Preliminary experience with mycophenolate mofetil used after lung transplantation

This study reports our preliminary experience with mycophenolate mofetil (MMF)-based immune suppression after lung transplantation. Thirteen patients (group 1) received MMF as primary therapy immediately after transplantation. Use of MMF was associated with a linearized rate of 0.85 episodes of acute rejection per 100 patient days during the first 3 months after transplantation, as compared with rates of 1.49 and 1.38, observed in two groups of historical control subjects (p = .094 and p = .053, respectively). Rejection rates after the first 3 months were not lower than in historical control subjects. Nine additional patients were switched from azathioprine to MMF because of recurrent episodes of high-grade acute rejection (group 2). In this group, the linearized rate of acute rejection episodes declined significantly (p = .004) after initiation of MMF therapy. These data suggest a potential role for MMF in reducing the rate of acute rejection episodes after lung transplantation.     

Bronchiolitis obliterans syndrome: thin-section CT diagnosis of obstructive changes in infants and young children after lung transplantation

PURPOSE: To characterize the thin-section computed tomographic (CT) appearance of bronchiolitis fibrosa obliterans syndrome in infants and young children after lung transplantation. MATERIALS AND METHODS: Thin-section CT studies in six patients with bronchiolitis obliterans syndrome (age range, 2 months to 5 1/2 years) and in 15 control patients without obstructive airway disease (age range, 2 months to 7 years) who underwent bilateral lung transplantation were retrospectively reviewed. The thin-section CT scans were obtained during quiet sleep at a median of 24 months (range, 6-36 months) after transplantation. The CT studies were evaluated for mosaic perfusion, bronchial dilatation, bronchial wall thickening, and mucous plugging Final diagnoses in all patients were based pulmonary function test results. RESULTS: Thin-section CT findings in the six patients with clinically proved bronchiolitis obliterans syndrome were mosaic perfusion in five (83%) bronchial dilation in three (50%), and bronchial wall thickening in one (17%). Of the 15 control patients with normal pulmonary function test results, six (40%) had mosaic perfusion; none had bronchial dilatation or bronchial wall thickening. Mucous plugging was not seen in either group. Only the association of bronchial dilatation with bronchiolitis obliterans syndrome was significant (P = .02). CONCLUSION: Infants and young children with bronchiolitis obliterans syndrome after lung transplantation are more likely to have CT abnormalities than those with normal pulmonary function test results.     

Prednisone withdrawal 14 days after liver transplantation with mycophenolate: a prospective trial of cyclosporine and tacrolimus

BACKGROUND: The long-term complications of immunosuppressive therapy such as diabetes, hypercholesterolemia, and hypertension are a major source of morbidity in liver transplant recipients. In this prospective, randomized, open-label study we completely withdrew prednisone (PRED) 14 days after liver transplantation in an effort to decrease these metabolic complications. Patients were maintained on mycophenolate mofetil (MMF) in combination with either cyclosporine (CsA; Neoral formulation) or tacrolimus (TAC). Thus, we also were able to compare CsA to TAC in patients not receiving PRED with respect to efficacy, toxicity, and effect on posttransplant metabolic complications. METHODS: A total of 71 patients were randomized to receive either TAC-MMF (n=35) or CsA-MMF (n=36) after liver transplantation and were analyzed for patient and graft survival. Fifty-eight patients continued the immunosuppressive protocol for at least 6 months after transplantation and were analyzed for the incidence of acute rejection and the prevalence of diabetes, hypertension, and hypercholesterolemia. RESULTS: The 6-month patient survival rates were 94.4% for CsA-MMF and 88.6% for TAC-MMF. Corresponding 6-month graft survival rates were 88.7% and 85.71% with no immunologic graft losses in either group. The incidence of biopsy-proven acute rejection was 46% for CsA-MMF and 42.3% for TAC-MMF. Six patients were converted from CsA to TAC (four for recurrent rejection) and seven patients were converted from TAC to CsA (four for neurotoxicity). Only one patient (in the TAC-MMF group) developed new-onset posttransplant diabetes. In contrast, four of eight patients in the CsA-MMF group who were diabetic before transplant became nondiabetic in the first 3 months after transplant. The mean serum cholesterol level was significantly lower in the TAC-MMF group than in the CsA-MMF group (145.2+/-41.8 mg/dl and 190.3+/-62.2, respectively; P<0.001) and the incidence of hypertension was lower in the TAC-MMF group (12% vs. 30.3% in the CsA-MMF group, P<0.01). Both groups had a lower incidence of metabolic complications compared with a historical group (n=100) maintained on CsA and PRED (10 mg/day at 6 months). CONCLUSIONS: MMF in combination with either TAC or CsA allows withdrawal of PRED 14 days after liver transplantation with a moderate rejection rate and no immunologic graft losses. Early PRED withdrawal decreases posttransplant diabetes, hypercholesterolemia, and hypertension, but patients maintained on TAC have lower serum cholesterol levels and a lower incidence of hypertension than CsA-treated patients.     

