Correlation of lung surface area to apoptosis and proliferation in human emphysema.

Pulmonary emphysema is associated with alterations in matrix proteins and protease activity. These alterations may be linked to programmed cell death by apoptosis, potentially influencing lung architecture and lung function. To evaluate apoptosis in emphysema, lung tissue was analysed from 10 emphysema patients and six individuals without emphysema (normal). Morphological analysis revealed alveolar cells in emphysematous lungs with convoluted nuclei characteristic of apoptosis. DNA fragmentation was detected using terminal deoxynucleotide transferase-mediated dUTP nick-end labelling (TUNEL) and gel electrophoresis. TUNEL revealed higher apoptosis in emphysematous than normal lungs. Markers of apoptosis, including active caspase-3, proteolytic fragment of poly (ADP-ribose) polymerase, Bax and Bad, were detected in emphysematous lungs. Linear regression showed that apoptosis was inversely correlated with surface area. Emphysematous lungs demonstrated lower surface areas and increased cell proliferation. There was no correlation between apoptosis and proliferation, suggesting that, although both events increase during emphysema, they are not in equilibrium, potentially contributing to reduced lung surface area. In summary, cell-based mechanisms associated with emphysematous parenchymal damage include increased apoptosis and cell proliferation. Apoptosis correlated with airspace enlargement, supporting epidemiological evidence of the progressive nature of emphysema. These data extend the understanding of cell dynamics and structural changes within the lung during emphysema pathogenesis.

Four-year prospective study of pulmonary venous thrombosis after lung transplantation.

The objective of this study was to prospectively assess pulmonary venous anastomosis by transesophageal echocardiography after lung transplantation. Thrombus formation at the pulmonary venous anastomotic site after lung transplantation may have catastrophic consequences, including allograft failure and stroke. Eighty-seven consecutive adult lung transplant recipients underwent transesophageal echocardiography within 48 hours after surgery. Thrombosis of a pulmonary vein was diagnosed in 13 (15%) of 87 patients in the early postoperative period after lung transplantation. Mean thrombus width was 0.9 +/- 0.4 cm (range, 0.5 to 1.7 cm), with an average peak flow velocity at the site of obstruction of 127 +/- 23 cm/s (range, 90 to 150 cm/s). Five patients with pulmonary vein thrombosis died in the perioperative period, yielding a 90-day mortality rate of 38%. Larger thrombus size and greater acceleration of flow through a narrowed pulmonary vein correlated with poor clinical outcome. During each year of the study, the incidence of pulmonary vein thrombosis declined progressively. Pulmonary vein thrombosis is a potentially ominous complication in the early postoperative period after lung transplantation. Transesophageal echocardiography is a valuable tool for detecting abnormalities of the pulmonary venous anastomosis. Thrombus size and flow velocity at the anastomotic site may guide prognosis and clinical management. Complications of the pulmonary venous anastomosis are in part technical in nature.

Human collagenase (matrix metalloproteinase-1) expression in the lungs of patients with emphysema.

Pulmonary emphysema is believed to result from an imbalance between proteolytic enzymes and their inhibitors. Multiple studies have examined the presence of various proteases within the bronchoalveolar lavage fluid from patients with chronic obstructive pulmonary disease (COPD). However, to date extensive examination of the lung parenchyma for the expression of destructive enzymes has not yet been determined. The following study examines the lung parenchyma of 23 patients with emphysema and 8 normal control samples for the expression of matrix matalloproteinase-1 (MMP-1), MMP-12, and MMP-9. We report here that interstitial collagenase (MMP-1) RNA, protein, and activity are present in the lung parenchyma of patients with emphysema and not in the lung of normal control subjects. In contrast, metalloelastase (MMP-12) expression is absent in these samples. Immunohistochemistry studies localized MMP-1 to the Type II pneumocyte in patients with emphysema and not normal control subjects or smokers without emphysema. This observation demonstrates that the lung is altered in emphysema such that the Type II pneumocyte secretes MMP-1 and suggests that MMP-1 may be an important enzyme involved in the destruction of the lung in the human disease. In addition, the induction of a proteolytic enzyme within the Type II pneumocyte suggests that the cells within the lung itself are capable of producing degradative enzymes in this disease process.

Influence of donor and recipient HLA locus mismatching on development of obliterative bronchiolitis after lung transplantation.

