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Biomedical subjects

M E Billingham

Publications and source records attributed to M E Billingham.

269 records · Page 15Linked to original sources
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Comparison of cyclosporin A and G with and without azathioprine regarding immunosuppressive efficacy, toxicity, and pharmacokinetics in Lewis rats.

Cyclosporin A-associated nephrotoxicity has precipitated the need to develop new immunosuppressive protocols or agents that have a higher therapeutic index than cyclosporin A. A new immunosuppressive agent, cyclosporin G or norvaline (Nva-2) cyclosporine, has been shown to be potent. The rat heterotopic transplant model (ACI to Lewis) and Lewis rats that had no operation were used to compare cyclosporin G with cyclosporin A (5 mg/kg/day per gavage) with and without azathioprine (5 to 10 mg/kg/day, intraperitoneally) in terms of immunosuppressive efficacy (graft survival), toxicity (mortality, renal histopathology, and serum creatinine and blood urea nitrogen values), and pharmacokinetics (trough whole blood cyclosporine levels as measured by radioimmunoassay on days 14 and 28 of treatment). In this model no statistically significant difference in immunosuppression was shown between the two cyclosporins both with and without azathioprine. Cyclosporin G, however, was associated with significantly less mortality when combination therapy with azathioprine was used. Both cyclosporins were associated with normal serum creatinine values and little histopathologic evidence of nephrotoxicity, except juxtaglomerular apparatus hyperplasia. Comparable cyclosporine levels were achieved when cyclosporin A or G was used as the sole immunosuppressive agent, but significantly higher cyclosporine levels were shown with cyclosporin A than with cyclosporin G when combination therapy with azathioprine was used. Further studies in humans are needed to evaluate whether cyclosporin G will be a clinically useful immunosuppressive agent either alone or combined with other immunosuppressive modalities.

Animals↗
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Myocardial innervation in long-term heart transplant survivors: a quantitative ultrastructural survey.

There is no physiologic evidence for reinnervation of the transplanted human heart, although some nerves have been observed histologically. Our purpose was to find out if there was any anatomic evidence of an increase in myocardial innervation density with time in long-term heart transplant survivors. We used electron microscopic methods to estimate the number of nerves per unit area in right-sided endomyocardial biopsies from five patients at 1 year after transplantation, five at 5 years, and one each at 9, 10, and 12 years. Five donor hearts with no disease were used as controls. The mean number of nerves (either single axons or bundles of axon profiles) per square millimeter was 216 (standard deviation [SD] 79) in control hearts, 10 (SD 12) in 1 year transplants, four (SD 7) at 5 years, and three (SD 4) at 9 to 12 years. The difference between control and transplanted hearts was significant (p less than 0.001, one-way analysis of variance). There was no significant difference in the mean number of axon profiles per nerve. The few nerves that can be found in the transplanted heart, even at 12 years, might be donor postganglionic parasympathetic neurons, which are never lost. Accordingly, we found rare axon varicosities, containing vesicles, near myocytes at 1, 5, 9, and 12 years. We conclude that normal myocardial innervation is not likely to be restored in transplanted human hearts.

Axons↗
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Comparison of cardiac rejection in heart and heart-lung transplantation.

Cardiac biopsy remains the principal tool for diagnosis of rejection in heart and heart-lung transplantation. In rare instances pulmonary rejection may occur without cardiac rejection, but the overall incidence of cardiac rejection may be less with heart-lung transplantation than with heart transplantation. During the 6 months from March to September 1986, 40 heart transplantations and nine heart-lung transplantations were performed. Heart transplant patients received cyclosporine (8 to 10 mg/kg/day), azathioprine (1 to 2 mg/kg/day), and prednisone (0.8 mg/kg/day, with tapering). Heart-lung transplant patients received cyclosporine and azathioprine in the same dosages, but steroids were withheld for 3 weeks. Heart-lung transplant patients received three postoperative dosages of rabbit antithymocyte globulin (200 mg intramuscularly). There were five early deaths in the heart transplant group, four from infection and one from cerebrovascular accident. Since the initial rejection analysis presented here, one additional heart transplant patient died from rejection (241 days), and one heart-lung transplant patient died from infection (99 days). Cyclosporine levels were determined by radioimmunoassay, and cardiac rejection was diagnosed by serial endomyocardial biopsy. Early cardiac rejection is notably less common after heart-lung transplantation than after heart transplantation. Although the prophylactic antithymocyte globulin given in heart-lung transplantation may be important in this regard, rejection is probably inherently less common after heart-lung transplantation.

