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446 CONCISE COMMUNICATIONS Prognostic Significance and Risk Factors of Untreated Cytomegalovirus Viremia in Liver Transplant Recipients Andrew D. Badley, Robin Patel, Daniel F. Portela, William S. Harmsen, Thomas F. Smith, Duane M. I1strup, Jeffery L. Steers, Russell H. Wiesner, and Carlos V. Paya Divisions of Infectious Diseases and Microbiology and Departments of Biostatistics and Liver Transplantation Unit, Mayo Clinic, Rochester, Minnesota To study whether cytomegalovirus(CMV)viremia is a reliable marker of impending CMV disease and thus a guide for preemptive antiviral therapy, 126 consecutive liver transplant recipients were followed by routine CMV blood cultures in the absence of antiviral prophylaxis or treatment for viremia. Seventy-three patients (58%) developed CMV infections, and 36 (29%)had more than one infection episode: 29 patients (23%) had organ involvement and 45 (36%) had viremia. Within a same episode, CMV viremia was 90% sensitive and 80% specific for predicting concurrent organ involvement but preceded organ involvement in only 9 (31%) of 29 patients. In a separate analysis, untreated isolated CMV viremia in the first CMV infection episode was followed by organ involvement in a subsequent episode in 9 (33%) of 28 patients, mainly in the donor-positive, recipientnegative (D+/R-) population. The results indicate that CMV viremia is not an ideal marker to guide preemptive antiviral treatment in liver transplant recipients but is a good marker in D+/Rpatients. Cytomegalovirus (CMV) is an important opportumstrc pathogen in solid-organ transplant recipients. It directly causes morbidity and mortality, indirectly influences immunosuppression, and possibly leads to chronic allograft dysfunction [1]. To decrease the incidence of CMV infection in liver transplant recipients and thus its impact on morbidity and mortality, recent clinical research has focused on the role of prophylaxis and preemptive therapy. Prophylactic strategies involve the administration of antiviral agents from the time of transplant to decrease the incidence of CMV infection. Because prophylactic therapy has been of moderate or little success in CMV-seronegative liver transplant recipients who receive CMV-seropositive organs [2,3], preemptive strategies have been proposed. These strategies are based on a clinical or laboratory characteristic that identifies patients deemed to be at high risk for developing CMV infection. Such measures are being used for liver transplant patients receiving OKT3 [4, 5], and their use has been suggested for patients with preclinical CMV infection, as measured by CMV antigenemia [6] or polymerase chain reaction (PCR) detection of viral DNA [7]. Preemptive therapy is used for patients with CMV viremia on the basis of the postulate that viremia is a reliable predictor of subsequent organ involvement. CMV viremia is a marker of CMV disease in renal transplant recipients [8]; however, in bone marrow transplant recipients, in whom the pathogenesis of CMV infection differs from that of solid-organ transplant recipients, the sensitivity ofCMV viremia is 45% for predicting subsequent organ involvement [9]. Moreover, in human immunodeficiency virus (HIV)-infected patients, the ability of CMV viremia to predict disease is significantly low [10]. To establish the predictive value of CMV viremia as a marker of concomitant and impending CMV organ involvement, a population of solid-organ transplant recipients is required. The study population must have prospective viral culture surveillance, but antiviral prophylaxis and treatment for isolated viremia must be precluded. Results from such studies, which may differ among different types of solid-organ transplants, would establish whether the easily accessible and relatively simple diagnosis of viremia should be used as a marker for preemptive therapy. For this purpose, we analyzed a defined and homogeneous cohort of liver transplant recipients who fulfilled the above characteristics. Materials and Methods Received 12 June 1995; revised 6 October 1995. Reprints or correspondence: Dr. Carlos V. Paya, Division of Infectious Diseases, Mayo Clinic, 200 First St. S.W., Guggenheim 501, Rochester, MN 55905. The Journal of Infectious Diseases 1996; 173:446-9 © 1996by The Universityof Chicago. All rights reserved. 