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Biomedical subjects

B P Griffith

Publications and source records attributed to B P Griffith.

At least 163 records · Page 9Linked to original sources

Pediatric lung transplantation. The years 1985 to 1992 and the clinical trial of FK 506.

The application of lung transplantation to the pediatric population was a natural extension of the success realized in our adult transplantation program, which began in 1982. Twenty pediatric patients (age range 3 to 18 years) have had heart-lung (n = 11), double lung (n = 8), and single lung (n = 1) transplantation procedures. The causes of end-stage lung disease were primary pulmonary hypertension (n = 7), congenital heart disease (n = 5), cystic fibrosis (n = 4), pulmonary arteriovenous malformation (n = 2), graft-versus-host disease (n = 1), and desquamative interstitial pneumonitis (n = 1). Four (20%) patients had thoracic surgical procedures before the transplantation operation. The survival was 80% at a mean follow-up of 2 years. Immunosuppressive drugs included cyclosporine (n = 9) or FK 506 (n = 11) based therapy with azathioprine and steroids. Children were followed up by means of spirometry, transbronchial biopsy, and primed lymphocyte testing of bronchoalveolar lavage fluid. The mean number of treated episodes of rejection was 1.4 at 30 days, 0.5 at 30 to 90 days, and 1.4 at more than 90 days, and the first treated rejection episode occurred on average 28 days after the operation. Obliterative bronchiolitis developed in four (25%) of 16 patients surviving more than 100 days. Results of pulmonary function tests have remained good in almost all recipients. The greatest infectious risk was that of cytomegalovirus: one death and one case of pneumonia. Posttransplantation lymphoproliferative disease was diagnosed in two (12.5%) patients; both recovered. The most common complications were hypertension (25%) and postoperative bleeding (15%). Early results indicate that lung transplantation is a most promising therapy for children with severe vascular and parenchymal lung disease.

Adolescent↗

A decade (1982 to 1992) of pediatric cardiac transplantation and the impact of FK 506 immunosuppression.

The decade from 1982 through 1992 witnessed tremendous growth in pediatric cardiac transplantation. At Children's Hospital of Pittsburgh 66 cardiac transplants were performed during this period (age range 7 hours to 18 years). The cause of cardiomyopathy was congenital (n = 30), cardiomyopathy (n = 29), myocarditis (n = 2), doxorubicin toxicity (n = 2), ischemic (n = 1), valvular (n = 1), and cardiac angiosarcoma (n = 1). Nine children (14%) required mechanical circulatory support before transplantation: extracorporeal membrane oxygenation (n = 8) and Novacor left ventricular assist system (n = 1) (Baxter Healthcare Corp., Novacor Div., Oakland, Calif.). The mean follow-up time was 2 years (range 4 months to 8 years). The overall survival in the group was 67%. In children with congenital heart disease (> 6 months of age) the perioperative (30 day) mortality was 66% before mid-1988 (n = 10) and 0% since mid-1988 (n = 11). The late mortality (> 30 days) in children with cardiomyopathy transplanted prior to mid-1988 was 66% (n = 14) and 7% since mid-1988 (n = 15). Since mid-1988 1- and 3-year survival was 82% in children with congenital heart disease and 90% in children with cardiomyopathy. Twenty-six children have had FK 506 as their primary immunosuppressive therapy since November 1989. Survival in this group was 82% at 1 and 3 years. The actuarial freedom from grade 3A rejection in the FK group was 60% at 3 and 6 months after transplantation versus 20% and 12%, respectively, in the 15 children operated on before the advent of FK 506, who were treated with cyclosporine-based triple-drug therapy (p < 0.001, Mantel-Cox and Breslow). Twenty of 24 children (83%) in the FK 506 group are receiving no steroids. The prevalence of posttransplantation hypertension was 4% in the FK 506 group versus 70% in the cyclosporine group (p < 0.001, Fisher). Renal toxicity in children treated with FK 506 has been mild. Additionally, eight children have been switched to FK 506 because of refractory rejection and drug toxicity. FK 506 has not produced hirsutism, gingival hyperplasia, or abnormal facial bone growth. The absence of these debilitating side effects, together with the observed immune advantage and steroid-sparing effects of FK 506, hold tremendous promise for the young patient facing cardiac transplantation and a future wedded to immunosuppression.

Adolescent↗

Improved survival following pediatric cardiac transplantation in high-risk patients.

BACKGROUND: Preoperative hemodynamic support, complex congenital heart disease, and elevated pulmonary vascular resistance present particular challenges for pediatric heart transplantation. This study was performed to identify preoperative factors that influence survival after pediatric heart transplantation over two eras of pediatric heart transplant experience. METHODS AND RESULTS: We retrospectively analyzed demographic, clinical, and hemodynamic data from 67 pediatric patients who underwent heart transplantation between February 1982 and June 1992 and compared survival between two eras (early experience versus late experience). During the early experience (group 1: February 1982 to August 1989), univariate analysis identified congenital heart disease, pretransplant extracorporeal membrane oxygenator (ECMO) support, inotropic and/or ventilatory support (UNOS status I), elevated transpulmonary gradient (at least 15 mm Hg), and elevated pulmonary vascular resistance index (at least 4 Wood units.m2) as preoperative risk factors for early death after pediatric heart transplantation. However, in the late experience (group 2: September 1989 to June 1992), the only risk factor for premature death by univariate analysis was elevated transpulmonary gradient. By multivariate analysis, elevated transpulmonary gradient was the only risk factor for our early, late, and entire experiences. One-year survival after transplantation for congenital heart disease was improved from 46% in group 1 to 73% in group 2 (P < .05). In group 1, only one patient (25%) with pretransplant ECMO support survived 1 year, whereas 66% (four of six) survived more than 1 year in group 2. CONCLUSIONS: Although elevated transpulmonary gradient continues to be a significant risk factor for pediatric heart transplantation, candidates with congenital heart disease, UNOS status I, and pretransplant ECMO support now can be successfully transplanted with reasonable hope for extended survival.

Cardiomyopathies↗

Isolated lung transplantation for patients with Eisenmenger's syndrome.

BACKGROUND: Eisenmenger's syndrome remains one of the greatest challenges in lung transplantation. METHODS AND RESULTS: Since October 1990, seven such patients with Eisenmenger's syndrome received isolated pulmonary grafts (six double lungs and one single lung). Mean patient age was 32 +/- 6 years (two men and five women). The preoperative mean pulmonary arterial pressure was 90.7 +/- 31.2 mm Hg, and the ventriculoscintigram showed markedly enlarged right ventricle and normal left ventricular function with ejection fraction of 0.660 +/- 0.115. Three atrial septal defects and four patent ducti arteriosus were repaired concomitantly. Excised lung histology showed plexogenic pulmonary arteriopathy with Heath-Edwards' grade 4 through 6. One double lung patient who had preexisting systemic vascular collapse died intraoperatively. The other six patients tolerated transplantation, and on the first operative day, mean pulmonary artery pressure decreased to 22.4 +/- 7.3 mm Hg (P < .002) and gas exchange was acceptable with an arterial/alveolar oxygen tension ratio of 0.47 +/- 0.15. Two patients died of mediastinal and pulmonary infection. The follow-up for the four survivors ranged from 13 to 25 months after transplantation. CONCLUSIONS: Our preliminary experience shows that concomitant isolated lung transplantation with cardiac repair could be a viable therapeutic option for patients with Eisenmenger's syndrome and normal left ventricular function. Dynamic right ventricular outflow obstruction is a potential hemodynamic problem in these pulmonary recipients.

Adult↗

Aspects of lung transplantation that contribute to increased severity of pneumonia. An experimental study.

In lung or heart-lung transplant recipients, complications as a result of pulmonary infections continue to be the most frequent causes of morbidity and mortality. This study was undertaken to identify the contributions of (1) thoracotomy, (2) interruption of lymphatic vessels and bronchial arteries, (3) transplant procedure, (4) drug-induced immunosuppression, and (5) graft allogenicity to the increased risk of pneumonia in lung transplantation. Lewis rats were inoculated with 10(5) colony-forming units of Legionella pneumophila serogroup 1 by direct instillation into the trachea after one of the following: a general anesthetic with no operation; a left thoracotomy; a left thoracotomy with pulmonary hilar stripping; an isogeneic orthotopic left lung transplant with or without immunosuppression; or an allogeneic transplant with immunosuppression with Brown-Norway rats as donors. Immunosuppression was induced with an intramuscular injection of cyclosporine (25 mg/kg of body weight) from the inoculation day to day 3. All rats were killed on day 6, and severity of infection was determined by quantitative culture of Legionella organisms in the lungs and spleen, titer of Legionella urinary antigen, differential cell count in bronchoalveolar lavage fluid, body weight loss, and gross inspection of the lung. Significant increases in lung Legionella concentration occurred as a result of the addition of pulmonary hilar stripping (from 10(5.13 +/- 0.34) in the thoracotomy group to 10(5.66 +/- 0.25) in the thoracotomy with hilar stripping group, p = 0.013) and the addition of immunosuppression (from 10(5.47 +/- 0.47) in the isogeneic transplant group to 10(6.94 +/- 0.52) in the isogeneic transplant with immunosuppression group, p = 0.00016). Thoracotomy, transplant procedures, and allogenicity itself resulted in no significant increases. The results for all other indicators paralleled those for lung culture. We conclude that the combination of drug-induced immunosuppression with lung denervation and interruption of lymphatic vessels and bronchial arteries results in the early development and increased severity of pneumonia in lung transplantation.

Animals↗

A clinical trial of University of Wisconsin solution for pulmonary preservation.

Suboptimal pulmonary preservation with modified Euro-Collins solution (9/90 to 4/91) prompted us to change to University of Wisconsin solution (4/91 to 4/92). Between September 1990 and April 1992, 94 patients received 100 pulmonary allografts (13 heart-lungs, 45 double lungs, 42 single lungs) that were flushed and preserved with either Euro-Collins (n = 30) or University of Wisconsin (n = 70) solution. Selection of donors and procurement and storage of donor lungs were identical. Bilateral single lung transplantation was performed more often in the University of Wisconsin group and resulted in a significantly longer graft ischemic time (University of Wisconsin group; 303 +/- 62 minutes; Euro-Collins group; 260 +/- 62 minutes; p = 0.007, t test). The use of cardiopulmonary bypass was not statistically significantly different. Preservation injury identified by the radiograph on day 1 was more severe (p = 0.036; Mann-Whitney U test) in the Euro-Collins group than in the University of Wisconsin group. In double lung and heart-lung recipients gas exchange of the allografts was evaluated by the arterial/alveolar oxygen tension ratios at nine intervals during the first 72 hours. The mean arterial/alveolar oxygen tension ratio was 0.62 +/- 0.26 in the University of Wisconsin group and 0.46 +/- 0.23 in the Euro-Collins group, but this difference did not reach significance (p = 0.119, analysis of variance). Despite the longer ischemic time, pulmonary preservation achieved by University of Wisconsin solution appears to be comparable with that achieved by Euro-Collins solution.

Adenosine↗

Psychosocial outcome six months after heart transplant surgery: a preliminary report.

With improvement in survival of patients treated with heart transplant, evaluation of recovery with respect to psychosocial function has become an important issue. In this study, psychosocial functioning of 44 heart transplant recipients pretransplant was compared to their functioning 6 months posttransplant. Before transplantation, patients experienced considerable psychosocial distress attributable to illness. At 6 months after transplantation, the majority of patients showed significant improvement in emotional, domestic, sexual, social, and vocational functioning. However, 25% of patients showed deterioration in psychosocial adjustment and 11% showed an increase in mood disturbance. Further effort is indicated to improve psychosocial outcome of heart transplantation.

Adaptation, Psychological↗

Hyperuricemia and gout among heart transplant recipients receiving cyclosporine.

PURPOSE: To determine the frequency and characteristics of hyperuricemia and gouty arthritis among cyclosporine-treated heart transplant recipients. PATIENTS AND METHODS: One hundred ninety-six surviving adult heart or heart/lung transplant recipients were evaluated. Medical records were reviewed to determine peak serum uric acid levels after transplantation, and to evaluate potential risk factors for hyperuricemia. Patients were surveyed by postal questionnaire for a history of gouty arthritis, with positive responses evaluated by telephone interview and/or examination of the patient. RESULTS: Hyperuricemia occurred in 72% of male and 81% of female patients and was not correlated with cyclosporine level, presence of hypertension, or degree of renal insufficiency. Eleven (6%) patients had gout prior to transplantation; 14 (8%) had onset of definite gout and seven (4%) had probable gout a mean of 17 months after transplantation. Polyarticular arthritis and/or tophi developed in six (43%) of the posttransplant-onset definite gout group within a mean of 31 months. CONCLUSION: Both hyperuricemia and gouty arthritis occur with increased frequency among cyclosporine-treated heart or heart/lung transplant recipients. The clinical course of gout in these patients is often accelerated, with management complicated by the patients' renal insufficiency and interaction with transplant-related medications.

Arthritis, Gouty↗

Acute rejection of lung allografts with various immunosuppressive protocols.

Between February 1990 and December 1991, 69 patients who survived for a minimum of 5 days after single-lung (27), double-lung (32), or heart-lung transplantation (10) were studied to learn the incidence and severity of acute rejection and the possible effects of various immunosuppressive protocols on this rejection. Acute rejection was less common (2.1 versus 3.1 episodes/patient) after transplantation in those 30 candidates who received rabbit antithymocyte globulin for the first 5 postoperative days versus the 28 who were maintained on cyclosporine, azathioprine, and prednisone alone (p < 0.05), but no patient escaped at least one episode. Patients given cyclosporine received more 3-day courses of methylprednisolone (p < 0.02) than those given rabbit antithymocyte globulin (2.5 versus 1.7 courses). Although no disadvantage in terms of infectious morbidity was noted in the rabbit antithymocyte globulin group, no obvious intermediate advantage was noted in survival (85% at 12 months) or grade of rejection or airway flows. The most common histopathologic grades were mild (A2) and moderate (A3); the average grade was A2.3. FK 506 was tested in 11 patients, and early results are promising relative to low early and likely fewer late episodes of rejection. No differences were noted in the likelihood of rejection for any procedures.

Acute Disease↗

University of Wisconsin solution for pulmonary preservation in a rat transplant model.

University of Wisconsin and modified Euro-Collins solutions for pulmonary preservation were compared in a rat orthotopic left lung isotransplant model. Heart-lung blocks of donor rats were flushed with and preserved in one of the preservation solutions at 0 degrees C. After 6 or 12 hours of cold ischemia, the left lungs were transplanted into recipient rats and reperfused for 1 hour. Pulmonary function was assessed by measuring oxygen and carbon dioxide tensions in arterial blood after removal of the right lung. Lipid peroxide concentrations were measured as thiobarbiturate acid-reactive substances. The ratios of wet to dry weight of grafts after ischemia and after reperfusion were calculated. Histologic changes of ischemia-reperfusion injury of the lung tissue were evaluated using a graded scale. Oxygen tension after 6 hours of preservation followed by reperfusion was significantly higher with University of Wisconsin solution (308.8 +/- 81.1 mm Hg) than with Euro-Collins solution (50.8 +/- 17.8 mm Hg; p less than 0.001). Carbon dioxide tension in the University of Wisconsin solution group was also significantly lower than in the Euro-Collins solution group (28.2 +/- 2.3 versus 46.0 +/- 4.5 mm Hg; p less than 0.05). Lipid peroxide concentration after 6 hours' preservation in University of Wisconsin solution was significantly lower (0.88 +/- 0.07 mumol/g) than that in Euro-Collins solution (1.26 +/- 0.12 mumol/g; p less than 0.05). After 12 hours of preservation only lipid peroxide concentration with University of Wisconsin solution was significantly lower (1.30 +/- 0.09 mumol/g) than with Euro-Collins solution (1.71 +/- 0.15 mumol/g; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

Clinical trial of FK 506 immunosuppression in adult cardiac transplantation.

The new immunosuppressive agent FK 506 was used as primary immunotherapy in conjunction with low-dose steroids and azathioprine in 72 patients subsequent to orthotopic cardiac transplantation. Overall patient survival at a mean follow-up of 360 days was 92%. The number of episodes of cardiac rejection (grade 3A or greater) within 90 days of transplantation was 0.95 per patient. The actuarial freedom from rejection at 90 days was 41%. Achievement of this level of immunosuppression is comparable with that of cyclosporine-based triple-drug therapy with OKT3 immunoprophylaxis. Thirty percent of patients were tapered off all steroids, and the average steroid dose in the group who received steroids was 8.6 mg of prednisone per day. The incidence of infection reflected the diminished necessity for steroids: seven major infections (10%) and 11 minor infections (16%). Renal dysfunction occurred during the perioperative period in most patients in this trial. However, the incidence of hypertension was 54% compared with 70% during the cyclosporine era. Ten adults underwent successful rescue therapy with FK 506 after cardiac rejection refractory to conventional immunotherapy. Side effects of FK 506 were notably few, and the results of the trial are encouraging for the future of the cardiac transplant recipient.

Adult↗

Comparison of enzyme-linked immunosorbent and indirect immunofluorescence assays for the detection of human T-cell lymphotropic virus type-I antibodies in sera from rural Haiti.

Serum samples were obtained from 340 healthy individuals without evidence of neurologic disease living in rural Haiti. Sera were screened for antibodies to human T-cell lymphotropic virus type I (HTLV-I) using two commercially available enzyme immunoassays (EIA) and by an indirect immunofluorescence assay (IFA) using a mixture of uninfected H9 cells and HTLV-I-infected MT-2 cells. Repeatedly positive samples were confirmed by Western blot (WB). Results with the two EIA systems were concordant and detected 13 positive samples, each of which was confirmed by WB. Only 9 (69%) of 13 WB-positive sera were detected by IFA, and four additional samples, positive by IFA, could not be confirmed by WB. The prevalence of HTLV-I seropositivity in this selected rural Haitian population was 3.8% (13 of 340).

Adolescent↗

Interstitial and airspace granulation tissue reactions in lung transplant recipients.

Twenty-three transbronchial and open-lung biopsies from patients who had received a lung allograft displayed fibromyxoid plugs of granulation tissue within airways, airspaces, and the interstitium in a patchy distribution. This granulation tissue-like reaction was identified in three clinicopathologic settings. First, 11 cases occurred with acute lung rejection, of which four cases had been partially treated with steroids for a previous rejection episode. Second, in seven cases the fibromyxoid tissue represented the healing phase of previously diagnosed diffuse alveolar damage resulting from preservation (harvest) injury to the allograft. Third, five cases were related to infection: herpes, Pseudomonas, Serratia, Staphylococcus, and Pneumocystis pneumonias. Although organizing pneumonia-like responses usually suggest an infectious episode, this reaction may be seen as a manifestation of acute lung rejection or ischemic lung injury.

Biopsy↗

Improved immunosuppression with aerosolized cyclosporine in experimental pulmonary transplantation.

Rejection remains a major obstacle to long-term success of pulmonary transplantation. Direct delivery of cyclosporine to lung allografts may produce better control of rejection by generating high intragraft concentrations of drug with decreased systemic delivery and toxicity. The efficacy of inhaled cyclosporine in preventing allograft rejection was compared with systemic delivery by intramuscular injections in a rat model of lung transplantation (Brown-Norway to Lewis). Group 1 animals were given no immunosuppression. Group 2 received a single i.m. injection of 25 mg/kg CsA on the day of operation while group 3 received daily doses on postoperative days 0-3. Groups 4-7 received aerosolized CsA daily for seven days. The aerosol generator produced an airborne concentration of CsA of 180 mg/m3 with a mean particle size of 0.7 mu and estimated pulmonary depositions of CsA of 0.98-3.6 mg/kg/day. Animals were killed on POD 7, and the transplanted lungs graded histologically in a blinded fashion. All control animals showed destructive grade 4 changes by POD 7. Animals receiving high-dose aerosolized CsA (groups 6 and 7) showed minimal changes with a mean rejection grade of 1.3. A single i.m. dose of CsA (group 2) failed to prevent rejection; the mean grade was 2.2. Animals given four i.m. doses of CsA had a mean grade of 1.8. Aerosolized CsA provided significantly better control of rejection than did systemic CsA (groups 6 and 7 vs. groups 2 and 3; P less than 0.0002 and less than 0.0054, respectively). Local delivery of CsA by aerosol inhalation is effective in limiting acute rejection of the rat lung allograft.

Aerosols↗

Mitogen responses of lymphocytes from lung transplant recipients--correlation with rejection and infection.

Proliferative responses to nonspecific mitogens were analyzed for 119 bronchoalveolar lavages and 108 concurrent peripheral blood samples from 35 lung transplant patients. The patients were classified at each time as normal, rejecting, or infected on the basis of trans-bronchial biopsy, culture results, clinical signs, and pulmonary function. During rejection episodes the bronchoalveolar lavage responses to concanavalin A and phytohemagglutinin were significantly increased (P less than 0.004 and P less than 0.006, respectively). The differences were less pronounced when rejection occurred within 30 days after bolus immunosuppressive therapy, either as immunoprophylaxis or as treatment for a previous rejection episode, and were not significantly different from normal. Differences in response during rejection were limited to the graft; analysis of circulating T cells was not helpful (P = NS). In contrast, markedly depressed responses to Con A and PHA were seen during infection. Significant differences were observed both in the graft (P less than 0.007) and in circulating lymphocytes (P less than 0.02), suggesting that global depression of mitogen response is associated with immunocompromise. Sequential analysis of 6 patients showed that individual changes in mitogen response paralleled those seen in the population (P less than 0.046, normal vs. rejection and P less than 0.043 normal). These findings suggest that mitogen assays of bronchoalveolar lavage lymphocytes and, to a lesser extent, PBL, are clinically useful in assessing intragraft immunocompetence and in distinguishing rejection from infection in lung transplant patients.

Bronchoalveolar Lavage Fluid↗

Tumor necrosis factor-alpha production by alveolar macrophages in heart-lung transplant recipients.

Tumor necrosis factor-alpha (TNF alpha) is a cytokine produced by mononuclear cells that amplifies inflammation and modulates expression of Class I and Class II histocompatibility antigens. Because of these properties, this cytokine may exert a central role in both the defense and the rejection of the transplanted lung. Utilizing an ELISA technique, we measured TNF alpha in vivo and in vitro in several compartments of lung transplant recipients and in normal subjects that included serum, bronchoalveolar lavage fluid (BAL), and media conditioned by alveolar macrophages (AM) and by autologous peripheral blood monocytes (PBM). Overall, stimulated production of TNF alpha by AM from lung recipients in vitro was less than that of cells from normal subjects in response to lipopolysaccharide (LPS) challenge, and stimulated production of TNF alpha by AM harvested during conditions of infection or acute and chronic rejection was less than that by cells from healthy lung recipients. AM from normal subjects and allograft recipients produced substantially more TNF alpha than autologous PBM, but release in vitro by PBM from recipients was the same as that from cells of normal subjects who were not immunosuppressed. Thus, systemic immunosuppression does not seem to affect the production of TNF alpha by PBM in vitro, but it may reduce production by AM, indicating different effects of immunosuppression on different compartments of mononuclear cells. This mediator was not detected at elevated levels in serum, and it was undetectable in BAL fluid. We conclude that AM from lung recipients are capable of producing TNF alpha, which would influence the defense and immunogenicity of the allograft.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Ganciclovir prophylaxis for cytomegalovirus infections in pulmonary allograft recipients.

Cytomegalovirus (CMV) is a substantial cause of morbidity in pulmonary allograft recipients. In an attempt to decrease the prevalence of this infection, we treated 13 recipients at risk for cytomegalovirus with 3 wk of intravenous ganciclovir (5 mg/kg twice a day for 14 days, starting 5 days after the procedure, followed by 1 wk of the drug at a dose of 5 mg/kg/day). Following the ganciclovir course, patients received oral acyclovir, 800 mg three times a day for at least 2 months more. CMV infections developed in 5 recipients (38%), and none of these episodes occurred during the ganciclovir therapy. Neither of the 2 deaths in this group could be attributed to CMV. In comparison, the prevalence of CMV in the preceding cohort of 11 transplant recipients who were administered acyclovir alone was 91% (p << 0.01 by log-rank test), and there were 3 deaths due to viral infections (p = 0.08 by Fisher's exact test). Groups were similar in terms of immunosuppression and renal function during treatment, and none of the recipients developed leukopenia. We conclude that ganciclovir prophylaxis is well tolerated and appears to have considerable efficacy for prevention of CMV infections in pulmonary transplant recipients.

Administration, Oral↗