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CMV in Organ Transplantation


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A brief presentation of CMV in Kidney Transplantation

A brief presentation of CMV in Kidney Transplantation

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  • 1. CMV in Kidney Transplant Arun Chawla, MD Hofstra North Shore –LIJ School of Medicine
  • 2. What is CMV??
    • Double-stranded, DNA herpesvirus that infects man and other species, producing unique large cells with inclusion bodies.
    • Also known as human herpesvirus # 5 or HHV-5
    • In immunocompentent individuals, most CMV infections are mild and may produce a viral syndrome resembling infectious mononucleosis.
    • Approximately 50 - 90% of immunocompetent adults >40 years old have antibodies (IgG) to CMV. In otherwise healthy adults, CMV remains inactive or latent, but ready to be become active under “favorable conditions”.
  • 3. Why should we know CMV??
    • CMV is the most common and single most important viral infection in solid organ transplant recipients.
    • CMV-positive patients had significantly higher incidence of CMV disease, allograft loss, and overall costs compared with CMV-negative recipients.
    • Even asymptomatic CMV infection was associated with a relative risk of overall mortality of 2.9
    • CMV is found in oropharyngeal secretions, urine, cervical and vaginal secretions, semen, breast milk, tissues and blood.
    • It can be transmitted via transplanted tissue, blood transfusion, perinatally, and through sexual contact
  • 4. CMV infection
    • seroconversion with the appearance of anti-CMV IgM antibodies;
    • a fourfold increase in preexisting anti-CMV IgG titers;
    • detection of CMV antigens in infected cells;
    • detection of CMV-DNAemia by molecular techniques;
    • and/or isolation of the virus by culture of the throat, buffy coat, or urine.
  • 5. CMV Disease
    • CMV Infection + clinical signs and symptoms, such as fever, leukopenia, or organ involvement
    • pneumonitis,
    • esophagitis,
    • encephalitis,
    • hepatitis,
    • pancreatitis,
    • adrenalitis,
    • esophagitis,
    • .gastritis
    • enteritis & colitis
    • rarely myocarditis
    • Retinitis
  • 6. Also…
    • Alters host response and depresses immunity
    • Presdisposes to bacterial and fungal infections
    • CMV-induced transplant glomerulopathy
    • independent risk factor for the development of rejection
    • development of coronary artery narrowing
    • significantly associated with renal artery stenosis
    • associated with thrombotic microangiopathy (HUS/TTP)
  • 7.  
  • 8. Types of CMV Infection
    • Primary infection - (asymptomatic to mononucleosis like syndrome in immune competent individuals)
    • Latent infection - (presence of viral genome in mononuclear leukocytes, endothelial cells, and organs in the absence of active replication of infectious virus)
    • Reactivation
    • Reinfection (new strain of CMV)
  • 9. Risk Factors
    • CMV status of donor and recipient
    • The number of CMV particles
    • Rate of increase of virus in the blood correlated with the risk of developing CMV disease
    Correlation of CMV DNA levels with response to antiviral therapy in cardiac and renal allograft recipients.Toyoda M et al Transplantation 1997 Apr 15;63(7):957-63.
  • 10. Donor Recipient Type D+ R- primary D- R+ reactivation D+ R+ superinfection D- R- risk with exposure
  • 11. Prevention
    • Infection rates of upto 60% without prophylaxis have come down to as low as 5 % with prophylaxis.
    • A prophylactic strategy - antiviral agents to patients at increased risk of developing CMV infection.
    • A preemptive strategy - periodic monitoring for viremia, principally using PCR to permit prompt treatment after the detection of very early systemic infection.
    • So what do we do?
    Meta-analysis: the efficacy of strategies to prevent organ disease by CMV in solid organ transplant recipients. Kalil AC et al Ann Intern Med. 2005 Dec 20;143(12):870-80.
  • 12. Agents for Prophylaxis
    • Ganciclovir was superior to acyclovir or CMV Ig
    • Gancilcovir (i.v. vs. po)
    • Valganciclovir vs. ganciclovir – PV 16000 - 1 percent of patients developing CMV disease while receiving therapy. Time-to-onset of CMV disease and to viremia were delayed with valganciclovir; rates of acute allograft rejection were generally lower with valganciclovir.Also, lower resistance (2% vs. none). Caution with neutropenia.
    • Investigative phase – leflunamide, valacyclovir.
    Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of CMV disease in solid organ transplant recipients. Paya C et al. J Transplant 2004 Apr;4(4):611-20.
  • 13. Choice and duration
    • D-/R- with acyclovir for 3 months
    • D-/R+ - with valganciclovir for 3 - 6 months
    • D+/R+ and D+/R- with valganciclovir for 6 - 9 months.
    • The worst graft and patient survival at three years post-transplantation is observed among the group in which the donor and recipient are both positive.
  • 14. CMV status & HLA-DR matching
    • CMV disease occurred most frequently in D+/R- recipients with zero HLA-DR matches.
    • In addition, allograft survival at five years was significantly decreased among those with CMV disease and zero matches compared to patients with CMV disease and one or two HLA-DR matches (16 versus 76 percent, respectively).
    • These results suggest that, to enhance allograft survival, consideration should be given to HLA-DR matching plus CMV status in the allocation of kidneys.
  • 15. Preemptive strategy
    • blood quantitative CMV-PCR weekly for 12 to 16 weeks post-surgery.
    • CMV-PCR becomes positive, > 2000 copies/mL, approach varies in part upon the severity of the infection:
    • Stop azt or MMF
    • Asymptomatic/Mild disease – valganciclovir for 21 days or longer if necessary to clear viremia.
    • Weekly quantitative PCRs should be obtained during treatment to determine response. If levels no less by 50% in two weeks, viral resistance should be suspected. Consider i.v. then.
  • 16. Diagnosis of CMVD
    • Symptoms and signs consistent with CMV disease together with detection of CMV by an appropriate method applied to a specimen from the involved tissue (AII).
    • Symptoms of organ involvement together with CMV detection in blood are not enough for diagnosis of CMV disease . Detection of CMV in tissue specimens is important (AII) .
    • Symptomatic CMV infections typically occur 1-4 months after transplantation if prophylaxis is not used or one to four months after discontinuation of prophylaxis
  • 17. Treatment
    • The mononucleosis-like syndrome may resolve without the administration of antiviral drugs.
    • Discontinue azt/MMF
    • Usually do not discontinue cyclosporine or tacrolimus unless there is evidence of life-threatening infection
    • i.v. ganciclovir (life threatening infections or npo)
    • Oral?? VICTOR study
    • Oral ganciclovir, acyclovir, or valacyclovir should not be used for treatment of CMV disease
    • The role of CMV immunoglobulin in the treatment of CMV disease is unclear. It may be considered as adjunc- tive therapy for severe forms of CMV disease such as pneumonitis
    Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Asberg A et al. J Transplant. 2007 Sep;7(9):2106-13
  • 18. Duration of t/t
    • monitoring weekly viral loads & continued until viral eradication is achieved, but not shorter than 2 weeks
    • Follow renal function and adjust dose
    • Secondary prophylaxis – 1-3 months
    • Longer if - primary CMV infection, DDT, high baseline viral load, persistent viremia when transferred to secondary prophylaxis, multiorgan disease, and treatment of rejection.
    • Several CMV vaccines are under development; none are currently available for routine clinical use.
  • 19. Thank You …………….