Emergency medicine: the Italian experience

BACKGROUND: Studies using tacrolimus and corticosteroids or the combination of cyclosporine, mycophenolate mofetil, and corticosteroids have been shown to reduce the incidence of biopsy-proven acute rejection episodes in cadaveric kidney recipients compared with cyclosporine-based immunosuppression. The current study is a retrospective analysis of our experience with tacrolimus combined with mycophenolate mofetil and steroids as primary immunosuppression for kidney transplant recipients. METHODS: In a retrospective analysis, 72 patients who received primary therapy with tacrolimus, mycophenolate mofetil, and corticosteroids (triple therapy) were compared with a control group of 98 kidney recipients who received tacrolimus and corticosteroids (double therapy). RESULTS: There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the triple therapy group (8.2%) compared with the double therapy group (21%; P=0.003). One-year patient and graft survival did not differ between groups. The incidence of posttransplant diabetes mellitus was 18% and 21% in the triple and double therapy groups, respectively. Leukopenia and gastrointestinal side effects were the most common cause for discontinuation of mycophenolate mofetil. CONCLUSIONS: The combination of tacrolimus with mycophenolate mofetil and corticosteroids is more effective at preventing early acute rejection than tacrolimus and corticosteroids alone. The use of mycophenolate mofetil was associated with a higher incidence of leukopenia and diarrhea, often leading to discontinuation of the drug.     

Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine

BACKGROUND: Historically, the acute rejection rates in simultaneous pancreas-kidney (SPK) recipients have been extremely high (50-80%), with many second and third rejection episodes despite the use of quadruple immunosuppression (antibody induction and cyclosporine [CsA]-azathioprine [AZA]-based maintenance immunosuppression). Although this acute rejection has rarely led to graft loss, it has been a great cause of morbidity and of significantly increased cost. In an attempt to decrease the acute rejection rate and related morbidity in SPK transplant recipients, we compared two "state-of-the-art" immunosuppression regimens in a prospective, randomized, single-center study. METHODS: Patients who received SPK transplants were randomized to receive either tacrolimus (TAC) and mycophenolate mofetil (MMF, n=18) or CsA (Neoral formulation) and MMF (n=18). All patients received OKT3 induction and prednisone, which was tapered to 5 mg/day by 6 months after transplantation. All rejection episodes were biopsy proven. In addition, metabolic control (HgbA1C, hypertension, serum cholesterol), drug toxicity, and infection also were measured. Data were compared with that of a historical group (n=18) who received conventional CsA (Sandimmune formulation) and AZA-based immunosuppression. RESULTS: The incidence of biopsy-proven acute rejection was 11% in both the TAC-MMF and CsA-MMF groups with only two patients in each group experiencing a rejection episode. This rejection rate was significantly decreased from that of the CsA-AZA historical group (77%, P<0.01). There were no significant differences in infection rates, including cytomegalovirus, or in metabolic control (HgbA1C, hypertension, and cholesterol levels). All patients remained on their initial immunosuppression regimen for the first 3 months after transplantation. Between 3 and 6 months after transplantation, three patients were switched from TAC to CsA for recurrent migraine headaches, posttransplant diabetes, and chronic cytomegalovirus infection. Two patients in the CsA-MMF group died of nonimmunologic causes (aspiration pneumonia and arrhythmia) between 3 and 6 months after transplantation. CONCLUSIONS: The data from this study show that MMF treatment significantly decreases the incidence of biopsy-proven acute rejection in SPK transplant recipients compared with AZA-treated historical controls. In addition, we conclude that TAC and CsA (Neoral), when combined with MMF, yield similar, low acute rejection rates with similar graft function and metabolic control.     

Comparison of theory and experiment in pulsatile flow in cat lung

OBJECTIVE: A retrospective analysis was performed to examine the role of HLA antibodies and cytomegalovirus mismatch on the development of bronchiolitis obliterans syndrome and survival after lung transplantation. METHODS: Of 339 consecutive lung transplantations performed over a 102-month interval, 301 patients survived at least 3 months. There was a minimum follow-up period of 13 months. Bronchiolitis obliterans syndrome was defined as a decline in forced expiratory volume in 1 second less than 80% of posttransplantation baseline and/or histologic presence of obliterative bronchiolitis and was defined as occurring "early" if documented within 3 years of transplantation. Variables analyzed included preoperative donor and recipient cytomegalovirus status and the development of antibodies to human leukocyte antigens after transplantation. Microcytotoxicity was used to determine the presence of antibodies to human leukocyte antigens. Variables were subjected to Kaplan-Meier analysis to determine their impact on freedom from bronchiolitis obliterans syndrome and survival. RESULTS: The development of antibodies to human leukocyte antigens after transplantation correlated significantly with bronchiolitis obliterans syndrome (P = .02). The development of antibodies to human leukocyte antigens did not affect survival (P = .33) unless they were detected within 2 years of transplantation (P = .04). There was greater frequency of early bronchiolitis obliterans syndrome in cytomegalovirus seronegative patients who received allografts from seropositive donors compared with all other combinations (P = .02). There was also a trend toward worse survival of cytomegalovirus seronegative patients who received allografts from seropositive donors (P = .13). CONCLUSION: These data suggest that bronchiolitis obliterans syndrome is the result of an immune-mediated process in which HLA antibodies and cytomegalovirus may play a significant role.     

Prospective study of the value of transbronchial lung biopsy after lung transplantation

Transbronchial lung biopsy (TBB) has become the gold standard for the diagnosis of acute rejection and cytomegalovirus (CMV) pneumonia in lung transplant recipients. The aim of this study was to assess the value of regular surveillance TBB in stable asymptomatic patients and to establish the role of TBB as a follow-up procedure 1 month after a previous pathological biopsy result. We prospectively evaluated 76 TBBs performed in 17 lung transplant recipients. A definite pathological results was found in 14 of 15 TBBs performed for clinical indications: CMV pneumonia (5), acute rejection grade > or = A2 according to the criteria of the International Society for Heart and Lung Transplantation (ISHLT) (4), bronchiolitis obliterans (3), and desquamative interstitial pneumonitis (2). Fifteen of 45 surveillance TBBs performed in asymptomatic patients revealed significant abnormalities. Ten episodes of acute rejection ISHLT grade > or = A2 and three episodes of CMV pneumonia detected by TBB had direct therapeutic consequences. Nine of 16 follow-up TBBs performed 1 month after a pathological biopsy result again showed relevant pathological findings. With the exception of one severe haemorrhage, no life-threatening complications occurred. Our results suggest that transbronchial lung biopsies performed on a regular basis after lung transplantation are important for the detection of asymptomatic and/or persistent acute rejection or injection. In the long-term, this strategy might be the most effective tool in reducing the incidence of bronchiolitis obliterans, which is still the main obstacle for further improvement of long-term survival after lung transplantation.     

