LIVER TRANSPLANTATION 17:446–455, 2011
ORIGINAL ARTICLE
Is Cytomegalovirus Infection Dangerous in Cytomegalovirus-Seropositive Recipients After Liver Transplantation? Jong Man Kim,1 Sung-Joo Kim,1 Jae-Won Joh,1 Choon Hyuck David Kwon,1 Sanghyun Song,1 Milljae Shin,1 Ju Ik Moon,1 Gaab Soo Kim,2 Seung Heui Hong,3 and Suk-Koo Lee1 1 Department of Surgery; and 2Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine; and 3Organ Transplantation Center, Samsung Medical Center, Seoul, Korea
Cytomegalovirus (CMV) infections contracted after liver transplantation put patients at an increased risk of morbidity and mortality. We analyzed the effects of CMV infection by time of onset, mortality, and graft failure risk factors in liver recipients who were CMV donor-positive/recipient-positive (Dþ/Rþ). We reviewed 618 medical records for consecutive adult liver transplant cases. CMV pp65 antigenemia assays to determine patient CMV status were administered monthly. The incidences of CMV infection and disease were 55.7% (344 of 618 records) and 5.5% (34 of 618 records), respectively. The differences in patient survival and graft failure rates for CMV-infected and CMV-uninfected patients were not significant (P ¼ 0.707 and P ¼ 0.973), but the rates were lower in patients with CMV disease than in CMV-uninfected patients (P ¼ 0.005 and P ¼ 0.030, respectively). The recurrence of hepatitis B virus and hepatocellular carcinoma, hepatic dysfunction, infection, numerous pp65-staining cells, and CMV disease were found to be the risk factors for mortality and graft failure in CMV Dþ/Rþ adult liver transplant patients. In conclusion, the occurrence of CMV disease, and not asymptomatic CMV infection, was a risk factor for mortality and graft failure in adult liver transplant recipients with CMV Dþ/Rþ. Liver Transpl 17:446-455, 2011. V 2011 AASLD. C
Received July 3, 2010; accepted December 13, 2010.
Cytomegalovirus (CMV) infection most commonly occurs in solid organ transplantation patients within the first 3 months following surgery, usually due to mismatched CMV serostatus, ie, a CMV-positive donor and a CMV-negative recipient (CMV Dþ/R).1,2 More than 75% of solid organ transplant recipients are newly infected with CMV or exhibit reactivation of a latent CMV infection after transplantation.3 CMV infection has adverse effects on graft and patient survival.2 In particular, graft survival in liver transplant
recipients is significantly lower in patients with a history of CMV infection compared to those without. In the absence of any preventive therapy, 30%-75% of transplant recipients develop CMV infection, and the reported incidence of CMV disease in liver transplant recipients is between 8% and 30%.4 Antiviral prophylaxis is associated with reduced biopsy-proven graft rejection and improved patient survival.5–7 However, the widespread use of prophylactic therapy to prevent CMV infection has resulted in an increase in
Abbreviations: CI, confidence interval; CMV, cytomegalovirus; CTP, Child-Turcotte-Pugh; DDLT, deceased donor liver transplantation; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; LDLT, living donor liver transplantation; LD-PC, leukocyte-depleted platelet concentrate; LD-RBC, leukocyte-depleted red blood cells; MELD, model for end-stage liver disease; MMF, mycophenolate mofetil. Address reprint requests to Sung-Joo Kim, M.D., Ph.D., Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50 Ilwon -Dong, Gangnam-Gu, Seoul, Korea 135-710. Telephone: 82-2-3410-3476; FAX: 82-2-3410-0040; E-mail:
[email protected] Address reprint requests to Jae-Won Joh, M.D., Ph.D., Professor, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50 Ilwon -Dong, Gangnam-Gu, Seoul, Korea 135-710. Telephone: 82-2-3410-3476; FAX: 82-2-3410-0040; E-mail:
[email protected] DOI 10.1002/lt.22249 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2011 American Association for the Study of Liver Diseases. V
LIVER TRANSPLANTATION, Vol. 17, No. 4, 2011
late CMV infections in solid organ transplant recipients.8 However, little is known about CMV infections in CMV donor-positive/recipient-positive (CMV Dþ/ Rþ) adult liver transplant cases without antiviral prophylaxis. We compared CMV-positive and CMV-negative patients and determined the incidence of early and late-onset CMV infections among CMV Dþ/Rþ Korean patients, regardless of antiviral prophylaxis. We also investigated mortality and graft failure risk factors in CMV Dþ/Rþ adult liver transplant recipients.
MATERIALS AND METHODS
KIM ET AL. 447
nemia assay was conducted. If the CMV antigenemia assay showed more than 10 pp65 antigen–positive cells per 4 105 leukocytes, the patient was admitted to the hospital and preemptive treatment was initiated, regardless of clinical manifestations. CMV assays were conducted 3 times a week until a negative result was obtained. Preemptive antiviral therapy consisted of intravenous ganciclovir and was administered daily for 10-14 days until a negative CMV assay was confirmed. The dose of intravenous ganciclovir was adjusted according to patient creatinine clearance. Patients who developed acute rejection received anti-CMV prophylaxis during the treatment course of antithymocyte globulin or muromonab-CD3.
Patients We reviewed 653 medical records of consecutive adult liver transplant cases between January 1996 and January 2009 at Samsung Medical Center, Seoul, Korea. Patients who died within 1 month of liver transplantation, retransplant cases due to graft failure, and 1 patient with a negative donor/positive recipient status were excluded. All medical records of all patients were reviewed for epidemiologic and clinical characteristics. All patients were followed until death or the end of the study in October 2009. The following data were collected before CMV infection detection: patient demographics, preoperative diagnosis, Child-Turcotte-Pugh (CTP) scores, Model for EndStage Liver Disease (MELD) scores, type of liver transplantation, amount of leukocyte-depleted red blood cell (LD-RBC) transfusion, amount of fresh frozen plasma, amount of leukocyte-depleted platelet concentrate (LD-PC), cryoprecipitate during liver transplantation, postoperative bleeding, reoperation, biliary complication, hepatic dysfunction, renal dysfunction, infection (positive bacterial or fungal culture in blood, sputum, ascites, and urine), acute rejection, recurrence of hepatitis B virus (HBV) or hepatitis C virus (HCV), use of antilymphocyte agents (antithymocyte globulin or muromonab-CD3), highest number of pp65-staining cells, preemptive therapy, CMV syndrome, tissue-invasive CMV disease, and date of death.
Immunologic Regimens Tacrolimus, steroids, and mycophenolate mofetil (MMF) were the primary agents used for immunosuppression after liver transplantation. All transplant recipients were given 500 mg intravenous methylprednisolone during the anhepatic phase until postoperative day 2, which was tapered to 60 mg/day for a period of 5 days, and then administered at 8 mg, twice per day, for 1 month starting on postoperative day 8. Tacrolimus treatment was started on postoperative day 3, and the optimal blood level was adjusted to maintain a trough plasma concentration of 10-15 ng/ mL during the first month and was reduced to 5-10 ng/mL thereafter. MMF was used in combination with tacrolimus and steroids. Starting on postoperative day 1, 750 mg MMF was administered twice a day. Cyclosporin (plasma concentration adjusted to 100-200 ng/mL) was used in the event of tacrolimus toxicity or tacrolimus refractory rejection, and was given orally twice a day. A liver biopsy was performed if acute rejection was clinically suspected. Methylprednisolone (500 mg) was administered intravenously every day for 3 days if acute rejection was confirmed by biopsy and was tapered to 60 mg/day over a period of 4 days thereafter.
HBV Prophylaxis Virologic Follow-Up and CMV Infection Treatment All patients were routinely tested for CMV after liver transplantation with the use of a CMV pp65 antigenemia assay. We did not routinely use antiviral prophylactic therapy in the liver transplant recipients. For the first month after transplantation, ethylene diamine tetraacetic acid–treated blood samples were examined weekly for the presence of CMV. Testing was performed 3 times a week if the patient had a known CMV infection. In the absence of symptoms, patients were routinely monitored for CMV once a month. If the patient had an unexplained fever or if a CMV infection was clinically suspected, a CMV antige-
All patients with HBV infection or recipients without hepatitis B surface antigen who received liver allograft with hepatitis B core antibody were given 10,000 units of hepatitis B immunoglobulin (Green Cross Corp., Yongin, Korea) intravenously during the anhepatic phase, which was followed by a 7-day intravenous course of 10,000 units hepatitis B immunoglobulin per day. Patients received 10,000 units intravenously every month to maintain anti–hepatitis B surface antibody titers at 200 IU/mL. Before 2008, patients who were reinfected with HBV received only lamivudine (100 mg/day) for treatment. After January 2008, patients received a combination of entecavir (0.5 mg/day) and hepatitis B immunoglobulin for HBV prophylaxis.
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Definition of CMV Infection and Disease CMV infection was defined as a CMV pp65 antigenpositive cell number greater than 1 positive cell per 400,000 white blood cells. Patients whose infections were detected in the first 3 months after liver transplantation were defined as early-onset CMV, with lateonset CMV defined as infections detected after the third month. Early and late-onset CMV cases were divided by onset time of the first CMV infection episode. CMV disease presented either as CMV syndrome or as tissue-invasive CMV disease. CMV syndrome was defined as a positive antigenemia assay with more than 1 of the following symptoms or signs: unexplained fever (>38.3 C), constitutional symptoms such as fatigue or general myalgia, leukopenia (white blood cell count
