Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders.
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Animals↗
Biomedical subjects
J P Lynch
Publications and source records attributed to J P Lynch.
Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8.
Obliterative bronchiolitis (OB) is a devastating complication in lung transplantation. We postulated that the pathogenesis of OB is mediated, in part, by neutrophils. We serially collected bronchoalveolar lavage (BAL) fluid from lung transplant recipients. Patients were divided into two groups depending on the presence or absence of OB. Samples from patients who never developed OB were further divided according to whether rejection was present. These samples were labeled healthy or rejection. Samples from patients who developed OB were divided according to whether the sample was obtained before (future OB) or at the time of diagnosis of OB (OB). The OB group, as compared with the healthy and rejection group, had significantly elevated neutrophil counts (3.9 x 10(5) +/- 1.8 x 10(5) vs 0.3 x 10(5) +/- 0.07 x 10(5) and 0.4 x 10(5) +/- 0.1 x 10(5), respectively, p < 0.01 for both) and levels of IL-8 (3131 +/- 1468 pg/ml vs 240 +/- 62 pg/ml and 172 +/- 47 pg/ml, p < 0.01 for both). Furthermore, we demonstrated immunolocalization of IL-8 associated with alpha smooth muscle actin-positive cells in the peribronchial region of OB. To confirm that the IL-8 present in BAL fluid from patients with OB was bioactive, we performed neutrophil chemotaxis experiments that showed that IL-8 accounted for a significant amount of the neutrophil chemotactic activity. We also found a trend toward higher levels of neutrophils and IL-8 in BALs from the future OB as compared with the healthy group (7.1 x 10(4) +/- 4.2 x 10(4) vs 3.4 x 10(4) +/- 0.7 x 10(4) and 500 +/- 306 pg/ml vs 240 +/- 62 pg/ml). In conclusion, we have provided the novel observation that in lung transplant recipients with OB, neutrophilia is present and highly correlated with the presence of IL-8.
Bronchiolitis Obliterans↗
Restricted V beta usage by T cells infiltrating rejecting human lung allografts.
TCR expression was evaluated in lung transplant patients to determine whether T cells infiltrating rejecting lung allografts employed restricted V beta elements. Serial bronchoalveolar lavage (BAL) specimens were obtained from six lung transplant recipients at approximately 3 wk, 6 wk, and 3 mo post-transplant. T cell lines were established by culturing lavage cells with irradiated donor splenocytes in the presence of low dose IL-2 for 3 wk, and TCR V beta usage was determined by quantitative reverse transcriptase-PCR. Patients were grouped into three categories based on TCR V beta profiles and the clinical status of the allograft. 1) In one patient, BAL-derived T cells expressed heterogeneous V beta repertoires at all time points evaluated. This patient did not experience graft rejection during the 16-mo period of observation, though respiratory infections were diagnosed. 2) In three patients, V beta usage by BAL-derived T cells was restricted during allograft rejection episodes, but was heterogeneous in the absence of rejection and during respiratory infections. In one of these patients, similar V beta repertoires were employed by BAL cells during multiple rejection episodes. 3) In two patients, restricted V beta usage by BAL-derived T cells was observed before and during rejection episodes. Collectively, these data illustrate that human lung allograft rejection, but not pulmonary infection, is associated with T cells expressing a limited number of V beta families. Restricted V beta usage by graft-reactive T cells may allow for the selective elimination of these cells using TCR-specific reagents, thereby promoting allograft-specific tolerance.
Bronchoalveolar Lavage Fluid↗
Lung transplantation in chronic airflow limitation.
Lung transplantation is an option for appropriately selected patients with end-stage chronic airflow limitation. The functional results have been excellent after single or bilateral lung transplantation, and the medium-term survival results have been good. Obliterative bronchiolitis, however, thought to be a manifestation of chronic rejection, occurs in approximately 40% of recipients, and it is the major cause of late morbidity and mortality in lung transplant recipients.
Contraindications↗
Lung mechanics and dyspnea after lung transplantation for chronic airflow obstruction.
Single lung transplantation (SLT) is widely used to treat chronic airflow obstruction (CAO). During exercise the native lung should increase end-expiratory lung volume (EELV) and result in a different respiratory sensation compared with double lung transplantation (DLT). Eight SLT recipients and 12 DLT recipients demonstrated a similar maximal work load and achieved VO2. VEmax/MVV was 67.2 +/- 4.0% in SLT recipients and 48.5 +/- 3.6% in DLT recipients (p = 0.003). All SLT recipients demonstrated an increase in EELV during exercise, which was seen in only three of 12 DLT recipients. The change in absolute EELV from rest to peak exercise was different between SLT recipients (+0.37 +/- 0.10 L) and DLT recipients (-0.10 +/- 0.06, p = 0.0002). Tidal flow volume loop analysis demonstrated encroachment of the expiratory limb in four of seven SLT patients but in only one of 12 DLT recipients. A lesser peak breathlessness in DLT recipients approached statistical significance (p = 0.051), although the relation of respiratory sensation versus VE or VO2% predicted did not differ between the two groups. EELV increases in SLT recipients at peak exercise, although overall aerobic response is preserved and respiratory sensation is similar.