0022-1899/96/7302~0023$0 1.00 Patients. One hundred twenty-six consecutive patients who underwent a first liver transplant at the Mayo Clinic between March 1986 and June 1989 were included in this study. These patients did not receive ganciclovir, immunoglobulin, or other anti-CMV prophylaxis. Ganciclovir, which was available only on a compassionate basis, was limited to treatment of documented organ involvement and was not available for patients with isolated vire- JID 1996; 173 (February) 447 Concise Communications mia. Patients who had more than one transplant were included in the analysis for the first transplant only. Twenty-five patients (19.8%) received prednisone immunosuppression within the 3 months prior to the transplant. Thirty-six patients (28.8%) had a Roux-en-Y procedure. The mean age at transplant was 41.5 years (median, 43.8; range, 4.5-61.5). Seventy-four patients (58.7%) were male. Pretransplant diagnoses included primary biliary cirrhosis (33 patients), primary sclerosing cholangitis (30 patients), hepatitis C (7 patients), hepatitis B (l patient), a-I-antitrypsin deficiency (3 patients), alcoholic liver disease (2 patients), cryptogenic cirrhosis (26 patients), autoimmune chronic active hepatitis (4 patients), fulminant hepatitis (10 patients), tumors (3 patients), and other (7 patients). Thirty-six transplant recipients were CMV seropositive but received CMV-negative donor organs (D-/R+), 20 were D+/R-, 22 were D-/R-, and 46 were D+/R +; 2 patients did not have complete CMV serologic data. Patients were given oral selective bowel decontamination starting on the day of liver transplant and continuing for 21 days or until hospital discharge, whichever was longer [II]. Perioperatively, patients were given a low bacterial diet, cefotaxime (l g/6 h), and tobramycin (80 mg/8 h) until 48 h after the transplant. CMVseronegative patients who received a CMV-seronegative organ (D-/R-) were given CMV-negative blood for the first 24 U of red blood cells required. The immunosuppressive regimen included prednisone, cyclosporin, and azathioprine as previously described [9]. Rejection was diagnosed histologically with liver biopsy specimens. Routine liver biopsies were done at weeks I, 3, 12, 26, and 52; other biopsies were obtained whenever hepatic dysfunction occurred. Cellular rejection episodes were treated intravenously with I g of methylprednisone every other day for 6 days or with 1 or 2 g of methylprednisone for 2 days, followed by a prednisone taper. For steroid-resistant rejection, OKT3 (Ortho Pharmaceuticals, Raritan, NJ) was administered (5 mg/kg/day for 10 days). Serology and viral culture. Anti-CMV IgG and IgM were measured by an indirect immunofluorescence assay [II]. Blood cultures were done by tube cell and rapid shell vial techniques, and urine cultures were done by shell vial techniques [7]. Blood and urine samples were cultured for CMV at weekly intervals for a minimum of 8 weeks after transplantation and whenever CMV infection was suspected. Thereafter, CMV cultures were done routinelyat 3, 6, and 12 months or whenever CMV infection was clinically suspected. Clinical definitions. CMV infection was defined as the isolation of CMV from any body fluid or tissue, the detection of CMV in tissue (see below), or the detection of new serum IgM against CMV. CMV infection was considered asymptomatic when it occurred without clinical symptoms and signs or laboratory abnormalities; CMV infection was considered symptomatic when it occurred in conjunction with clinical symptoms or signs compatible with CMV disease or with documented evidence of organ invasion (i.e., a tissue biopsy specimen demonstrating cytomegalic inclusion bodies, positive cultures, DNA hybridization. and/or positive immunofluorescence for CMV). CMV viremia was defined when a blood specimen was positive for CMY by shell vial assay or tube cell culture. A patient was considered to have a relapsing episode of CMV infection when one or more of the above definitions for CMV infection were met> 30 days after the previous manifestation of CMV infection. Ganciclovir (5 mg/kg) was given intravenouslyevery 12 h for 14 days only when organ invasion by CMV Table 1. Manifestations of CMV infection in 73 of 126 liver transplant recipients. Viremia No. of patients 28 Viruria Asymptomatic Symptomatic Organ involvement + + 1 + 6 + 2 + + 6 2 + + + 1 26 + + + Total NOTE. 37 + + + I 10 35 29 53 transplant patients did not develop CMV infection. was documented, as part of the criteria established by the manufacturer for its use on a compassionate basis. Statistics. For risk factors that could be measured before or at the time of transplantation, the log-rank test was used. Continuous variables, such as age, were analyzed by the Cox proportional hazards model and the log-rank test, with which values above the 75th percentile were