ytomegalovirus disease among donor-positive / ecipient-negative lung transplant recipients in the ra of valganciclovir prophylaxis

BACKGROUND: Valganciclovir prophylaxis is advocated for lung transplant recipients, but its efficacy is unknown. METHODS: Retrospective review was done of 109 donor-positive/recipient-negative lung transplant patients who received alemtuzumab induction and valganciclovir for cytomegalovirus prophylaxis. RESULTS: Median duration of follow-up after transplant was 27 months. Valganciclovir dose reductions ( 900 mg/day or renal-equivalent) were required for 18 patients (17%) due to toxicity, most commonly for neutropenia (n 15) or gastrointestinal symptoms (n 2). Of the 109 patients, 34 (31%) had no CMV infections, 45 (41%) had asymptomatic viremia, and 30 (27%) had CMV disease. CMV disease developed off prophylaxis in 10 patients (18%) at a median of 8.7 months after transplant and 2 months after valganciclovir discontinuation. Breakthrough disease occurred during prophylaxis in 10 patients (9%) at a median of 6.7 months. Patients with asymptomatic viremia or no CMV infection received prophylaxis for median 8.6 and 8.7 months, respectively. Risk factors for CMV disease by univariate analysis were increased age (p 0.01), single-lung transplant (p 0.03), chronic obstructive pulmonary disease (p 0.05), reduced-dose valganciclovir (p 0.001), and less than 6 months of prophylaxis (p 0.005). By multivariate analysis, advanced age (p 0.01) and reduced-dose valganciclovir (p 0.0006) were independent risk factors for CMV disease. CMV disease developed in 4 patients (4%) due to ganciclovir-resistant viruses. CMV-attributable mortality was 5% (5 of 109), including 100% (4 of 4) with ganciclovir-resistant disease. CONCLUSIONS: Valganciclovir prophylaxis among donor-positive/recipient-negative lung transplant recipients delayed but did not eliminate CMV disease or CMV-related deaths and was limited by toxicity and ganciclovir-resistance. Our experience suggests that valganciclovir at reduced-doses or for less than 6 months is sub-optimal in preventing CMV disease. J Heart Lung Transplant 2010;29:1014–20 Published by Elsevier Inc.

[1]  G. Mårtensson,et al.  Cytomegalovirus and long-term outcome after lung transplantation in Gothenburg, Sweden , 2010, Scandinavian journal of infectious diseases.

[2]  J. Stoner,et al.  Valganciclovir for Cytomegalovirus Prevention in Solid Organ Transplant Patients: An Evidence-Based Reassessment of Safety and Efficacy , 2009, PloS one.

[3]  A. Pastor,et al.  A Multicenter Study of Valganciclovir Prophylaxis up to Day 120 in CMV‐Seropositive Lung Transplant Recipients , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  T. Buclin,et al.  Population Pharmacokinetics of Ganciclovir in Solid-Organ Transplant Recipients Receiving Oral Valganciclovir , 2009, Antimicrobial Agents and Chemotherapy.

[5]  O. Manuel,et al.  Lack of Association Between ß-herpesvirus Infection and Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients in the Era of Antiviral Prophylaxis , 2009, Transplantation.

[6]  G. Lang,et al.  Cytomegalovirus prevention in high-risk lung transplant recipients: comparison of 3- vs 12-month valganciclovir therapy. , 2008, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[7]  R. Speich,et al.  Ganciclovir/valganciclovir prophylaxis decreases cytomegalovirus-related events and bronchiolitis obliterans syndrome after lung transplantation. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[8]  David E. Taylor,et al.  Ganciclovir for cytomegalovirus: a call for indefinite prophylaxis in lung transplantation. , 2007, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[9]  A. Zaas,et al.  A single-center experience with ganciclovir-resistant cytomegalovirus in lung transplant recipients: treatment and outcome. , 2007, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[10]  W. Kremers,et al.  Clinical features and outcomes of delayed-onset primary cytomegalovirus disease in cardiac transplant recipients. , 2007, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[11]  A. Limaye,et al.  Incidence and clinical features of ganciclovir-resistant cytomegalovirus disease in heart transplant recipients. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[12]  A. Cochrane Antiviral dosing and efficacy for prophylaxis of cytomegalovirus disease in solid organ transplant recipients. , 2006, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[13]  H. Ulmer,et al.  Combined CMV Prophylaxis Improves Outcome and Reduces the Risk for Bronchiolitis Obliterans Syndrome (BOS) after Lung Transplantation , 2006, Transplantation.

[14]  F. Morell,et al.  Preemptive therapy with intravenous ganciclovir for the prevention of cytomegalovirus disease in lung transplant recipients. , 2005, Transplantation proceedings.

[15]  B. Alexander,et al.  Pharmacodynamics of Oral Ganciclovir and Valganciclovir in Solid Organ Transplant Recipients , 2005, Transplantation.

[16]  Barbara Alexander,et al.  Pharmacokinetic Profile of Ganciclovir After its Oral Administration and From its Prodrug, Valganciclovir, in Solid Organ Transplant Recipients , 2005, Clinical pharmacokinetics.

