Subspecialty Clinics: Nephrology Management and Prevention of Cytomegalovirus Infection After Renal Transplantation
EMANUEL FARRUGIA, M.D., * THOMAS R. SCHWAB, M.D., Division of Nephrology and Internal Medicine
We reviewed the epidemiologic characteristics, diagnosis, clinical features, and management of cytomegalovirus (CMV) infection after renal transplantation. CMV, the major viral pathogen after renal transplantation, increases patient morbidity and mortality. The spectrum of CMV infection ranges from latent infection to asymptomatic viral shedding to life-threatening multisystem disease. The two major risk factors for the development of CMV infection in renal transplant recipients are (1) preexisting CMV antibody seropositivity of either the organ donor or the recipient and (2) host immunosuppression. Blood cultures (but not urine cultures) positive for CMV predict the progression of asymptomatic infection to CMV disease, characterized by fever, malaise, myalgia, leukopenia, abnormal transaminase levels, and often involvement of the lung and gut. New genomic methods of viral detection now offer diagnostic advantages, including methods of detecting only actively replicating CMV. No evidence shows that CMV directly causes allograft rejection or glomerulonephritis, but patients with tissue-invasive CMV disease have higher rates of allograft loss and mortality than do those without the disease. Therapy for established CMV disease includes decreasing the immunosuppressive therapy and administering the antiviral agent ganciclovir sodium. Proven prophylactic strategies include limitation of exposure to the virus from CMV seropositive blood or organ donors, administration of CMV-specific immune globulin, and use of high-dose acyclovir therapy. Preemptive therapy with ganciclovir is a promising alternative to propbylaxis for patients at highest risk for progression to symptomatic CMV disease, such as those with CMV viremia and seropositive recipients receiving antilymphocyte therapy.
Cytomegalovirus (CMV) is a DNA herpesvirus that silently infects up to 90% of the adult population.' CMV has long been recognized as the major viral pathogen during the first months after renal transplantation.' In a review of the literature, Glenn" estimated that CMV causes symptomatic disease in 35% and death in 2% of recipients of renal trans*Current address: St. Luke's Hospital, Malta. Address reprint requests to Dr. T. R. Schwab, Division of Nephrology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:879-890,1992
plants. CMV infection also substantially increases costs of renal transplantations because of extended durations of hospitalization. In a recent Canadian study, 4 patients with CMV disease were hospitalized a mean of 43 more days during the first year after kidney transplantation than patients without CMV disease. Control of CMV remains imperfect, and the optimal approach to prevention and treatment of this infection has yet to be determined. Advances in the diagnosis and management of CMV infection have raised hope that virus-associated morbidity and mortality in renal transplant patients may
879
880
Mayo Clio Proc, September 1992, Vol 67
MANAGEMENT AND PREVENTION OF CYTOMEGALOVIRUS
ultimately be eradicated. Herein we review the epidemiologic characteristics, diagnosis, clinical features, and management of CMV infection after renal transplantation.
EPIDEMIOLOGIC CHARACTERISTICS During renal transplantation, both the allograft and leukocyte-rich blood products can transmit exogenous virus from latently infected donors to the recipients.' (The terminology for CMV is listed in Table 1.) CMV DNA sequences have been identified in the walls of arteries, kidney tissue, and peripheral blood (CD3- and CD 14+ cells, most likely monocytes) of healthy seropositive persons.v" The estimated incidences of CMV infection and its progression to symptomatic disease in renal transplant patients are summarized in Table 2.9- 11 Differences in the intensity of posttransplant virologic monitoring, diagnostic test sensitivity, and immunosuppressive protocols are responsible for the wide range of reported rates of infections after transplantation. The seronegative donor-recipient combination is the only circumstance in which renal transplant patients are not exposed to a high risk of CMV infection (Table 2).12 Primary CMV infection is more likely to progress to CMV disease than is secondary CMV infection. 13 Secondarily infected recipients, however, outnumber those with primary infection; therefore, patients with CMV disease are evenly distributed between both groups. In seropositive renal transplant recipients, the frequency of CMV reactivation and reinfection with different CMV "strains" is not well established.":" Analysis of restriction endonuclease of viral DNA now makes it possible to distinguish between reinfection and reactivation by identifying different CMV strains." This technique may eventually be used in routine clinical management if the various CMV strains are shown to differ in either their pathogenic potential or their susceptibility to antiviral therapy. Several variables have been associated with an increased frequency of CMV infection in renal transplant patients (Table 3). Besides the CMV serologic status of the donor and recipient, the most important risk factor for the development of CMV infection is the degree of host immunosuppression. The net state of immunosuppression in the recipient is determined by the dose, type, duration, and temporal sequence of immunosuppressive therapy and by such variables as neutropenia, uremia, and the presence of immunomodulating viruses. 16 Although precise estimates for the risk of CMV infection with various immunosuppressive regimens are unavailable, cyclosporine- and azathioprine-treated patients apparently have similar incidences of CMV infection. 10 Polyclonal or monoclonal antilymphocyte preparations such as antilymphocyte globulin, antithymocyte globulin, and OKT3 are the most potent reactivators of active CMV
