response to treatment Operator-dependent assay. Limited utility in neutropenic patients. Requires immediate processing. The ability to mount antibody production is impaired by immunosuppressive therapy

3 Table 4. Antiviral Drugs for the Treatment of CMV Infection and Disease. Drug Ganciclovir IV induction Doses CrCl >70: 5 mg/kg q 12h CrCl 50-69: 2.5 mg/kg q 12h CrCl 25-49: 2.5 mg/kg q 24h CrCl 10-24: 1.25 mg/kg q 24h CrCl <10: 1.25 mg/kg 3 times/week IHD: 1.25 mg/kg 3 times/week; on dialysis days, give after HD Ganciclovir IV maintenance CRRT: 2.5 mg/kg q24h CrCl >70: 5 mg/kg q 24h CrCl 50-69: 2.5 mg/kg q 24h CrCl 25-49: 1.25 mg/kg q 24h CrCl 10-24: mg/kg q 24h CrCl <10: mg/kg 3 times/week IHD: mg/kg 3 times/week; on dialysis days, give after HD Ganciclovir PO CRRT: 2.5 mg/kg q 12h (also consider 5 mg/kg q24h) CrCl >70: 1 g tid CrCl 50-69: 1,500 mg q 24h or 500 mg tid CrCl 25-49: 1 g q 24h or 500 mg bid CrCl 10-24: 500 mg q 24h CrCl <10: 500 mg 3 times/week Valgancivlovir PO induction IHD: 500 mg 3 times/week; on dialysis days, give after HD CrCl >60: 900 mg bid CrCl 40-59: 450 mg bid CrCl 25-39: 450 mg q 24h CrCl 10-24: 450 mg q 48h CrCl <10: Not recommended IHD: Not recommended

4 Valganciclovir PO maintenance CrCl 60: 900 mg q 24h CrCl 40-59: 450 mg q 24h CrCl 25-39: 450 mg q 48h CrCl 10-24: 450 mg two times/week CrCl <10: Not recommended Foscarnet IV induction Foscarnet IV maintenance Cidofovir IV induction [Contraindicated if CrCl 55, SCr >1.5 mg/dl, or urine protein >100 mg/dl (2+) Administer with probenecid and intravenous fluids] CrCl: Creatinine clearance given in ml/min IHD: Not recommended CrCl >80: 60 mg/kg q 8h or 90 mg/kg q 12h CrCl* Equal to 60 Equal to 90 (ml/min/kg) mg/kg q 8h mg/kg q 12h > q 8h 90 q 12h > q 8h 70 q 12h > q 12h 50 q 12h > q 12h 80 q 24h > q 24h 60 q 24h q 24h 50 q 24h < 0.4 Not Not recommended recommended IHD: No specific data; could start with mg/kg after each HD CrCl >80: mg/kg q 24h CrCl (ml/min/kg) Equal to 90 mg/kg q 24h > q 24h 120 q 24h > q 24h 90 q 24h > q 24h 65 q 24h > q 48h 105 q 48h > q 48h 80 q 48h q 48h 65 q 48h Equal to 120 mg/kg q 24h < 0.4 Not recommended IHD: No specific data; could start with mg/kg after each HD Induction CrCl 80: 5 mg/kg weekly for 2 consecutive weeks Not recommended Maintenance CrCl 80: 5 mg/kg q 2 weeks Reduce dose to 3 mg/kg if SCr increases mg/dl above baseline Discontinue if SCr increases >0.5 mg/dl above baseline or with 3+ proteinuria IHD: Intermittent hemodialysis CRRT: Continuous renal replacement therapy

5 SCr: Serum creatinine The optimal duration of treatment is not well defined. It is generally suggested that patients receive treatment for at least 2 to 4 weeks, and preferably until 2 weeks after clearance of CMV viremia. The use of maintenance therapy, wherein antiviral drugs are administered at prophylactic doses, has also been recommended in order to complete usually up to 3 months of treatment.

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