[17]  J. Preiksaitis,et al.  A Trial of Valganciclovir Prophylaxis for Cytomegalovirus Prevention in Lung Transplant Recipients , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[18]  S. Gruber,et al.  Cytomegalovirus prophylaxis with valganciclovir in African–American renal allograft recipients based on donor/recipient serostatus , 2005, Clinical transplantation.

[19]  M. Tamm,et al.  Treated cytomegalovirus pneumonia is not associated with bronchiolitis obliterans syndrome. , 2004, American journal of respiratory and critical care medicine.

[20]  M. Zamora,et al.  Following Universal Prophylaxis with Intravenous Ganciclovir and Cytomegalovirus Immune Globulin, Valganciclovir is Safe and Effective for Prevention of CMV Infection Following Lung Transplantation , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[21]  S. Baroletti,et al.  Efficacy and Safety of Low‐Dose Valganciclovir for Prevention of Cytomegalovirus Disease in Renal Transplant Recipients: A Single‐Center, Retrospective Analysis , 2004, Pharmacotherapy.

[22]  B. Alexander,et al.  Efficacy and Safety of Valganciclovir vs. Oral Ganciclovir for Prevention of Cytomegalovirus Disease in Solid Organ Transplant Recipients , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[23]  S. Hossain,et al.  Cytomegalovirus Disease in High‐Risk Transplant Recipients Despite Ganciclovir or Valganciclovir Prophylaxis , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[24]  D. McGiffin,et al.  Combination Prophylaxis with Ganciclovir and Cytomegalovirus (CMV) Immune Globulin After Lung Transplantation: Effective CMV Prevention Following Daclizumab Induction , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[25]  C. Craddock,et al.  High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution. , 2002, Blood.

[26]  S. Gautam,et al.  Prevention of cytomegalovirus infection and disease after lung transplantation: results using a unique regimen employing delayed ganciclovir. , 2002, Chest.

[27]  G. Raghu,et al.  High incidence of ganciclovir-resistant cytomegalovirus infection among lung transplant recipients receiving preemptive therapy. , 2002, The Journal of infectious diseases.

[28]  M. Zamora Use of cytomegalovirus immune globulin and ganciclovir for the prevention of cytomegalovirus disease in lung transplantation , 2001, Transplant infectious disease : an official journal of the Transplantation Society.

[29]  B. Alexander,et al.  Infectious complications of lung transplantation , 2001, Transplant infectious disease : an official journal of the Transplantation Society.

[30]  A. Husain,et al.  Quantification of cytomegalovirus (CMV) viral load by the hybrid capture assay allows for early detection of CMV disease in lung transplant recipients. , 2001, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[31]  G. Raghu,et al.  Comparison of the efficacy and cost effectiveness of pre-emptive therapy as directed by CMV antigenemia and prophylaxis with ganciclovir in lung transplant recipients. , 2000, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[32]  D. DuBois,et al.  Costs and outcomes of prolonged cytomegalovirus prophylaxis to cover the enhanced immunosuppression phase following lung transplantation. , 1999, Chest.

[33]  L. Sharples,et al.  Intravenous ganciclovir prophylaxis for cytomegalovirus in heart, heart-lung, and lung transplant recipients , 1999, Transplant international : official journal of the European Society for Organ Transplantation.

[34]  R. Speich,et al.  Efficacy and cost effectiveness of oral ganciclovir in the prevention of cytomegalovirus disease after lung transplantation. , 1999, Transplantation.

[35]  C. Couchoud‐Heyer Cytomegalovirus prophylaxis with antiviral agents for solid organ transplantation , 1998 .

[36]  R. Bolman,et al.  Randomized trial of daily versus three-times-weekly prophylactic ganciclovir after lung and heart-lung transplantation. , 1998, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[37]  M. Krajden,et al.  Cytomegalovirus viremia in lung transplant recipients receiving ganciclovir and immune globulin. , 1998, Chest.

[38]  G. Berry,et al.  Risk factors for the development of obliterative bronchiolitis after lung transplantation. , 1996, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[39]  G. Berry,et al.  Impact of ganciclovir prophylaxis on heart-lung and lung transplant recipients. , 1996, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[40]  B. Griffith,et al.  Obliterative bronchiolitis after lung and heart-lung transplantation. An analysis of risk factors and management. , 1995, The Journal of thoracic and cardiovascular surgery.

[41]  B. Griffith,et al.  A comparison of ganciclovir and acyclovir to prevent cytomegalovirus after lung transplantation. , 1994, American journal of respiratory and critical care medicine.

[42]  J. Maurer,et al.  Outcomes of lung transplantation using three different cytomegalovirus prophylactic regimens. , 1993, Transplantation proceedings.

[43]  E. Spitznagel,et al.  Cytomegalovirus infection and pneumonitis. Impact after isolated lung transplantation. Washington University Lung Transplant Group. , 1993, The American review of respiratory disease.

[44]  B. Griffith,et al.  Sequelae of cytomegalovirus pulmonary infections in lung allograft recipients. , 1992, The American review of respiratory disease.

[45]  B. Griffith,et al.  Cytomegalovirus infection and survival in lung transplant recipients. , 1991, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.