Prevention of cytomegalovirus infection in lung transplant recipients
- Martin Zamora, MD
Martin Zamora, MD
- Professor of Medicine, Medical Director Lung Transplant Program
- University of Colorado School of Medicine
- Section Editors
- Kieren A Marr, MD
Kieren A Marr, MD
- Section Editor — Compromised Host Infections; Fungal Infections
- Professor of Medicine and Oncology
- Johns Hopkins University School of Medicine
- Martin S Hirsch, MD
Martin S Hirsch, MD
- Editor-in-Chief — Infectious Diseases
- Section Editor — Viral Infections
- Professor of Medicine
- Harvard Medical School
Cytomegalovirus (CMV), a member of the betaherpesvirus group, remains an important cause of infection, resulting in substantial morbidity and increased mortality in lung transplant recipients [1,2]. It is the second most common infection among lung transplant recipients after bacterial pneumonia [3,4].
While the development and availability of potent antiviral agents has decreased CMV-related mortality, there is a growing body of evidence that the indirect effects of CMV may be equally important or even more important than its direct effects of tissue injury and infection . CMV-induced immunosuppression may lead to infection with other opportunistic organisms. In addition, CMV infection and disease have been associated with acute and chronic rejection (bronchiolitis obliterans syndrome) in some but not all studies [5-7].
The approach to prevention of CMV infections in lung transplant recipients continues to evolve as transplant specialists gain experience using molecular diagnostic techniques and the potent oral antiviral agent valganciclovir. The prevention of CMV infection in lung transplant recipients will be discussed here. The clinical manifestations, diagnosis, and treatment of CMV infection in lung transplant recipients and infectious complications due to agents other than CMV are discussed elsewhere. (See "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients" and "Bacterial infections following lung transplantation" and "Nontuberculous mycobacterial infections in solid organ transplant candidates and recipients" and "Tuberculosis in solid organ transplant candidates and recipients" and "Fungal infections following lung transplantation".)
Primary CMV infection is acquired through close physical contact involving direct inoculation with infected cells or body fluids. Following primary infection, CMV infection persists for life. Population studies document a gradual increase in CMV seropositivity through young adulthood. Although there is considerable variability, more than one-half of adults in the United States have serologic evidence of previous infection. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults".)
CMV infection following transplantation can be acquired in one of several ways :To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Kotton CN, Kumar D, Caliendo AM, et al. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2013; 96:333.
- Razonable RR, Humar A, AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:93.
- Balfour HH Jr. Cytomegalovirus: the troll of transplantation. Arch Intern Med 1979; 139:279.
- Zamora MR. Cytomegalovirus and lung transplantation. Am J Transplant 2004; 4:1219.
- Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002; 21:297.
- Sharples LD, McNeil K, Stewart S, Wallwork J. Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant 2002; 21:271.
- Tamm M, Aboyoun CL, Chhajed PN, et al. Treated cytomegalovirus pneumonia is not associated with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2004; 170:1120.
- Zamora MR, Davis RD, Leonard C, CMV Advisory Board Expert Committee. Management of cytomegalovirus infection in lung transplant recipients: evidence-based recommendations. Transplantation 2005; 80:157.
- Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis 2017; 64:87.
- Hibberd PL, Tolkoff-Rubin NE, Cosimi AB, et al. Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3. Transplantation 1992; 53:68.
- Jamil B, Nicholls KM, Becker GJ, Walker RG. Influence of anti-rejection therapy on the timing of cytomegalovirus disease and other infections in renal transplant recipients. Clin Transplant 2000; 14:14.
- Cope AV, Sabin C, Burroughs A, et al. Interrelationships among quantity of human cytomegalovirus (HCMV) DNA in blood, donor-recipient serostatus, and administration of methylprednisolone as risk factors for HCMV disease following liver transplantation. J Infect Dis 1997; 176:1484.