Table I.-Terminology for the Spectrum of Cytomegalovirus (CMV) Spectrum
Definition
CMV disease
Symptomaticor tissue-invasive active CMV infection; responsi'Jle for virus-associated morbidity and mortality
Active CMV infection
A primary or secondaryinfection that may be asymptomatic or symptomatic; characterizedby viral replication,viral shedding,and a specific immune responseto CMV Infection in previously uninfected,seronegativehosts; often causes symptomsin immunocompromised persons
Primary CMV infection
Secondary CMV infection
Infection in previously infected, seropositivehosts; caused by either reactivationof latent endogenousvirus or reinfection with new virus
Latent CMV infection
Lifelong persistenceof virus in healthy seropositivehosts; absent viral replication; immunosuppressed state frequently converts latent to active infection
infection. Antilymphocyte globulin not only increases the incidence of CMV disease threefold to fourfold in renal transplant patients'S" but also is associated with substantially increased mortality due to primary CMV infection. II The risk of active CMV infection developing is especially high if patients receive more than one antilymphocyte preparation-for example, antilymphocyte globulin for induction and OKT3 for subsequent rejection. Cyclosporine is a poor reactivator of CMV, but once the virus is activated, cyclosporine effectively blocks the cytotoxic T-cell response against CMV and thereby increases viral replication.'? These findings may explain the high incidence of relapses and the delay in onset of symptoms of CMV disease in the current era of transplantation in which sequential use of antilymphocyte therapy and cyclosporine is common. New immunosuppressive agents such as FK-506 and raparnycin will likely stimulate the development of CMV infection inasmuch as these drugs impair cell-mediated immunity. HLA antigens in renal transplant recipients may influence the development of CMV infection after transplantation. HLA-DR2 is associated with production of CMV-specific antibodies, and overt CMV disease occurs most frequently in recipients positive for HLA-B5 or A1. 20,21 Further work is
MANAGEMENT AND PREVENTION OF CYTOMEGALOVIRUS
Mayo Clio Proc, September 1992,Vol 67
Table 2.-Iocidences of Cytomegalovirus (CMV) Infection and Its Progression to Disease in Renal Transplant Patients Pretransplantation CMV IgG antibody status
Incidence (%) Infection
Symptomatic disease
Primary infection Donor positive and recipient negative Donor negative and recipient negative
70-90
50-60
Secondary infection Donor positive and recipient positive Donor negative and recipient positive
50-80*
0-10
20-40
EMANUEL FARRUGIA, M.D., * THOMAS R. SCHWAB, M.D., Division of Nephrology and Internal Medicine
We reviewed the epidemiologic characteristics, diagnosis, clinical features, and management of cytomegalovirus (CMV) infection after renal transplantation. CMV, the major viral pathogen after renal transplantation, increases patient morbidity and mortality. The spectrum of CMV infection ranges from latent infection to asymptomatic viral shedding to life-threatening multisystem disease. The two major risk factors for the development of CMV infection in renal transplant recipients are (1) preexisting CMV antibody seropositivity of either the organ donor or the recipient and (2) host immunosuppression. Blood cultures (but not urine cultures) positive for CMV predict the progression of asymptomatic infection to CMV disease, characterized by fever, malaise, myalgia, leukopenia, abnormal transaminase levels, and often involvement of the lung and gut. New genomic methods of viral detection now offer diagnostic advantages, including methods of detecting only actively replicating CMV. No evidence shows that CMV directly causes allograft rejection or glomerulonephritis, but patients with tissue-invasive CMV disease have higher rates of allograft loss and mortality than do those without the disease. Therapy for established CMV disease includes decreasing the immunosuppressive therapy and administering the antiviral agent ganciclovir sodium. Proven prophylactic strategies include limitation of exposure to the virus from CMV seropositive blood or organ donors, administration of CMV-specific immune globulin, and use of high-dose acyclovir therapy. Preemptive therapy with ganciclovir is a promising alternative to propbylaxis for patients at highest risk for progression to symptomatic CMV disease, such as those with CMV viremia and seropositive recipients receiving antilymphocyte therapy.
Cytomegalovirus (CMV) is a DNA herpesvirus that silently infects up to 90% of the adult population.' CMV has long been recognized as the major viral pathogen during the first months after renal transplantation.' In a review of the literature, Glenn" estimated that CMV causes symptomatic disease in 35% and death in 2% of recipients of renal trans*Current address: St. Luke's Hospital, Malta. Address reprint requests to Dr. T. R. Schwab, Division of Nephrology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 67:879-890,1992
plants. CMV infection also substantially increases costs of renal transplantations because of extended durations of hospitalization. In a recent Canadian study, 4 patients with CMV disease were hospitalized a mean of 43 more days during the first year after kidney transplantation than patients without CMV disease. Control of CMV remains imperfect, and the optimal approach to prevention and treatment of this infection has yet to be determined. Advances in the diagnosis and management of CMV infection have raised hope that virus-associated morbidity and mortality in renal transplant patients may
879
880
Mayo Clio Proc, September 1992, Vol 67
MANAGEMENT AND PREVENTION OF CYTOMEGALOVIRUS
ultimately be eradicated. Herein we review the epidemiologic characteristics, diagnosis, clinical features, and management of CMV infection after renal transplantation.
