CMV in Organ Transplantation


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A brief presentation of CMV in Kidney Transplantation

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CMV in Organ Transplantation

  1. 1. CMV in Kidney Transplant Arun Chawla, MD Hofstra North Shore –LIJ School of Medicine
  2. 2. What is CMV?? <ul><li>Double-stranded, DNA herpesvirus that infects man and other species, producing unique large cells with inclusion bodies. </li></ul><ul><li>Also known as human herpesvirus # 5 or HHV-5 </li></ul><ul><li>In immunocompentent individuals, most CMV infections are mild and may produce a viral syndrome resembling infectious mononucleosis. </li></ul><ul><li>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”. </li></ul>
  3. 3. Why should we know CMV?? <ul><li>CMV is the most common and single most important viral infection in solid organ transplant recipients. </li></ul><ul><li>CMV-positive patients had significantly higher incidence of CMV disease, allograft loss, and overall costs compared with CMV-negative recipients. </li></ul><ul><li>Even asymptomatic CMV infection was associated with a relative risk of overall mortality of 2.9 </li></ul><ul><li>CMV is found in oropharyngeal secretions, urine, cervical and vaginal secretions, semen, breast milk, tissues and blood. </li></ul><ul><li>It can be transmitted via transplanted tissue, blood transfusion, perinatally, and through sexual contact </li></ul>
  4. 4. CMV infection <ul><li>seroconversion with the appearance of anti-CMV IgM antibodies; </li></ul><ul><li>a fourfold increase in preexisting anti-CMV IgG titers; </li></ul><ul><li>detection of CMV antigens in infected cells; </li></ul><ul><li>detection of CMV-DNAemia by molecular techniques; </li></ul><ul><li>and/or isolation of the virus by culture of the throat, buffy coat, or urine. </li></ul>
  5. 5. CMV Disease <ul><li>CMV Infection + clinical signs and symptoms, such as fever, leukopenia, or organ involvement </li></ul><ul><li>pneumonitis, </li></ul><ul><li>esophagitis, </li></ul><ul><li>encephalitis, </li></ul><ul><li>hepatitis, </li></ul><ul><li>pancreatitis, </li></ul><ul><li>adrenalitis, </li></ul><ul><li>esophagitis, </li></ul><ul><li>.gastritis </li></ul><ul><li>enteritis & colitis </li></ul><ul><li>rarely myocarditis </li></ul><ul><li>Retinitis </li></ul>
  6. 6. Also… <ul><li>Alters host response and depresses immunity </li></ul><ul><li>Presdisposes to bacterial and fungal infections </li></ul><ul><li>CMV-induced transplant glomerulopathy </li></ul><ul><li>independent risk factor for the development of rejection </li></ul><ul><li>development of coronary artery narrowing </li></ul><ul><li>significantly associated with renal artery stenosis </li></ul><ul><li>associated with thrombotic microangiopathy (HUS/TTP) </li></ul>
  7. 8. Types of CMV Infection <ul><li>Primary infection - (asymptomatic to mononucleosis like syndrome in immune competent individuals) </li></ul><ul><li>Latent infection - (presence of viral genome in mononuclear leukocytes, endothelial cells, and organs in the absence of active replication of infectious virus) </li></ul><ul><li>Reactivation </li></ul><ul><li>Reinfection (new strain of CMV) </li></ul>
  8. 9. Risk Factors <ul><li>CMV status of donor and recipient </li></ul><ul><li>The number of CMV particles </li></ul><ul><li>Rate of increase of virus in the blood correlated with the risk of developing CMV disease </li></ul>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.
  9. 10. Donor Recipient Type D+ R- primary D- R+ reactivation D+ R+ superinfection D- R- risk with exposure
  10. 11. Prevention <ul><li>Infection rates of upto 60% without prophylaxis have come down to as low as 5 % with prophylaxis. </li></ul><ul><li>A prophylactic strategy - antiviral agents to patients at increased risk of developing CMV infection. </li></ul><ul><li>A preemptive strategy - periodic monitoring for viremia, principally using PCR to permit prompt treatment after the detection of very early systemic infection. </li></ul><ul><li>So what do we do? </li></ul>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.
  11. 12. Agents for Prophylaxis <ul><li>Ganciclovir was superior to acyclovir or CMV Ig </li></ul><ul><li>Gancilcovir (i.v. vs. po) </li></ul><ul><li>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. </li></ul><ul><li>Investigative phase – leflunamide, valacyclovir. </li></ul>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.
  12. 13. Choice and duration <ul><li>D-/R- with acyclovir for 3 months </li></ul><ul><li>D-/R+ - with valganciclovir for 3 - 6 months </li></ul><ul><li>D+/R+ and D+/R- with valganciclovir for 6 - 9 months. </li></ul><ul><li>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. </li></ul>
  13. 14. CMV status & HLA-DR matching <ul><li>CMV disease occurred most frequently in D+/R- recipients with zero HLA-DR matches. </li></ul><ul><li>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). </li></ul><ul><li>These results suggest that, to enhance allograft survival, consideration should be given to HLA-DR matching plus CMV status in the allocation of kidneys. </li></ul>
  14. 15. Preemptive strategy <ul><li>blood quantitative CMV-PCR weekly for 12 to 16 weeks post-surgery. </li></ul><ul><li>CMV-PCR becomes positive, > 2000 copies/mL, approach varies in part upon the severity of the infection: </li></ul><ul><li>Stop azt or MMF </li></ul><ul><li>Asymptomatic/Mild disease – valganciclovir for 21 days or longer if necessary to clear viremia. </li></ul><ul><li>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. </li></ul>
  15. 16. Diagnosis of CMVD <ul><li>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). </li></ul><ul><li>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) . </li></ul><ul><li>Symptomatic CMV infections typically occur 1-4 months after transplantation if prophylaxis is not used or one to four months after discontinuation of prophylaxis </li></ul>
  16. 17. Treatment <ul><li>The mononucleosis-like syndrome may resolve without the administration of antiviral drugs. </li></ul><ul><li>Discontinue azt/MMF </li></ul><ul><li>Usually do not discontinue cyclosporine or tacrolimus unless there is evidence of life-threatening infection </li></ul><ul><li>i.v. ganciclovir (life threatening infections or npo) </li></ul><ul><li>Oral?? VICTOR study </li></ul><ul><li>Oral ganciclovir, acyclovir, or valacyclovir should not be used for treatment of CMV disease </li></ul><ul><li>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 </li></ul>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
  17. 18. Duration of t/t <ul><li>monitoring weekly viral loads & continued until viral eradication is achieved, but not shorter than 2 weeks </li></ul><ul><li>Follow renal function and adjust dose </li></ul><ul><li>Secondary prophylaxis – 1-3 months </li></ul><ul><li>Longer if - primary CMV infection, DDT, high baseline viral load, persistent viremia when transferred to secondary prophylaxis, multiorgan disease, and treatment of rejection. </li></ul><ul><li>Several CMV vaccines are under development; none are currently available for routine clinical use. </li></ul>
  18. 19. Thank You …………….