494: Changing Trends in Infectious Complications among Heart Transplant Recipients

494: Changing Trends in Infectious Complications among Heart Transplant Recipients

The Journal of Heart and Lung Transplantation Volume 28, Number 2S tion during SRL immunosuppression may be an important mechanism for the prevention...

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The Journal of Heart and Lung Transplantation Volume 28, Number 2S

tion during SRL immunosuppression may be an important mechanism for the prevention of CAV. 492 New Tools for Tacrolimus (Tac) Dose Optimization in Lung Transplant Recipients during the First Post-Transplant Year: Preliminary Results of STIMMUGREP Study C. Monchaud1,2, M. Estenne3, M. Reynaud-Gaubert4, C. Pison5, M. Stern6, R. Kessler7, C. Dromer8, R. Guillemain9, A. Rousseau1, P. Marquet1,2 1Univ Limoges, Limoges, France; 2CHU Limoges, Limoges, France; 3Erasme University Hospital, Universite´ Libre de Bruxelles, Brussels, Belgium; 4Ho ˆ pital Ste Marguerite, Marseille, France; 5CHU Grenoble, Univ Grenoble, Grenoble, France; 6 Ho ˆ pital Foch, Suresnes, France; 7Ho ˆ pitaux Universitaires de Strasbourg, Strasbourg, France; 8Ho ˆ pital du Haut-Le´veˆque, CHU ˆ pital Europe´en Georges Pompidou, Bordeaux, Pessac, France; 9Ho Assistance Publique-Ho ˆ pitaux de Paris, Paris, France Purpose: The purposes of this study were to explain interpatient pharmacokinetic (PK) variability and create new tools for Tac dose adjustment in cystic fibrosis (CF) and non-CF lung transplant recipients, to be used on the ISBA website (https://pharmaco.chu-limoges.fr/abis.htm) developed for the therapeutic drug monitoring (TDM) of immunosuppressants. Methods and Materials: In 120 lung transplant patients prospectively enrolled in the STIMMUGREP trial, full PK profiles (10-12 blood samples over 12 h) were collected at 2 or more of the following periods: between day 7 and day 14, month 1 (M1), M3 and M12. Tac whole blood levels were assayed by LC-MS/MS. Data were analyzed in 45 patients (33 CF) who were on Tac de novo and 25 patients shifted from cyclosporine to Tac during follow-up. We developed a Tac Bayesian estimator (BE) based on a population model built in NONMEM®. CYP3A5*1/*3 genotype was investigated by allelic discrimination. Results: The model was built in a population group (74 profiles) and the BE was validated in an independent group (68 profiles). Mean absorption time was found to be twice longer in CF than in non-CF patients. CYP3A5*1/*3 polymorphism significantly influenced Tac apparent oral clearance (Cl/F): Cl/F was approximately twice higher in CYP3A5 expressors (i.e., carrier of at least one CYP3A5*1 allele) than in non expressors. After inclusion of CF and CYP3A5 polymorphism as covariates, Bayesian forecasting based on 3 blood samples obtained within the first 4 hours post-dose provided good estimation of Tac area-under-the-curve (AUC), with a mean bias of 3.2⫾12.0% (min: -13.8% - max: ⫹51.1%). Bias was ⬎ ⫹20% in only 8.8% cases. Conclusions: The tools developed using the STIMMUGREP database provide an accurate prediction of Tac exposure in CF and non-CF lung transplant patients throughout the first year post-transplantation. They may allow routine Tac dose individualization and will be used in upcoming TDM clinical trials. 493 Ex-Vivo Repair of Donor Pig-Lungs Damaged by Aspiration S. Wipper, L. Janna, A. Dupree, C. Pahrmann, H. Reichenspurner, F.M. Wagner University Heart Center Hamburg, Hamburg, Germany Purpose: The aim of our study was to use our previously established reperfusion circuit to recondition lungs predamaged by aspiration of gastric acid and blood. Methods and Materials: Three study groups (n⫽6 each: I⫽control without aspiration, II⫽aspiration, III⫽aspiration⫹medical treatment with NO-ventilation, ACC, antibiotics and methylprednisolon) were perfused for 6hrs in our reperfusion circuit (rotary-pump, leucocyte-



