Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant recipients
- Carlos AQ Santos, MD, MPHS
Carlos AQ Santos, MD, MPHS
- Assistant Professor of Medicine
- Rush University Medical Center
- John Vella, MD, FACP, FRCP, FASN
John Vella, MD, FACP, FRCP, FASN
- Associate Professor of Medicine
- Tufts University School of Medicine
- Daniel C Brennan, MD, FACP
Daniel C Brennan, MD, FACP
- Editor-in-Chief — Nephrology
- Section Editor — Renal Transplantation
- Professor of Medicine
- Washington University School of Medicine
- Section Editors
- Barbara Murphy, MB, BAO, BCh, FRCPI
Barbara Murphy, MB, BAO, BCh, FRCPI
- Section Editor — Renal Transplantation
- Professor of Medicine
- Mount Sinai School of Medicine
- 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
Cytomegalovirus (CMV) is a globally widespread virus that becomes latent following primary infection but reactivates frequently and, in the setting of immunocompromise, causes disease in solid organ transplant patients, including kidney transplant recipients . After kidney transplantation, active CMV infection and disease are associated with increased risk of allograft failure and death; thus, CMV prevention strategies are commonly used in such patients. Preventive therapy decreases reactivation in the setting of latent infection in the transplant recipient and/or acquisition of acute infection in CMV-seronegative recipients of seropositive grafts. However, CMV disease may still occur despite preventive therapies, especially when they are not dosed adequately [2,3]. It also occurs following discontinuation of preventive therapy.
The epidemiology, clinical manifestations, diagnosis, and treatment of CMV disease in kidney transplant recipients are reviewed here. The approach to the prevention of CMV infection in transplant recipients is discussed elsewhere. (See "Prevention of active cytomegalovirus infection and disease in kidney transplant recipients".)
The diagnosis of CMV infection and the epidemiology, clinical manifestations, and treatment of CMV infection and disease in immunocompetent adults are also presented separately. (See "Overview of diagnostic tests for cytomegalovirus infection" and "Approach to the diagnosis of cytomegalovirus infection" and "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults".)
Like other members of the Herpesvirus family, CMV establishes latent infection after the resolution of acute (or primary) infection. Patients who are CMV seropositive have latent infection. Secondary, symptomatic disease may present later, reflecting either reactivation of latent CMV or, less commonly, reinfection with a novel exogenous strain. The risk of CMV reactivation is highest in the setting of systemic immunosuppression.
CMV can present in kidney transplant recipients as either active CMV infection or CMV disease [1,4,5]:
- Razonable RR, Humar A, AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:93.
- Arthurs SK, Eid AJ, Pedersen RA, et al. Delayed-onset primary cytomegalovirus disease and the risk of allograft failure and mortality after kidney transplantation. Clin Infect Dis 2008; 46:840.
- Santos CA, Brennan DC, Fraser VJ, Olsen MA. Delayed-onset cytomegalovirus disease coded during hospital readmission after kidney transplantation. Transplantation 2014; 98:187.
- Santos CA, Brennan DC, Olsen MA. Accuracy of Inpatient International Classification of Diseases, Ninth Revision, Clinical Modification Coding for Cytomegalovirus After Kidney Transplantation. Transplant Proc 2015; 47:1772.
- 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.
- Schnitzler MA, Woodward RS, Brennan DC, et al. Impact of cytomegalovirus serology on graft survival in living related kidney transplantation: implications for donor selection. Surgery 1997; 121:563.
- Schnitzler MA, Woodward RS, Brennan DC, et al. The effects of cytomegalovirus serology on graft and recipient survival in cadaveric renal transplantation: implications for organ allocation. Am J Kidney Dis 1997; 29:428.
- Khoury JA, Storch GA, Bohl DL, et al. Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant 2006; 6:2134.
- Hartmann A, Sagedal S, Hjelmesaeth J. The natural course of cytomegalovirus infection and disease in renal transplant recipients. Transplantation 2006; 82:S15.
- Abbott KC, Hypolite IO, Viola R, et al. Hospitalizations for cytomegalovirus disease after renal transplantation in the United States. Ann Epidemiol 2002; 12:402.
- Kumar D, Chernenko S, Moussa G, et al. Cell-mediated immunity to predict cytomegalovirus disease in high-risk solid organ transplant recipients. Am J Transplant 2009; 9:1214.
- Eid AJ, Arthurs SK, Deziel PJ, et al. Clinical predictors of relapse after treatment of primary gastrointestinal cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2010; 10:157.
- Eid AJ, Bakri SJ, Kijpittayarit S, Razonable RR. Clinical features and outcomes of cytomegalovirus retinitis after transplantation. Transpl Infect Dis 2008; 10:13.