Dyspnea↗
Wegener's granulomatosis in the elderly.
STUDY OBJECTIVE: To determine if elderly patients with Wegener's granulomatosis (WG) exhibit distinctive clinical features or outcomes compared with patients whose conditions were diagnosed at younger ages. DESIGN: Retrospective cohort study. SETTING: University medical center. PATIENTS: Thirty-three patients with WG diagnosed when 60 years old or older and 34 patients with WG diagnosed at age younger than 60 years, identified by record review of all WG patients seen over an 11-year period. RESULTS: The prevalence of specific clinical features, progression to end-stage renal disease, mortality rate, and infectious and noninfectious complications of therapy were examined. The prevalence of upper respiratory tract involvement (rhinitis, sinusitis, otitis, epistaxis) and hemoptysis were significantly less common as initial manifestations in the elderly patients, although pulmonary infiltrates were seen more commonly during the course of their disease. Renal insufficiency was more common at the time of diagnosis in the elderly patients (64% vs 35%; p < 0.05). Most notably, CNS involvement was 4.5-fold more common in elderly patients (27% vs 6%; p = 0.02). The overall incidence of infectious and noninfectious complications of therapy was similar between the groups, although the mortality rate was markedly higher in the elderly patients (54% vs 19%; p < 0.01). Almost all deaths were due to overwhelming infection. CONCLUSIONS: Elderly patients with WG present with distinctive clinical features, particularly a relatively low incidence of upper respiratory tract complaints and a high incidence of CNS involvement. The mortality risk from infectious complications of WG is substantially higher in elderly patients, although this cannot be attributed directly to adverse affects of therapy.
Aged↗
Transthoracic needle aspiration in patients with severe emphysema. A study of lung transplant candidates.
PURPOSE: To describe the risks of transthoracic needle aspiration (TTNA) in a population of patients with severe lung disease: candidates for lung transplantation. MATERIALS AND METHODS: Eight of 190 patients evaluated for lung transplantation underwent TTNA of nine pulmonary nodules (mean diameter, 14 mm; range, 0.8 to 2.2 cm). We evaluated pneumothorax rate, chest tube rate, duration of placement, and pulmonary function test results. RESULTS: All patients had emphysema; two had alpha 1-antitrypsin deficiency. The mean FEV1 of all patients was 0.64 L (22% of predicted; range, 17 to 28%), indicating severe air-flow obstruction. Six patients required a chest tube (50%); three chest tubes were placed emergently on the CT scanner table. Three patients required a second chest tube for persistent air leak. Tubes were in place for 1 to 22 days (mean, 10 days). One patient had chest tubes for 22 days and required intubation. CONCLUSION: TTNA in patients with marked emphysema is complicated by a high incidence of pneumothorax, rapid development of tension pneumothorax and chest tube placement. Since nodules in lung transplant candidates may represent bronchogenic carcinoma, serial CT scans to demonstrate lesion stability or growth, or thoracoscopic resection should be considered as an alternate approach to TTNA to avoid the significant morbidity of the procedure in these patients.
Adult↗
High-dose etoposide, cyclophosphamide and total body irradiation with allogeneic bone marrow transplantation for resistant acute myeloid leukemia: a study by the North American Marrow Transplant Group.
We evaluated the toxicity and efficacy of high-dose etoposide, cyclophosphamide and total body irradiation (TBI) followed by allogeneic bone marrow transplantation (BMT) for patients with resistant, acute myeloid leukemia (AML). Between 9/84 and 11/92 we treated 70 patients with etoposide (900-1800 mg/m2), cyclophosphamide (120-180 mg/kg) and TBI (1000-1200 cGy) followed by allogeneic BMT from histocompatible siblings. Forty patients were in untreated first relapse. Median time from diagnosis to transplant was 10 months. Toxicity was similar to that observed with cyclophosphamide/TBI with the median duration of neutropenia (ANC < 500/microliters) being 19 days (range 10-27) and the median duration of thrombocytopenia being 23 days (range 13-173). Twenty-three patients remain in continuous complete remission at a median of 56 months after transplant (range 36-132 months). Probabilities of disease-free survival, persistent/recurrent disease and transplant related mortality are .32, .47, and .37 respectively. Multivariate analysis indicated that grade > or = 2 acute graft-vs-host disease and transplant in untreated first relapse were associated with increased DFS due to reduced relapse risk. We conclude that high-dose etoposide with cyclophosphamide and TBI followed by allogeneic BMT is effective therapy for resistant AML, producing durable remission in approximately one-third of those treated. Disease persistence or recurrence was the major cause of treatment failure. Further improvement in DFS following allogeneic BMT for resistant AML might be achieved by using less intensive GVHD prophylaxis or through infusion of donor peripheral blood cells in patients who fail to develop significant acute GVHD.
