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CMV and Thoracic Transplantation

Adam B Cochrane, PharmD, BCPS
Organ Transplant Clinical Pharmacy Specialist
Inova Fairfax Hospital

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adam cochraneOnce we had potent enough immunosuppression to allow heart and lung transplant recipients to leave the hospital after transplant and live to 1 year and beyond, the new problem—cytomegalovirus disease—was created. CMV also has direct and indirect effects that can cause a spectrum of illness and death.

Zuk et al reported on the responses they received to the CMV Management Practices Survey that was sent to 102 lung transplant programs.1 Of the 59 centers that responded the majority gave CMV prophylaxis to D+/R- patients for 3 - 6 months, with a small number giving prophylaxis for 1 year or indefinitely. In the D+/R+ and D-/R+ patients the overwhelming majority gave prophylaxis for 3 - 6 months. These durations are generally based on guidelines but the guidelines tend to be broad. The British Transplant Society recommends that for D+/R- lung transplant patients they should receive valganciclovir for 100 - 360 days, The Transplant Society Consensus guidelines recommend no less than 6 months of prophylaxis in the D+/R- patients and the American Society of Transplantation recommends 6 months with or without CMV IVIg.2,3,4

Since valganciclovir is not approved for CMV prophylaxis in lung transplant, the lung transplant community has been left to define the optimal duration of prophylaxis. Zamora et al. showed that IV ganciclovir in combination CMV IVIg followed by valganciclovir for a period of 180, 275, and 365 days effectively decreased the incidence of CMV disease and infection compared to a control group that received acyclovir.5

Palmer et al published their findings when looking at 3 months (followed by 9 months placebo) compared to 12 months prophylaxis in lung transplant patients at high (D+/R-) or intermediate risk (D+/R+ or D-/R+) for CMV. They found CMV disease eight times more often (4% vs. 23%, p<0.001) in the 3 month versus 12 month prophylaxis group. Often there is a concern that with prolonged prophylaxis we are merely delaying the CMV infection until after prophylaxis is complete. But the authors of this study showed that in the 6-month follow-up there was a low incidence of CMV disease in both groups, so CMV disease was not just delayed but avoided.6

Although it is acknowledged that not all lung transplant patients who are CMV D+/R- may be able to tolerate 1 year of prophylaxis, perhaps it is time as a community to strive for 1 year of prophylaxis in CMV D+/R-. The intermediate risk (D+/R+, D-/R+) patients should be prolonged to 6 months though there has not been a study that examines the optimal duration for these patients.

Current guidelines for D+/R- heart transplant recipients recommend preemptive treatment or CMV prophylaxis for 3 - 6 months [2-4]. Our understanding of the causes of CAV are not definite, some research has been done examining the relationship between CMV and cardiac allograft vasculopathy.7 Potena et al, showed that there was less intimal thickening with universal prophylaxis versus a pre-emptive strategy but also documented that a substantial number of patients receiving either anti-CMV approach developed CMV infection (though significantly fewer prophylaxis patients had CMV disease compared to preemptive).8 Since CMV may contribute to the development or progression of CAV then preemptive treatment, with its allowance of viral replication before treatment, may not be the optimal approach to CMV prevention. Perhaps this finding should cause us to examine a prophylaxis strategy that will reduce the rate of CMV infection in order to decrease the impact that CMV may have on CAV progression. This may include extended prophylaxis and/or more aggressive late preemptive monitoring.

The future of CMV management may be a CMV vaccine. When studied in a kidney transplant population the vaccine attenuated CMV infections. Patients that received the vaccine and subsequently had CMV had a shorter duration of viremia and fewer days of ganciclovir therapy compared to patients that received a placebo vaccine.9

Disclosure Statement: The author has no conflicts of interest to disclose.

References:

  1. Zuk DM, et al. An international survey of cytomegalovirus management practices in lung transplantation. Transplantation. 2010; 90: 672-76.
  2. Andrews PA, et al. Summary of the British transplantation society guidelines for the prevention and management of cmv disease after solid organ transplantation. Transplantation. 2011; 92: 1181-87.
  3. Kotton CN, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010; 89:779-95.
  4. Humar A, et al. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009; 9(S4): S78-S86.
  5. Zamora MR, et al. Following universal prophyalaxis with intravenous ganciclovir and cytomegalovirus immune globulin, valganciclovir is safe and effective for prevention of cmv infection following lung transplantation. Am J Transplant 2004; 4: 1635-42.
  6. Palmer SM, et al. Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation. Ann Intern Med. 2010; 152: 761-69.
  7. Weis M, et al. Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis. Circulation. 2004; 109: 500-505.
  8. Potena L, et al. Prophylaxis versus preemptive anti-cytomegalovirus approach for prevention of allograft vasculopathy in heart transplant recipients. J Heart Lung Transplant. 2009; 28: 461-7.
  9. Griffiths PD, et al. Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet. 2011; 377:1256-63.