- Kang SH, Abdel-Massih RC, Brown RA, et al. Homozygosity for the toll-like receptor 2 R753Q single-nucleotide polymorphism is a risk factor for cytomegalovirus disease after liver transplantation. J Infect Dis 2012; 205:639.
- Cervera C, Lozano F, Saval N, et al. The influence of innate immunity gene receptors polymorphisms in renal transplant infections. Transplantation 2007; 83:1493.
- Manuel O, Pascual M, Trendelenburg M, Meylan PR. Association between mannose-binding lectin deficiency and cytomegalovirus infection after kidney transplantation. Transplantation 2007; 83:359.
- Manuel O, Wójtowicz A, Bibert S, et al. Influence of IFNL3/4 polymorphisms on the incidence of cytomegalovirus infection after solid-organ transplantation. J Infect Dis 2015; 211:906.
- Ettinger NA, Bailey TC, Trulock EP, et al. Cytomegalovirus infection and pneumonitis. Impact after isolated lung transplantation. Washington University Lung Transplant Group. Am Rev Respir Dis 1993; 147:1017.
- Duncan AJ, Dummer JS, Paradis IL, et al. Cytomegalovirus infection and survival in lung transplant recipients. J Heart Lung Transplant 1991; 10:638.
- Balthesen M, Messerle M, Reddehase MJ. Lungs are a major organ site of cytomegalovirus latency and recurrence. J Virol 1993; 67:5360.
- Glanville AR, Valentine VG, Aboyoun CL, Malouf MA. CMV mismatch is not a risk factor for survival or severe bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 2004; 23:S43.
- Zamora MR. Controversies in lung transplantation: management of cytomegalovirus infections. J Heart Lung Transplant 2002; 21:841.
- Schoeppler KE, Lyu DM, Grazia TJ, et al. Late-onset cytomegalovirus (CMV) in lung transplant recipients: can CMV serostatus guide the duration of prophylaxis? Am J Transplant 2013; 13:376.
- Hammond SP, Martin ST, Roberts K, et al. Cytomegalovirus disease in lung transplantation: impact of recipient seropositivity and duration of antiviral prophylaxis. Transpl Infect Dis 2013; 15:163.
- Paradis IL, Williams P. Infection after lung transplantation. Semin Respir Infect 1993; 8:207.
- Seed CR, Piscitelli LM, Maine GT, et al. Validation of an automated immunoglobulin G-only cytomegalovirus (CMV) antibody screening assay and an assessment of the risk of transfusion transmitted CMV from seronegative blood. Transfusion 2009; 49:134.
- Weber B, Fall EM, Berger A, Doerr HW. Screening of blood donors for human cytomegalovirus (HCMV) IgG antibody with an enzyme immunoassay using recombinant antigens. J Clin Virol 1999; 14:173.
- Lazzarotto T, Brojanac S, Maine GT, Landini MP. Search for cytomegalovirus-specific immunoglobulin M: comparison between a new western blot, conventional western blot, and nine commercially available assays. Clin Diagn Lab Immunol 1997; 4:483.
- Manuel O, Husain S, Kumar D, et al. Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant recipients: a multicenter cohort study. Clin Infect Dis 2013; 56:817.
- Bando K, Paradis IL, Komatsu K, et al. Analysis of time-dependent risks for infection, rejection, and death after pulmonary transplantation. J Thorac Cardiovasc Surg 1995; 109:49.
- Le Page AK, Jager MM, Kotton CN, et al. International survey of cytomegalovirus management in solid organ transplantation after the publication of consensus guidelines. Transplantation 2013; 95:1455.
- Zuk DM, Humar A, Weinkauf JG, et al. An international survey of cytomegalovirus management practices in lung transplantation. Transplantation 2010; 90:672.
- Duncan SR, Paradis IL, Dauber JH, et al. Ganciclovir prophylaxis for cytomegalovirus infections in pulmonary allograft recipients. Am Rev Respir Dis 1992; 146:1213.