Obliterative bronchiolitis after lung and heart-lung transplantation

Obliterative bronchiolitis (OB) has emerged as the main cause of morbidity and mortality in the long-term follow-up after lung and heart-lung transplantation. The pathogenesis of OB is multifactorial, with acute rejection and cytomegalovirus infection being the main risk factors for the development of OB. The final common pathway of all inciting events seems to be an alloimmune injury, with subsequent release of immunologic mediators and production of growth factors leading to luminal obliteration and fibrous scarring of the small airways. Analyzing the 14 years of experience in 163 patients at Stanford University, we found a current incidence of bronchiolitis obliterans syndrome or histologically proven OB within the first 3 years after lung and heart-lung transplantation of 36.3%, with an overall prevalence of 58.1% after heart-lung and 51.4% after lung transplantation. Both pulmonary function indices (forced expiratory flow between 25% and 75% of forced vital capacity and forced expiratory volume in 1 second) and transbronchial biopsies have proven helpful in diagnosing bronchiolitis obliterans syndrome or OB at an early stage. Early diagnosis of OB and improved management have achieved survival rates in patients with OB after 1, 3, 5, and 10 years of 83%, 66%, 46%, and 22%, compared with 86%, 83%, 67%, and 67% in patients without OB. Recently, different experimental models have been developed to investigate the cellular and molecular events leading to OB and to evaluate new treatment strategies for this complication, which currently limits the long-term success of heart-lung and lung transplantation.     

Revascularization of the bronchial arteries in lung transplantation: an overview

Development of the surgical technique has minimized the incidence of airway problems associated with single as well as sequential bilateral lung transplantation. Although early results are good, long-term results remain unsatisfactory. The main problems after lung transplantation are pulmonary infections and the bronchiolitis obliterans syndrome. The bronchiolitis obliterans syndrome is usually considered to be chronic rejection, but a multifactorial genesis including airway ischemia has been suggested. We reviewed the literature relevant to direct bronchial artery revascularization during lung transplantation. Although information is limited, there are good reasons to believe that reestablishment of the dual blood supply to the transplanted lung is beneficial not only for healing of the airway anastomoses, but also for the airway and the lung responses to pathologic conditions. In small series, methods of bronchial artery revascularization have proved successful and have been associated with good early results. We believe it is justified to test the impact of direct bronchial artery revascularization on outcome after lung transplantation in large clinical series.     

Primary immunosuppression with mycophenolate mofetil and antithymocyte globulin for kidney transplant recipients of a suboptimal graft

BACKGROUND: In renal transplantation the beneficial immunosuppressive effects of cyclosporin (CsA) may be curtailed by its nephrotoxicity, specially in patients receiving a cadaveric allograft from suboptimal donors or at risk of delayed graft function. Mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) have each demonstrated to be potent immunosuppressants in renal transplantation. In a prospective analysis we have studied the results at 6 months of the combination of MMF, ATG and low-dose steroids in patients with low immunological risk receiving a first cadaveric renal allograft from a suboptimal donor or at risk of delayed graft function. METHODS: Patients with preformed reactive antibodies < 500% receiving a first graft from a suboptimal donor (age > or = 40 years, non-heart-beating, acute renal failure, arterial hypertension) or at risk of delayed graft function (cold ischaemia time > or = 24 h) were eligible for this open single-arm pilot trial. From September 1996 to March 1997 we recruited 17 patients. They were treated with MMF 2 g p.o. preoperatively, and after transplantation at 3 g/day; rabbit ATG i.v. at 2 mg/kg preoperatively, and 1.5 mg/kg/day the first day after transplantation, followed by four doses of 1 mg/kg on alternate days; prednisone was given at 0.25 mg/kg/day and reduced progressively to 0.1 mg/kg/day at 3 months. Primary outcomes were incidence of biopsy-proven acute rejection, delayed graft function, opportunistic infections, graft and patient survival, and the need for introduction of CsA treatment. RESULTS: delayed graft function occurred in two cases (12%). Four of 17 patients (24%) had a biopsy-proven acute rejection (2 grade I and 2 grade II) within the first 3 months after transplantation. CsA was added in two cases with grade II biopsy-proven acute rejection, and in one with grade I biopsy-proven acute rejection. In one patient MMF was replaced by CsA because of gastrointestinal intolerance. Mean serum creatinine 6 months after transplantation was 159+/-59 micromol/1. Cytomegalovirus tissue invasive disease occurred in one patient (6%). At 6 months follow-up all patients are alive with functioning allografts. CONCLUSIONS: These preliminary results suggest that in low-immunological-risk patients who receive a suboptimal renal allograft or at risk of delayed graft function, the combination of MMF, ATG, and steroids is an efficient immunosuppressive regime that may avoid the use of CsA in 70% of the recipients.     

FK 506 'rescue' immunosuppression for obliterative bronchiolitis after lung transplantation

PRELIMINARY EXPERIENCE: In a consecutive case series (level V evidence) involving 10 recipients of unilateral lung transplantation (LT) with bronchiolitis obliterans, in conjunction with Fujisawa protocol 93-0-003, the physiologic responses to FK 506 (tacrolimus) "rescue" immunosuppression were assessed. Recipients were 22+/-18 months post-LT and demonstrated progressive allograft dysfunction that was refractory to pulsed-dose methylprednisolone therapy. All recipients received induction immunosuppression with Minnesota antilymphocyte globulin (10 to 15 mg/kg/d) for 5 to 10 days, cyclosporine (CsA) (whole-blood Abbott TDX fluorescence polarization immunoassay (Abbott Inc, Abbott Park, IL)=600 to 800 ng/mL), azathioprine (2 mg/kg/d), and prednisone (tapered to 0.2 mg/kg/d). The "rescue" regimen consisted of oral FK 506 adjusted to maintain a whole-blood Abbott IMX microparticle enzyme immunoassay (Abbott Inc, Abbott Park, IL) of 10 to 15 ng/mL with an initial increase in prednisone (1.0 mg/kg/d) during conversion that was subsequently tapered to 0.2 mg/kg/d. Spirometry was performed monthly in accordance with accepted American Thoracic Society criteria. Recipients were classified in accordance with the International Society for Heart and Lung Transplantation (ISHLT) "Working Formulation for Standardization of Nomenclature and for Clinical Staging of Chronic Dysfunction in Lung Allografts" as stages Ib (n=2), IIb (n=4), and IIIb (n=4) upon entry to the protocol. The deltaFEV1/month relationships during CsA- and FK 506-based regimens were analyzed by linear regression and compared by signed rank test (p<0.05). RESULTS: The deltaFEV1/month slopes were -0.0687+/-0.0221 and +0.0300+/-0.033 L/mo (mean+/-SEM) for CsA and FK 506, respectively (p=0.037). Although no significant spirometric improvement was noted in most recipients, no further decline in FEV1 occurred after conversion to FK 506. Recipients with less severe chronic dysfunction (ie, obliterative bronchiolitis [OB] stages Ib and IIb) stabilized their spirometric indexes at higher levels. Two recipients with OB stage IIIb died of hypercapnic respiratory failure at 6 and 8 months after conversion. CONCLUSIONS: The deltaFEV1/mo slopes stabilized after FK 506 conversion. Earlier conversion may be beneficial in stabilizing FEV1 at a higher plateau. Significant economic impact may be anticipated with FK 506 compared to alternative cytolytic strategies for OB. However, multicenter prospective controlled investigations are necessary to further address the potential role of FK 506 after LT (level I evidence). Furthermore, the ISHLT "Staging of OB Syndrome" may have significant clinical implications vis-à-vis prognosis and potential therapies.     

Pediatric lung transplantation. Indications, techniques, and early results

From July 1990 to April 1993, 36 lung transplantations in 33 patients were performed in our pediatric transplant program (0.25 to 23 years, mean age 10.3 years). Eight children had been continuously supported with a ventilator for 3 days to 4.5 years before transplantation and three were supported by extracorporeal membrane oxygenation. Indications for lung transplantation in this pediatric population included the following: cystic fibrosis (n = 13), pulmonary hypertension, and associated congenital heart disease (n = 10), pulmonary atresia, ventricular septal defect and nonconfluent pulmonary arteries (n = 3), pulmonary fibrosis (n = 6), and acute respiratory distress syndrome (n = 1). Three children underwent retransplantation for acute graft failure (n = 2) or chronic rejection (n = 1). Pulmonary fibrosis was related to complications of treatment of acute of myelogenous leukemia with bone marrow transplantation in two children and to bronchiolitis obliterans, bronchopulmonary dysplasia, interstitial pneumonitis, and Langerhans cell histiocytosis in four others. Thirteen children underwent lung transplantation and concomitant cardiac repair. Bilateral lung transplantation, ventricular septal defect closure and pulmonary homograft reconstruction of the right ventricular outflow tract to the transplanted lungs was performed in three children by means of a new technique that avoids the need for combined heart-lung transplantation. Two patients had ventricular septal defect closure and single lung transplant for Eisenmenger's syndrome, two had ligation of a patent ductus arteriosus and transplantation, three additional children underwent atrial septal defect closure and lung transplantation, and two underwent lung transplantation for congenital pulmonary vein stenosis. Eight early deaths and three late deaths occurred (actuarial 1-year survival 62%). Lung transplantation in children has been associated with acceptable early results, although modification of the adult implantation technique has been necessary. Lung transplantation and repair of complex congenital heart defects is possible; heart-lung transplantation may only be required for patients with severe left heart dysfunction and associated pulmonary vascular disease. Bronchiolitis obliterans remains a major concern for long-term graft function in pediatric lung transplant recipients.     

Renal function improves in liver transplant recipients when switched from a calcineurin inhibitor to sirolimus

Sirolimus (Rapamune; Wyeth-Ayerst, Philadelphia, PA) is a newer immunosuppressive drug with no known acute or chronic nephrotoxic effects; however, limited data are available in liver transplant recipients. We prospectively evaluated changes in renal function in liver transplant recipients after conversion from a calcineurin inhibitor to sirolimus monotherapy. We measured serial serum creatinine levels in liver transplant recipients with chronic nephrotoxicity caused by calcineurin inhibitors before and after conversion to sirolimus therapy. Estimated glomerular filtration rate (eGFR) was calculated from the Modification of Diet in Renal Disease formula. Change in eGFR over time, incidence of acute hepatocellular rejection, and adverse events while being administered sirolimus monotherapy were recorded. Mean interval between liver transplantation and initiation of sirolimus therapy was 310 weeks (range, 9 to 780 weeks). Of 21 patients included in our study, 18 patients were converted to sirolimus monotherapy and 3 patients were switched to sirolimus and low-dose steroid therapy. Patients were followed up for a mean of 66.8 +/- 38.9 (SD) weeks after conversion. Renal function improved in 71% of patients (15 of 21 patients). Median eGFR improved significantly from 34 mL/min/1.73 m2 at the time of conversion to 43 mL/min/1.73 m2 at the last follow-up (27% increase in eGFR; P = 001). Median monthly change in eGFR was from -0.25 mL/min/1.73 m2 pre-sirolimus therapy to +1.28 mL/min/1.73 m2 post-sirolimus therapy (P =.09). Adverse events were mostly mild and self-limited. Only 1 patient developed biopsy-proven acute cellular rejection, which was treated with sirolimus and mycophenolate mofetil. Two patients discontinued sirolimus therapy because of toxicity (oral ulceration, 1 patient; interstitial pneumonitis, 1 patient). Renal function improved significantly in the majority of liver transplant recipients with renal insufficiency caused by calcineurin inhibitors when converted to sirolimus therapy. Sirolimus monotherapy provided adequate immunosuppression with a low incidence of acute cellular rejection and minimal adverse events.     

Influence of panel-reactive antibody on survival and rejection after lung transplantation

BACKGROUND: Panel-reactive antibody (PRA) is commonly used before thoracic organ transplantation to estimate a potential recipient's degree of humoral sensitization. METHODS: To assess the influence of an elevated PRA on survival and the incidence of rejection in pulmonary transplantation, the records of 247 patients that underwent single or double lung transplantation were reviewed. RESULTS: Twenty-one of 247 patients (8.5%) had PRA values greater than 10%. Survival of this population was not significantly different from that of patients with low PRA levels: 74% (low PRA) vs 65% (elevated PRA) at 1 year and 58% in both groups at 3 years. The acute rejection rates (episodes/first 100 days) for the elevated and low PRA groups were 2.1 and 1.9, respectively (p = NS). Obliterative bronchiolitis developed in 38.9% of the high and 31.2% of the low PRA groups (p = NS). Six of 247 patients had a retrospective positive lymphocytotoxic cross-match result; three had PRA values greater than 10%. Patients with a positive cross-match result experienced similar survival and incidence of rejection as the remainder of the population. Among 957 patients evaluated for lung transplantation, 16 (1.7%) had a PRA (with dithiothreitol) greater than 15%. All had a history of pregnancy, blood transfusion, connective tissue disease, or previous transplantation. CONCLUSIONS: Humoral sensitization is uncommon in the lung transplantation population. A modestly elevated PRA does not predict survival or the development of acute rejection or bronchiolitis obliterans. PRA testing before lung transplantation should be reserved for those patients with specific risk factors for humoral sensitization.     

Suramin inhibits glucose-induced Ca2+ response in single rat pancreatic beta cells

To perform a retrospective pilot study of the potential role of mast cells in acute and chronic rejection of the lung allograft, transbronchial biopsies of 29 patients with acute rejection and six patients with bronchiolitis obliterans were stained with antibodies to mast cell tryptase. The number of mast cells per unit area were counted, and compared with a control group of normal lung biopsies stained in a similar fashion. Increasing grades of acute rejection were associated with progressively more mast cells per high-power microscopic field. The presence of bronchiolitis obliterans was accompanied by the greatest numbers of mast cells. Mast cells may play a role in the acute rejection response to the lung allograft and in the development of bronchiolitis obliterans.     

Bronchiolitis obliterans: pathogenesis, prevention, and management

Increasing early success-post lung transplant has been tempered by the long-term development of histologic bronchiolitis obliterans (OB) or of the progressive airway obstruction which is called bronchiolitis obliterans syndrome (BOS). Multiple lines of evidence suggest that OB/BOS is due to an injury directed against the epithelial cells in the airways of the donor lung by the immune system of the recipient. Acute rejection is the strongest risk factor for the subsequent development of this process. Efforts to prevent or minimize acute rejection may reduce the prevalence of OB/BOS. Results of treatment with augmented immunosuppression have been disappointing but the treatment of complicating infections in the allograft can be beneficial. Multicenter studies are needed to assess the efficacy of new immunosuppressive agents in preventing or treating OB/BOS.     

Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group

BACKGROUND: Photopheresis is an immunoregulatory technique in which lymphocytes are reinfused after exposure to a photoactive compound (methoxsalen) and ultraviolet A light. We performed a preliminary study to assess the safety and efficacy of photopheresis in the prevention of acute rejection of cardiac allografts. METHODS: A total of 60 consecutive eligible recipients of primary cardiac transplants were randomly assigned to standard triple-drug immunosuppressive therapy (cyclosporine, azathioprine, and prednisone) alone or in conjunction with photopheresis. The photopheresis group received a total of 24 photopheresis treatments, each pair of treatments given on two consecutive days, during the first six months after transplantation. The regimen for maintenance immunosuppression, the definition and treatment of rejection episodes, the use of prophylactic antibiotics, and the schedule for cardiac biopsies were standardized among all 12 study centers. All the cardiac-biopsy samples were graded in a blinded manner at a central pathology laboratory. Plasma from the subgroup of 34 patients (57 percent) who were enrolled at the nine U.S. centers was analyzed by polymerase-chain-reaction amplification for cytomegalovirus DNA. RESULTS: After six months of follow-up, the mean (+/-SD) number of episodes of acute rejection per patient was 1.44+/-1.0 in the standard-therapy group, as compared with 0.91+/-1.0 in the photopheresis group (P=0.04). Significantly more patients in the photopheresis group had one rejection episode or none (27 of 33) than in the standard-therapy group (14 of 27), and significantly fewer patients in the photopheresis group had two or more rejection episodes (6 of 33) than in the standard-therapy group (13 of 27, P=0.02). There was no significant difference in the time to a first episode of rejection, the incidence of rejection associated with hemodynamic compromise, or survival at 6 and 12 months. Although there were no significant differences in the rates or types of infection, cytomegalovirus DNA was detected significantly less frequently in the photopheresis group than in the standard-therapy group (P=0.04). CONCLUSIONS: In this pilot study, the addition of photopheresis to triple-drug immunosuppressive therapy significantly decreased the risk of cardiac rejection without increasing the incidence of infection.     

Mycophenolic acid: a welcome adjunct immunosuppressant after organ transplants

Three major double-blind trials in kidney transplantation patients have shown that mycophenolic acid (mycophenolate mofetil), added to an immunosuppressive regimen consisting of cyclosporine and prednisone, reduces the incidence of acute rejection after kidney transplantation by 50%, during the first six months. This statistically significant reduction is achieved equally with daily doses of 2 or of 3 g. In view of the fact that the side effects (diarrhoea, abdominal cramps, leukopenia) are more frequently found in the patients treated with 3 g, it is advised to prescribe 2 g mycophenolic acid. As acute rejection is a risk factor for the development of chronic rejection and because a beneficial effect of mycophenolic acid on chronic rejection in animal models has been observed, there may also be an effect on late graft loss due to chronic rejection after kidney transplantation in man.     

Pediatric and adult lung transplantation for cystic fibrosis

OBJECTIVE: This paper was undertaken to review the experience at our institution with bilateral sequential lung transplantation for cystic fibrosis. METHODS: Since 1989, 103 bilateral sequential lung transplants for cystic fibrosis have been performed (46 pediatric, 48 adult, 9 redo); the mean age was 21 +/- 10 years. Cardiopulmonary bypass was used in all but one pediatric (age <18) transplant, and in 15% of adults. RESULTS: Hospital mortality was 4.9%, with 80% of early deaths related to infection. Bronchial anastomotic complications occurred with equal frequency in the pediatric and the adult populations (7.3%). One- and 3-year actuarial survival are 84% and 61%, respectively (no significant difference between pediatric and adult age groups; average follow-up 2.1 +/- 1.6 years). Mean forced expiratory volume in 1 second increased from 25% +/- 9% before transplantation to 79% +/- 35% 1 year after transplantation. Acute rejection occurred 1.7 times per patient-year, with most episodes taking place within the first 6 months after transplantation. The need for treatment of lower respiratory tract infections occurred 1.2 times per patient in the first year after transplantation. Actuarial freedom from bronchiolitis obliterans was 63% at 2 years and 43% at 3 years. Redo transplantation was performed only in the pediatric population and was associated with an early mortality of 33%. Eight living donor transplants (four primary transplants, four redo transplants) were performed with an early survival of 87.5%. CONCLUSION: Patients with end-stage cystic fibrosis can undergo bilateral lung transplantation with morbidity and mortality comparable to that seen in pulmonary transplantation for other disease entities.     

Lung transplantation for lymphangioleiomyomatosis

BACKGROUND: Lymphangioleiomyomatosis is a rare disease of unknown origin that usually leads to progressive deterioration of lung function and eventual death from respiratory failure. It occurs in women of reproductive age and people with tuberous sclerosis. Lung transplantation is a recent therapeutic approach. METHODS: We conducted a retrospective study by questionnaire of 34 patients, treated at 16 transplantation centers, who underwent lung transplantation for end-stage lymphangioleiomyomatosis between 1983 and 1995. RESULTS: Of the 34 patients, 27 received single-lung transplants; 6, bilateral transplants; and 1, a heart-lung transplant. As of August 31, 1995, the actuarial survival calculated by the Kaplan-Meier method was 69 percent after one year and 58 percent after two years. Eighteen patients were alive 33 +/- 20 months (range, 3 to 74) after transplantation. Forced expiratory volume in one second increased from 24 +/- 12 percent of the predicted value before transplantation to 48 +/- 16 percent six months after transplantation. Five early deaths (within one month) were due to hemorrhage (in one patient), acute lung injury (in three), and dehiscence of the bronchial anastomosis (in one). Eleven late deaths (after one month) were due to infections (in eight patients), bronchiolitis obliterans (in two), and metastatic nephroblastoma (in one). Disease-associated problems were extensive pleural adhesions in 18 patients, leading to moderate-to-severe intraoperative hemorrhage in 4; pneumothorax in the native lung after single-lung transplantation in 6 patients; postoperative chylothorax in 3; and recurrent lymphangioleiomyomatosis in the allograft in 1 patient, who died of disseminated aspergillosis. CONCLUSIONS: Although disease-related complications are frequent, lung transplantation can be a valuable therapy for patients with end-stage lymphangioleiomyomatosis.