Obliterative bronchiolitis (OB) after lung transplantation is the end result of multiple immunologic, virologic, genetic, and environmental effects on the transplanted lung. In this study, we first analyzed risk factors for OB in a single-center population of 152 lung transplant recipients. We then examined the influence of donor and recipient HLA mismatching on progression to OB, and on the identified risk factors for OB. The median time to onset of OB for the entire study population was 2.7 yr. The significant risk factors for OB by multivariate analyses were grade A2 or A3 acute rejection (p = 0.0126) and cytomegalovirus (CMV) pneumonitis (p = 0.0358). The only significant HLA risk factor for OB was mismatching at the HLA-A locus (p = 0.0144). On the basis of Cox proportional hazards modeling, a predictive formula was derived to estimate the risk of OB after lung transplantation. Although mismatching at the HLA-DR locus was a significant risk factor for CMV pneumonitis in recipients exposed to CMV before transplantation (p = 0.0199), and protected against acute rejection, it did not independently protect against OB. These results indicate that HLA mismatches between donors and recipients significantly influence the development of OB both directly, and indirectly, by influencing the major risk factors for OB.

Superiority of end-to-end versus telescoped bronchial anastomosis in single lung transplantation for pulmonary emphysema.

OBJECTIVE: To assess the influence of surgical technique (telescoped versus end-to-end anastomosis) on the incidence of bronchial anastomotic complications in patients who underwent single lung transplantation for pulmonary emphysema. METHODS: Seventy-six adult recipients of single lung transplants for pulmonary emphysema were evaluated for the presence of 3 types of major bronchial anastomotic complications: ischemia, dehiscence, and severe stenosis. Surgical technique, clinical course, and mortality were reviewed retrospectively. RESULTS: The 3 major complications were observed in 11 (34%; ischemia), 8 (25%; dehiscence), and 11 (34%; severe stenosis) of 32 telescoped bronchial anastomoses. In contrast, ischemia, dehiscence, and severe stenosis occurred in only 4 (9%), 1 (2%), and 2 (5%) of 44 end-to-end anastomoses (P =.0087, P =.0034, and P =.0012, respectively). The relative risk of ischemia, dehiscence, and severe stenosis in telescoped anastomoses was 2.1, 2.5, and 2.5, respectively, compared with end-to-end anastomoses. Five (13%) telescoped anastomoses required stent placement as compared with only 2 (5%) end-to-end anastomoses (P =.1244). Early postoperative pneumonia was more common in the telescoped anastomosis group (56%) than in the end-to-end group (32%; P =.0380). There was a trend toward shorter survival in the telescoped anastomosis group (mean survival 1045 +/- 145 days) as compared with the end-to-end group (mean survival 1289 +/- 156 days), but these differences did not achieve statistical significance (P =.2410). CONCLUSIONS: In patients who underwent single lung transplantation for pulmonary emphysema, telescoped anastomoses were associated with a higher incidence of bronchial anastomotic complications than end-to-end anastomoses.

Pulmonary nodules and masses after lung and heart-lung transplantation.

The authors assess clinical and radiographic findings of pulmonary nodules and masses after lung and heart-lung transplantation. One hundred and fifty nine patients who survived at least 3 months after lung and heart-lung transplantation were followed by serial chest radiographs for a median of 27 months. Single or multiple lung nodules or masses were noted at chest radiography in 15 (9.4%) of 159 patients. Imaging findings and causes of these nodules and masses were reviewed retrospectively. Infection was found in 10 (6%) of 159 patients. Specific pathogens (11 pathogens in 10 patients) were Aspergillus (n = 4), Mycobacteria (n = 4), and other bacteria (n = 3). Noninfectious causes were found in 5 (3%) of patients and included B-cell lymphoma (n = 2), bronchogenic carcinoma (n = 2), and pulmonary infarcts (n = 1). Nodules and masses appeared a median of 11 months after transplantation (range: 0.2 to 36 months). Five patients (33%) had single lesions; the other 10 (67%) patients had multiple lesions (range 2 to 50). Aspergillus lesions were most commonly located in the upper lobes, were cavitary in three of four patients, and all were fatal. Nodules and masses arose in the transplanted lung in 12 (80%) of the patients, and in the native lung in 3 (20%) of the patients (2 bronchogenic carcinoma, 1 M. tuberculosis simulating bronchogenic carcinoma). Nodules and masses detected by chest radiography are not uncommon (9.4%) after lung and heart-lung transplantation. Infections are more common than noninfectious causes of posttransplant nodules and masses. Specific clinical and imaging characteristics may provide clues to etiology.

Deleterious effects of telescoped bronchial anastomosis in single and bilateral lung transplantation.

