Management and Prevention of Cytomegalovirus Infection After Renal Transplantation

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

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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

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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 <55t

*Reflects CMV reactivation or reinfection. tRefiects CMV reactivation.

needed to confirm these findings and to establish the involved mechanisms. CMV infection in renal transplant patients does not always progress to symptomatic, tissue-invasive disease. In a recent study of CMV-infected kidney and kidney-pancreas transplants, increased rates of allograft loss and mortality were observed only in patients with tissue-invasive CMV disease." Early identification of this subset of patients at high risk for the development of severe CMV disease and prompt therapy for CMV should theoretically decrease CMV-associated morbidity and mortality. Several clinical and laboratory variables that have been associated with the progression of CMV infection to symptomatic CMV disease are listed in Table 4. Although CMV viremia is predictive of eventual CMV disease, its precise predictive value in renal transplant patients has not yet been determined. A recent multivariate analysis by Dunn and associates" revealed that rejection therapy, age older than 50 years, and transplantation of an organ from a seropositive donor were all significant variables that predisposed renal transplant patients to tissue-invasive CMV. Urine cultures

Table 3.-Factors Predisposing to Cytomegalovirus (CMV) Infection in Renal Transplant Patients Donor CMV seropositivity Recipient CMV seropositivity Posttransplantation blood transfusions from CMV seropositive donors Cadaveric transplant* HLA mismatch between donor and recipient* Acute rejection* Antilymphocyte therapy* Recipient HLA phenotype (DR2 and AI) *These factors reflect an enhanced net state of immunosuppression. Data from references 3, II, 13, and 17-23.

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positive for CMV and lymphocyte subset counts after transplantation are not predictive of symptomatic CMV infection." Clearly, further studies are needed for better identification of the subset of patients in whom CMV infection will progress to clinically important disease. DIAGNOSTIC TESTS Diagnostic tests for CMV infection rely on demonstration of a serologic response or detection of the virus. During viral replication, gene expression occurs in three sequential phases-immediate early, early, and late. The resultant proteins, especially the immediate early antigen as well as various membrane and viral capsid proteins, elicit both humoral and cellular immune responses in the host. 1.29-32 In renal transplant patients, techniques that demonstrate the presence of virus provide a rapid diagnosis, allow confirmation of the anatomic site of infection (for example, CMV esophagitis in a patient with dysphagia), and, most importantly, do not rely on the ability of the patient to mount an IgM antibody response inasmuch as it may not be produced during primary CMV infection in immunocompromised transplant recipients.Y' Serologic Testing for CMV.-Serologic detection of CMV is most useful for pretransplant stratification of patients because both donor and recipient seropositivities are associated with an increased risk of development of CMV infection. Several serologic tests with various sensitivities and specificities are commercially available for detecting IgG and IgM antibodies." The anticomplement immunofluorescence test is the serologic method used at the Mayo Clinic. An IgG titer that equals or exceeds 1:10 is indicative of past infection, whereas a fourfold increase in IgG titer or IgM that equals or exceeds 1:lOis diagnostic of acute infection. The passive transfer of CMV IgG antibodies with blood products may produce "seroconversion" if sensitive IgG assays are used. Thus, all renal transplant recipients with apparent primary infections should be reassessed to ensure that the antibody persists.' Immunoblotting techniques facilitate analysis of the pattern of anti-CMV antibodies produced but still do not diagnose CMV earlier than do viral detection techniques."

Histopathologic or CytopathologicFeatures ofCMV.-

CMV can be recognized in histologic preparations by the characteristic "owl's eye" inclusion bodies (Fig. 1). These diagnostic Cowdry type A intranuclear inclusions indicate tissue-invasive CMV infection but are not sensitive. Electron microscopy has a limited, if any, role in the diagnosis of CMV because this method fails to distinguish among the various human herpesviruses and also because of an unacceptable high false-negative rate. 1 Viral Cultures.-The isolation of CMV in cell culture systems remains the most widely used test to diagnose active

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Table4.-Factors AssociatedWith Progression of Cytomegalovirus(CMV)Infection to Symptomatic CMV Disease CMVviremia or antigenemia":" (especially if detected early aftertransplantation) Primary greaterthan secondary CMVinfection" Reinfection greaterthan reactivation" Absence of CMVIgM production in renal transplant recipient" Antilymphocyte therapy'<'? Infection of allograft by CMV (?)13

CMV infection because of the sensitivity and high specificity. Unlike conventional tube-cell cultures, current shell-vial culture techniques do not necessitate the demonstration of a CMV-specific cytopathic effect as a diagnostic endpoint. A monoclonal antibody against early viral antigen is used to detect CMV in this fluorescence assay.":" Results are rapid-often within 24 to 48 hours. New Methods of Viral Detection.-Antigenic and genomic methods of detection for the diagnosis of CMV infection are increasingly being applied to tissue specimens (such as lung or kidney), blood, and urine samples and offer advantages over culture methods. 26,3? 42 These methods provide a rapid diagnosis and have sensitivities and specificities similar to or better than those obtained with viral culture. The presence of CMV in the blood can also be detected earlier by using the antigenemia test or polymerase chain reaction rather than viral culture. As expected, CMV antigen

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and DNA have been shown to persist in the blood longer than culturable virus. Earlier diagnosis of viremia facilitates earlier institution of therapy. Although viremia detected by culture or by the antigenemia test has been shown to predict progression to CMV disease, the clinical significance of polymerase chain reaction positivity in blood or tissue is as yet unclear. Recent studies suggest that, although polymerase chain reaction-positive viremia may reflect a latent CMV state, polymerase chain reaction positivity in the renal allograft is likely to indicate active CMV disease. 38,4o.42 Quantification of viral load by CMV DNA or antigen can potentially be used to predict clinical CMV in addition to providing precise monitoring and guiding treatment." Polymerase chain reaction of CMV RNA potentially will detect only actively replicating CMV. Finally, in the future, investigators may be able to use polymerase chain reaction techniques to test allografts and blood products for the presence of latent CMV infection rather than relying solely on the serologic status of prospective organ or blood donors. In this regard, persons with positive polymerase chain reaction for CMV in blood but negative CMV serology have recently been identified."