Adult↗
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The role of right ventricular endomyocardial biopsy in the long-term management of heart-lung transplant recipients.

Right ventricular endomyocardial biopsy remains the gold standard for the diagnosis of acute rejection of the heart allograft. Surveillance right ventricular endomyocardial biopsies are performed routinely at 3-month intervals in heart-lung transplant patients with uncomplicated conditions who have long-term follow-up. Recent observations of asynchronous heart and lung rejection, plus the impression that acute rejection was a rare phenomenon in long-term heart-lung transplant survivors, led us to analyze our experience with this technique to determine its clinical role. During the first 6 years of the heart-lung transplantation program at Stanford University Medical Center, only one episode of moderate acute rejection has occurred at greater than 4 months after heart-lung transplantation, despite greater than 160 surveillance right ventricular endomyocardial biopsies. This was in a patient who was recovering from a viral illness and had a subtherapeutic cyclosporine level of 38 ng/ml (as measured by radioimmunoassay). Fourteen patients (40%) have never had acute rejection, but freedom from acute rejection did not correlate with freedom from obliterative bronchiolitis or concentric coronary artery intimal hyperplasia. We conclude that in the long-term management phase (greater than 6 months after heart-lung transplantation), right ventricular endomyocardial biopsy should be performed for specific indications, rather than as a surveillance procedure.

Adult↗
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Analysis of the immunosuppressive and nephrotoxic effects of cyclosporin G.

Nephrotoxicity has limited the effectiveness of cyclosporine in transplantation therapy and has precipitated the need to develop a new immunosuppressive agent that lacks this nephrotoxicity or has a higher therapeutic index. Prior studies have suggested that cyclosporin G may be equally effective immunosuppressively, but less nephrotoxic than cyclosporine. To compare the immunosuppressive effects of the two agents, graft survival was analyzed in Lewis-Brown Norway rats, which received heterotopic ACl heart allografts and were treated orally with cyclosporin G or cyclosporine at 5 and 10 mg/kg/day. To compare nephrotoxicity the group of rats that had transplantations and an additional group of surgically intact Lewis-Brown Norway rats, treated orally with cyclosporin G or cyclosporine at dosages ranging from 10 to 50 mg/kg/day and for durations ranging from 50 to 180 days, were analyzed in terms of kidney morphology (fibrosis, glomerular damage, interstitial infiltrate, and tubular dilation) and kidney function (blood urea nitrogen and serum creatinine levels) in this model cyclosporin G was significantly less effective than cyclosporine in prolonging graft survival at 5 mg/kg/day but equally effective at 10 mg/kg/day. In addition, cyclosporin G was substantially less nephrotoxic both morphologically and functionally at low (10 mg/kg/day) and high (50 mg/kg/day) dosages. Further studies are indicated to determine the therapeutic index of cyclosporin G and to evaluate its use in combination with other immunosuppressive agents.

Animals↗
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Ultrasonic characterization of acute cardiac rejection from temporal evolution of echocardiograms.

Two ultrasonic parameters that characterize cardiac contractile performance were tested for their ability to detect the early stages of acute rejection. Five dogs received heart transplants with a heterotopic abdominal model and were given echographic examinations 1, 4, and 8 days after surgery. The ultrasonic measurements were extracted from pairs of cross-sectional echocardiograms, separated in time by approximately half of a cardiac cycle. The contraction-related changes in the portions of the images corresponding to myocardium were characterized by ratio of mean video amplitude and image-pair correlation. Full-thickness biopsies were taken from the left and right ventricles after each examination so that the correlations between the ultrasonic measurements and the histologic state of the tissue could be determined. Each biopsy was ranked according to the following scale of increasing levels of rejection: 0 (normal), 1 (lymphocyte infiltration), 2 (focal necrosis), 3 (diffuse necrosis), 4 (presence of hemorrhages). The average histologic state for the left ventricle increased from 0.2 +/- 0.4 for the first examination, to 2.0 +/- 0.7 for the second, and 3.6 +/- 0.5 for the third. Similar results were obtained for the right ventricle. The progressions of mean amplitude ratio and correlation were 1.55 +/- 0.14, 1.49 +/- 0.17, 1.19 +/- 0.15, and 0.22 +/- 0.10, 0.28 +/- 0.10, 0.74 +/- 0.25, respectively. Thus in this experiment, these parameters were useful for distinguishing advanced stages of rejection from the normal state and from mild rejection.

Animals↗
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Heart allograft rejection under varying immunosuppressive protocols as evaluated by endomyocardial biopsy.

Rejection episodes in 259 heart allograft recipients and 29 heart-lung transplant patients at Stanford University were examined from the viewpoint of endomyocardial biopsy. The patients were divided into the following six groups by immunosuppressive regimen: Group 1 (100 patients) was treated with conventional immunosuppression. Group 2 (26 patients) was treated with cyclosporine in combination with low-dose corticosteroids and an initial 3- to 4-day course of rabbit antithymocyte globulin. Group 3 (76 patients) was treated with cyclosporine and low-dose corticosteroids. Group 4 (34 patients) was treated with low-dose cyclosporine, azathioprine, and low-dose corticosteroids. Group 5 (23 patients) was treated with low-dose cyclosporine and azathioprine, but initially without low-dose corticosteroids. Group 6 was composed of 29 heart-lung transplant recipients. Groups 1, 2, and 6 had significantly less rejection episodes than group 3, and groups 4 and 5 had more rejection episodes than group 3. In patients with a diagnosis of mild acute rejection on cyclosporine, a repeat biopsy shows progression to a moderate acute rejection in 21% to 43% of cases, emphasizing the importance of this diagnosis even in cyclosporine-treated patients. The characteristics of acute heart allograft rejection as assessed by endomyocardial biopsy are important to recognize. In part as a result of the data presented here, further modifications in the immunosuppressive regimen of the Stanford heart and heart-lung transplant recipients are being undertaken.

Adolescent↗
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Cardiac sarcoidosis: response to steroids and transplantation.

From 1976 to 1986, six cases of cardiac sarcoidosis have been documented by myocardial biopsy in three of five instances; on examination of the explanted heart after transplantation in two, and at autopsy in one patient. Right ventricular end-diastolic pressure was elevated in all four patients with right ventricular involvement with sarcoidosis. Of three patients treated with steroids, improvement in ventricular function and decrease in arrhythmia occurred in two, whereas failure to respond led to transplantation in the other patient. Two further patients have undergone heart transplantation, one for resistant ventricular arrhythmia and the other for congestive heart failure. No recurrence of sarcoidosis has occurred in the grafts. Because two of five patients had sarcoidosis diagnosed on gross examination, a negative endomyocardial biopsy does not exclude the diagnosis of myocardial sarcoidosis, which should therefore be pursued in the setting of unexplained heart failure, conduction abnormalities, and ventricular arrhythmia, particularly when right ventricular end-diastolic pressure is raised. Steroids may result in improvement in some patients even in the presence of severe morphological damage. Heart transplantation may be performed without increased risk of recurrence of sarcoidosis.

Adult↗
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Comparative effect of cyclosporin A and G on weight gain of primates during the pubertal growth period.

A double-blind study with six cynomolgus monkeys (mean age, 2.0 years) was carried out. All animals received immunosuppression therapy with 16 mg/kg/day of cyclosporin A or G (Norvaline cyclosporine), given intramuscularly in two divided daily dosages. All animals received a small dosage of steroids (0.1 mg/kg/day). After 14 months the dosage of cyclosporin G was increased to 20 mg/kg/day. During the first study year, weight velocity was normal in the cyclosporin G group and impeded in the group receiving cyclosporin A. During the second year of the study, the weight velocity was impeded in both groups. The weight gain was significantly less in the cyclosporin A group than in the group receiving cyclosporin G (p = 0.001). The results suggested that cyclosporine impeded weight gain in primates during the pubertal period. The effect was dosage-related and was less with cyclosporin G than with cyclosporin A. The mechanism is unclear, but the possible effect on the growth hormone merits further studies.

Animals↗
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Reliability and usefulness of immunofluorescence in heart transplantation.

BACKGROUND AND METHODS: To study the reliability and usefulness of immunofluorescence on heart biopsy specimens for routine monitoring of heart transplant recipients for rejection, frozen sections of 72 consecutive endomyocardial biopsy specimens from 18 heart transplant recipients during the first 6 weeks after transplantation (and later) and from 11 control specimens from donor hearts and other nontransplantation patients were studied. Fifteen patients received OKT3 induction. The diagnosis of vascular (humoral) rejection pattern as defined by Hammond was based on the microvascular deposition of immunoglobulin and C3 or C1q. Echocardiographic data and right-sided heart catheterization were obtained simultaneously. RESULTS: The results showed that immunofluorescence was positive for a vascular rejection pattern in 60% (43 of 72) overall, in heart transplant recipients it was positive in 59% (36 of 61), and in control subjects it was positive in 63% (7 of 11). Most of the patients who had positive immunofluorescence had no hemodynamic compromise. Humoral rejection was not predicted by positive immunofluorescence in our study. We also found no correlation with either positive or negative immunofluorescence for the short-term or long-term outcome during the first 6 weeks after transplantation. CONCLUSION: The usefulness of routine immunofluorescence in all surveillance heart biopsies is questionable as determined by this study.

Adult↗
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Acute rejection: significance of elapsed time after transplantation.

In July 1990 the new standardized grading scheme for the International Society for Heart and Lung Transplantation was established. One of the purposes of "splitting" the grades was to learn the significance and outcome of the various grades proposed. Between January 1990 and November 1992, 263 grade 1A, 19 grade 1B, and 100 grade 2 "new" rejection episodes were identified at our institution. These episodes occurred in 86 adult recipients who underwent transplantation between January 1990 and August 1992 and 98 recipients who underwent transplantation before January 1990, in whom the episodes occurred more than 1 year from the date of transplantation. The outcome of the episode was determined on subsequent endomyocardial biopsy samples to be resolution or "progression" to a higher grade. The percentage of focal mild (grade 1A) rejection episodes progressing to a moderate (grade 3A) rejection in the first 6 months after transplantation was 24.4% (20 of 82) compared with a progression rate of 5.1% (3 of 59) and 2% (3 of 149) in episodes occurring beyond 6 months and 1 year after transplantation, respectively (p < 0.005). Of the focal moderate (grade 2) rejection episodes receiving no augmentation of immunosuppression, 35.7% (5 of 14) occurring within the initial 6 months and 7.3% (3 of 41) of all such episodes diagnosed beyond 1 year after transplantation progressed to a moderate rejection. A similar trend was seen in the focal moderate rejection episodes that received augmentation of immunosuppression: 26.3% (5 of 19) of episodes occurring within 6 months and 0 of 15 of all episodes occurring beyond 1 year after transplantation progressed to a moderate rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
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Long-term results of combined heart-lung transplantation: the Stanford experience.

We assessed the long-term results of our experience with 109 patients with end-stage cardiopulmonary disease who underwent primary combined heart-lung transplantation at Stanford University Medical Center between March 1981 and January 1994. Average recipient age was 31 +/- 10 years (mean +/- standard deviation) median, 31 years; range, 1 month to 52 years. Recipient diagnoses included primary pulmonary hypertension (31%), Eisenmenger's syndrome (39%), complex congenital heart disease (8%), cystic fibrosis (14%), bronchiectasis (2%), and emphysema (3%). Immunosuppression was with cyclosporine and a tapering regimen of corticosteroids. In 1986 azathioprine was added, and since 1987 induction therapy with OKT3 has been employed. Actuarial survival rates at 1, 5, and 10 years were 68% +/- 4.6%, 43% +/- 5.4%, and 23% +/- 8.1%, respectively (mean +/- 1 standard error of the mean). Fourteen deaths occurred in the hospital for an operative mortality rate of 12.8% +/- 3.3%, and 61 deaths occurred overall. Causes of death included hemorrhage (five patients), infection (21), rejection (one), nonspecific pulmonary failure (four), graft coronary artery disease (six), and obliterative bronchiolitis (eight). Infection, rejection, and obliterative bronchiolitis were the major complications. Only 20% +/- 3.9% of patients were free from any infection 3 months after transplantation. Heart and lung rejection commonly occurred asynchronously; actuarial estimates of freedom from isolated lung rejection at 1 and 5 years were 47% +/- 5.2% and 40% +/- 5.6%, respectively. For simultaneous heart and lung rejection these estimates were 87% +/- 3.5% and 86% +/- 3.8%, and for isolated heart rejection 63% +/- 5.1% and 51% +/- 6.4%, respectively. Although graft coronary artery disease developed less frequently than in patients after isolated heart transplantation (90% +/- 4.6% of patients were free of graft coronary artery disease at 5 years), obliterative bronchiolitis remains a major long-term complication and cause of morbidity and mortality. Actuarial estimates of freedom from obliterative bronchiolitis at 1, 5, and 10 years were 71% +/- 5.1%, 51% +/- 6.1%, and 42% +/- 7.8%, respectively. These results show satisfactory early and medium-term outcome after combined heart-lung transplantation but also underscore that much progress is needed in controlling infection, rejection, and obliterative bronchiolitis, all of which remain as major impediments to long-term survival.

Actuarial Analysis↗
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Graft coronary disease in pediatric heart and combined heart-lung transplant recipients: a study of fifteen cases.

Graft coronary disease (GCD) has emerged as the most important deterrent to long-term survival in adult heart transplant recipients. The incidence, natural history, and pathobiology of GCD is less well understood in the pediatric transplant population. This study evaluated the histopathologic and immunohistochemical features of GCD in the Stanford pediatric heart and heart-lung group. Eighty-eight patients, ages 1 week to 18 years, received heart transplants between 1974 and 1992, and 15 patients, ages 1 month to 18 years received heart-lung transplants between 1981 and 1992 at Stanford University Hospital. There were 50 males and 38 females in the heart transplant group; 39 (11%) had idiopathic cardiomyopathy, 26 (30%) had congenital heart disease, 13 (15%) had viral cardiomyopathy, seven (8%) had familial cardiomyopathy, two (2%) had cardiomyopathy resulting from doxorubicin therapy, and one other case was not further delineated. In the heart-lung transplant group, there were eight males and seven females; pretransplantation diagnoses included nine (60%) with congenital heart disease and Eisenmenger's physiology, three (20%) with primary pulmonary hypertension, and one (7%) each with cystic fibrosis, bronchopulmonary dysplasia, and congenital lymphangiectasia. Fifteen (17%) of the heart transplant recipients and three (20%) of the heart-lung transplant recipients had GCD on angiographic or pathologic examination. Histopathologic samples were available on 14 cases (11 heart transplants and three heart-lung transplants).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
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The role of transbronchial biopsies in the management of lung transplant recipients.

We examined the utility of the transbronchial biopsy in the management of 53 lung transplant patients. One hundred thirty-three protocol biopsies were performed to ascertain the frequency and nature of abnormalities in clinically stable or asymptomatic patients; 128 diagnostic biopsies were performed in clinically ill patients to assess the morphologic abnormalities before the institution of therapy, and 105 biopsies were performed to assess the response to therapy. Histologic evidence of acute rejection was found in 24% of the protocol biopsies, and infection was found in 17%. Twenty-five patients with grade 1 or grade 2 perivascular infiltrates in protocol biopsies did not receive antirejection therapy. Follow-up biopsy in these patients showed spontaneous resolution of the infiltrates in 19% and increased infiltrates in 6. Only two of these patients became clinically ill, representing "progression" to clinical rejection in only 8% of the nontreated patients. Forty percent of the biopsies performed to rule out acute rejection or infection had histologic features of acute rejection, and another 23% had features of infection. Treatment of patients with clinical and histologic evidence of rejection was associated with rapid resolution of clinical symptoms in nearly 90% of the patients, but follow-up biopsies showed residual infiltrates compatible with ongoing or resolving rejection in 52%. Despite repeat antirejection therapy in some patients, these infiltrates persisted for an average of 30 days after the diagnostic biopsy. Follow-up biopsies also showed asymptomatic infection, usually cytomegalovirus pneumonitis, which often persisted for weeks despite the lack of symptoms. Perivascular infiltrates compatible with acute rejection were also found in 38% of biopsy specimens with evidence of infection. These perivascular infiltrates resolved with antibiotic treatment alone in nearly 50% of the patients with these features. Although perivascular mononuclear cell infiltrates are the cardinal histologic feature of acute rejection, similar infiltrates occur in patients who apparently have infection alone and other patients who have both infection and rejection; infiltrates compatible with minimal, mild, and moderate acute rejection also occur in clinically asymptomatic patients. These histologic findings are a challenge to both the pathologists' and the clinicians' skills in the management of the lung transplant patient.

Biopsy, Needle↗