filter, heparin-coated deoxigenator, reservoir, priming erythrocyteconcentrate and Steen-solution 1:1, Hb5,5mg/dl) according to standardized protocol. Respiratory and hemodynamic parameters were monitored pre-harvest and hourly during reperfusion. Pre- and postreperfusion wet-dry ratios were performed, histology evaluated by a semiquantitative score. Results: Compared to control (groupI) aspiration (groupII) resulted in decreasing pulmonary compliance (31⫾15 vs. 46⫾7 ml/cmH2O), increase of PVR (1490⫾412 vs. 1224⫾544dynes), decrease of pulmonary oxygenation capacity(POC) (172⫾115 vs. 371⫾52mmHg), interstitial and intraalveolar edema formation and massive pulmonary cellular infiltration at study end-point. Macroscopically most lungs in Gr.II were massively edematous, heavy and hyperaemic, one lung even failed after 4hrs, while in groupI and III it was possible to sustain all lungs for 6hrs. Additional medical treatment (groupIII) improved pulmonary compliance (59⫾8ml/cmH2O) and PVR (585⫾150dynes) significantly compared to groupI and II(p⬍0.01), POC normalized at study end point (383⫾45mmHg). Histology and wet-dry ratio confirmed these results. After 6hrs of reperfusion 2/6 lungs in group II improved, but none reached transplantable status. In group III 4 organ blocks improved, of those two double and two further single lungs were in transplantable condition. Conclusions: Repair of aspiration damaged donor-lungs seems possible by in-vitro-reperfusion with additional medical treatment in a significant percentage of cases. 494 Changing Trends in Infectious Complications among Heart Transplant Recipients F. Haddad1, T. Deuse2, F. Rosso3, M. Pham1, P. Khazanie4, H. Luikart1, H.A. Valantine1, S.A. Hunt1, T. Vu1, P.E. Oyer2, R.C. Robbins2, J.G. Montoya3 1Stanford University, Stanford, CA; 2 Stanford University, Stanford, CA; 3Stanford University, Stanford, CA; 4Stanford University, Stanford, CA Purpose: The objective of our study was to determine whether infectious complications in heart transplant patients have significantly changed over time, and if so, whether these changes have been influenced by the introduction of different immunosuppressive regimens and antimicrobial interventions. Methods and Materials: We analyzed the occurrence of various types of infections in 4 different cohorts of patients who underwent heart transplantation between 1978 and 2005 (672 patients). Each cohort corresponded to the use of a specific immunosuppressive regimen. The 1st cohort consisted of the pre-cyclosporine era (antithymocyte globulin or ATG followed by azathioprine and high doses of corticosteroids); the 2nd cohort consisted of the early cyclosporine era (ATG followed by cyclosporine and high doses of corticosteroids); the 3rd cohort was defined as the late cyclosporine era (cyclosporine, azathioprine, lower doses of corticosteroids, and trimethoprim-sulfamethoxazole); and the last cohort corresponded to the introduction of newer immunosuppressants and induction agents (daclizumab followed by cyclosporine and mycophenolate mofetil) and more aggressive cytomegalovirus prophylaxis regimens. Results: The overall incidence of infections significantly decreased in the 4 cohorts from 3.35 episodes/patient, to 2.03, 1.35 and 0.60 in the more recent cohort (p⬍0.001). There was a significant decrease in bacterial (p⬍0.001), viral (p ⬍0.001), fungal (p⫽0.009) and Pneumocystis infections (p⬍0.001). A greater proportion of bacterial infections in the recent eras were caused by Gram positive bacteria (28.6%, 31.4%, 51.0%, 67.6%, p⫽0.001). CMV infections but not Aspergillus infections occurred later after transplantation (88⫾77 days, 84⫾128, 224⫾254, 304⫾238, p ⬍0.001). Conclusions: In the most recent era, immunosuppression and antimicrobial prophylaxis regimens continue to decrease the overall



incidence of infections. With lower doses of MMF and more aggressive antiviral prophylaxis, MMF based regimens were not associated with an increase in invasive CMV infections. 495 You Are What You Eat or the Fatter the Better? Obesity as Risk Factor in Cardiac Transplant Receipients S.L. Mahr, D. Dunkler, M. Groemmer, A. Aliabadi, D. Zimpfer, M. Grimm, E. Wolner, A.O. Zuckermann Medical University of Vienna, Vienna, Austria Purpose: Few studies have described the impact of obesity on morbidity and mortality in cardiac transplant receipients. Therefore the purpose of this study was to determine wether a change in body mass index (BMI) from before transplant through 5 years after transplant is associated with post transplant morbidity and mortality. Methods and Materials: We retrospectively reviewed 993 consecutive adult patients (821 male, 172 female mean age 51,8) who received a heart transplant from January 1984 to june 2008 at our center. Patients were divided into groups using cut-offs for categories of BMI (⬍20, 20-24,25-29, ⱖ30). Survival and incidence of cardiac allograft vasculopathy (CAV⫽irregularity detected by angiography) were compared by Kaplan-Meier analysis. Multiple regression and Cox models were generated to evaluate obesity in multivariate models. p⬍0.05 was defined as significant. Results: Average pre-transplant BMI was 24.5⫾3.34. BMI increased to 26.1⫾3.49,26.7⫾3.75, 27.1⫾3.85, 27.2⫾3.95 and 27.3⫾4.08 1,2,3,4 and 5 years post transplant respectively. Overall survival was similar between all BMI groups (10 years: ⬍20: 62%, 20-24: 57%, 25-29: 54% and ⱖ30: 56%, p⫽ns). Multivariate analysis showed patient age (Hazard Ratio (HR):1.013, p⫽0.0063), later transplant era (HR:0.806, p⬍0.0001) and BMI ⬎25 (HR:1.201, p⫽0.0677) as risk factors for long term survival. Freedom from graftvasculopathy (CAV) was different between 1-year survivors in different BMI groups (10 years: ⬍20: 81%, 20-24: 83%, 25-29: 75% and ⱖ30: 75%, p⫽0.0155). Multivariate analysis for risk of CAV at 10 years showed patient: age (HR:0.983, p⫽0.0031), female sex (HR:0.579, p⬍0.0045) and BMI ⬎25 (HR:1.913, p⬍0.0001) as risk factors. Conclusions: Post transplant obesity is a risk factor for development of CAV. On the other hand results are less evident in terms of survival showing a tendency towards decreased survival in obese patients though sex and age as well as other clinical factors play an important role. 496 Perfusion MRI Lacks Sensitivity in the Detection of Cardiac Allograft Vasculopathy S. Petros1, R. Wilson1, G. Raveendran1, M. Pritzker1, J. Connett2, M. Colvin-Adams1 1University of Minnesota, Minneapolis, MN; 2 University of Minnesota, Minneapolis, MN Purpose: Cardiac allograft vasculopathy (CAV) is a major complication after heart transplantation, requiring frequent surveillance angiography. While cardiac angiography is the gold standard, it is insensitive in detecting transplant vasculopathy. Cardiac MRI with myocardial perfusion reserve (MPR) provides a noninvasive evaluation of myocardial perfusion and may provide a useful modality for studying transplant vasculopathy. The objective of our study is to compare the accuracy of spatial MR perfusion imaging to coronary angiography in detecting CAV after heart transplantation. Methods and Materials: We performed a retrospective analysis of data from 68 heart transplant recipients who had simultaneous surveillance cardiac MRI and coronary angiogram to detect CAV. We

The Journal of Heart and Lung Transplantation February 2009

compared results of qualitative MPR to those of the cardiac angiogram. Sensitivity and specificity of MR was calculated. Results: A total of 68 patients underwent both cardiac MRI and coronary angiogram. 73.5% were male; the mean age was 45.37 ⫹/14 years. The mean time from the heart transplant to the studies was 7.9 ⫹/- 5.2 years. There were no retransplants. The mean ejection fraction was 55% in the patients without CAV and 57.4% in those with CAV. There were 50 normal and 18 abnormal cardiac perfusion MRI studies. The sensitivity and specificity of the MRI in detecting disease were analyzed based on severity of coronary artery disease. Conclusions: Cardiac MRI with qualitative MPR has low sensitivity and moderate specificity for detecting CAV. The sensitivity of MRI was slightly improved when only proximal lesions were considered and improved with severity of disease. The lack of sensitivity, however, may reflect the high degree of microcirculatory disease in patients with CAV and the difficulty in detecting this on angiogram, resulting in a presumably false positive perfusion MRI. A quantitative MPR measurement may provide a more precise method to detect CAV. Sensitivity and Specificity of MRI Percent Stenosis on Angiogram >25%



Sensitivity Specificity

38.9% 78%

50% 76.7%

32.3% 79.4%

497 Incidence and Underlying Cause of Anemia in Cardiac Transplant Recipients Treated with Sirolimus A. Almasood, F. Gustafsson, D. Barth, D. Delgado, S. Kozuszko, H. Ross Toronto General Hospital, Toronto, ON, Canada Purpose: Sirolimus is being used increasingly in cardiac transplantation due to its calcineurin sparing and antiproliferative effects. However, little is known about the incidence and potential causes of anemia in heart transplant patients treated with sirolimus. Methods and Materials: Retrospective review of 84 consecutive adult cardiac transplant recipients who were more than three months post transplant and treated with sirolimus for more than 3 months. Results: Mean age was 54.5⫾13 years, 87 % were male. Indications to start sirolimus were (some patients had more than one indication): renal dysfunction (45%), rejection (30%), allograft vasculopathy (18%), cancer (12%), other (4%). Concomitant immunosuppression included cyclosporine (46%), tacrolimus (14%), mycophenolate mofetil (64%), azathioprine (6%) and prednisone (80%). Mean haemoglobin (Hb) at the time of sirolimus initiation (baseline) was 118.8⫾21 g/L, decreasing to 112.4⫾18.5 and 111.4⫾19.6g/L one and three months after sirolimus initiation, respectively (P⬍0.001). The prevalence of anemia, defined as Hb ⬍ 120 g/L at baseline was 54 % and increased to 64% and 66 % after 1 and 3 months. Similar figures for severe anemia (Hb ⬍ 100 g/L) were 21%, 29% and 27%. In a logistic regression analysis containing sex, age, creatinine, baseline Hb and treatment with aspirin or coumadin, only baseline Hb and serum creatinine predicted severe anemia 3 months after sirolimus initiation (P⬍0.05). Anemia was normocytic in 68%, macrocytic in 3% and microcytic in 29%. In anemic patients low platelet or white blood cell count was seen in 27% and 1%, respectively. Bone marrow examination was done for 18 patients; showed Burkett’s lymphoma (n⫽1), myeloid dysplasia (n⫽3), hypocellularity (n⫽2) and normal (n⫽12). Anemia did not result in termination of sirolimus treatment in any patient. Conclusions: Anemia is common and multifactorial in etiology in heart transplant recipients and is exacerbated by treatment with sirolimus. Risk factors for anemia in sirolimus treated patients include pre treatment Hb and renal function.