Cytomegalovirus infection after liver transplantation using different prophylaxes

Cytomegalovirus infection after liver transplantation using different prophylaxes

Cytomegalovirus Infection After Liver Transplantation Using Different Prophylaxes A. Kornberg, Th. Grube, M. Hommann, U. Schotte, and J. Scheele T H...

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Cytomegalovirus Infection After Liver Transplantation Using Different Prophylaxes A. Kornberg, Th. Grube, M. Hommann, U. Schotte, and J. Scheele

T

HE INFECTION WITH the cytomegalovirus (CMV) after liver transplantation (LT) is associated with considerable morbidity and high costs. Incidence of CMV infection and CMV disease could be significantly decreased by prophylaxis or preemptive therapy.1,2 Due to differences in primary immunosuppression, the sensitivity and specificity of diagnostic tools, the distribution of serological status, and the type of treatment for CMV infection and disease, studies of different prophylactic regimens are hardly seriously comparable. Thus, each transplant center has to reevaluate their results of CMV prophylaxis and CMV disease according to the above stated parameters. PATIENTS AND METHODS

Between January 1996 and December 2000 a total of 155 liver transplant patients could be evaluated. Immunosuppression consisted of a quadruple regimen based on either cyclosporine (CsA, n ⫽ 132) or tacrolimus (Tac, n ⫽ 23). Induction therapy was performed by anti-T-lymphocyte globulin (ALG, n ⫽ 125) or interleukin 2-receptor antibody (IL2-Rab, n ⫽ 30). Additional immunosuppression consisted of prednisolone and azathioprine (AZA, n ⫽ 89) or mycophenolat mofetil (MMF, n ⫽ 66). CMV monitoring consisted of weekly determination of CMV pp65-antigenemia, qualitative CMV PCR, and CMV Ig-antibody titer. CMV infection was defined as positive pp65-antigenemia of at least one up to a maximum of five cells of 100,000 leukocytes without symptoms of CMV disease and a reduction of numbers of cells in repeated tests. CMV disease was postulated in the case of CMV infection (antigen-positivity) with symptoms of CMV syndrome (leukopenia, thrombopenia, fever) or tissue invasion (CMV hepatitis, CMV pneumonia, CMV enteritis) or in the case of increasing antigenemia (⬎5 cells/100,000 leucocytes). Patients with lower-risk seroconstellation (D⫺/R⫺; D⫺/R⫹; D⫹/R⫹) received CMV hyperimmunglobulin (CMVIG, Fa. Bayer, Leverkusen, Germany) on days 1 and 14 posttransplant. Patients with high-risk seroconstellation (D⫹/R⫺) additionally received CMVIG on days 7 and 21. In addition, those group of patients underwent antiviral prophylaxis by application of gancyclovir (Cymevene, Fa Roche, 1 ⫻ 5 mg/kg/d intravenously for 14 days, orally 2 ⫻ 250 mg/d for 86 days) for 100 days posttransplant. Rejection was con-

firmed by graft biopsy and treated by application of methylprednisolone 500 mg/d for 3 days. RESULTS

There were no cases of CMV-related mortality, graft dysfunction, and bacterial or fungal superinfection. The incidence of CMV infection and disease was 20% and 32%, respectively. All patients developing more than five positive cells revealed symptoms of CMV disease. Leukocytopenia (98%) and mild hepatitis (70%) were the predominant symptoms of CMV disease. There were only two cases of severe CMV disease with CMV pneumonia without requiring ventilation. Despite long-term gancyclovir prophylaxis, 17/31 (54.8%) patients with high-risk constellation (D⫹/ R⫺) developed CMV disease (P ⬍ .05). A total of 39% of patients receiving an organ D⫹ developed CMV disease. Patients receiving MMF (39.3%) versus AZA (26.9%) were at higher risk for developing CMV disease (P ⬎ .05). Then, patients with MMF revealed significantly higher pp65-antigenemia and lower levels of aminotransferases (P ⬍ .05). Only eight patients (5.2%) had to be treated because of rejection; four of them developed CMV disease, another patient suffered from CMV infection, and three patients had no CMV infection (P ⫽ .53). A total of 12 patients suffered from recurrent CMV infection (n ⫽ 4) and CMV disease (n ⫽ 8). Patients with D⫹/R⫺ seroconstellation were at highest risk (n ⫽ 5, P ⫽ .015). Patients developing CMV disease had no compromised long-term survival (73.9% after 5 years). DISCUSSION

We report about our center experiences with a targeted CMV prophylaxis according to expected risk for developing CMV disease. Apart from rejection and rejection therapy3 as well as the application of induction therapy with antilymphocyte agent,4 the donor-recipient serostatus is the main risk factor for developing CMV disease.5 In contrast to other reports,6 long-term prophylaxis with gancyclovir did not prevent development of CMV disease in seronegative patients receiving a seropositive graft in our serious, but it From the Department of General and Visceral Surgery, Friedrich-Schiller University, Jena, Germany. Address reprint requests to A. Kornberg, Department of General and Visceral Surgery, Friedrich-Schiller-University, Jena, 07743 Jena, Germany.

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Transplantation Proceedings, 33, 3624–3625 (2001)

CMV INFECTION AFTER TRANSPLANTATION

proved to be sufficient in keeping the incidence of severe CMV disease very low. The application of MMF instead of AZA seems to promote development of disease. The determination of pp65-antigenemia was feasible and efficient for early diagnosis and monitoring of therapy. Thus, patients with CMV disease achieved a comparable 5-year survival rate of 73.9%. Regarding the low incidence of rejection in our serious, immunosuppression must be suggested to be a responsible factor for the high rate of CMV disease. In the future, reduction of immunosuppression or augmentation of prophylaxis, such as more frequent applications of CMVIG, must be discussed.

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REFERENCES 1. Saliba F, Eyraud D, Samuel D, et al: Transplant Proc 25:1444, 1993 2. Winston DJ, Wirin D, Shaked A, et al: Lancet 346:69, 1995 3. Paya CV, Wiesner RH, Hermans PE, et al: J Hepatol 19:325, 1993 4. Hooks MA, Perino CA, Henderson JM, et al: J Med Virol 26:617, 1992 5. Paya CV, Marin E, Keating M, et al: J Med Virol 1:123, 1993 6. Seu P, Winston DJ, Holt CD, et al: Transplantation 64:1614, 1997