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Risk Factors Associated With Cytomegalovirus Infection in Orthotopic Liver Transplant Patients
Risk Factors Associated With Cytomegalovirus Infection in Orthotopic Liver Transplant Patients L. Hoppe, C.A. Marroni, R. Bressane, L. Lago, F.L. Schiavo, G.C. Cigerza, A.B.M. Brandão, M.L. Zanotelli, and G.P.C. Cantisani ABSTRACT Our objective was to investigate the potential risk factors associated with cytomegalovirus (CMV) infection. Patients and Methods. From January 1999 to December 2001, 163 liver transplantations were performed in 154 patients. The study inclusion criteria were absence of retransplantation and survival of more than 6 months. One hundred fifteen patients met the inclusion criteria. We determined variables such as age, gender, and number of hemecomponents as well as serum IgG CMV status of donors and recipients. We recorded the immunosuppression used by each patient. CMV infection was detected by positive antigenemia. Results. Recipient mean age was 50 years. The etiology of cirrhosis was viral (n ⫽ 57; 49.6%), alcoholic (n ⫽ 20; 17.4%), virus and alcohol (n ⫽ 15; 13.0%), cryptogenic (n ⫽ 14; 12.2%), or other causes (n ⫽ 9; 7.8%). CMV infection was positive in 75 patients (65.8%). There was no relation between infection and age, gender, or CMV IgG donor recipient status, or the number of hemecomponent units. The risk was 3.8-fold higher for patients receiving a three-drug compared with a two-drug regimen. When cyclosporine was used instead of tacrolimus, the risk of CMV infection was 4.3-fold higher. Logistic regression analysis revealed cyclosporine (OD⫽5.8) and a three-drug regimen (OD⫽6.7) to have stronger associations with CMV infection. Conclusion. The use of cyclosporine (OD⫽5.8) and a three-drug regimen (OD⫽6.7) are risk factors for CMV infection.
C
YTOMEGALOVIRUS (CMV) infection is a common complication in orthotopic liver transplantation (OLT), which without prophylaxis may affect 30% to 50% of the recipients. This rate is lower with prophylaxis.1 A seropositive donor coupled with a seronegative recipient is a risk factor for primary CMV infection. Secondary infection by reactivation or superinfection may also lead to CMV disease during immunosuppression.2,3 The risk of CMV disease is also dependent on the immunosuppressive regimen, especially the use of OKT3.4 The aim of this study was to investigate potential risk factors associated with CMV infection.
paramyloidosis. The etiology of cirrhosis was viral (49.6%), alcoholic (17.4%), virus and alcoholic (13.0%), cryptogenic (12.2%), or other causes (7.8%). Immunosuppression included two- or threedrug regimens. In the two-drug regimen, cyclosporine (51.7%) or tacrolimus (35.1%) was used in addition to prednisone. In the three-drug regimen, prednisone and mycophenolate mofetil were combined with cyclosporine (5.3%) or tacrolimus (7.9%). Immunosuppressive control was performed using blood levels of calcineurin antagonists. We recorded the units of hemecomponents transfused in the surgery and within the 30 days of the procedure. All hemecomponents had been washed with saline solution before transfusion. Donor and recipient CMV serologic status were determined
PATIENTS AND METHODS From January 1999 to December 2001, 163 liver transplantations were performed in 154 patients. Inclusion criteria for the 115 study subjects were absence of retransplantation and survival more than 6 months. Indications for liver transplantation were cirrhosis in all patients, except two who had fulminant hepatitis or familial
From the Santa Casa, Porto Alegre, FFFCMPA, Rio Grande do Sul, Brazil. Address reprint requests to Lísia Hoppe, Rua Uruguai, 2001, 312/B, Passo Fundo, Rio Grande do Sul, CEP 99010-112, Brazil. E-mail: [email protected]
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.06.075
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1922
Transplantation Proceedings, 38, 1922–1923 (2006)
CYTOMEGALOVIRUS INFECTION IN LIVER TRANSPLANTS
1923
Table 1. Risk Factors for CMV Infection Based on Bivariate Analysis and Multiple Logistic Regression Analysis, Using the Odds Ratio, 95% Confidence Interval and Statistic Significance Bivariate analysis
Age (years) Gender male number (%) Hemocomponent, U TIS, number (%) CyC, number (%) CMV-d, number (%) CMV-r, number (%)
CMV* n ⫽ 75
n-CMV n ⫽ 39
50.6 ⫾ 10.4 47 (62.7) 13 (0 to 32) 13 (17.3) 52 (69.3) n ⫽ 46 43 (93.5) n ⫽ 56 52 (92.9)
50.0 ⫾ 11.1 26 (66.7) 12 (0 to 24) 2 (5.1) 13 (33.3) n ⫽ 26 26 (96.3) n ⫽ 24 23 (95.8)
Logistic regression
OR
CI95%
P
OR
CI95%
P
1.0 0.8 1.0 3.9 4.5
1.0–1.1 0.4–1.9 1.0–1.1 0.8–18.2 2.0–10.3
.77 .67 .20 .09 ⬍.01
1.0 0.8 1.0 6.7 5.8
1.0–1.1 0.3–2.1 1.0–1.1 1.3–35.0 2.4–14.0
.80 .73 .28 .02 ⬍.001
0.6
0.1–5.6
.61
—
0.5
0.1–5.1
.59
—
Data are listed as mean ⫾ standard deviation. n° (%), median (P25–P75), CMV: cytomegalovirus, n-CMV: without cytomegalovirus, OR: odds ratio, CI95%: confidence interval of 95%, P: statistic significance, TIS: three-drug regimen versus two-drug regimen(reference category), CyC: use of cyclosporine versus tacrolimus (reference category), CMV-d: presence of CMV in the donor, CMV-r: presence of CMV in the recipient. *In one case it was not possible to define the presence of CMV.
preoperatively by enzyme-linked immunosorbent assay for CMV IgG. CMV infection was diagnosed based on positive results using CMV-pp65 antigenemia (APAAP technique, Clonab, Biotest, Dreieich, Germany).
Statistical Analysis Data were analyzed by mean values and standard deviations for quantitative variables, and frequency and percentages for qualitative categorical variables. CMV-infected patients were compared with the disease-free group using bivariate analysis, odds ratios, and 95% confidence intervals. P values were calculated using the chi-square test. Comparison adjustments were performed by multiple logistic regression analysis. The level of significance was set at 5% (P ⫽ .05). The statistical analysis was performed using SPSS 12.0.
RESULTS
The characteristics of patients with or without CMV infection, such as age, gender, number of hemecomponents, and serologic CMV status of donor/recipient, are shown in Table 1. None of these variables reached statistical significance as a risk factor for CMV infection. The risk of CMV infection was 3.8-fold higher for patients who received a three-drug compared with a twodrug regimen. When cyclosporine was used, the risk of CMV infection was 4.3-fold higher. In the logistic regression analysis, these results were confirmed with cyclosporine (OD⫽5.8) and the three-drug regimen (OD⫽6.7). There were no differences between the mean dose of prednisone and the cyclosporine and tacrolimus blood levels in the first trimester among infected versus noninfected patients. DISCUSSION
In transplant patients, when prophylaxis is not routinely used the prevalence of CMV infection ranges from 30% to 50%.5 In this study, CMV antigenemia was positive in 65% of OLT, consistent with the literature. The high prevalence of antibodies in donors and recipients was due to the fact that infection is widespread among infants in developing countries.6
Immunosuppression was a risk factor for CMV infection; when the three-drug regimen was used it was 6.7% higher, demonstrating that the severity of CMV illness correlates with the degree of immunosuppression in the transplant setting.6 Tacrolimus is 30 to 100 times more potent than cyclosporine in vitro, but maximal in vivo inhibition has been shown to be greater with cyclosporine.7 When cyclosporine was used, we observed a 5.8-fold higher risk for development of CMV infection. There was no association between CMV infection and the transfusion of hemecomponents, because we routinely used washed blood components. We did not use leukodepletion, which is currently recommended, but patients were equally protected. In conclusion, CMV infection is a frequent situation in OLT with immunosuppression being an important risk factor. REFERENCES 1. Angelis M, Cooper JT, Freeman RB: Impact of donor infection on outcome of orthotopic liver transplantation. Liver Transpl 9:451, 2003 2. Jong MD, Galasso GJ, Gazzard B, et al: Summary of II international symposium on cytomegalovirus. Antiviral Research 39:141, 1998 3. Singh N, Wannstedt C, Keyes L, et al: Impact of evolving trends in recipients and donor characteristics on cytomegalovirus infection in liver transplant recipients. Transplantation 79:1428, 2005 4. Rowshani A, Bemelman F, Leeuwen EMM, et al: Clinical and immunologic aspects of cytomegalovirus infection in solid organ transplant recipients. Transplantation 79:381, 2005 5. Seehofer D, Rayes N, Tullius SG, et al: CMV hepatitis after liver transplantation: incidence, clinical course, and long-term follow-up. Liver Transpl 8:1138, 2002 6. Meer JTM, Drew WL, Bowden RA, et al: Summary of the international consensus symposium on advances in the diagnosis, treatment and prophylaxis of cytomegalovirus infection. Antiviral Res 32:119, 1996 7. Maes BD, Vanrenterghem YFC: Cyclosporine: advantages versus disadvantages vis-à-vis tacrolimus. Transplant Proc 36 (suppl 2S):40S, 2004
C
YTOMEGALOVIRUS (CMV) infection is a common complication in orthotopic liver transplantation (OLT), which without prophylaxis may affect 30% to 50% of the recipients. This rate is lower with prophylaxis.1 A seropositive donor coupled with a seronegative recipient is a risk factor for primary CMV infection. Secondary infection by reactivation or superinfection may also lead to CMV disease during immunosuppression.2,3 The risk of CMV disease is also dependent on the immunosuppressive regimen, especially the use of OKT3.4 The aim of this study was to investigate potential risk factors associated with CMV infection.
paramyloidosis. The etiology of cirrhosis was viral (49.6%), alcoholic (17.4%), virus and alcoholic (13.0%), cryptogenic (12.2%), or other causes (7.8%). Immunosuppression included two- or threedrug regimens. In the two-drug regimen, cyclosporine (51.7%) or tacrolimus (35.1%) was used in addition to prednisone. In the three-drug regimen, prednisone and mycophenolate mofetil were combined with cyclosporine (5.3%) or tacrolimus (7.9%). Immunosuppressive control was performed using blood levels of calcineurin antagonists. We recorded the units of hemecomponents transfused in the surgery and within the 30 days of the procedure. All hemecomponents had been washed with saline solution before transfusion. Donor and recipient CMV serologic status were determined
PATIENTS AND METHODS From January 1999 to December 2001, 163 liver transplantations were performed in 154 patients. Inclusion criteria for the 115 study subjects were absence of retransplantation and survival more than 6 months. Indications for liver transplantation were cirrhosis in all patients, except two who had fulminant hepatitis or familial
From the Santa Casa, Porto Alegre, FFFCMPA, Rio Grande do Sul, Brazil. Address reprint requests to Lísia Hoppe, Rua Uruguai, 2001, 312/B, Passo Fundo, Rio Grande do Sul, CEP 99010-112, Brazil. E-mail: [email protected]
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.06.075
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1922
Transplantation Proceedings, 38, 1922–1923 (2006)
CYTOMEGALOVIRUS INFECTION IN LIVER TRANSPLANTS
1923
Table 1. Risk Factors for CMV Infection Based on Bivariate Analysis and Multiple Logistic Regression Analysis, Using the Odds Ratio, 95% Confidence Interval and Statistic Significance Bivariate analysis
Age (years) Gender male number (%) Hemocomponent, U TIS, number (%) CyC, number (%) CMV-d, number (%) CMV-r, number (%)
CMV* n ⫽ 75
n-CMV n ⫽ 39
50.6 ⫾ 10.4 47 (62.7) 13 (0 to 32) 13 (17.3) 52 (69.3) n ⫽ 46 43 (93.5) n ⫽ 56 52 (92.9)
50.0 ⫾ 11.1 26 (66.7) 12 (0 to 24) 2 (5.1) 13 (33.3) n ⫽ 26 26 (96.3) n ⫽ 24 23 (95.8)
Logistic regression
OR
CI95%
P
OR
CI95%
P
1.0 0.8 1.0 3.9 4.5
1.0–1.1 0.4–1.9 1.0–1.1 0.8–18.2 2.0–10.3
.77 .67 .20 .09 ⬍.01
1.0 0.8 1.0 6.7 5.8
1.0–1.1 0.3–2.1 1.0–1.1 1.3–35.0 2.4–14.0
.80 .73 .28 .02 ⬍.001
0.6
0.1–5.6
.61
—
0.5
0.1–5.1
.59
—
Data are listed as mean ⫾ standard deviation. n° (%), median (P25–P75), CMV: cytomegalovirus, n-CMV: without cytomegalovirus, OR: odds ratio, CI95%: confidence interval of 95%, P: statistic significance, TIS: three-drug regimen versus two-drug regimen(reference category), CyC: use of cyclosporine versus tacrolimus (reference category), CMV-d: presence of CMV in the donor, CMV-r: presence of CMV in the recipient. *In one case it was not possible to define the presence of CMV.
preoperatively by enzyme-linked immunosorbent assay for CMV IgG. CMV infection was diagnosed based on positive results using CMV-pp65 antigenemia (APAAP technique, Clonab, Biotest, Dreieich, Germany).
Statistical Analysis Data were analyzed by mean values and standard deviations for quantitative variables, and frequency and percentages for qualitative categorical variables. CMV-infected patients were compared with the disease-free group using bivariate analysis, odds ratios, and 95% confidence intervals. P values were calculated using the chi-square test. Comparison adjustments were performed by multiple logistic regression analysis. The level of significance was set at 5% (P ⫽ .05). The statistical analysis was performed using SPSS 12.0.
RESULTS
The characteristics of patients with or without CMV infection, such as age, gender, number of hemecomponents, and serologic CMV status of donor/recipient, are shown in Table 1. None of these variables reached statistical significance as a risk factor for CMV infection. The risk of CMV infection was 3.8-fold higher for patients who received a three-drug compared with a twodrug regimen. When cyclosporine was used, the risk of CMV infection was 4.3-fold higher. In the logistic regression analysis, these results were confirmed with cyclosporine (OD⫽5.8) and the three-drug regimen (OD⫽6.7). There were no differences between the mean dose of prednisone and the cyclosporine and tacrolimus blood levels in the first trimester among infected versus noninfected patients. DISCUSSION
In transplant patients, when prophylaxis is not routinely used the prevalence of CMV infection ranges from 30% to 50%.5 In this study, CMV antigenemia was positive in 65% of OLT, consistent with the literature. The high prevalence of antibodies in donors and recipients was due to the fact that infection is widespread among infants in developing countries.6
Immunosuppression was a risk factor for CMV infection; when the three-drug regimen was used it was 6.7% higher, demonstrating that the severity of CMV illness correlates with the degree of immunosuppression in the transplant setting.6 Tacrolimus is 30 to 100 times more potent than cyclosporine in vitro, but maximal in vivo inhibition has been shown to be greater with cyclosporine.7 When cyclosporine was used, we observed a 5.8-fold higher risk for development of CMV infection. There was no association between CMV infection and the transfusion of hemecomponents, because we routinely used washed blood components. We did not use leukodepletion, which is currently recommended, but patients were equally protected. In conclusion, CMV infection is a frequent situation in OLT with immunosuppression being an important risk factor. REFERENCES 1. Angelis M, Cooper JT, Freeman RB: Impact of donor infection on outcome of orthotopic liver transplantation. Liver Transpl 9:451, 2003 2. Jong MD, Galasso GJ, Gazzard B, et al: Summary of II international symposium on cytomegalovirus. Antiviral Research 39:141, 1998 3. Singh N, Wannstedt C, Keyes L, et al: Impact of evolving trends in recipients and donor characteristics on cytomegalovirus infection in liver transplant recipients. Transplantation 79:1428, 2005 4. Rowshani A, Bemelman F, Leeuwen EMM, et al: Clinical and immunologic aspects of cytomegalovirus infection in solid organ transplant recipients. Transplantation 79:381, 2005 5. Seehofer D, Rayes N, Tullius SG, et al: CMV hepatitis after liver transplantation: incidence, clinical course, and long-term follow-up. Liver Transpl 8:1138, 2002 6. Meer JTM, Drew WL, Bowden RA, et al: Summary of the international consensus symposium on advances in the diagnosis, treatment and prophylaxis of cytomegalovirus infection. Antiviral Res 32:119, 1996 7. Maes BD, Vanrenterghem YFC: Cyclosporine: advantages versus disadvantages vis-à-vis tacrolimus. Transplant Proc 36 (suppl 2S):40S, 2004