EPIDEMIOLOGIC CHARACTERISTICS During renal transplantation, both the allograft and leukocyte-rich blood products can transmit exogenous virus from latently infected donors to the recipients.' (The terminology for CMV is listed in Table 1.) CMV DNA sequences have been identified in the walls of arteries, kidney tissue, and peripheral blood (CD3- and CD 14+ cells, most likely monocytes) of healthy seropositive persons.v" The estimated incidences of CMV infection and its progression to symptomatic disease in renal transplant patients are summarized in Table 2.9- 11 Differences in the intensity of posttransplant virologic monitoring, diagnostic test sensitivity, and immunosuppressive protocols are responsible for the wide range of reported rates of infections after transplantation. The seronegative donor-recipient combination is the only circumstance in which renal transplant patients are not exposed to a high risk of CMV infection (Table 2).12 Primary CMV infection is more likely to progress to CMV disease than is secondary CMV infection. 13 Secondarily infected recipients, however, outnumber those with primary infection; therefore, patients with CMV disease are evenly distributed between both groups. In seropositive renal transplant recipients, the frequency of CMV reactivation and reinfection with different CMV "strains" is not well established.":" Analysis of restriction endonuclease of viral DNA now makes it possible to distinguish between reinfection and reactivation by identifying different CMV strains." This technique may eventually be used in routine clinical management if the various CMV strains are shown to differ in either their pathogenic potential or their susceptibility to antiviral therapy. Several variables have been associated with an increased frequency of CMV infection in renal transplant patients (Table 3). Besides the CMV serologic status of the donor and recipient, the most important risk factor for the development of CMV infection is the degree of host immunosuppression. The net state of immunosuppression in the recipient is determined by the dose, type, duration, and temporal sequence of immunosuppressive therapy and by such variables as neutropenia, uremia, and the presence of immunomodulating viruses. 16 Although precise estimates for the risk of CMV infection with various immunosuppressive regimens are unavailable, cyclosporine- and azathioprine-treated patients apparently have similar incidences of CMV infection. 10 Polyclonal or monoclonal antilymphocyte preparations such as antilymphocyte globulin, antithymocyte globulin, and OKT3 are the most potent reactivators of active CMV
Table I.-Terminology for the Spectrum of Cytomegalovirus (CMV) Spectrum
Definition
CMV disease
Symptomaticor tissue-invasive active CMV infection; responsi'Jle for virus-associated morbidity and mortality
Active CMV infection
A primary or secondaryinfection that may be asymptomatic or symptomatic; characterizedby viral replication,viral shedding,and a specific immune responseto CMV Infection in previously uninfected,seronegativehosts; often causes symptomsin immunocompromised persons
Primary CMV infection
Secondary CMV infection
Infection in previously infected, seropositivehosts; caused by either reactivationof latent endogenousvirus or reinfection with new virus
Latent CMV infection
Lifelong persistenceof virus in healthy seropositivehosts; absent viral replication; immunosuppressed state frequently converts latent to active infection
infection. Antilymphocyte globulin not only increases the incidence of CMV disease threefold to fourfold in renal transplant patients'S" but also is associated with substantially increased mortality due to primary CMV infection. II The risk of active CMV infection developing is especially high if patients receive more than one antilymphocyte preparation-for example, antilymphocyte globulin for induction and OKT3 for subsequent rejection. Cyclosporine is a poor reactivator of CMV, but once the virus is activated, cyclosporine effectively blocks the cytotoxic T-cell response against CMV and thereby increases viral replication.'? These findings may explain the high incidence of relapses and the delay in onset of symptoms of CMV disease in the current era of transplantation in which sequential use of antilymphocyte therapy and cyclosporine is common. New immunosuppressive agents such as FK-506 and raparnycin will likely stimulate the development of CMV infection inasmuch as these drugs impair cell-mediated immunity. HLA antigens in renal transplant recipients may influence the development of CMV infection after transplantation. HLA-DR2 is associated with production of CMV-specific antibodies, and overt CMV disease occurs most frequently in recipients positive for HLA-B5 or A1. 20,21 Further work is
MANAGEMENT AND PREVENTION OF CYTOMEGALOVIRUS
Mayo Clio Proc, September 1992,Vol 67
Table 2.-Iocidences of Cytomegalovirus (CMV) Infection and Its Progression to Disease in Renal Transplant Patients Pretransplantation CMV IgG antibody status
Incidence (%) Infection
Symptomatic disease
Primary infection Donor positive and recipient negative Donor negative and recipient negative
70-90
50-60
Secondary infection Donor positive and recipient positive Donor negative and recipient positive
50-80*
0-10
20-40
