Pegylated interferon-alpha2a/ribavirin treatment of recurrent hepatitis C after liver transplantation

Hepatitis C virus (HCV) infection invariably recurs after liver transplantation (LT), leading to significant morbidity and mortality. Although the combination of pegylated interferon-alpha (IFN-alpha)/ribavirin is the preferred treatment for these patients, the optimal schedule remains undetermined. In an uncontrolled trial, 19 patients with HCV infection recurring after LT received pegylated IFN-alpha(2a), 180 mug weekly, and ribavirin, 10 mg/kg body weight daily, for 48 weeks. The proportion of patients with undetectable HCV RNA in their serum after 12 weeks of treatment was 53%. Five patients (26%) dropped out of the study due to intolerance (in 2 cases), depression (in 1), or infectious complications (in 2). A sustained virological response (SVR), defined as undetectable serum HCV RNA 24 weeks after the end of treatment, was observed in 9/19 patients (47%). SVR was associated with an early virological response after 12 weeks of therapy (P<0.001) and a treatment duration >80% (P=0.02), but not with baseline HCV RNA level or a cumulative dose of pegylated IFN-alpha(2a) or ribavirin >80% of the scheduled dose. All 4 patients with genotype 2 or 3 reached SVR, as compared with 33% of patients with genotype 1 or 4 (P=0.03). A 48-week course of pegylated IFN-alpha(2a)/ribavirin therapy is effective in patients with recurrent HCV infection after LT.

C1-esterase inhibitor reduces reperfusion injury after lung transplantation

BACKGROUND: Activation of the complement system and polymorphonuclear neutrophilic leukocytes plays a major role in mediating reperfusion injury after lung transplantation. We hypothesized that early interference with complement activation would reduce lung reperfusion injury after transplantation. METHODS: Unilateral left lung autotransplantation was performed in 6 sheep. After hilar stripping the left lung was flushed with Euro-Collins solution and preserved for 2 hours in situ at 15 degrees C. After reperfusion the right main bronchus and pulmonary artery were occluded, leaving the animal dependent on the reperfused lung (reperfused group). C1-esterase inhibitor group animals (n = 6) received 200 U/kg body weight of C1-esterase inhibitor as a short infusion, half 10 minutes before, the other half 10 minutes after reperfusion. Controls (n = 6) underwent hilar preparation only. Pulmonary function was assessed by alveolar-arterial oxygen difference and pulmonary vascular resistance. The release of beta-N-acetylglucosaminidase served as indicator of polymorphonuclear neutrophilic leukocyte activation. Extravascular lung water was an indicator for pulmonary edema formation. Biopsy specimens were taken from all groups 3 hours after reperfusion for light and electron microscopy. RESULTS: In the reperfused group, alveolar-arterial oxygen difference and pulmonary vascular resistance were significantly elevated after reperfusion. All animals developed frank alveolar edema. The biochemical marker beta-N-acetylglucosaminidase showed significant leukocyte activation. In the C1-esterase inhibitor group, alveolar-arterial oxygen difference, pulmonary vascular resistance, and the level of polymorphonuclear neutrophilic leukocyte activation were significantly lower. CONCLUSIONS: Treatment with C1-esterase inhibitor reduces reperfusion injury and improves pulmonary function in this experimental model.

Progression of steroid-associated osteoporosis after heart transplantation

BACKGROUND: Osteoporosis has been recognized as an important side effect of long-term and of pulsed steroid application after heart transplantation. METHODS: In June 1989 a prospective clinical trial was started to study bone demineralization by quantitative computed tomographic scan. All patients received vitamin D and calcium. In group I (n = 30) synthetic calcitonin (40 Medical Research Council Standard Units subcutaneously per day was administered in 14-day cycles, whereas group II patients (n = 31) received a placebo preparation. Repeat trabecular and cortical quantitative computed tomographic scans of the thoracic (T12) and lumbar spine (L1, L2, L3) were obtained within 48 weeks after heart transplantation. RESULTS: Expressed as the means of T12, L1, L2, and L3, trabecular bone density decreased significantly from 100+/-24 to 79+/-29 mg/mL within 3 weeks after heart transplantation, followed by a further reduction to 67+/-29 mg/mL after 3 months in the calcitonin group. The values for cortical bone density decreased significantly from 229+/-37 to 202+/-40 mg/mL (calcitonin) 3 weeks after heart transplantation. Comparable results were obtained in the placebo group. In both groups bone density remained stable thereafter. Intergroup differences were not of statistical significance. CONCLUSIONS: In heart transplant recipients progressive trabecular bone demineralization is limited to the first 3 postoperative months. Thereafter, bone density remained stable. A positive effect of synthetic calcitonin in addition to prophylactic calcium and vitamin D application could not be proved by repeat quantitative computed tomography.

[Lung transplantation in chronic obstructive lung diseases]

Lung transplantation (uni- or bilateral) is an accepted treatment option for patients with end-stage chronic obstructive pulmonary disease. Pulmonary function improves significantly and 5-year-actuarial survival is more than 70% at acceptable early mortality rates. Careful evaluation of risks and benefits in necessary because of the known donor-organ shortage and the risks of life-long immunosuppressive treatment. The bronchiolitis obliterans syndrome is still a nonsolved problem in the long-term course after LTx and it can influence late graft function and patient survival.

Valve reconstruction or replacement for long-term biopsy-induced tricuspid regurgitation following heart transplantation

Tricuspid regurgitation following heart transplantation can become a severe problem in a subset of patients, where medical therapy fails. Operative findings are described and results of subsequent results with surgical intervention including repair and replacement are analysed. Although follow-up is short, tricuspid replacement seems superior to reconstruction following heart transplantation. Best results are obtained, if replacement is performed, before right ventricular function deteriorates.

Treatment of recurrent rejection in heart transplantation: cytolytic therapy or bolus steroids?

OBJECTIVES: The treatment of recurrent rejection in heart transplant recipients has been a controversial issue for many years. The intent of this retrospective study was to perform a risk-benefit analysis between treatment strategies with bolus steroids only versus anti-thymocyte globulins (RATG; 1.5 mg/kg q 4 days). METHODS: Between 1986 and 1993, 69 of 425 patients (17 male, 52 female; mean age 44 +/- 11 years) who had more than one rejection/patient per month (rej/pt per mo) in the first 3 postoperative months were defined as recurrent rejectors. RESULTS: Repetitive methylprednisolone bolus therapy (70 mg/kg q 3 days) was given in 27 patients (group M; 1.4 +/- 0.2 rej/pt per mo) and RATG therapy for one of the rejection episodes of the 42 remaining patients (group A; 1.5 +/- 0.2 rej/pt per mo). The quality of triple drug immunosuppression in the two study groups was comparable. The rejection-free interval (RFI) following RATG treatment in group A was 21.6 +/- 10 days and 22 +/- 11 in group M. In group M, 3 of 27 patients (11%) had a rejection treatment-related infection (2 bacterial; 1 viral) versus 6 of the 42 patients of group A (14.2%; bacterial 1, viral 5). During postoperative months 3-24, 0.15 +/- 0.12 rej/pat per mo were observed in group M and 0.21 +/- 0.13 rej/pat per mo in group A (n.s.). In this 21-month period cytolytic therapy for rejection was initiated in 8 of the remaining 21 patients of group M (38%) and 15 of the remaining 37 patients of group A (40.5%). The absolute survival and the individual causes of death were not affected by the type of initial treatment of recurrent rejection. The actuarial freedom of graft atherosclerosis is comparable in the two groups with 78% in group A versus 79% in group M free of graft atherosclerosis at 3 years postoperatively. CONCLUSIONS: A comparison of cytolytic therapy versus repeated applications of bolus steroids for treatment of recurrent rejection reveals no significant difference in the long-term patient outcome with respect to the incidence of future rejection episodes and survival.

Graft coronary vasculopathy in cardiac transplantation--evaluation of risk factors by multivariate analysis

The development of coronary vasculopathy is the main determinant of long-term survival in cardiac transplantation. The identification of risk factors, therefore, seems necessary in order to identify possible treatment strategies. Ninety-five out of 397 patients, undergoing orthotopic cardiac transplantation from 10/1985 to 10/1992 were evaluated retrospectively on the basis of perioperative and postoperative variables including age, sex, diagnosis, previous operations, renal function, cholesterol levels, dosage of immunosuppressive drugs (cyclosporin A, azathioprine, steroids), incidence of rejection, treatment with calcium channel blockers at 3, 6, 12, and 18 months postoperatively. Coronary vasculopathy was assessed by annual angiography at 1 and 2 years postoperatively. After univariate analysis, data were evaluated by stepwise multiple logistic regression analysis. Coronary vasculopathy was assessed in 15 patients at 1 (16%), and in 23 patients (24%) at 2, years. On multivariate analysis, previous operations and the incidence of rejections were identified as significant risk factors (P < 0.05), whereas the underlying diagnosis had borderline significance (P = 0.058) for the development of graft coronary vasculopathy. In contrast, all other variables were not significant in our subset of patients investigated. We therefore conclude that the development of coronary vasculopathy in cardiac transplant patients mainly depends on the rejection process itself, aside from patient-dependent factors. Therapeutic measures, such as the administration of calcium channel blockers and regulation of lipid disorders, may therefore only reduce the progress of native atherosclerotic disease in the posttransplant setting.

Double-lung transplantation in the rat: an acute, syngeneic in situ model

BACKGROUND. The high rate of reperfusion injury in clinical lung transplantation mandates significant improvements in lung preservation. Innovations should be validated using standardized and low-cost experimental models. METHODS. The model introduced here is analyzed by comparing global lung function after varying ischemic times (2, 4, 8, 16, and 24 hours). A rat double-lung block is flush-perfused, and the main pulmonary artery and left atrium are connected to the left pulmonary artery and vein of a syngeneic recipient using a T-shaped stent. With pressure side ports and incorporated flow crystals, measurement of vascular resistance and graft oxygenation can be performed. The transplant is ventilated separately, and compliance and resistance are determined. RESULTS. The increase in the ischemic interval from 2 to 24 hours caused an increase in the alveolar arterial oxygen difference from 220 +/- 20 to 600 +/- 34 mm Hg, pulmonary vascular resistance from 198 +/- 76 to 638 +/- 212 mm Hg.mL-1.min-1, and resistance to airflow from 274 +/- 50 to 712 +/- 30 cm H2O/L H2O, and a decrease in pulmonary compliance from 0.4 +/- 0.05 to 0.12 +/- 0.06 mL/cm H2O. CONCLUSIONS. This in situ, syngeneic rat lung transplantation model offers an alternative to large animal models for verification of lung preservation solutions and for modification of donor or recipient treatment regimens.

Tricuspid valve regurgitation attributable to endomyocardial biopsies and rejection in heart transplantation

In the present report the prevalence, severity, and risk factors of tricuspid valve regurgitation (TR) in 251 heart transplant recipients have been analyzed retrospectively. Tricuspid valve function was studied by color-flow Doppler echocardiogram and annual heart catheterization. The presence or severity of TR was graded on a scale from 0 (no TR) to 4 (severe). Additional postoperative data included rate of rejection, number of endomyocardial biopsies, incidence of transplant vasculopathy, and preoperative and postoperative hemodynamics. The incidence of grade 3 TR increases from 5% at 1 year to 50% at 4 years after transplantation. Multivariate analysis showed rate of rejection and donor heart weight to be significant risk factors. The ischemic intervals as well as the preoperative and postoperative pulmonary hemodynamics did not affect the severity or prevalence of TR. These results indicate that various factors appear to have an impact on the development of TR and that the prevalence might be lowered by a reduction of the number of biopsies performed and when possible, oversizing of donor hearts.

Strategies for routine biopsies in heart transplantation based on 8-year results with more than 13,000 biopsies

The endomyocardial biopsy (EMB) in heart transplant recipients has been considered the "gold standard" for diagnosis of graft rejection (REJ). The purpose of this retrospective study is to develop long-term strategies (frequency and postoperative duration of EMB) for REJ monitoring. Between 1985 and 1992, 346 patients (mean age 44.5 years, female patients = 14%) received 382 heart grafts. For graft surveillance EMBs were performed according to a fixed schedule depending on postoperative day and the results of previous biopsies. In the first year the average number (no.) of EMBs/patient was 20 with 19% positive for REJ in the first quarter, dropping to 7% REJ/EMB by the end of the first year. The percentage of REJ/EMB declined annually from 4.7% to 4.5%, 2.2% and less than 1% after the fifth year. Individual biopsy results in the first 3 postoperative months had little predictive value. Patients with fewer than two REJ (group 1), vs patients with two or more REJ in the first 6 postoperative months (group 2), were significantly less likely to reject in the second half of the first year (group 1: 0.29 +/- 0.6 REJ/patient; group 2:0.83 +/- 1.3 REJ/patient; P < 0.001) and third postoperative year (group 1:0.12 +/- 0.33 REJ/patients; group 2:0.46 +/- 0.93 REJ/patient; P < 0.05). In conclusion, routine EMBs in the first 3 postoperative months have only limited predictive value, however the number of routine EMBs can be drastically reduced later depending on the intermediate postoperative REJ pattern.

Early biochemical indicators of the obliterative bronchiolitis syndrome in lung transplantation

The diagnosis of the obliterative bronchiolitis syndrome in lung transplantation is presently best established by evaluation of postoperative lung function tests. Unfortunately the decline in lung function occurs only when obliteration has progressed significantly and is therefore not an early predictive indicator. To distinguish patients at increased risk for the development of obliterative bronchiolitis, we regularly assessed the chemiluminescence response of polymorphonuclear leukocytes, opsonic capacity, and plasma elastase/beta-N-acetylglucosaminidase in 52 outpatients (25 women and 27 men; mean age 45 +/- 12 years) who underwent transplantation between January 1991 and January 1992. Recent onset bronchiolitis within the described observation period occurred in 16 patients (group obliterative bronchiolitis). A matched cohort of 16 patients was formed according to type of procedure, age and follow-up (control) from the remaining 36 patients. Data obtained from a period 6 months before clinical onset of the syndrome showed a significant drop of the opsonic capacity (group obliterative bronchiolitis = 87% +/- 7%; control = 100% +/- 9%; p < 0.023) and rise of the N-acetyl-D-glucosaminidase (group obliterative bronchiolitis = 7.5 +/- 2 U/L; control = 5.8 +/- 1.8 U/L; p < 0.04). No correlation was found between the number of infectious events or rejection episodes and the incidence of obliterative bronchiolitis. According to these results, it can be concluded that a decrease in the plasma opsonic capacity and a rise in beta-N-acetylglucosaminidase may be early markers before clinical onset of obliterative bronchiolitis. The nonspecific immune system may therefore play an important role in the development of obliterative bronchiolitis.

[Post-traumatic ARDS--a potential indication for lung transplantation?]

Posttraumatic adult respiratory distress syndrome (ARDS) still involves significant mortality, despite progress in management concepts. Current therapeutic strategies are briefly described, including kinetic therapy, high-frequency jet ventilation and extracorporeal membrane oxygenation. In addition, a spectacular case of the first successful lung transplantation for posttraumatic ARDS after failed ECMO (extracorporeal membrane oxygenation) support is reported. This young man with severe posttraumatic ARDS developed a potentially lethal bilateral pulmonary hemorrhage under treatment with ECMO, and on the basis of this bilateral pulmonary transplantation was considered to be indicated. The patient is alive and well 2 years after the procedure.