- Razonable RR, Hayden RT. Clinical utility of viral load in management of cytomegalovirus infection after solid organ transplantation. Clin Microbiol Rev 2013; 26:703.
- Hirsch HH, Lautenschlager I, Pinsky BA, et al. An international multicenter performance analysis of cytomegalovirus load tests. Clin Infect Dis 2013; 56:367.
- Razonable RR, Åsberg A, Rollag H, et al. Virologic suppression measured by a cytomegalovirus (CMV) DNA test calibrated to the World Health Organization international standard is predictive of CMV disease resolution in transplant recipients. Clin Infect Dis 2013; 56:1546.
- Razonable RR, Paya CV, Smith TF. Role of the laboratory in diagnosis and management of cytomegalovirus infection in hematopoietic stem cell and solid-organ transplant recipients. J Clin Microbiol 2002; 40:746.
- Mattes FM, McLaughlin JE, Emery VC, et al. Histopathological detection of owl's eye inclusions is still specific for cytomegalovirus in the era of human herpesviruses 6 and 7. J Clin Pathol 2000; 53:612.
- Paya CV, Holley KE, Wiesner RH, et al. Early diagnosis of cytomegalovirus hepatitis in liver transplant recipients: role of immunostaining, DNA hybridization and culture of hepatic tissue. Hepatology 1990; 12:119.
- Sagedal S, Nordal KP, Hartmann A, et al. The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant 2002; 2:850.
- Sagedal S, Hartmann A, Nordal KP, et al. Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival. Kidney Int 2004; 66:329.
- Dieterich DT, Kotler DP, Busch DF, et al. Ganciclovir treatment of cytomegalovirus colitis in AIDS: a randomized, double-blind, placebo-controlled multicenter study. J Infect Dis 1993; 167:278.
- Hecht DW, Snydman DR, Crumpacker CS, et al. Ganciclovir for treatment of renal transplant-associated primary cytomegalovirus pneumonia. J Infect Dis 1988; 157:187.
- Asberg A, Humar A, Rollag H, et al. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2007; 7:2106.
- Lisboa LF, Asberg A, Kumar D, et al. The clinical utility of whole blood versus plasma cytomegalovirus viral load assays for monitoring therapeutic response. Transplantation 2011; 91:231.
- Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev 2010; 23:689.
- Limaye AP. Ganciclovir-resistant cytomegalovirus in organ transplant recipients. Clin Infect Dis 2002; 35:866.
- Eid AJ, Arthurs SK, Deziel PJ, et al. Emergence of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes. Clin Transplant 2008; 22:162.
- Myhre HA, Haug Dorenberg D, Kristiansen KI, et al. Incidence and outcomes of ganciclovir-resistant cytomegalovirus infections in 1244 kidney transplant recipients. Transplantation 2011; 92:217.
- Chou S, Waldemer RH, Senters AE, et al. Cytomegalovirus UL97 phosphotransferase mutations that affect susceptibility to ganciclovir. J Infect Dis 2002; 185:162.
- Smith IL, Cherrington JM, Jiles RE, et al. High-level resistance of cytomegalovirus to ganciclovir is associated with alterations in both the UL97 and DNA polymerase genes. J Infect Dis 1997; 176:69.
- D'Alessandro AM, Pirsch JD, Stratta RJ, et al. Successful treatment of severe cytomegalovirus infections with ganciclovir and CMV hyperimmune globulin in liver transplant recipients. Transplant Proc 1989; 21:3560.
- George MJ, Snydman DR, Werner BG, et al. Use of ganciclovir plus cytomegalovirus immune globulin to treat CMV pneumonia in orthotopic liver transplant recipients. The Boston Center for Liver Transplantation CMVIG-Study Group. Transplant Proc 1993; 25:22.
- Brown CB, Nicholls AJ, Edward N, et al. Hyperimmune immunoglobulin therapy for cytomegalovirus infections in renal transplant patients. Proc Eur Dial Transplant Assoc 1983; 20:271.
- Marty FM, Winston DJ, Rowley SD, et al. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. N Engl J Med 2013; 369:1227.
- Lischka P, Hewlett G, Wunberg T, et al. In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob Agents Chemother 2010; 54:1290.
- Melendez DP, Razonable RR. Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus. Infect Drug Resist 2015; 8:269.
- CLINICAL MANIFESTATIONS
- Active CMV infection
- CMV disease
- - Reduction of immunosuppression
- - Antiviral therapy
- Initial therapy
- Duration of therapy
- Adverse effects
- Laboratory monitoring for treatment response
- Resistance testing
- Drug-resistant CMV
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS