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Minimal impact of CMV infection on long-term survival after liver transplantation
Minimal Impact of CMV Infection on Long-Term Survival After Liver Transplantation D. Seehofer, N. Rayes, T. Steinmu¨ller, C.A. Schmidt, U. Settmacher, A.R. Mu¨ller, and P. Neuhaus
C
YTOMEGALOVIRUS (CMV) INFECTION is frequently observed after solid organ transplantation. After orthotopic liver transplantation (OLT) the incidence is reported to be as high as 25% to 80% in different series.1–3 Most infections currently have a relatively mild course; nevertheless, the correlation, between CMV infection and increased morbidity and mortality is unclear,4 – 6 but most reports showing an impaired patient survival caused by CMV infection do not reflect the contemporary management of CMV. Especially newer diagnostic tools like pp65 antigen testing7 and effective treatment strategies (eg, preemptive approaches) seem to reduce the threat of CMV infection and disease. Therefore, the impact of CMV infection or disease on long-term survival rates after liver transplantation was retrospectively analyzed in a large single-center experience without application of ganciclovir prophylaxis. PATIENTS AND METHODS Patient Population The analysis included liver transplantations that were performed at our center between May 1993 and April 2000. After exclusion of grafts in patients under 18 years of age and of grafts surviving less than 30 days, 739 liver transplantations (445 in male and 294 in female patients) were retrospectively analyzed. Indications for primary liver transplantation were viral hepatitis (n ⫽ 255), alcoholic cirrhosis (n ⫽ 162), cholestatic liver disease (n ⫽ 91), autoimmune cirrhosis (n ⫽ 30), cryptogenic liver cirrhosis or failure (n ⫽ 64), Budd-Chiari syndrome (n ⫽ 15), and miscellaneous causes (n ⫽ 122). Immunosuppression consisted of a tacrolimus (n ⫽ 429) or cyclosporine (n ⫽ 310) based dual, triple or quadrupe regimen.
CMV Surveillance CMV serostatus of donors and recipients was determined preoperatively by detection of CMV IgG and CMV IgM by ELISA. CMV infection was diagnosed by the presence of CMV-pp65 antigenemia (Clonab, Biotest, Dreieich, Germany) as described previously.7 Blood samples were examined weekly during the primary hospitalization after OLT and additionally if CMV infection was suspected.
Definitions Asymptomatic CMV infection was defined as pp65 antigenemia of at least 0.5 positive cells per 10,000 leukocytes. CMV disease was classified as CMV syndrome (antigenemia plus fever, leukopenia,
or thrombcytopenia), or tissue-invasive disease (antigenemia plus hepatitis, pneumonia, gastroenteritis, or involvement of other organs). In cases of suspected organ involvement, a biopsy was examined histomorphologically and immunohistochemically for CMV. According to the manifestation of CMV (no CMV, CMV infection, CMV syndrome, or CMV tissue-invasive disease), the whole population was divided in four groups. If one patient had more than one episode of CMV with different manifestations, he was assigned to the group described by the most severe manifestation.
Antiviral Treatment All patients received low-dose oral acyclovir (200 mg tds) as herpes simplex prophylaxis for 6 weeks; no ganciclovir prophylaxis was utilized. Between 1993 and 1996, 50% of the pp65-positive asymptomatic patients were treated preemptively with IV ganciclovir.8 From 1996 to 2000, 50% were treated preemptively with oral ganciclovir,9 both within randomized studies. Treatment of CMV disease consisted of intravenous ganciclovir (Cymeven, Roche, Germany, 4 to 5 mg/kg body weight twice daily or adapted to renal function) for a minimum of 14 days.
Statistical Analysis All values are presented as mean and standard error of mean (SEM). Actuarial patient and graft survival rates were analyzed using the Kaplan-Meier method; differences between groups were compared by a log-rank test. All differences were considered significant at P values of less than .05. Statistical analyses were performed with SPSS 10.0.
RESULTS CMV-Seroconstellation And CMV Infection
The recipient was CMV-IgG seropositive (R⫹) in 713 transplantations (65%), negative (R⫺) in 335 (31%) and the pretransplant serostatus was not available in 42 cases (4%). The donor-recipient constellation was as follows: 103 patients (14%) were donor-negative and recipient-negative; From the Department of General-, Visceral- and Transplant Surgery (D.S., N.R., T.S., U.S., A.R.M., P.N.) and Department of Haematology and Oncology (C.A.S.), Charite´ Campus Virchow, Humboldt University of Berlin, Berlin, Germany. Address reprint request to Daniel Seehofer, MD, Department of General-, Visceral-, and Transplant Surgery, Charite´ Campus Virchow, Augustenburger Platz 1, D-13353 Berlin, Germany. E-mail: [email protected]
0041-1345/02/$–see front matter PII S0041-1345(02)03231-1
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
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Transplantation Proceedings, 34, 2272–2273 (2002)
CMV INFECTION AND LONG-TERM SURVIVAL
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Table 1. Actuarial Patient and Graft Survival Rates in Correlation With Different Manifestations of CMV Infection
No CMV
Asymptomatic CMV Infection
CMV Viral Syndrome
CMV Tissue Invasive Disease
Number of OLTs 547 (74.1%) 123 (16.7%) 48 (6.5%) 20 (2.7%) Graft survival 1 year 93% 90% 85% 80* 5 year 83% 81% 77% 68* Patient survival 1 year 95% 94% 93% 80* 5 year 86% 88% 84% 74* *P ⬍ .05 vs no CMV infection by log-rank test.
224 (30%) patients were donor-negative and recipientpositive (D⫹ R⫹), donor-positive and recipient-positive in 244 patients (33%) and 101 patients (14%) had the highrisk constellation donor-positive and recipient-negative. In 66 patients (9%) the status of either donor or recipient was not available. After 547 liver transplantations (74.1%) no CMV infection (ie, no positive pp65 antigen test) was found, whereas after 191 liver transplantations (25.9%) pp65 antigenemia occurred at least once. Of these patients 123 remained asymptomatic (16.7%), 48 developed a CMV viral syndrome (6.5%), and 20 patients (2.7%) tissue-invasive disease. Patient And Graft Survival Rates
Overall 1-, 3-, and 5-year graft survival rates in 547 patients without CMV infection were 93%, 86%, and 83%, respectively, rates which were not significantly different from 87%, 82%, and 78% among 191 transplantations with CMV infection (P ⫽ .09 by log-rank test). Patient and graft survival rates among patients with different manifestations of CMV infection showed only a significantly lower survival among the small group with tissue invasive disease (see Table 1). Among the members of the group with CMV tissue-invasive disease, 5 of the 20 patients died during the follow-up period. However, all reasons of death in these group were not apparently related to CMV infection [graftversus-host disease, recurrent malignancy (n ⫽ 3), and aspergillosis (n ⫽ 1; aspergillosis is questionably related to CMV infection, although this is not finally verified)]. Also in the other groups, no patient died in proximety to the CMV-related infection. DISCUSSION
The present report demonstrates that CMV infection has no significant impact on long-term survival rates after liver transplantation. In contrast, some earlier reports observed that CMV infection and/or disease was a predictor of impaired survival rates.4,6 Also in a historical control group of our own patients before introduction of
pp65 testing (data not shown), significantly decreased patient survival was found in patients with CMV syndrome or CMV disease. In contrast, CMV antigenemia and CMV syndrome did not predict reduced survival rates in the present analysis of patients with current approaches to the diagnosis and treatment of CMV infections. Also Stratta et al found that the survival rates of patients with and without CMV infection were not significantly different.10 The overall incidence of CMV infection in the present series was relatively low (25.9%). These data compare well to other series, even with prophylactic application of oral ganciclovir for up to 100 days: in a series of 304 liver transplantations, 24.5% of patients developed CMV infection as reported by Gane et al.11 In the same report 4.8% developed CMV disease under ganciclovir prophylaxis. Since these results are not markedly different from the present series, general CMV prophylaxis does not appear to be necessary, if a balanced immunosuppressive regimen and an adequate monitoring of CMV infection is performed. Therefore preemptive treatment of asymptomatic CMV infection does not appear to be superior to symptom-triggered treatment of CMV disease. Our results9 suggest that at least in CMV-seropositive recipients symptom triggered treatment is equally effective. In conclusion, using modern diagnostic tools and treatment, CMV infection and CMV viral syndrome do not significantly influence graft survival rates. A general ganciclovir prophylaxis is therefore not obligatory. Only the small group of patients with CMV tissue-invasive disease experience significantly lower survival rates, but none of these patients died due to CMV, which is therefore rather an epiphenomenon than a poor prognostic factor per se. REFERENCES 1. Stratta RJ, Shaeffer MS, Markin RS, et al: Dig Dis Sci 37:673, 1992 2. Gorensek MJ, Carey WD, Vogt D, et al: Gastroenterology 98:1326, 1990 3. Paya CV, Hermans PE, Washington JA, et al: Mayo Clin Proc 64:555, 1989 4. Falagas ME, Snydman DR, Griffith J, et al: Ann Intern Med 126:275, 1997 5. Falagas ME, Snydman DR, Griffith J, et al: Clin Inf Dis 25:314, 1997 6. de Otero J, Gavalda` J, Murio E, et al: Clin Inf Dis 26:865, 1998 7. Schmidt CA, Oettle H, Peng R, et al: Transplantation 59: 1133, 1995 8. Rayes N, Oettle H, Schmidt CA, et al: Ann Transplantation 4:12, 1999 9. Rayes N, Seehofer D, Schmidt CA, et al: Transplantation 72:881, 2001 10. Stratta RJ, Shaeffer MS, Markin RS, et al: Dig Dis Sci 37:673, 1992 11. Gane E, Saliba F, Valdecasas GJ, et al: Lancet 350:1729, 1997
C
YTOMEGALOVIRUS (CMV) INFECTION is frequently observed after solid organ transplantation. After orthotopic liver transplantation (OLT) the incidence is reported to be as high as 25% to 80% in different series.1–3 Most infections currently have a relatively mild course; nevertheless, the correlation, between CMV infection and increased morbidity and mortality is unclear,4 – 6 but most reports showing an impaired patient survival caused by CMV infection do not reflect the contemporary management of CMV. Especially newer diagnostic tools like pp65 antigen testing7 and effective treatment strategies (eg, preemptive approaches) seem to reduce the threat of CMV infection and disease. Therefore, the impact of CMV infection or disease on long-term survival rates after liver transplantation was retrospectively analyzed in a large single-center experience without application of ganciclovir prophylaxis. PATIENTS AND METHODS Patient Population The analysis included liver transplantations that were performed at our center between May 1993 and April 2000. After exclusion of grafts in patients under 18 years of age and of grafts surviving less than 30 days, 739 liver transplantations (445 in male and 294 in female patients) were retrospectively analyzed. Indications for primary liver transplantation were viral hepatitis (n ⫽ 255), alcoholic cirrhosis (n ⫽ 162), cholestatic liver disease (n ⫽ 91), autoimmune cirrhosis (n ⫽ 30), cryptogenic liver cirrhosis or failure (n ⫽ 64), Budd-Chiari syndrome (n ⫽ 15), and miscellaneous causes (n ⫽ 122). Immunosuppression consisted of a tacrolimus (n ⫽ 429) or cyclosporine (n ⫽ 310) based dual, triple or quadrupe regimen.
CMV Surveillance CMV serostatus of donors and recipients was determined preoperatively by detection of CMV IgG and CMV IgM by ELISA. CMV infection was diagnosed by the presence of CMV-pp65 antigenemia (Clonab, Biotest, Dreieich, Germany) as described previously.7 Blood samples were examined weekly during the primary hospitalization after OLT and additionally if CMV infection was suspected.
Definitions Asymptomatic CMV infection was defined as pp65 antigenemia of at least 0.5 positive cells per 10,000 leukocytes. CMV disease was classified as CMV syndrome (antigenemia plus fever, leukopenia,
or thrombcytopenia), or tissue-invasive disease (antigenemia plus hepatitis, pneumonia, gastroenteritis, or involvement of other organs). In cases of suspected organ involvement, a biopsy was examined histomorphologically and immunohistochemically for CMV. According to the manifestation of CMV (no CMV, CMV infection, CMV syndrome, or CMV tissue-invasive disease), the whole population was divided in four groups. If one patient had more than one episode of CMV with different manifestations, he was assigned to the group described by the most severe manifestation.
Antiviral Treatment All patients received low-dose oral acyclovir (200 mg tds) as herpes simplex prophylaxis for 6 weeks; no ganciclovir prophylaxis was utilized. Between 1993 and 1996, 50% of the pp65-positive asymptomatic patients were treated preemptively with IV ganciclovir.8 From 1996 to 2000, 50% were treated preemptively with oral ganciclovir,9 both within randomized studies. Treatment of CMV disease consisted of intravenous ganciclovir (Cymeven, Roche, Germany, 4 to 5 mg/kg body weight twice daily or adapted to renal function) for a minimum of 14 days.
Statistical Analysis All values are presented as mean and standard error of mean (SEM). Actuarial patient and graft survival rates were analyzed using the Kaplan-Meier method; differences between groups were compared by a log-rank test. All differences were considered significant at P values of less than .05. Statistical analyses were performed with SPSS 10.0.
RESULTS CMV-Seroconstellation And CMV Infection
The recipient was CMV-IgG seropositive (R⫹) in 713 transplantations (65%), negative (R⫺) in 335 (31%) and the pretransplant serostatus was not available in 42 cases (4%). The donor-recipient constellation was as follows: 103 patients (14%) were donor-negative and recipient-negative; From the Department of General-, Visceral- and Transplant Surgery (D.S., N.R., T.S., U.S., A.R.M., P.N.) and Department of Haematology and Oncology (C.A.S.), Charite´ Campus Virchow, Humboldt University of Berlin, Berlin, Germany. Address reprint request to Daniel Seehofer, MD, Department of General-, Visceral-, and Transplant Surgery, Charite´ Campus Virchow, Augustenburger Platz 1, D-13353 Berlin, Germany. E-mail: [email protected]
0041-1345/02/$–see front matter PII S0041-1345(02)03231-1
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
2272
Transplantation Proceedings, 34, 2272–2273 (2002)
CMV INFECTION AND LONG-TERM SURVIVAL
2273
Table 1. Actuarial Patient and Graft Survival Rates in Correlation With Different Manifestations of CMV Infection
No CMV
Asymptomatic CMV Infection
CMV Viral Syndrome
CMV Tissue Invasive Disease
Number of OLTs 547 (74.1%) 123 (16.7%) 48 (6.5%) 20 (2.7%) Graft survival 1 year 93% 90% 85% 80* 5 year 83% 81% 77% 68* Patient survival 1 year 95% 94% 93% 80* 5 year 86% 88% 84% 74* *P ⬍ .05 vs no CMV infection by log-rank test.
224 (30%) patients were donor-negative and recipientpositive (D⫹ R⫹), donor-positive and recipient-positive in 244 patients (33%) and 101 patients (14%) had the highrisk constellation donor-positive and recipient-negative. In 66 patients (9%) the status of either donor or recipient was not available. After 547 liver transplantations (74.1%) no CMV infection (ie, no positive pp65 antigen test) was found, whereas after 191 liver transplantations (25.9%) pp65 antigenemia occurred at least once. Of these patients 123 remained asymptomatic (16.7%), 48 developed a CMV viral syndrome (6.5%), and 20 patients (2.7%) tissue-invasive disease. Patient And Graft Survival Rates
Overall 1-, 3-, and 5-year graft survival rates in 547 patients without CMV infection were 93%, 86%, and 83%, respectively, rates which were not significantly different from 87%, 82%, and 78% among 191 transplantations with CMV infection (P ⫽ .09 by log-rank test). Patient and graft survival rates among patients with different manifestations of CMV infection showed only a significantly lower survival among the small group with tissue invasive disease (see Table 1). Among the members of the group with CMV tissue-invasive disease, 5 of the 20 patients died during the follow-up period. However, all reasons of death in these group were not apparently related to CMV infection [graftversus-host disease, recurrent malignancy (n ⫽ 3), and aspergillosis (n ⫽ 1; aspergillosis is questionably related to CMV infection, although this is not finally verified)]. Also in the other groups, no patient died in proximety to the CMV-related infection. DISCUSSION
The present report demonstrates that CMV infection has no significant impact on long-term survival rates after liver transplantation. In contrast, some earlier reports observed that CMV infection and/or disease was a predictor of impaired survival rates.4,6 Also in a historical control group of our own patients before introduction of
pp65 testing (data not shown), significantly decreased patient survival was found in patients with CMV syndrome or CMV disease. In contrast, CMV antigenemia and CMV syndrome did not predict reduced survival rates in the present analysis of patients with current approaches to the diagnosis and treatment of CMV infections. Also Stratta et al found that the survival rates of patients with and without CMV infection were not significantly different.10 The overall incidence of CMV infection in the present series was relatively low (25.9%). These data compare well to other series, even with prophylactic application of oral ganciclovir for up to 100 days: in a series of 304 liver transplantations, 24.5% of patients developed CMV infection as reported by Gane et al.11 In the same report 4.8% developed CMV disease under ganciclovir prophylaxis. Since these results are not markedly different from the present series, general CMV prophylaxis does not appear to be necessary, if a balanced immunosuppressive regimen and an adequate monitoring of CMV infection is performed. Therefore preemptive treatment of asymptomatic CMV infection does not appear to be superior to symptom-triggered treatment of CMV disease. Our results9 suggest that at least in CMV-seropositive recipients symptom triggered treatment is equally effective. In conclusion, using modern diagnostic tools and treatment, CMV infection and CMV viral syndrome do not significantly influence graft survival rates. A general ganciclovir prophylaxis is therefore not obligatory. Only the small group of patients with CMV tissue-invasive disease experience significantly lower survival rates, but none of these patients died due to CMV, which is therefore rather an epiphenomenon than a poor prognostic factor per se. REFERENCES 1. Stratta RJ, Shaeffer MS, Markin RS, et al: Dig Dis Sci 37:673, 1992 2. Gorensek MJ, Carey WD, Vogt D, et al: Gastroenterology 98:1326, 1990 3. Paya CV, Hermans PE, Washington JA, et al: Mayo Clin Proc 64:555, 1989 4. Falagas ME, Snydman DR, Griffith J, et al: Ann Intern Med 126:275, 1997 5. Falagas ME, Snydman DR, Griffith J, et al: Clin Inf Dis 25:314, 1997 6. de Otero J, Gavalda` J, Murio E, et al: Clin Inf Dis 26:865, 1998 7. Schmidt CA, Oettle H, Peng R, et al: Transplantation 59: 1133, 1995 8. Rayes N, Oettle H, Schmidt CA, et al: Ann Transplantation 4:12, 1999 9. Rayes N, Seehofer D, Schmidt CA, et al: Transplantation 72:881, 2001 10. Stratta RJ, Shaeffer MS, Markin RS, et al: Dig Dis Sci 37:673, 1992 11. Gane E, Saliba F, Valdecasas GJ, et al: Lancet 350:1729, 1997