CLINICAL FEATURES

CMV disease usually manifests within 2 to 6 months after renal transplantation. Occasionally, CMV disease occurs years after renal transplantation, probably because of a community-acquired infection. CMV infection can directly affect almost every organ system in the body. Frequently, however, the initial manifestations are fever and constitutional symptoms such as malaise, fatigue, anorexia, myalgias, and arthralgias (Table 5). Leukopenia, thrombocytopenia, atypical lymphocytosis, and serum transaminase disturbance are common laboratory findings. This mononucleosis-like syndrome, however, can also occur in patients with Epstein-Barr virus infection after transplantation. CMV directly suppresses the host's cellular immune response. CMV infection is associated with suppression of monocyte and natural killer cell functions, lymphocyte hyporeactivity, a severe decrease in helper T cells, and an increase in cytotoxic/suppressor T cells. 43A4 This enhanced immunosuppression predisposes the recipient to life-threatening opportunistic infections with organisms such as Pneumocystis carinii, Listeria monocytogenes, Aspergillus, Candida, and gram-negative bacteria.'? At highest risk for superinfection are those CMV-infected recipients with severe leukopenia (less than I,SOO/mm3) and inverted CD4/ CD8 ratios." Site-specific CMV disease typically becomes apparent I Fig, 1. Characteristic histologic appearance of cytomegalic or 2 weeks after initial symptoms. In renal transplant paintranuclear inclusion bodies in alveolar cellsof lung. (Hematoxytients, the respiratory and gastrointestinal tracts are the two lin-eosin; original magnification, x800.)

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Table 5.-Clinical Manifestations of Cytomegalovirus Disease in Renal Transplant Recipients Common manifestations Fever Malaise, anorexia, myalgias, arthralgias Hematologic abnormalities Superinfection with other microorganisms Pneumonitis Gastrointestinal ulcers Hepatitis Chorioretinitis (late onset) Allograft dysfunction (cytomegalovirus-related glomerulopathy, acute rejection, or both) (?) Rare manifestations Skin rashes or ulcers, hepatosplenomegaly, lymphadenopathy, myopericarditis, pancreatitis, acalculous cholecystitis, encephalitis, Guillain-Barre syndrome, adrenalitis

organ systems most commonly affected. Clinical features of CMV pneumonitis include a subacute onset, dry cough, tachypnea, dyspnea, hypoxemia, and abnormal findings on a chest roentgenogram that may range from a subtle micronodular appearance to a diffuse bilateral whiteout.v'? CMV pneumonitis is diagnosed by detecting virus in biopsy specimens of lung tissue or from a bronchoalveolar lavage specimen. Abdominal or chest pain, nausea, vomiting, weight loss, dysphagia, altered bowel habit, or occult bleeding can all be initial symptoms of CMV disease affecting the gUt. 45 The virus may cause ulceration, bleeding, or, rarely, perforation of any part of the gut, although the stomach, proximal small bowel, and cecum seem preferentially af-fected." A definitive diagnosis necessitates detection of CMV in biopsy specimens of gut tissue because gross endoscopic findings are nonspecific. CMV retinitis is a frequent complication in patients with acquired immunodeficiency syndrome (AIDS) but is relatively uncommon in renal transplant patients."? Chorioretinitis may either follow an early episode of CMV disease or be the sole manifestation of CMV infection. 17 Diagnosis is based on the distinctive clinical funduscopic appearance of a gradually expanding, whitish necrotic retinitis. Does CMV infection cause renal allograft dysfunction? Some indirect evidence supports the theory that CMV can trigger acute rejection or cause a specific CMV renal lesion distinct from classic rejection (or both). First, CMV can infect and replicate in various types of cells of human kidney." CMV DNA, antigen, and, rarely, characteristic intranuclear inclusion bodies have been demonstrated in renal tissue from CMV-infected patients with renal allograft dysfunction. 40 ,4 1,49,50 Second, CMV infection seems to infect the grafted organ preferentially. CMV-related hepatitis and CMV-associated myocarditis are most common among liver

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and cardiac transplant patients, respectively. 13 Therefore, the occurrence of CMV-related nephritis in renal transplant patients should not be surprising. Third, in renal transplant patients who have viremia and immediate deterioration in allograft function, allograft biopsy specimens have revealed a glomerular lesion characterized by swelling of endothelial cells, necrosis, and deposition of fine fibrillary material between cells." An inconsistent improvement in allograft function was also observed after decreasing immunosuppressive medications. In the original description of this "CMV glomerulopathy," however, CMV was not detected in the kidney by either electron microscopic or immunohistochemical studies. Direct evidence that CMV causes renal graft rejection or glomerulonephritis is lacking, however. Investigators have been unable to confirm that the aforementioned glomerular lesion seen in renal transplant recipients is related to CMV infection.F-" Rather, this lesion is morphologically akin, if not identical, to the transplantation-related glomerulopathy that typically occurs in the context of vascular 'rejection. Furthermore, CMV glomerulopathy has not been noted in native kidneys of CMV-infected patients who have not undergone kidney transplantation. Clinical rejection also has not been shown to correlate with CMV activity, as assessed by serology or by the presence of CMV early nuclear antigen in the allograft. 54.55 MANAGEMENT Efforts to control the effects of CMV infection in renal transplant patients will be addressed in three categories: treatment-the aim is to eradicate established symptomatic CMV disease; prophylaxis-the goal is to prevent primary or secondary CMV infection; and preemptive therapy-the aim is to prevent progression from active but asymptomatic CMV infection (usually, positive blood or urine cultures or both) to symptomatic CMV disease.

Treatment of Established CMV Disease.-Decreasing

immunosuppressive therapy is a highly desirable first step, but close surveillance is necessary to avoid breakthrough acute allograft rejection. If possible, ongoing use of antilymphocyte globulin or OKT3 therapy should be discontinued. In patients with leukopenia, use of azathioprine is decreased or discontinued. In patients without leukopenia who are receiving triple immunosuppressive treatment, the dose of both cyclosporine and azathioprine may be decreased. Supportive treatment includes adequate hydration, analgesia, antipyretic agents, and specific organ support-for example, mechanical ventilation as necessary. In cases of CMV disease, prophylaxis against P. carinii infection with either trimethoprim-sulfamethoxazole or aerosolized pentamidine is continued or resumed as appropriate.

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GancicIovir Sodium.-Specific antiviral therapy with ganciclovir sodium is now considered first-line treatment in the management of CMV disease in renal transplant patients. Ganciclovir is a structural analogue of the nucleoside deoxyguanosine, an essential building block of DNA. Ganciclovir is preferentially phosphorylated inside the CMV-infected cell, and the product ganciclovir triphosphate competes with deoxyguanosine for uptake by the viral DNA polymerase; eventually, viral DNA chain elongation is terminated. In most immunocompromised patients with CMV disease, CMV is eliminated from the blood, urine, and respiratory secretions within 8 days after the initiation of ganciclovir treatment. 56 In renal transplant patients, ganciclovir decreases rates of viral shedding, improves clinical findings, alleviates symptoms, and arrests progression of CMV disease. 23,45,57.60 Although no placebo-controlled or comparative studies of ganciclovir in the treatment of CMV disease in solid organ transplantation have been reported, the consensus is that therapy with ganciclovir improves both allograft and patient survival in patients with CMV disease. With ganciclovir therapy, concurrent CMV disease and acute rejection in renal transplant patients can be treated simultaneously without detrimental effects on allograft surviva1. 6 1. 64 Currently, ganciclovir is available only in an intravenous form. Bioavailability after oral administration is low. Ganciclovir is administered as a l-hour infusion.f mg/kg of body weight every 12 hours for 14 to 21 days. The kidney is the major route of excretion of ganciclovir; therefore, the dosage should be decreased in patients with renal impairment. Recommended dosage modifications during ganciclovir induction therapy are based on calculated creatinine clearance, as follows: 50 to 80 mUmin-2.5 mg/kg every 12 hours; 25 to 50 ml/min-2.5 mg/kg every 24 hours; and less than 25 mUmin-1.25 mg/kg every 24 hours. Levels of ganciclovir in the blood are decreased by 50% after 4 hours of hemodialysis; thus, ganciclovir must be readministered shortly after dialysis." The optimal duration of ganciclovir therapy in renal transplant patients is unknown. Unlike treatment of CMV in patients with AIDS, long-term maintenance therapy is seldom required in recipients of solid organs and bone marrow. At the Mayo Clinic, we continue ganciclovir therapy for at least 1 week after the patient becomes afebrile or after a blood culture is negative for CMV. In studies of bone marrow transplant recipients, a negative result of a polymerase chain reaction assay in either blood or urine at the conclusion of antiviral therapy seemed a better marker for effective antiviral treatment than did clinical improvement or negative blood cultures. 66 •67 In renal transplant patients, a polymerase chain reaction-positive assay might also indicate that ganciclovir therapy should be continued.

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CMV disease may fail to respond (no diminution in symptoms or persistent viral shedding) to the initial treatment course of ganciclovir, but this finding is uncommon. Dunn and colleagues" found that ganciclovir produced an 89.2% 30-day cure rate in renal transplant patients with tissue-invasive CMV disease. CMV disease recurs or relapses, however, in about 20% of renal transplant patients." The Mayo Clinic practice is to re-treat relapses of CMV disease with ganciclovir. Viral resistance to ganciclovir should be suspected in patients whose condition fails to improve or who have frequent relapses during ganciclovir therapy. Resistant strains have been noted in clinical isolates before and after ganciclovir therapy. 68 Development of resistance seems mediated principally by mutations in the viral DNA polymerase gene. When CMV disease is refractory to therapy, different CMV strains may have different sensitivities to ganciclovir. Adverse effects of ganciclovir therapy include reversible neutropenia and thrombocytopenia, azoospermia, and central nervous system symptoms. In renal transplant patients, the incidence of neutropenia is much lower than in CMVinfected patients with AIDS who receive long-term treatment. Although mild increases in serum creatinine concentration are occasionally noted after institution of ganciclovir therapy, no evidence shows that short-term use of ganciclovir is responsible for renal dysfunction. The longterm safety of this drug in adults and especially in pediatric renal transplant recipients remains to be established." Foscarnet Sodium.-Foscarnet sodium (trisodium phosphonoformate) is a viral DNA polymerase inhibitor that has been shown to be effective in treating CMV retinitis in patients with AIDS.70 Like ganciclovir, foscarnet is virustatic and does not eradicate latent CMV infection. Experience with its use in renal transplant patients has been anecdotal, and the indications for use of this drug in the treatment of CMV disease remain to be determined." The short plasma half-life of the drug necessitates its administration as a continuous intravenous infusion, although l-hour infusions every 8 hours seem an acceptable alternative. In patients with normal renal function, foscarnet is eliminated primarily by the kidney and does not undergo hepatic metabolism or biliary secretion. Further study is needed to delineate target peak and trough concentrations and optimal dosing regimens for patients with normal or impaired renal function." Adverse effects include nephrotoxicity, seizures, hypomagnesemia, and hypocalcemia.P" however, little, if any, myelosuppression occurs with this agent. Increases in serum creatinine concentration attributed to foscarnet therapy add anothercomplex issue during the follow-up of renal transplant patients. Combination Strategies.-The combination of ganciclovir and CMV-specific or polyvalent immune globu-

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lin has been reported to improve survival significantly after the first episode of CMV pneumonitis in recipients of allogeneic bone marrow transplants." Combination therapy may also have a role in bone marrow transplant recipients with gastrointestinal CMV disease because ganciclovir alone has not been shown to benefit this subset of patients." In recipients of solid organ transplants, including kidney, investigators have been unable to determine whether adding immune globulin to ganciclovir or foscarnet therapy improves survival rates observed with the use of monotherapy. Although intravenously administered CMV hyperimmune globulin has been successfully used as sole treatment of CMV infection in allograft recipients, interest now focuses mainly on combination therapy with ganciclovir." Combination therapy may have a role in renal transplant patients with fulminant CMV disease, relapsing CMV disease, CMV pneumonitis, or CMV gastrointestinal disease. Combination antiviral therapy with ganciclovir and foscarnet also should be investigated because, in vitro, these agents are synergistic for antiviral activity." Combination therapy has the added advantage that it may decrease toxicities and the development of clinically important drug-resistant strains." Investigational Agents.-Besides ganciclovir and foscarnet, other agents exhibit in vitro activity against CMV. These antiviral drugs include oral forms of ganciclovir and foscarnet, prodrug forms of acyclovir and ganciclovir, fluorinated pyrimidines, and cyclobutyl compounds.Y" Several important and novel approaches are currently being investigated in the treatment of CMV disease. The ultimate goal is to use these new agents prophylactically. One approach is designed to restore or augment CMV-specific immunity in the host by adoptive immunotherapy that transfers "protective" CMV-specific T-cell clones from the donor to the recipient. Currently, clinical trials are under way in bone marrow transplant recipients." Another approach is to administer anti-CMV monoclonal antibodies that will kill CMV-infected cells in patients with CMV disease." Prevention of CMV Infection.- The available options for preventing CMV infection and disease are summarized in Table 6. Currently, it is impossible to provide specific recommendations about which strategy is most effective in preventing CMV-associated morbidity and mortality. For example, a direct comparison of the benefit, toxicity, and cost of prophylactic therapy with either CMV-specific immune globulin or high-dose acyclovir and preemptive ganciclovir therapy has not been performed. Protective Matching of Donor and Recipient-The role of protective matching to avoid transplanting a kidney from a seropositive donor into a seronegative recipient is controversial. Debate exists in the literature about the effect of this strategy on the incidence of clinical CMV disease and on graft and patient survival.v" Allocation of kidneys on

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the basis of CMV compatibility further limits the already small pool of available donor organs and prolongs the waiting time for a transplant. Therefore, at the Mayo Clinic, we do not use protective matching of the donor and recipient for either cadaveric or living-related donor organs. Avoidance of Blood Producta-c-Avoiding blood products from CMV-seropositive donors appreciably decreases the incidence of primary CMV infection in renal transplant recipients. Reducing the leukocyte concentration in blood products by filtration also substantially decreases the risk of infection." Currently, we administer only CMV-negative blood to seronegative recipients. The extent of the effect of preventing transfusion-transmitted CMV infection in CMVseropositive recipients is still unclear. Active Immunization.-In one study, immunization of candidates for renal transplantation with the live attenuated Towne vaccine significantly decreased the severity of CMV disease in seronegative patients who received kidneys from seropositive donors." Between the placebo- and vaccinetreated patients, however, no difference was noted in rates of CMV infection or disease. Because even naturally acquired infection does not confer immunity to reactivation of CMV or reinfection with another strain, it is not surprising that efficacy of vaccination in preventing infection has not been demonstrated. Furthermore, patients with chronic renal failure mount an attenuated humoral and cellular immune response to the vaccine in comparison with healthy volunteers. Nevertheless, modification of CMV infection by vaccination may still be a worthwhile option. Efforts to develop an effective subunit (for example, an envelope glycoprotein) vaccine are currently under way." The subunit approach is preferred because it potentially lacks the hazard of oncogenicity. Passive Immunization.-In two studies by Snydman and co-workers.t"? anti-CMV immune globulin was shown to decrease the incidence of symptomatic CMV-associated disease by 65% in seronegative recipients of kidneys from seropositive donors. The incidence of CMV infection, however, was unaffected by anti-CMV immune globulin. The decrease in CMV disease was observed even when the patients were grouped on the basis of type of therapy for rejection, and the tendency (although not statistically significant) was toward a decrease in patient mortality. Whether CMV -specific immune globulin will protect seropositive renal transplant patients who seem at risk for CMV disease either from reinfection or from reactivation is unknown. Currently, anti-CMV immune globulin is licensed by the Food and Drug Administration only for prophylaxis of CMV infection in donor-positive and recipientnegative combinations. The mechanism of action of anti-CMV immune globulin is unknown. The antibody may directly neutralize CMV

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Table 6.-8trategies for Prevention of Cytomegalovirus (CMV) Infection and Disease* Recipient pos, donor pos or neg

Recipient neg, donor neg

Recipient neg, donorpos

Prophylaxis Give only CMV-negative blood Transplant only CMV-negative kidneys High-dose acyclovir] CMV-specific immune globulint

Yes Yes No No

Yes Yes Yes

No No Yes Yes

Preemptive therapy Ganciclovir sodium during ALG or OKT3 induction therapy or for rejection Ganciclovir for pos urine culture Ganciclovir for pos blood culture

No Yes Yes

Yes Yes Yes

Yes No Yes

Strategy

*ALG =antilymphocyte globulin; neg =negative for CMV; pos tRegimens tested in randomized controlled trials.

antigen, block cytotoxic T-cell recognition of virus-infected cells, or enhance antibody-dependent cell-mediated cytotoxicity against the virus. The optimal dose, duration, and timing of CMV immune globulin remain to be established. Snydman and associatesw'? administered 150 mglkg of antiCMV immune globulin within 72 hours after transplantation, 100 mglkg at 2, 4, 6, and 8 weeks after transplantation, and 50 mglkg at 12 and 16 weeks after transplantation. Although a complete course costs approximately $4,800 per patient, prophylaxis with anti-CMV immune globulin has been determined to be cost-effective in recipient-negative and donor-positive combinations." Several studies have used pooled intravenously administered immunoglobulin instead of anti-CMV immune globulin; however, no evidence shows that one product is superior to the other." Both products are safe and have no risk of transfusion-associated disease. Antiviral Agents.-In one study, oral administration of high-dose acyclovir (0.8 to 3.2 g daily) instituted at the time of transplantation and continued for 12 weeks significantly decreased the incidence of CMV disease in renal transplant recipients." Despite small numbers of patients and an unusual 100% attack rate in control subjects, acyclovir-treated seronegative recipients who received grafts from seropositive donors were strongly protected from the development of CMV infection and disease. Acyclovir therapy was associated with no adverse effects. The absence of nephrotoxicity was likely due to dose adjustments for renal dysfunction. The mechanism for the anti-CMV activity of acyclovir is not completely understood. Of interest, acyclovir is clinically effective even when plasma concentrations of the drug are below the mean in vitro concentrations necessary for 50% inhibition of the patient's viral isolates." Currently, no controlled data are available on the role of ganciclovir or foscamet in the prophylaxis of CMV disease

=positive for CMV.

in renal transplant patients. Several trials are examining ganciclovir monotherapy, ganciclovir in combination with anti-CMV immune globulin, and ganciclovir followed by a high-dose acyclovir regimen in the prevention of primary and secondary infection and disease in renal and other solid organ transplant patients. In a recent randomized controlled study in which ganciclovir was administered prophylactically for 28 days after cardiac transplantation, the incidence of CMV disease in seropositive patients was significantly decreased." Preemptive Therapy.-Preemptive therapy has been broadly defined as highly effective therapy administered during a brief period to a few patients who are at highest risk for serious disease." By using this definition, candidates for preemptive therapy include not only recipients with asymptomatic viremia but also patients with latent infection at high risk for CMV reactivation. Thus, preemptive strategies reserve antiviral therapy for those patients who are most likely to benefit. In contrast, prophylactic regimens are administered to numerous recipients. A substantial proportion of these recipients (perhaps half), however, are not at risk for CMV-associated morbidity and mortality and therefore, while incurring the cost of therapy, are unlikely to benefit from prophylaxis. Preemptive therapy strategies have successfully prevented progression of asymptomatic active CMV infection to tissue-invasive disease in bone marrow transplant recipients.T" G~mciclovir.-Preemptive therapy with ganciclovir is still experimental in renal transplant recipients. The success of this strategy relies heavily on early identification of patients who are at high risk for the development of morbid CMV disease. Thus, routine blood and urine cultures (for example, at 2-week intervals during the first 3 months) are necessary in all recipients except the donor-negative and recipient-negative combination, provided the latter group

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receives only CMV-negative blood products during that period. The optimal frequency of surveillance cultures remains to be determined. Since early 1991, all Mayo Clinic asymptomatic patients with CMV viremia have been treated with ganciclovir. In addition, we have administered ganciclovir to patients receiving antilymphocyte therapy if either the donor or the recipient is CMV -antibody seropositive. Whether the latter category of patients (who are not actively shedding virus) is receiving preemptive rather than prophylactic antiviral therapy is semantic. The rationale for using CMV seropositivity as an indication to initiate therapy is that, in some patients, clinical CMV disease develops without a preceding CMV viremia." Preliminary uncontrolled studies also indicate a promising role for preemptive therapy with ganciclovir after renal transplantation. In one study, CMV viremia developed in 6 of 20 recipients of combined kidney-pancreas transplants who received induction antilymphocyte globulin therapy and ganciclovir for 20 days followed by high-dose acyclovir as outpatients." In a pilot study, symptomatic CMV disease occurred in only Zof 19 seropositive renal transplant patients who received ganciclovir (2.5 mglkg daily) during treatment with OKT3 for acute rejection.'?' Immune Globulin.-Polyimmune y-globulin intravenously administered to seropositive renal transplant recipients who are receiving antilymphocyte therapy may decrease the incidence and severity of CMV reactivation.P'v" Further studies are needed to determine whether preemptive therapy with ganciclovir or immune globulin (or both) should replace or complement the traditional prophylaxis of anti-CMV immune globulin or acyclovir.

ACKNOWLEDGMENT We thank Randall C. Walker, M.D., for reviewing our manuscript and Monica I. Poncelet for secretarial assistance. REFERENCES I. Griffiths PD: Cytomegalovirus. In Principles and Practice of Clinical Virology. Second edition. Edited by AJ Zuckerman, JE Banatvala, JR Pattison. Chichester, England, John Wiley & Sons, 1990, pp 69-102 2. Rifkind D: Cytomegalovirus infection after renal transplantation. Arch Intern Med 116:554-558,1965 3. Glenn J: Cytomegalovirus infections following renal transplantation. Rev Infect Dis 3:1151-1178,1981 4. McCarthy M, Karim M, Krueger H, Keown P: The cost impact of cytomegalovirus disease in renal transplant recipients (abstract). J Am Soc Nephrol 2:807, 1991 5. Zaia JA: Epidemiology and pathogenesis of cytomegalovirus disease. Semin Hematol 27 (Suppll):5-1O, 1990 6. Taylor-Wiedeman J, Sissons JGP, Borysiewicz LK, Sinclair JH: Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol 72:20592064, 1991 7. Hendrix MGR, Daemen M, Bruggeman CA: Cytomegalovirus nucleic acid distribution within the human vascular tree. Am J Pathol 138:563-567, 1991

MANAGEMENT AND PREVENTION OF CYTOMEGALOVIRUS

8.

887

Nelson JA, Gnann JW Jr, Ghazal P: Regulation and tissue-specific expression of human cytomegalovirus. Curr Top Microbiol Immunol 154:75-100,1990 9. Davis CL: The prevention of cytomegalovirus disease in renal transplantation. Am J Kidney Dis 16:175-188, 1990 10. Metselaar HJ, Weimar W: Cytomegalovirus infection and renal transplantation. J Antimicrob Chemother 23 (Suppl E):37-47, 1989 11. Rubin RH, Tolkoff-Rubin NE, Oliver D, Rota TR, Hamilton J, Betts RF, Pass RF, Hillis W, Szmuness W, Farrell ML, Hirsch MS: Multicenter seroepidemiologic study of the impact of cytomegalovirus infection on renal transplantation. Transplantation 40:243249, 1985 12. Rocha E, Campos HH, Rouzioux C, Le Bihan C, Landais P, Legendre C, Kreis H: Cytomegalovirus infections after kidney transplantation: identical risk whether donor or recipient is the virus carrier. Transplant Proc 23:2638-2640, 1991 13. Ho M: Cytomegalovirus infection and indirect sequelae in the immunocompromised transplant patient. Transplant Proc 23 (Suppll):2-7,1991 14. Chou S: Acquisition of donor strains of cytomegalovirus by renaltransplant recipients. N EnglJ Med 314:1418-1423,1986 15. Grundy JE, Lui SF, Super M, Berry NJ, Sweny P, Fernando ON, Moorhead J, Griffiths PD: Symptomatic cytomegalovirus infection in seropositive kidney recipients: reinfection with donor virus rather than reactivation of recipient virus. Lancet 2:132-135, 1988 16. Morris DJ, Longson M, Poslethwaite RI, Mallick NP, Johnson RWG: Donor seropositivity and prednisolone therapy as risk factors for cytomegalovirus infection and disease in cycJosporintreated renal allograft recipients. Q J Med 77:1165-1173, 1990 17. Rubin RH: Infection in the renal and liver transplant patient. In Clinical Approach to Infection in the Compromised Host. Second edition. Edited by RH Rubin, LS Young. New York, Plenum Medical Book Company, 1988, pp 557-582 18. Aylward RG, Karim MA, Chiu A, Landsberg D, Shackleton CR, Keown PA: The role of monoclonal antibody (OKT3), antilymphocyte globulins (ALG) and CMV serology as risk factors for the development of cytomegalovirus (CMV) infections following renal transplantation (abstract). J Am Soc Nephrol 2:791, 1991 19. Rubin RH, Tolkoff-Rubin NE: The impact of infection on the outcome of transplantation. Transplant Proc 23:2068-2074,1991 20. Martin S, Morris D, Dyer PA, Gokal R, Mallick NP, Johnson RWG: The association between cytomegalovirus-specific antibodies, lymphocytotoxic antibodies, HLA-DR phenotype, and graft outcome in renal transplant recipients. Transplantation 51:1303-1305, 1991 21. Harfmann P, Dittmer R, Tenschert W, Cremaschi L, MeyerMoldenhauer W-H, Arndt R, Klosterhalfen H: Association of HLA-AI, -A3, and -B15 with CMV disease in cytomegalovirus IgG-positive recipients of renal allografts. Transplant Proc 23:2660-2661, 1991 22. Dunn DL, Mayoral IL, Gillingham KJ, Loeffler CM, Brayman KL, Kramer MA, Erice A, Balfour HH Jr, Fletcher CV, Bolman RM ill, Matas AI, Payne WD, Sutherland DER, Najarian JS: Treatment of invasive cytomegalovirus disease in solid organ transplant patients with gancicJovir. Transplantation 51:98-106, 1991 23. Pouteil-Noble C, Betuel H, Raffaele P, Megri K, Louvier C, Lefrancois N, Bosshard S, Dubemard JM, Aymard M, Touraine IL: Influence of HLA compatibility on cytomegalovirus infection in kidney transplantation. Presse Med 20:2022-2024,1991 24. Braun WE, Nankervis G: Cytomegalovirus viremia and bacteremia in renal-allograft recipients (letter to the editor). N Engl J Med 299:1318-1319, 1978 25. Marsano L, Perrillo RP, Flye MW, Hanto DW, Spitzer ED, Thomas JR, Murray PR, Windus DW, Brunt EM, Storch GA: Comparison of culture and serology for the diagnosis of cytomegalovirus infection in kidney and liver transplant recipients. J Infect Dis 161:454461,1990 26. Boland OJ, de Gast GC, Hene RI, Jambroes G, Donckerwolcke R, The TH, Mudde GC: Early detection of active cytomegalovirus

888

27.

28. 29. 30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40. 41. 42.

MANAGEMENT AND PREVENTION OF CYTOMEGALOVIRUS

(CMV) infection after heart and kidney transplantation by testing for immediate early antigenemia and influence of cellular immunity on the occurrence of CMV infection. J Clin Microbiol 28:20692075, 1990 Rasmussen L, Kelsall D, Nelson R, Carney W, Hirsch M, Winston D, Preiksaitis J, Merigan TC: Virus-specific IgG and IgM antibodies in normal and immunocompromised subjects infected with cytomegalovirus. J Infect Dis 145:191-199,1982 Herchline TE, Para M, Tesi R: Clinical correlation of cytomegalovirus cultutes, serology and lymphocyte counts following renal transplantation. Clin Transpl 5:345-350, 1991 Morris DJ, Fox AJ, Klapper PE: Diagnosis of cytomegalovirus infection in cyclosporin-treated renal allograft recipients. J Med Virol 32:124-127,1990 Van Zanten J, Van Der Giessen M, Van Der Voort LHM, Van Son WJ, VanDer Bij W, The TH: Cytomegalovirus-specific antibodies to an immediate early antigen and a late membrane antigen and their possible role in controlling secondary cytomegalovirus infection. Clin Exp Immunol 83:102-107,1991 Shiraki K, Ishibashi M, Okuno T, Yamanishi K, Takahashi M, Tanaka K, Baba K, Yabuuchi H, Kokado Y, Takahara S, Sonoda T: Antibody response to the immediate early protein of cytomegalovirus in renal transplant recipients. J Med Virol 34:280-283, 1991 Mathiesen T, Brattstrom C, Andersson J, Linde A, Ljungman P, Wahren B: Immunoglobulin G subclasses and lymphocyte stimulatory responses to cytomegalovirus in transplant patients with primary cytomegalovirus infections. J Med Virol 36:65-69,1992 Miller H, McCulloch B, Landini MP, Rossier E: Comparison of immunoblotting with other serological methods and virus isolation for the early detection of primary cytomegalovirus infection in allograft recipients. J Clin Microbiol 27:2672-2677, 1989 Paya CV, Wold AD, Smith TF: .Detection of cytomegalovirus infections in specimens other than urine by the shell vial assay and conventional tube cell cultures. J Clin Microbiol 25:755-757, 1987 Stirk PR, Griffiths PD: Use of monoclonal antibodies for the diagnosis of cytomegalovirus infection by the detection of early antigen fluorescent foci (DEAFF) in cell culture. J Med Virol 21:329-337,1987 Paya CV, Smith TF, Ludwig J, Hermans PE: Rapid shell vial culture and tissue histology compared with serology for the rapid diagnosis of cytomegalovirus infection in liver transplantation. Mayo Clin Proc 64:670-675, 1989 Van der Bij W, Schirm J, Torensma R, van Son WJ, Tegzess AM, The TH: Comparison between viremia and antigenemia for detection of cytomegalovirus in blood. J Clin Microbiol 26:2531-2535, 1988 Jiwa NM, Van Gernert GW, Raap AK, Van de Rijke PM, Mulder A, Lens PF, Salimans MMM, Zwaan FE, Van Dorp W, Van der Ploeg M: Rapid detection of human cytomegalovirus DNA in peripheral blood leukocytes of viremic transplant recipients by the polymerase chain reaction. Transplantation 48:72-76, 1989 Rowley AH, Wolinsky SM, Sambol SP, Barkholt L, Ehrnst A, Andersson JP: Rapid detection of cytomegalovirus DNA and RNA in blood of renal transplant patients by in vitro enzymatic amplification. Transplantation 51:1028-1033,1991 Chen Y-T, Mercer GO, Cheigh JS, Mouradian JA: Cytomegalovirus infection of renal allografts: detection by polymerase chain reaction. Transplantation 53:99-102,1992 Loning T, Stilo K, Riviere A, Helmchen U: Cytomegalovirus detection in kidney transplants: results obtained from the polymerase chain reaction. Clin Nephrol 37:78-83, 1992 Gerdes JC, Spees ER, Fitting K, Hiraki J, Dudda D, Jarvi T, Roehl C: Detection of cytomegalovirus DNA in blood of renal transplant patients by the polymerase chain reaction (abstract). In Program and Abstracts of the Eleventh Scientific Meeting of the American Society of Transplant Physicians. Chicago, Illinois, May 26 to 27, 1992, P 127

Mayo CliD Proc, September 1992, Vol 67

43. 44.

45.

46.

47. 48. 49.

50. 51.

52.

53. 54. 55.

56. 57.

58. 59.

60.

61.

Schrier RD, Rice GPA, Oldstone MBA: Suppression of natural killer cell activity and T cell proliferation by fresh isolates of human cytomegalovirus. JInfect Dis 153:1084-1091, 1986 Schooley RT, Hirsch MS, Colvin RB, Cosimi AB, Tolkoff-Rubin NE, McCluskey RT, Burton RC, Russell PS, Herrin JT, Delmonico FL, Giorgi JV, Henle W, Rubin RH: Association of herpesvirus infections with T-Iymphocyte-subset alterations, glomerulopathy, and opportunistic infections after renal transplantation. N Engl J Med 308:307-313, 1983 Mayoral JL, Loeffler CM, Fasola CG, Kramer MA, Orrom WJ, Matas AI, Najarian JS, Dunn DL: Diagnosis and treatment of cytomegalovirus disease in transplant patients based on gastrointestinal tract manifestations. Arch Surg 126:202-206,1991 Peterson PK, Balfour HH Jr, Marker SC, Fryd DS, Howard RI, Simmons RL: Cytomegalovirus disease in renal allograft recipients: a prospective study of the clinical features, risk factors and impact on renal transplantation. Medicine 59:283-300, 1980 Petersen EA: Extrapulmonary cytomegalovirus disease in transplant patients. Transplant Proc 23 (Suppl I): 13-16, 1991 Ustinov J, Mattila P, Hayry P, Lautenschlager I: CMV infection in various cell types of human kidney. Transplant Proc 24:285, 1992 Andersen CB, Ladefoged SD, Lauritsen HK, Hansen PR, Larsen S: Detection of CMV DNA and CMV antigen in renal allograft biopsies by in situ hybridisation and immunohistochemistry. Nephrol Dial Transplant 5:1045-1050,1990 Cameron J, Rigby RI, van Deth AG, Pettie JIB: Severe tubulointerstitial disease in a renal allograft due to cytomegalovirus infection. Clin Nephrol 18:321-325, 1982 Richardson WP, Colvin RB, Cheeseman SH, Tolkoff-Rubin NE, Herrin IT, Cosimi AB, Collins AB, Hirsch MS, McCluskey RT, Russell PS, Rubin RH: Glomerulopathy associated with cytomegalovirus viremia in renal allografts. N Engl J Med 305:57-63, 1981 Boyce NW, Hayes K, Gee D, Holdsworth SR, Thomson NM, Scott D, Atkins RC: Cytomegalovirus infection complicating renaltransplantation and its relationship to acute transplant glomerulopathy. Transplantation 45:706-709, 1988 Herrera GA, Alexander RW, Cooley CF, Luke RG, Kelly DR, Curtis JJ, Gockerman JP: Cytomegalovirus glomerulopathy: a controversial lesion. Kidney Int 29:725-733, 1986 Sherlock CH, Denegri JF, Ashley RL: Serological responses to cytomegalovirus during renal transplant rejection. Transplantation 52:272-275, 1991 Nast CC, Wilkinson A, Rosenthal JT, Barba L, Bretan PN, Beaumont P, Danovitch GM: Differentiation of cytomegalovirus infection from acute rejection using renal allograft fine needle aspirates. J Am Soc Nephrol 1:1204-1211, 1991 Faulds D, Heel RC: Ganciclovir: a review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs 39:597-638, 1990 Paya CV, Hermans PE, Smith TF, Rakela J, Wiesner RH, Krom RAF, Torres VE, Sterioff S, Wilkowske CJ: Efficacy of ganciclovir in liver and kidney transplant recipients with severe cytomegalovirus infection. Transplantation 46:229-234, 1988 Nicholson ML, Veitch PS, Donnelly PK, Flower AIE, Bell PRF: Treatment of renal transplant-associated cytomegalovirus infection with ganciclovir. Transplant Proc 22:1811-1812, 1990 Hrebinko R, Jordan ML, Dummer JS, Hickey DP, Shapiro R, Vivas C, Starzl TE, Simmons RL, Hakala TR: Ganciclovir for invasive cytomegalovirus infection in renal allograft recipients. Transplant Proc 23:1346-1347,1991 Ross CN, Beynon HLC, Savill JS, Watkins RP, Cohen J, Pusey CD, Rees AJ: Ganciclovir treatment for cytomegalovirus infection in immunocompromised patients with renal disease. Q J Med 81:929936, 1991 Q'Hair DP, Johnson CP, Roza AM, Adams MB: Treatment of transplant rejection in the presence of cytomegalovirus viremia. Transplant Proc 22:1815-1817,1990

Mayo CUn Proc, September 1992, Vol 67

62.

63.

64.

65. 66.

67.

68. 69. 70.

71.

72.

73.

74. 75.

76.

77.

Bums KD, Johnson-Whittaker L, Couture RA, Eidus L, Garber G: Successful treatment of renal allograft rejection in the presence of cytomegalovirus disease: a report of two cases. Am J Nephrol 10:162-166, 1990 Dunn DL, Mayoral JL, Kristen J, Gillingham MS, Statz CL, McHugh L, Najarian JS: Simultaneous treatment of concurrent rejection and tissue invasive cytomegalovirus disease without detrimental effects upon patient or allograft survival (abstract). In Program and Abstracts of the 17th Annual Meeting of the American Society of Transplant Surgeons. Chicago, Illinois, May 29 to 31, 1991, P 41 Van den Berg AP, Tegzess AM, Scholten-Sampson A, van der Giessen M, The TH, van Son WJ: Quo Vadis?-the clinical dilemma of simultaneous cytomegalovirus infection and steroid-resistant rejection. Transplantation 52:1081-1083,1991 Swan SK, Munar MY, Wigger MA, Bennett WM: Pharmacokinetics of ganciclovir in a patient undergoing hemodialysis. Am J Kidney Dis 17:69-72,1991 Einsele H, Ehninger G, Steidle M, Val1bracht A, Milller M, Schmidt H, Saal JG, Waller RD, Milller CA: Polymerase chain reaction to evaluate antiviral therapy for cytomegalovirus disease. Lancet 338:1170-1172,1991 Gerna G, Zipeto D, Parea M, Revello MG, SHini E, Percivalle E, Zavattoni M, Grossi P, Milanesi G: Monitoring of human cytomegalovirus infections and ganciclovir treatment in heart transplant recipients by determination of viremia, antigenemia, and DNAemia. J Infect Dis 164:488-498, 1991 Erice A, Chou S, Biron KK, Stanat SC, Balfour HH Jr, Jordan MC: Progressive disease due to ganciclovir-resistant cytomegalovirus in immunocompromised patients. N Eng1J Med 320:289-293, 1989 DeArmond B: Safety considerations in the use of ganciclovir in immunocompromised patients. Transplant Proc 23 (Suppl 1):2629, 1991 Palestine AG, Polis MA, De Smet MD, Baird BF, Falloon J, Kovacs JA, Davey RT, Zurlo Jf, Zunich KM, Davis M, Hubbard L, Brothers R, Ferris FL, Chew E, Davis JL, Rubin BI, Mellow SD, Metcalf JA, Manischewitz J, Minor JR, Nussenblatt RB, Masur H, Lane HC: A randomized, controlled trial of foscamet in the treatment of cytomegalovirus retinitis in patients with AIDS, Ann Intern Med 115:665-673, 1991 Klintmalm G, Lonnqvist B, Oberg B, Gahrton G, Lernestedt J-O, Lundgren G, Ringden 0, Robert K-H, Wahren B, Groth C·G: Intravenous foscamet for the treatment of severe cytomegalovirus infection in allograft recipients. Scand J Infect Dis 17:157-163, 1985 MacGregor RR, Graziani AL, Weiss R, Grunwald JE, Gambertoglio JG: Successful foscamet therapy for cytomegalovirus retinitis in an AIDS patient undergoing hemodialysis: rationale for empiric dosing and plasma level monitoring. J Infect Dis 164:785-787, 1991 Deray G, Martinez F, Katlama C, Levaltier B, Beaufils H, Danis M, Rozenheim M, Baumelou A, Dohin E, Gentilini M, Jacobs C: Foscamet nephrotoxicity: mechanism, incidence and prevention. AmJNephroI9:316-321,1989 Reed EC: Treatment of cytomegalovirus pneumonia in transplant patients. Transplant Proc 23 (Supp11):8-12, 1991 Reed EC, Wolford JL, Kopecky KJ, Lilleby KE, Dandliker PS, Todaro JL, McDonald GB, Meyers JD: Ganciclovir for the treatment of cytomegalovirus gastroenteritis in bone marrow transplant patients: a randomized, placebo-controlled trial. Ann Intern Med 112:505-510, 1990 Rancewicz Z, Halama G, Smogorzewski M, Durlik M, Rowinska D, Lao M, Juskowa J, Wyzgal J: The usefulness of hyperimmune globulin for treatment of overt cytomegalovirus infection in allograft recipients. Transplant Proc 22:1818-1819,1990 Manischewitz JF, Quinnan GV Jr, Lane HC, Wittek AE: Synergistic effect of ganciclovir and foscamet on cytomegalovirus replication in vitro. Antimicrob Agents Chemother 34:373-375, 1990

MANAGEMENT AND PREVENTION OF CYTOMEGALOVIRUS

78. 79. 80. 81. 82.

83.

84.

85.

86.

87.

88. 89.

90.

91.

92. 93.

94.