Acute Disease↗
High-dose etoposide, cyclophosphamide, and total body irradiation with allogeneic bone marrow transplantation for patients with acute myeloid leukemia in untreated first relapse: a study by the North American Marrow Transplant Group.
Relapse is a major cause of treatment failure following allogeneic bone marrow transplantation (BMT) for acute myeloid leukemia (AML). To reduce the risk of relapse following BMT for patients with hematologic malignancy, our group developed a novel preparative regimen which combines high-dose etoposide with cyclophosphamide and total body irradiation (VPCyTBI). We now report the outcome of therapy with VPCyTBI followed by allogeneic BMT for 40 patients with AML in untreated first relapse. With the exception of increased stomatitis, the toxicity of this regimen was similar to that reported by others for CyTBI. Forty-four months after transplant the actuarial probabilities of disease-free survival (DFS), persistent or recurrent leukemia, and transplant related mortality were .29, .44, and .47 respectively. DFS was improved (P < .01) and risk of persistent or recurrent leukemia reduced (P = .005) among patients with significant (grade > or = 2) acute GVHD. Patients with 30% or more blasts on pre-BMT bone marrow examination were not at increased risk for persistent or recurrent leukemia. We conclude that VPCyTBI with allogeneic BMT is effective therapy for AML in untreated first relapse and that a randomized trial comparing this regimen with CyTBI is warranted.
Actuarial Analysis↗
Influence of sample number and biopsy site on the histologic diagnosis of diffuse lung disease.
BACKGROUND: Although open biopsy is considered the optimal method for obtaining lung tissue for the diagnosis of diffuse infiltrative pulmonary disorders, there are no universally established guidelines concerning biopsy site selection and the ideal number of tissue samples. Relatively few investigations have been devoted to the influence exerted by the site and number of biopsy samples on the histologic diagnosis. METHODS: Seventy-seven open biopsy samples obtained from different lobes of 28 patients with idiopathic pulmonary fibrosis were analyzed. The histopathologic features were evaluated semiquantitatively and the results from each sample compared with those of the other samples obtained from each patient. RESULTS: Statistically significant differences in histopathologic features were not observed between samples. CONCLUSIONS: A single generous (2 cm or greater diameter) sample, obtained from a representative region of the radiographically most involved lobe, will suffice for diagnostic and evaluation purposes.
Adult↗
Immunosuppressive treatment of the pulmonary manifestations of progressive systemic sclerosis.
In this article, we review recent studies on the use of immunosuppressive agents in autoimmune diseases, especially cyclophosphamide. In addition, we begin with a special section on the treatment of scleroderma lung disease, including controversies regarding the indications for immunosuppressive therapy. Scleroderma lung disease is justifiably regarded as one of the "frontiers of medicine" because of its gravity, its often rapidly progressive nature, and the urgency with which improved therapy is needed.
Autoantibodies↗
Stenosis of the central airways: evaluation by using helical CT with multiplanar reconstructions.
PURPOSE: To assess the accuracy of helical computed tomography (CT) with multiplanar reconstructions (MPRs) in the evaluation of stenoses of the central airways. MATERIALS AND METHODS: Thin-section axial CT and helical CT with MPRs were used to examine the central tracheobronchial tree for the presence of stenosis in 27 patients who underwent lung transplantation and 17 nontransplantation patients. The findings from these modalities were then compared with the findings obtained at conventional tomography and bronchoscopy, when available. RESULTS: Axial CT alone was 91% accurate in depicting stenosis, CT with MPRs was 94% accurate, and conventional tomography was 89% accurate in the evaluation of bronchial anastomosis in transplant recipients. CT and CT scans with MPRs were each 91% accurate in depicting stenosis in nontransplantation patients; the single false-negative finding showed focal tracheomalacia at bronchoscopy. CONCLUSION: CT with MPRs may be more accurate than thin-section axial CT in the demonstration of mild stenosis, the length of a stenosis, and horizontal webs.
Anastomosis, Surgical↗
Increased interleukin-1 receptor antagonist in idiopathic pulmonary fibrosis. A compartmental analysis.
Idiopathic pulmonary fibrosis (IPF) is a poorly understood interstitial disease that usually proves refractory to therapy and results in irreversible tissue scarring and pulmonary dysfunction. Previous investigations have suggested a number of possible mediators of inflammation and fibrosis that typify IPF. We report increases in lung interleukin-1 receptor antagonist protein (IRAP) content in patients with IPF, as compared with normal control subjects. Importantly, this increase in IRAP was not accompanied by concomitant increases in interleukin-1 beta (IL-1 beta), resulting in a local environment that may be profibrotic. Tissue homogenates and bronchoalveolar lavage fluid from patients with IPF both demonstrate elevated IRAP content compared with that in normal subjects. Immunohistochemical staining and in situ hybridization localize IRAP to hyperplastic type II pneumocytes, macrophages, and local stromal cells. Finally, in vitro studies utilizing fibroblasts isolated from patients with IPF demonstrated no difference in constitutive IRAP production compared with that in normal subjects, but they revealed an exaggerated response to stimulation with transforming growth factor-beta (TGF-beta). These findings suggest that the fibrotic tissue changes of IPF and possibly other chronic interstitial lung diseases may result in part from the local effects of IRAP, and they also demonstrate that pulmonary nonimmune cells may influence local tissue changes through the elaboration of IRAP.
Bronchoalveolar Lavage Fluid↗
Cardiopulmonary exercise testing following allogeneic lung transplantation for different underlying disease states.
OBJECTIVES: To assess the exercise response to single lung transplantation in chronic airflow obstruction (CAO), idiopathic pulmonary fibrosis (IPF), and pulmonary vascular disease (PVD) vs double lung transplantation at well-defined time points after transplantation, and to define the change in exercise response in SLT and DLT over the first year after transplantation. DESIGN: Prospective study. SETTING: Tertiary referral hospital. PATIENTS: Fourteen stable SLT recipients (6 with CAO, 4 with IPF, 4 with PVD) and 11 stable DLT recipients. MEASUREMENTS: Spirometry, lung volumes, diffusion lung capacity for carbon monoxide (DLco) and MVV measured prior to exercise at 3 months (n = 25) then at 3-month intervals up to a maximum of 12 months post-transplantation (n = 18 [12 SLT and 6 DLT]). Symptom-limited cardiopulmonary exercise tests at same time points (n = 25 at 3 months, n = 18 [12 SLT and 6 DLT] at 3-month intervals up to 12 months). Breathlessness was estimated by visual analogue scale prior to exercise and at peak exercise. RESULTS: At 3 months, FEV1 percent predicted was lower for SLT-CAO and SLT-IPF vs DLT (p < or = 0.05). Mean FEV1/FVC was lower for SLT-CAO vs all other groups (p < or = 0.05). The FVC, MVV, and DLco/VA were similar for all groups. The TLC and RV were higher for the SLT-CAO group compared with all others. The TLC was lower for SLT-PVD compared with DLT. Exercise responses were similar in all groups studied without a statistically significant difference in achieved VO2, work rate, O2 pulse, anaerobic threshold, heart rate response, respiratory rate, VE/MVV, and VT/VC. The change in O2 saturation during exercise was the least in recipients of DLT. Maximal achieved VO2 rose from 3 to 6 months after SLT but dropped by 9 to 12 months after transplantation. Maximal achieved VO2 trended up from 3 to 6 months after DLT but dropped by 9 to 12 months after transplantation. Maximal achieved work rate rose in both SLT and DLT from 3 to 9 to 12 months after transplantation. There was no significant difference in breathlessness at rest and peak exercise measured between recipients of SLT or DLT. CONCLUSIONS: Minor differences in pulmonary function and change in O2 saturation occur between recipients of SLT and DLT during the first posttransplant year. These differences are most pronounced when comparing SLT-CAO with DLT. However, there is no significant difference in exercise capacity between SLT for CAO, IPF, PVD, and DLT. The rise in maximum achieved VO2 over the first 6 months after transplantation may reflect the effects of exercise training and should be taken into account when examining aerobic response after transplantation.
Anaerobic Threshold↗
The sensitivity of high-resolution CT in detecting idiopathic pulmonary fibrosis proved by open lung biopsy. A prospective study.
OBJECTIVES: To assess the sensitivity of high-resolution chest computed tomography (HRCT) in detecting idiopathic pulmonary fibrosis proved by biopsy specimen. To determine the degree of physiologic and pathologic abnormalities in patients with idiopathic pulmonary fibrosis who have a false-negative HRCT. DESIGN: Prospective 2-year study. SETTING: Tertiary care university hospital. PATIENTS: All patients with dyspnea and suspected interstitial lung disease referred to the University of Michigan for enrollment in the Idiopathic Pulmonary Fibrosis Specialized Center of Research (SCOR) protocol were included; 25 underwent open lung biopsy and formed the final study group. MEASUREMENTS: All patients underwent physiologic (pulmonary function, gas exchange, and exercise testing), radiologic (chest x-ray film and HRCT), and pathologic assessments (bronchoscopic and open lung biopsy). The results of HRCT were prospectively compared with results of standard pulmonary function tests, cardiopulmonary exercise testing, and open lung biopsy. RESULTS: Of 25 patients who had both HRCT and open lung biopsy, 3 patients (12%) had HRCTs that demonstrated no evidence of interstitial lung disease. These three patients had less severe disease based on clinical, radiographic, and physiologic (CRP) scores, gas exchange abnormalities, and pathologic scoring of open lung biopsy specimens, compared with those with an abnormal HRCT. CONCLUSION: We conclude that in the evaluation of patients with dyspnea and abnormal results of pulmonary function studies, a normal HRCT does not exclude early and clinically significant interstitial lung disease. In our patient population, physiologic testing was more sensitive than HRCT in detecting mild abnormalities in patients with idiopathic pulmonary fibrosis proved by biopsy specimen.
Adult↗
Preoperative examination of lung transplant candidates: value of chest CT compared with chest radiography.
OBJECTIVE: The purpose of our study was to determine the usefulness of CT in examining candidates for lung transplantation to detect cancer not visible on plain chest radiographs (a finding that would exclude a patient from transplantation) and to determine which lung is more severely diseased to aid in the decision of which side to transplant. MATERIALS AND METHODS: We reviewed the chest radiographs and CT scans of 190 transplant candidates during a 3-year period for findings suggestive of neoplasm, including lung nodules and atelectasis; we also reviewed the symmetry of disease. In the latter category, patients with primary pulmonary hypertension, Eisenmenger's complex (pulmonary vascular, not parenchymal, disease), and cystic fibrosis (for which bilateral transplantation is performed) were excluded. A total of 190 plain chest radiographs, 180 thin-section CT scans, and 31 standard CT scans were reviewed retrospectively. RESULTS: Plain chest radiographs revealed 20 noncalcified nodules; 13 were 8 mm or more in diameter, and 7 were less than 8 mm. CT scans revealed 66 noncalcified nodules; 37 were 8 mm or more in diameter, and 29 were less than 8 mm. Eight non-calcified nodules seen on plain chest radiographs were either absent on CT scans (and follow-up plain chest radiographs) or appeared calcified on CT scans. Solitary nodules in three patients proved to be bronchogenic carcinomas; two of these lesions were identified only on CT scans. CT prompted a change in the determination of which lung was more severely diseased from that made on the basis of plain radiography for 27 of 169 patients (16%) evaluated. Of the 45 patients who subsequently underwent transplantation, CT prompted a change in the determination of which side to transplant from that made on the basis of plain radiography for 4 patients (9%). CONCLUSION: CT provides additional information to supplement plain radiography in the examination of lung transplant candidates. This information can alter patient management, particularly when bronchogenic carcinoma is detected, and enable a better determination of which lung is more severely diseased to aid in the decision of which lung to transplant for single-lung transplantation.
Adolescent↗
Selective lung or heart-lung transplantation for pulmonary hypertension associated with congenital cardiac anomalies.
Fixed pulmonary hypertension has been a contraindication to correction of congenital heart defects. Beginning in February 1991, we pursued a policy of performing single-lung transplantation with intracardiac repair for selected patients with this physiology, reserving heart-lung transplantation for those with unreconstructable heart disease. Of 7 patients treated under this protocol, 5 underwent single-lung transplantation and intracardiac repair. The cardiac anomalies included complete atrioventricular canal (1), aortopulmonary window (1), atrial septal defect (1), and ventricular septal defect (2). One patient died perioperatively. All 4 patients surviving operation remained alive through the first postoperative year, but 3 died 13, 17, and 22 months after operation. Two other patients with pulmonary hypertension (1 with tricuspid atresia, 1 after failed Mustard procedure) received a heart-lung transplant and are well 15 and 18 months after operation. This experience demonstrates that selected patients with major intracardiac defects and pulmonary hypertension may have good early results after cardiac repair and single-lung transplantation, but that long-term results are considerably less favorable.
Adolescent↗