compared to values below that percentile. For risk factors that occurred at various times after transplantation, such as allograft rejection or its treatment, time-dependent Cox proportional hazards models were used. These methods for this type of analysis in transplant recipients have been previously described by our group [II]. Risk factors initially defined from this analysis were evaluated using a multivariate time-dependant Cox model analysis and included pretransplantation diagnosis; sex; age; CMY donor and recipient serostatus; HLA matching; active CMV infection at the time of transplantation; immunosuppression within 3 months before transplantation; Roux-en-Y biliary anastomosis; preoperative levels of creatinine, bilirubin, alanine aminotransferase, globulin, and pseudocholinesterase; prothrombin time; total intraoperative surgical time; amounts of transfused total and autologous red blood cells, fresh frozen plasma, and cryoprecipitate; amount of transfused and postoperative platelets; type of immunosuppression; number of rejection episodes; treatment of rejection with OKT3; and, when appropriate, CMV infection and asymptomatic and symptomatic viremia. Results CMV infections. Seventy-three (58%) of the 126 patients developed CMV infection. The initial virologic manifestation of CMV disease was organ involvement alone in 2 patients, viruria in 29, symptomatic viremia with organ involvement in 17, symptomatic viremia without organ involvement in 15, and asymptomatic viremia either alone or with viruria in 10 patients (table I). Only 2 episodes ofCMY disease occurred z-S weeks after transplantation. Thirty-eight (52.0%) of the 73 CMY-infected patients had CMY disease, and more than one indication of disease occurred 448 Concise Communications Table 2. Number of liver transplant recipients organ involvement as a function of CMV viremia. Organ involvement Present Absent Total Viremia Present Absent 26 3 19 78 45 28 Total 29 97 126 NOTE. Positive predictive value = 26/(26 + 19) = 58%; negative predictive value = 78/(78 + 3) = 96% sensitivity = 26/29 = 90% (95% confidence interval [eI] = 73%-98%); specificity = 78/97 = 80% (95% CI = 65%-93%). in 36 (49.3%) of them. The frequency of CMY disease was highest in D+/R- patients. The cumulative probabilities of being free of disease at 60 days were as follows for the different transplant groups: D-/R-, 80.2% (95% confidence interval [CI] = 64.6%-99.6%); D-/R+, 88.9% (95% CI = 79.2%99.8%); D+/R-, 21.1% (95% CI = 8.8%-50.3%); and D+/ R+, 56.5% (95% CI = 43.5%-73.3%). Ability of viremia to predict concurrent organ involvement. While 19 patients had CMY organ involvement as their initial CMY manifestation, 29 had CMY organ involvement at some point during the study. Eleven patients had CMY hepatitis, 8 had pneumonia, 2 had gastrointestinal CMY, and 1 had CMY retinitis. Seven remaining patients had more than one organ involved. Of these 29 patients, 26 (90%) also had viremia at the time of CMY organ infection. The value of concurrent viremia as a predictor of organ involvement was assessed by a 2 X 2 table analysis (table 2). This analysis revealed a sensitivity of 90%, a specificity of 80%, and positive and negative predictive values of 58% and 96%, respectively. Frequency of viremia preceding organ involvement. The low positive predictive value of concurrent viremia to predict organ involvement prompted us to determine the frequency with which viremia (either symptomatic or asymptomatic) preceded organ involvement. This was done in two ways. First, we determined in how many patients organ involvement was preceded by viremia within the same CMY infection episode, and, second, we determined in how many patients with CMY viremia organ involvement developed in a subsequent CMY infection episode. The former analysis examines the frequency that patients with organ involvement have preceding viremia (and thus the utility of viremia as a preemptive marker). The latter analysis examines the risk of untreated viremia. The first analysis disclosed that among the 29 patients with CMY organ involvement, 17 (58%) had viremia that developed at the same time as the organ involvement, 9 (31%) had viremia (8 symptomatic, 1 asymptomatic) a minimum of3 days (mean, 16.6; median, 9) preceding organ involvement, and 3 never had documented viremia. In the second analysis, 28 patients JID 1996; 173 (February) had viremia (26 symptomatic, 2 asymptomatic) as the first CMY episode, which was initially not associated with organ involvement and was not treated. Of the second group of 28 patients, 9 subsequently developed organ involvement in another infection episode > 30 days after the first, generating an incidence of CMY organ involvement of 32% in patients with untreated CMY viremia. Among these 9 patients, 5 (56%) were classified as D+/R-, 2 (22%) as D+/R+, and I each (11%) as D-IR- and D-/R+. Risk-factor analysis. Univariate risk-factor analysis for the development of CMY viremia (symptomatic or asymptomatic) revealed that fulminant hepatitis (P = .03) and preoperative liver dysfunction (P = .05), as measured by total bilirubin above the 75th percentile (> 16.2 mg/dl.), were significant risk factors. CMY donor-positive serostatus was most highly correlated with the development of viremia (P < .01). When data were analyzed for the development of symptomatic viremia alone (with or without organ involvement), CMY recipientpositive serostatus (P = .02) and CMY donor-positive serostatus (P < .01) were associated with an increased risk of symptomatic viremia. Having received OKT3 immunosuppression was not statistically associated with an enhanced risk of symptomatic viremia (P = .08). The only identified risk factor for the development of asymptomatic viremia was a low preoperative level of pseudocholinesterase «2 U/mL; P = .02). Multivariate risk factor modeling for the development of any CMY viremia confirmed the importance of CMY donor serostatus (relative risk [RR] = 5.6, CI = 2.5-12.7, P < .01) and preoperative liver dysfunction, as measured by increased bilirubin (>16.2 mg/dL; RR = 2.2, C1 = 1.2-4.3, P = .01). Multivariate modeling also confirmed that CMV donor-positive serostatus was a risk factor for symptomatic viremia (RR = 6.7, CI = 2.6-17.6, P < .01). Similarly, multivariate analysis identified CMY donor-positive serostatus (RR = 5.9, CI = 2.4-14.4, P <.01) as a risk factor for the development of symptomatic viremia with organ involvement. No risk factors were significantly associated with asymptomatic viremia by multivariate analysis. Last, symptomatic viremia proved to be a risk factor for death or retransplant (RR = 1.9, CI = 1.03.6, P = .04). Discussion This study was designed to analyze whether CMY viremia can be used as a marker for preemptive therapy in liver transplant patients not receiving anti-CMY prophylaxis and to identify risk factors that lead to the development of viremia in this cohort of patients. Our data indicate that CMY viremia is a sensitive but not specific marker of concurrent organ involvement. In addition, only one-third of patients with organ involvement have preceding viremia and only one-third of patients with isolated viremia will progress to organ involvement. Therefore, viremia is a poor marker by which to guide preemptive therapy. lID 1996; 173 (February) Concise Communications Given the substantial morbidity, mortality, and cost associated with CMY organ disease in patients with solid-organ transplants, clinically useful markers of impending CMY organ invasion are needed to target preemptive therapy strategies. CMY viruria and serologic assays are nonspecific markers for CMY tissue infection [12], and isolation of CMY from bronchoalveolar lavage done prospectively is impractical in abdominal solid-organ transplant recipients. However, isolation of CMY in peripheral blood mononuclear cells is relatively simple and economical and has been suggested as a marker of CMY disease. In our study population, 32% of patients with untreated isolated viremia developed CMY organ infection. In addition, only 31% of patients with CMY organ infection had CMY viremia that preceded organ involvement by ?3 days, thereby indicating that viremia was a poor predictor of impending organ infection. These data are consistent with results from a recently published trial, in which a smaller number of liver transplant recipients receiving prophylaxis with either acyclovir or ganciclovir had CMY viremia that preceded organ involvement in 25% and 22% of cases, respectively [13]. CMY viremia is a poor predictor of CMY organ involvement (positive predictive value of 58%). Despite this, with a negative predictive value of 96%, the chance of a patient having organ involvement without coexisting viremia is extremely low. Therein lies the clinical utility of CMY viremia as a marker of CMY tissue infection. In addition, there was a disproportionate number ofD+/R- viremic patients (5/9, 55%) compared with D+/R- patients (20/124, 16%) in our study who progressed to develop CMY organ infection in subsequent episodes. This finding suggests a higher risk for mismatch organ transplant patients (D+/R-) with viremia to develop invasive disease in subsequent (> 30 days later) CMY infection episodes. It is not known whether treating isolated CMY viremia will result in decreased incidence of subsequent organ involvement; however, on the basis of these data, it seems logical that D+/Rtransplant patients should receive antiviral therapy at the time of viremia, but organ recipients who belong to the other CMY serogroups should not. Aside from demonstrating that the previously identified risk factor of donor CMY seropositivity predisposes to symptomatic and asymptomatic CMY viremia, we also demonstrated that the degree of preoperative liver dysfunction is an important risk factor for the development of any clinically defined viremia. Although OKT3 was found not to be strictly a statistically significant risk factor (P = .08), a recent study with a larger number of patients found it significant, although the end point was CMY infection, not viremia in general [14]. In addition, untreated symptomatic viremia is a risk factor for death or retransplantation. What was surprising from this analysis is that we could not find a specific risk factor that could identify and differentiate symptomatic from asymptomatic viremia, although the fact that D+/R - patients have a higher incidence of subsequent organ involvement if viremia is left untreated places this group in the high-risk category. 449 Since CMY viremia is a nonspecific predictor of CMY tissue infection, more accurate markers of impending invasive CMY disease are needed. The roles that CMY antigenemia and PCR detection of viral DNA play in predicting subsequent CMY tissue invasion remain to be defined. Once a clinically useful method for predicting CMY disease in solid-organ transplant patients is validated, meaningful preemptive strategies can be designed. References I. Rubin RH. Infection in the organ transplant recipient. In: Rubin RH, Young LS, eds. Clinical approach to infection in the compromised host. 3rd ed. New York: Plenum Medical Book, 1994:647-59. 2. Snydman DR, Werner BG, Dougherty NN, et al. Cytomegalovirus immune globulin prophylaxis in liver transplantation. A randomized, doubleblind, placebo-controlled trial. The Boston Center for Liver Transplantation CMVIG Study Group. Ann Intern Med 1993; I 19:984-91. 3. Martin M, Manez R, Linden P, et al. A prospective randomized trial comparing sequential ganciclovir-high dose acyclovir to high dose acyclovir for prevention of cytomegalovirus disease in adult liver transplant recipients. Transplantation 1994;58:779-85. 4. Stratta Rl, Shaefer MS, Cushing KA, et al. A randomized prospective trial of acyclovir and immune globulin prophylaxis in liver transplant recipients receiving OKT3 therapy. Arch Surg 1992; 127:55-64. 5. Hibberd PL, Tolkoff-Rubin NE, Conti 0, et al. Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. A randomized controlled trial. Ann Intern Med 1995; 123:18-26. 6. van den Berg AP, Klompmaker IJ, Haagsma EB, et al. Antigenemia in the diagnosis and monitoring of active cytomegalovirus infection after liver transplantation. 1 Infect Dis 1991; 164:265-70. 7. Patel R, Smith TF, Espy M, et al. A prospective comparison of molecular diagnostic techniques for the early detection of cytomegalovirus in liver transplant recipients. 1 Infect Dis 1995; 171:1010-4. 8. Pillay 0, Ali AA, Liu SF, Kops E, Sweny P, Griffiths PD. The prognostic significance of positive CMV cultures during surveillance of renal transplant recipients. Transplantation 1993; 56: 103-8. 9. Meyers 10, Ljungman P, Fischer LD. Cytomegalovirus excretion as a predictor of disease after marrow transplantation: importance of cytomegalovirus viremia. J Infect Dis 1990; 162:373-80. 10. Zurlo JJ, O'Neill 0, Polis MA, et al. Lack of clinical utility of cytomegalovirus blood and urine cultures in patients with HIV infection. Ann Intern Med 1993; 118:12- 7. II. Paya CV, Hermans PE, Wiesner RH, Smith TF, Ilstrup 0, Krom RAF. Risk factors for cytomegalovirus and severe bacterial infections following liver transplantation: a prospective multivariate time-dependent analysis. J Hepatol 1993; 18:185-95. 12. Paya CV, Smith TF, Ludwig 1, 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 1989;64:670-5. 13. Singh N, Yu VL, Mieles L, Wagener MM, Miner RC, Gayowski T. Highdose acyclovir compared with short-course preemptive ganciclovir therapy to prevent cytomegalovirus disease in liver transplant recipients. A randomized trial. Ann Intern Med 1994; 120:375-81, comment in 1994; 121:385. 14. Portela 0, Patel R, Larson-Keller 11, et al. OKT3 treatment for allograft rejection is a risk factor for CMV disease in liver transplantation. 1 Infect Dis 1995; 171:1014-8.