889

Sullivan V, Coen DM: Isolation of foscarnet-resistant human cytomegalovirus patterns of resistance and sensitivity to other antiviral drugs. JInfect Dis 164:781-784,1991 Clement Jf, Kern ER: Cyclobutyl compounds as antiviral agents. Transplant Proc 23 (SuppI3):159-161, 1991 King DH: Fluorinated pyrimidines: a new change for old drugs. Transplant Proc 23 (SuppI3):168-170, 1991 Riddell SR, Reusser P, Greenberg PD: Cytotoxic T cells specific for cytomegalovirus: a potential therapy for immunocompromised patients. Rev Infect Dis 13 (Supplll):S966-S972, 1991 Aulitzky WE, Schulz TF, Tilg H, Niederwieser D, Larcher K, Ostberg L, Scriba M, Martindale J, Stem AC, Grass P, Mach M, Dierich MP, Huber C: Human monoclonal antibodies neutralizing cytomegalovirus (CMV) for prophylaxis of CMV disease: report of a phase I trial in bone marrow transplant recipients. J Infect Dis 163:1344-1347, 1991 Ackermann JR, leFor WM, Weinstein S, Kahana L, Shires DL, Tardif G, Baxter J: Four-year experience with exclusive use of cytomegalovirus antibody (CMV-Ab)-negative donors for CMVAb-negative kidney recipients. Transplant Proc 20 (Suppl 1):469471, 1988 Shackleton CR, Keown PA, Landsberg DN, McCarthy JM, Scudamore CH, Kane LM, Cameron EC, Yeung CK, Chiu AS: The impact of donor/recipient matching for cytomegalovirus compatibility or identity on the incidence of disease and outcome following renal transplantation. Transplant Proc 23:1350-1351,1991 Henell KR, Chou S, Norman DJ: Use of cytomegalovirusseropositive donor kidneys in seronegative patients: results of prospective serotesting and matching in one center. Transplant Proc 21:2082-2083, 1989 Sayers MH, Anderson KC, Goodnough LT, Kurtz SR, Lane TA, Pisciotto P, Silberstein LE: Reducing the risk for transfusiontransmitted cytomegalovirus infection. Ann Intern Med 116:55-62, 1992 Plotkin SA, Starr SE, Friedman HM, Brayman K, Harris S, Jackson S, Tustin NB, Grossman R, Dafoe D, Barker C: Effect of Towne live virus vaccine on cytomegalovirus disease after renal transplant: a controlled trial. Ann Intern Med 114:525-531, 1991 Starr SE, Friedman HM, Plotkin SA: The status of cytomegalovirus vaccine. Rev Infect Dis 13 (Supplll):S964-S965, 1991 Snydman DR, Werner BG, Heinze-Lacey B, Berardi VP, Tilney NL, Kirkman RL, Milford EL, Cho SI, Bush HL Jr, Levey AS, Strom TB, Carpenter CB, Levey RH, Harmon WE, Zimmerman CE II, Shapiro ME, Steinman T, LoGerfo F, Ide1son B, Schroter GPJ, Levin MJ, McIver J, Leszczynski J, Grady GF: Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renaltransplant recipients. N EnglJ Med 317:1049-1054,1987 Snydman DR, Werner BG, Tilney NL, Kirkman RL, Milford EL, Cho SI, Bush HL Jr, Levey AS, Strom TB, Carpenter CB, Berardi VP, Levey RH, Harmon WE, Zimmerman CE II, Katz A, HeinzeLacey B, Shapiro ME, Steinman T, LoGerfo F, Ide1son B, McIver J, Leszczynski J, Griffith J, Grady GF: Final analysis of primary cytomegalovirus disease prevention in renal transplant recipients with a cytomegalovirus-immune globulin: comparison of the randomized and open-label trials. Transplant Proc 23:1357-1360, 1991 Tsevat J, Snydman DR, Pauker SG, Durand-Zaleski I, Werner BG, Levey AS: Which renal transplant patients should receive cytomegalovirus immune globulin? A cost-effectiveness analysis. Transplantation 52:259-265, 1991 Glowacki LS, Smaill F: Use of immunoglobulin to prevent cytomegalovirus infections in transplantation-a meta-analysis (abstract). J Am Soc Nephrol 2:799, 1991 Balfour RH Jr, Chace BA, Stapleton IT, Simmons RL, Fryd DS: A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N EnglJ Med 320:1381-1387, 1989 Fletcher CV, Englund JA, Edelman CK, Gross CR, Dunn DL, Balfour HH Jr: Pharmacologic basis for high-dose oral acyclovir

890

95.

96. 97.

98.

Mayo Clin Proc, September 1992, Vol 67

MANAGEMENT AND PREVENTION OF CYTOMEGALOVIRUS

prophylaxis of cytomegalovirus disease in renal allograft recipients. Antimicrob Agents Chemother 35:938-943, 1991 Merigan TC, Renlund DG, Keay S. Bristow MR, Starnes V, O'Connell JB, Resta S, Dunn D, Gamberg P, Ratkovec RM, Richenbacher WE, Millar RC, DuMond C, DeArmond B, Sullivan V, Cheney T, Buhles W, Stinson EB: A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation. N EnglJ Med 326:1182-1186,1992 Rubin RH: Preemptive therapy in immunocompromised hosts (editorial). N EnglJ Med 324:1057-1059, 1991 Schmidt GM, Horak DA, Niland JC, Duncan SR, Forman SJ, Zaia JA, City of Hope-Stanford-Syntex CMV Study Group: A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants. N Engl J Med 324:1005-1011,1991 Goodrich JM, Mori M, Gleaves CA, Du Mond C, Cays M, Ebeling DF, Buhles WC, DeArmond B, Meyers JD: Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. N Engl J Med 325:1601-1607, 1991

99.

100.

101. 102.

Melzer J, Alas G, Stock P, Tomlanovich S, Vincenti F, Amend W, Salvatierra 0: Prophylactic ganciclovir/acyclovir reduces cytomegalovirus disease following simultaneous pancreaslkidney transplantation (abstract). In Program and Abstracts of the Third International Congress on Pancreatic and Islet Transplantation. Lyon, France, June 6 to 8, 1991, P 130 Hibberd PL, To1koff-Rubin NE, Cosimi AB, Schooley RT, Isaacson D, Doran M, Delvecchio A, Delmonico FL, Auchincloss H Jr, Rubin RH: Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3. Transplantation 53:68-72, 1992 Steinmuller DR, Novick AC, Streem SB, Graneto D, Swift C: Intravenous immunoglobulin infusions for the prophylaxis of secondary cytomegalovirus infection. Transplantation 49:68-70, 1990 McCune TR, Johnson HK, MacDonell RC Jr, Richie RE, Nylander WA, Van Buren DH, Helderman JH: The effect of polyimmune garnmaglobulin for prophylaxis against reactivation cytomegalovirus infection in kidney and kidney/pancreas transplant recipients. J Am Soc Nephrol 2:1469-1474,1992