- Bailey TC, Ettinger NA, Storch GA, et al. Failure of high-dose oral acyclovir with or without immune globulin to prevent primary cytomegalovirus disease in recipients of solid organ transplants. Am J Med 1993; 95:273.
- Palmer SM, Limaye AP, Banks M, et al. Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation: a randomized, controlled trial. Ann Intern Med 2010; 152:761.
- Zamora MR, Nicolls MR, Hodges TN, 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. Am J Transplant 2004; 4:1635.
- Paya C, Humar A, Dominguez E, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2004; 4:611.
- Jaksch P, Zweytick B, Kerschner H, et al. Cytomegalovirus prevention in high-risk lung transplant recipients: comparison of 3- vs 12-month valganciclovir therapy. J Heart Lung Transplant 2009; 28:670.
- Chmiel C, Speich R, Hofer M, et al. Ganciclovir/valganciclovir prophylaxis decreases cytomegalovirus-related events and bronchiolitis obliterans syndrome after lung transplantation. Clin Infect Dis 2008; 46:831.
- Finlen Copeland CA, Davis WA, Snyder LD, et al. Long-term efficacy and safety of 12 months of valganciclovir prophylaxis compared with 3 months after lung transplantation: a single-center, long-term follow-up analysis from a randomized, controlled cytomegalovirus prevention trial. J Heart Lung Transplant 2011; 30:990.
- Emery VC, Griffiths PD. Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy. Proc Natl Acad Sci U S A 2000; 97:8039.
- McGavin JK, Goa KL. Ganciclovir: an update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients. Drugs 2001; 61:1153.
- Duncan SR, Grgurich WF, Iacono AT, et al. A comparison of ganciclovir and acyclovir to prevent cytomegalovirus after lung transplantation. Am J Respir Crit Care Med 1994; 150:146.
- Gutiérrez CA, Chaparro C, Krajden M, et al. Cytomegalovirus viremia in lung transplant recipients receiving ganciclovir and immune globulin. Chest 1998; 113:924.
- Bailey TC, Trulock EP, Ettinger NA, et al. Failure of prophylactic ganciclovir to prevent cytomegalovirus disease in recipients of lung transplants. J Infect Dis 1992; 165:548.
- Palmer SM, Grinnan DC, Diane Reams B, et al. Delay of CMV infection in high-risk CMV mismatch lung transplant recipients due to prophylaxis with oral ganciclovir. Clin Transplant 2004; 18:179.
- Valantine HA, Luikart H, Doyle R, et al. Impact of cytomegalovirus hyperimmune globulin on outcome after cardiothoracic transplantation: a comparative study of combined prophylaxis with CMV hyperimmune globulin plus ganciclovir versus ganciclovir alone. Transplantation 2001; 72:1647.
- Kruger RM, Paranjothi S, Storch GA, et al. Impact of prophylaxis with cytogam alone on the incidence of CMV viremia in CMV-seropositive lung transplant recipients. J Heart Lung Transplant 2003; 22:754.
- Kliem V, Fricke L, Wollbrink T, et al. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial. Am J Transplant 2008; 8:975.
- Gandhi MK, Khanna R. Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments. Lancet Infect Dis 2004; 4:725.
- Plotkin SA, Higgins R, Kurtz JB, et al. Multicenter trial of Towne strain attenuated virus vaccine in seronegative renal transplant recipients. Transplantation 1994; 58:1176.
- INFECTION VERSUS DISEASE
- RISK FACTORS
- Serologic status
- DIAGNOSTIC TESTS
- Pretransplant serologic testing
- CMV DNA and antigen assays
- CMV-specific immunity
- PREVENTION OF DISEASE
- Universal prophylaxis
- - Approach to prophylaxis
- - Valganciclovir
- - Ganciclovir
- - CMV immune globulin
- Preemptive therapy
- Other approaches
- - Blood products
- - Vaccination
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS