Cyclosporine and itraconazole interaction in heart and lung transplant recipients.
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Aspergillosis↗
Biomedical subjects
J Theodore
Publications and source records attributed to J Theodore.
Lung transplantation comes of age.
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Humans↗
Long-term cardiopulmonary function after human heart-lung transplantation.
We present cardiac and pulmonary function data obtained at serial annual reviews in 21 heart-lung transplant (HLT) recipients followed for up to four years postoperatively, reflecting the entire Stanford experience as of June 1987. A total of 50 cardiac catheterisation procedures and endomyocardial biopsies yielded the following results: rejection on biopsy (0/50) (0% of patients), angiographic coronary artery disease (1/50) (5%), pulmonary hypertension (2/50) (10%), elevated pulmonary vascular resistance (PVR) (1/50) (5%), and low cardiac index (CI) (4/50) (14%). Systemic hypertension was common, with an elevated systemic vascular resistance (SVR) (26/44) (76%) and an elevated mean aortic pressure (MAP) (22/44) (67%). Pulmonary function testing frequently revealed abnormalities. Airflow limitation was manifested by a reduction in both FEV1/FVC ratio (17/50) (52%) and FEF25-75 (30/50) (71%), and was often associated with arterial hypoxaemia (13/50) (52%). Subsequently, five patients with these findings have died with obliterative bronchiolitis (OB), one underwent retransplantation for OB, six have stable OB, and one has progressive OB. Length of survival was highly correlated with the resting PaO2 at the first annual review (r = 0.99) (p less than 0.001), and, to a lesser degree, on the reduction in FEF25-75 (r = 0.73) (p less than 0.05) and FEV1/FVC ratio (r = 0.77) (p less than 0.05). Resting PaO2 was determined by ventilatory (r = 0.80) (p less than 0.001) rather than circulatory factors and all patients with airflow limitation who died had OB at post-mortem examination. These results support the continued study of HLT as a therapeutic modality for selected patients with irreversible pulmonary hypertension. They demonstrate that, in the absence of severe OB, haemodynamics, cardiac function, and coronary patency are preserved for several years after HLT. Whereas the value of regular pulmonary function testing has become evident, there does not appear to be a clinical need for annual surveillance with invasive cardiac procedures in long-term survivors of HLT.
Adolescent↗
Home monitoring of the transplanted lung.
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Graft Rejection↗
Bronchial responsiveness after human heart-lung transplantation.
We evaluated bronchial responsiveness to inhaled albuterol (salbutamol), ipratropium bromide, methacholine, and propranolol in eight heart-lung transplant (HLT) recipients 2.3 +/- 1.5 months (mean +/- SD) (range, 1 to 4.5 months) after HLT. All patients had a restrictive ventilatory defect but none had airflow limitation (FEV1/FVC = 0.93 +/- 0.05) (range, 0.86 to 0.97). Specific airway conductance (sGaw) improved significantly with both albuterol (p less than 0.01) and ipratropium bromide (p less than 0.01) but FEV1 did not. Only one HLT patient had bronchoconstriction with propranolol, whereas all but one were hyperresponsive to methacholine. Prior inhalation of ipratropium bromide blocked the response to methacholine (p less than 0.005). Serial methacholine provocation tests performed in seven long-term survivors of HLT 24.6 +/- 16.0 months (range, 12 to 51 months) after HLT revealed no time-dependent evolution of bronchial hyperresponsiveness to methacholine. Limited maximal airway narrowing to methacholine was seen in five HLT recipients who showed a 29 +/- 4 percent (range, 23 to 35 percent) fall in FEV1 compared with two patients who did not achieve a plateau with a 47 percent and 63 percent fall in FEV1, respectively. These results further our understanding of bronchial responsiveness in the denervated transplanted lung. The findings of stable hyperresponsiveness to methacholine over a prolonged time interval, limited maximal airway narrowing to methacholine, and blockade of methacholine hyperresponsiveness by ipratropium bromide support the concept of denervation hypersensitivity of muscarinic receptors.
Adult↗
Selection and evaluation of recipients for heart-lung and lung transplantation.
Heart-lung and lung transplantation is being successfully performed with increasing frequency in patients with end-stage cardiopulmonary and pulmonary disease. Transplantation must now be considered as a therapeutic option in selected patients, and physicians are required to understand the principles involved for determining suitable candidates and operative procedures of choice. Indications, contraindications, and choice of operation with respect to underlying disease are discussed herein, as are methods of evaluation and appropriate timing for transplantation. Special considerations regarding specific patient populations are also addressed. In properly selected patients, heart-lung and lung transplantation provide a viable therapeutic option in those with end-stage disease who are unresponsive to conventional management.
Contraindications↗
Obliterative bronchiolitis.
The mass of evidence suggests that OB is a manifestation of allograft rejection in the time period later than that usually associated with acute postoperative rejection. Respiratory infection may serve to amplify (and possibly trigger) this process. A maintenance immunosuppression regimen utilizing cyclosporine A, prednisone, and azathioprine appears to be much more effective than an earlier regimen utilizing only the first two drugs. Aggressive surveillance utilizing prospective measurement of pulmonary function and arterial blood gases and a willingness to look for histologic evidence of OB with the earliest symptomatology has lowered significantly the mortality and the morbidity of this disorder at Stanford and elsewhere. We believe that the current ability to treat and even reverse this serious complication brightens the prospect of heart-lung and lung transplantation for assuming a role in the medical practice of the future.
Adult↗
Improved survival after heart-lung transplantation.
Sixty-two patients underwent 65 heart-lung transplant operations before April 1989. Thirty of these patients (operated on March 1981 to February 1986) were given cyclosporine and prednisone for immunosuppression. These 30 patients (group 1) are compared with the 32 most recent patients (group 2) treated with cyclosporine, prednisone, and azathioprine. Patient characteristics (group 1 versus group 2) were similar including age (mean 32 versus 26 years) and indication for operation (51% versus 38%, primary pulmonary hypertension; 46% versus 45%, Eisenmenger complex; 3% versus 17%, other). The perioperative (in-hospital) mortality rate was 35% in group 1 versus 16% in group 2. Obliterative bronchiolitis developed in 12 (63%) of 19 hospital survivors in group 1 from 2 months to 49 months postoperatively (mean 12 months). This complication has developed in five (20%) of the 25 hospital survivors in group 2 from 3 to 13 months postoperatively (mean 8 months). Overall, 24 of the 30 patients in group 1 died (infection in eight, obliterative bronchiolitis in five, graft coronary artery disease in two, other causes in nine). Eight of the 32 patients in group 2 died (infection in six, other cases in two). Survival rates for group 1 patients were 60% at 1 year, 50% at 2 years, 43% at 3 years, and 25% at 5 years. Survival rates for group 2 patients were 73% at 1 year, 73% at 2 years, and 65% at 3 years (p less than 0.05). When group 2 patients were compared with 134 patients undergoing heart transplantation during the same time period, there was no difference in survival. Routine bronchoscopic surveillance in the more recent group of patients has led to the earlier detection of rejection and infection. In combination with decreased perioperative mortality and augmented immunosuppression, this had led to improved survival in our more recent heart-lung transplant recipients. In addition, the earlier recognition of infection and rejection has led to a decrease in severity of obliterative bronchiolitis.
Adult↗
Physiology of the lung in human heart-lung transplantation.
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Blood Gas Analysis↗
The distribution of MHC class I and II antigens on bronchial epithelium.
The distribution and degree of expression of Class I and Class II major histocompatibility (MHC) antigens on human lower respiratory tract epithelium were evaluated in five freshly obtained pneumonectomy and lobectomy specimens using an immunoperoxidase technique. Multiple sites were examined from each specimen, and two independent observers graded each sample as positive, equivocal, or negative compared with control slides. Interobserver agreement was high. From a total of 120 grade determinations, 114 showed complete concordance and only one showed a positive/negative discordance. Both Class I (HLA-A,B,C) and Class II (HLA-DR) antigens were uniformly and strongly expressed throughout the major, lobar, and segmental bronchi of each sample, the bronchiolar epithelium, and the alveolar epithelium. Paired samples of adjacent lower respiratory tract epithelium harvested with the fiberoptic bronchoscope and during pathologic examination, respectively, revealed an identical staining pattern for these antigens. Staining for HLA-DQ expression (a subset of MHC Class II antigens) was generally weaker and appeared more variable, with four negative, six equivocal, and 30 positive samples. Our observations demonstrate the widespread expression of Class I antigens on airway epithelium and reveal for the first time the ubiquitous nature of Class II MHC antigen (HLA-DR) expression throughout the lower respiratory tract. Furthermore, they attest to the adequacy of bronchoscopically obtained samples for immunologic staining. These results provide a basis for both a putative mechanism of bronchocentric rejection phenomena after human heart-lung transplantation and for the means to monitor it prospectively.
Biopsy↗
Bronchial responsiveness to exercise after human cardiopulmonary transplantation.
Heart-lung transplant (HLT) recipients characteristically display marked bronchial hyperresponsiveness (BHR) to inhaled methacholine, but their bronchial responsiveness (BR) to exercise has not been reported. We measured BR to exercise in 13 stable HLT recipients, 13 normal control (NC) subjects and 13 asthmatic patients (AS). All subjects exercised for eight minutes on a bicycle ergometer at a work level designed to obtain and maintain 80 percent maximum heart rate, or to tolerance. The postexercise fall in FEV1 was equivalent in the HLT group and the NC group (0 +/- 0.2 L vs 0 +/- 0.2 L:p = NS) in contrast to the AS group (-0.6 +/- 0.5 L:p less than 0.01). Stable HLT recipients do not exhibit BHR to exercise at tolerable work loads. This observation supports the hypothesis that BHR to methacholine after HLT is due to denervation hypersensitivity of muscarinic receptors rather than other causes.
Adolescent↗
Evaluation of heart-lung transplant recipients with prospective, serial transbronchial biopsies and pulmonary function studies.
The insidious development of obliterative bronchiolitis after heart-lung transplantation is thought to be due to rejection and possibly infection (cytomegalovirus). To evaluate further, we prospectively managed the last 16 consecutive heart-lung transplant recipients with serial transbronchial biopsies with lavage and pulmonary function studies as part of a surveillance protocol or as dictated by clinical presentation. A total of 123 transbronchial biopsies with lavage were performed, 77 for clinical indications (group I) and 46 for routine surveillance (group II). Results of 64 (83.1%) group I biopsies were positive for rejection or infection. Thirty-one of these biopsy specimens showed signs of rejection (29 in group I and two in group II), characterized by a perivascular mononuclear infiltrate, lymphocytic bronchiolitis, and occasionally alveolar septal mononuclear infiltrate. Forty-six serial pulmonary function tests were performed. The forced expiratory volume in 1 second (percent predicted), forced expiratory flow rate between 25% and 75% of the forced vital capacity (percent predicted), and arterial oxygen tension (millimeters of mercury) were significantly reduced from baseline values during rejection episodes: forced expiratory volume in 1 second, 75.7% +/- 20.1% versus 52.7% +/- 18.3% (p less than or equal to 0.05); forced expiratory flow rate between 25% and 75% of the forced vital capacity, 97.6% +/- 30.5% versus 49.8% +/- 22.3% (p less than or equal to 0.05); and arterial oxygen tension, 92.1 +/- 8.8 mm Hg versus 71.4 +/- 18.8 mm Hg (p less than or equal to 0.05). The fall in pulmonary function was reversible with pulse methylprednisolone. Asynchronous heart and lung rejection was documented. Of the 29 episodes of pulmonary rejection, 18 (62%) occurred asynchronously. Ten of the 16 (62%) heart-lung recipients had at least one episode of cardiac rejection. Thirteen of 16 (81%) had at least one episode of lung rejection. Serial transbronchial biopsies with lavage, as dictated by pulmonary function tests and clinical status, have guided early and more specific therapy directed against rejection and infection. With early detection, small airway dysfunction has been reversible.
Adult↗
Pulmonary infiltrates after heart-lung transplantation: evaluation by serial transbronchial biopsies.
Since January 1988, prospective serial transbronchial lung biopsies have been performed as a diagnostic procedure to facilitate the care of recipients of heart-lung transplants. Eighty-five cardiac and 70 transbronchial lung biopsies have been prospectively performed in 10 patients beginning within the first week of transplantation. Forty-eight percent (34/70) of the transbronchial lung biopsies and 16.5% (14/85) of the heart biopsies were positive for either rejection or infection. Pulmonary rejection was evident by a perivascular lymphocytic infiltrate that cleared with pulse steroid therapy. Pulmonary and cardiac rejection were present synchronously on six occasions and asynchronously on 16 occasions (nine pulmonary and seven cardiac). Four patients had early cytomegalovirus pneumonitis on biopsy specimen and were successfully treated with ganciclovir. Of the 40 clinically indicated biopsies, 29 (72.5%) were positive for rejection or infection and guided subsequent therapy. In summary, transbronchial lung biopsies have provided prompt (within 24 hours) serial diagnostic information that has guided successful treatment of infection (cytomegalovirus, aspergillosis, and Pneumocystis) and rejection. Asynchronous rejection of the heart and lungs has been conclusively demonstrated. With the early detection of rejection and infection, we are optimistic that chronic airway disease in patients with a heart-lung transplant may be reduced.
Adolescent↗
Effect of single respiratory manoeuvres on specific airway conductance in heart-lung transplant recipients.
1. The time course and magnitude of the effect of single slow and rapid respiratory manoeuvres on specific airway conductance (sGaw) was assessed in seven normal control subjects and in seven heart-lung transplant (HLT) recipients before and after experimentally induced bronchoconstriction. 2. Neither full inspiration, full exhalation nor vital capacity manoeuvres significantly altered sGaw in normal controls or HLT recipients under baseline conditions despite the presence of hyper-responsiveness to methacholine (MC) in the latter group. 3. After induced bronchoconstriction, single slow and rapid inspirations to total lung capacity transiently abolished or attenuated the bronchoconstriction in normal controls. This effect was absent in the HLT recipients. 4. In HLT recipients, the combination of hyper-responsiveness to MC, the absence of bronchoconstriction with respiratory manoeuvres and the absence of significant bronchodilatation after deep inspiration suggest lack of normal pulmonary innervation.
Adult↗
Elastic behavior of the transplanted lung. Exponential analysis of static pressure-volume relationships.
We compared indices of muscle strength, parameters of mechanical lung function, and static pressure-volume curves in 12 heart-lung transplant (HLT) recipients to determine whether observed restrictive ventilatory defects represented abnormal elastic behavior of the transplanted lungs. Pressure-volume curves were analyzed using an exponential equation to generate the shape constant K, which describes the nonlinear behavior of pressure-volume relationships over a substantial range. For the group, K was 91% predicted, implying that there was not a diffuse abnormality of elastic properties of the transplanted lungs despite a mean TLC of 80% predicted. However, the mean maximal transpulmonary pressure (PLmax) was significantly low at 23.4 cm H2O (61% predicted) possibly related to the effects of surgery on thoracic cage mobility, but also in keeping with a reduction in power and efficiency of the thoracic musculature. The ability to achieve predicted TLC post-HLT was related to the preservation of optimal inspiratory force as TLC (% predicted) was highly correlated with maximal inspiratory pressure (PImax) (% predicted) (r = 0.83) (p less than 0.001). The ratio (TLC post-HLT)/(TLC pre-HLT) was 1.00 +/- 0.18 (r = 0.82) (p less than 0.005), suggesting donor organs were well matched to recipient chest cavities, but also emphasizing that the recipients had a low TLC prior to HLT. We conclude that the presence of a stable restrictive defect post-HLT is determined primarily by the volumetric constraints of the recipient chest cavity and within these constraints by the strength and efficiency of the thoracic musculature rather than a diffuse intrinsic abnormality of pulmonary elastic properties as a consequence of the transplantation process.
Adolescent↗
Hypoxic pulmonary vasoconstriction persists in the human transplanted lung.
The preservation of hypoxic pulmonary vasoconstriction (HPV) in the denervated lung was studied in five human heart-lung transplant recipients. All five patients showed significant increases in mean pulmonary artery pressure and pulmonary vascular resistance during hypoxic exposure, returning toward normoxic values during recovery. Aside from PAO2 and Pao2, other factors known to influence pulmonary vascular resistance did not change significantly during the hypoxic period. There was no relation between the length of the post-transplantation period and the intensity of HPV, suggesting that reinnervation of the pulmonary vascular bed did not account for persistent HPV and that HPV persists in the human transplanted lung despite the loss of autonomic neural innervation.
Adult↗
Bronchial hyper-responsiveness after human cardiopulmonary transplantation.
1. Bronchial responsiveness to inhaled methacholine was studied in ten heart-lung transplant (HLT) recipients a mean 10.6 months (range 1.5-28 months) post-HLT and in ten normal subjects. 2. The mean provocation dose of methacholine producing a 20% fall in FEV1 (PD20 FEV1) was significantly lower in the HLT recipients (1.70 +/- 3.96 mg vs 11.55 +/- 3.79 mg; P less than 0.001), as was the mean provocation dose of methacholine producing a 50% fall in specific airway conductance (PD50 sGAW) (0.08 +/- 0.08 mg vs 5.13 +/- 5.47 mg; P less than 0.005). 3. These results establish the presence of significant bronchial hyper-responsiveness to inhaled cholinergic agonists in the transplanted lung.
Administration, Inhalation↗
Pulmonary function in advanced pulmonary hypertension.
Pulmonary mechanical function and gas exchange were studied in 33 patients with advanced pulmonary vascular disease, resulting from primary pulmonary hypertension in 18 cases and from Eisenmenger physiology in 15 cases. Evidence of airway obstruction was found in most patients. In addition, mean total lung capacity (TLC) was only 81.5% of predicted and 27% of our subjects had values of TLC less than one standard deviation below the mean predicted value. The mean value for transfer factor (TLCO) was 71.8% of predicted and appreciable arterial hypoxaemia was present, which was disproportionate to the mild derangements in pulmonary mechanics. Patients with Eisenmenger physiology had significantly lower values of arterial oxygen tension (PaO2) (p less than 0.05) and of maximum mid expiratory flow (p less than 0.05) and significantly higher pulmonary arterial pressure (p less than 0.05) than those with primary pulmonary hypertension, but no other variables were significantly different between the two subpopulations. It is concluded that advanced pulmonary vascular disease in patients with primary pulmonary hypertension and Eisenmenger physiology is associated not only with severe hypoxaemia but also with altered pulmonary mechanical function.
Adolescent↗