PURPOSE: To compare complication rates of telescoped versus end-to-end bronchial anastomoses in single and bilateral lung transplantation. METHODS: One hundred and thirty adult lung transplant recipients were evaluated during a seven-year period for the presence of three types of major bronchial anastomotic complications (ischemia, dehiscence, and severe stenosis). Surgical technique, clinical course, and mortality in all patients were reviewed retrospectively. RESULTS: The three major complications, ischemia, dehiscence, and severe stenosis, were observed in 13 (32%), 10 (24%), and 13 (32%), respectively, of 41 telescoped bronchial anastomoses. In contrast, ischemia, dehiscence, and severe stenosis, occurred in 25 (19%), 14 (10%), and 11 (8%) of 135 end-to end anastomoses. These differences were statistically significant for the occurrence of dehiscence and severe stenosis (p=0.0350 and 0.0004, respectively), and not statistically significant for ischemia (p=0.0846). Five (12%) telescoped anastomoses required stent placement as compared with six (4%) end-to end anastomoses (p=0.1313). Early postoperative pneumonia was more common in the telescoped anastomosis group (57%) as compared to the end-to-end group (35%; p=0.0271). There was a trend to shorter survival in the telescoped anastomosis group (mean survival 1172+/-149 d) as compared to the end-to-end group (mean survival 1542+/-126 d), but these differences did not achieve statistical significance (p=0.2400). CONCLUSION: In single and bilateral lung transplants, telescoped anastomoses are associated with a higher incidence of bronchial anastomotic complications and postoperative pneumonia than end-to-end anastomoses.

Development and evaluation of the PRIME plume rise and building downwash model.

A new Gaussian dispersion model, the Plume Rise Model Enhancements (PRIME), has been developed for plume rise and building downwash. PRIME considers the position of the stack relative to the building, streamline deflection near the building, and vertical wind speed shear and velocity deficit effects on plume rise. Within the wake created by a sharp-edged, rectangular building, PRIME explicitly calculates fields of turbulence intensity, wind speed, and streamline slope, which gradually decay to ambient values downwind of the building. The plume trajectory within these modified fields is estimated using a numerical plume rise model. A probability density function and an eddy diffusivity scheme are used for dispersion in the wake. A cavity module calculates the fraction of plume mass captured by and recirculated within the near wake. The captured plume is re-emitted to the far wake as a volume source and added to the uncaptured primary plume contribution to obtain the far wake concentrations. The modeling procedures currently recommended by the U.S. Environmental Protection Agency (EPA), using SCREEN and the Industrial Source Complex model (ISC), do not include these features. PRIME also avoids the discontinuities resulting from the different downwash modules within the current models and the reported overpredictions during light-wind speed, stable conditions. PRIME is intended for use in regulatory models. It was evaluated using data from a power plant measurement program, a tracer field study for a combustion turbine, and several wind-tunnel studies. PRIME performed as well as or better than ISC/SCREEN for nearly all of the comparisons.

Short air bubble in the gastric fundus during fasting: radiographic sign of gastroparesis after lung transplantation.

This study was undertaken to assess whether gastroparesis, as a chronic complication of lung transplantation, correlates with height of the gastric air bubble on chest radiographs of erect fasting subjects. Height of the gastric air bubble and presence or absence of a gastric air-fluid level were assessed on chest radiographic examinations (posteroanterior, lateral, upright position, during fasting, immediately after bronchoscopy, median 148 days after transplantation) obtained on 3 separate days for each of 19 recipients of lung transplantation. Seven of the subjects (five women, two men) had chronic upper gastrointestinal symptoms after transplantation and a confirmed diagnosis of gastroparesis. The gastroparesis was idiopathic in six of the subjects and associated with cytomegalovirus gastritis in one subject. The other 12 subjects, each without upper gastrointestinal symptoms, served as controls. Median height of the gastric air bubble was significantly less in the gastroparetic (2.8 cm; range, 1.0-4.6 cm) than in the control (4.7 cm; range, 1.0-12.4 cm) group (p<0.05). Height of the gastric air bubble was at most 4.6 cm among the seven gastroparetic subjects, whereas it exceeded 5.0 cm on at least one occasion in 8 (67%) of the 12 control subjects (p<0.005). The likelihood of a gastric air-fluid level was 86% for symptomatic subjects and 25% for the control group (p<0.01). When lung transplantation is complicated by chronic gastroparesis, postbronchoscopic chest radiographic examinations of fasting subjects are associated with a gastric air bubble limited to high in the fundus, usually including a fluid level.

Influence of lung injury on early postoperative survival after lung transplantation.

OBJECTIVES: To identify the various risk factors for early (90 day) mortality after lung transplantation and to evaluate the relationship between lung injury and postoperative survival. METHODS: 152 recipients of single (100) or bilateral (52) lung allografts were evaluated for the presence of postoperative lung injury assessed by a composite four-component lung injury score. Preoperative variables, postoperative course, and mortality were reviewed retrospectively. RESULTS: There was a high risk of death during the first 90 d after transplantation, followed by a decline in risk during the remainder of the first postoperative year. By univariate analysis, lung injury score (p = 0.0001), chest radiograph score (p = 0.0001), and hypoxemia (PaO2/FIO2) ratio (p = 0.0002) were the most statistically significant risk factors for 90-day mortality. Other parameters such as length of intensive care stay (p = 0.0175), length of intubation (p = 0.0212), and preoperative diagnosis of pulmonary fibrosis (p = 0.0123) were also significant risk factors for 90-day mortality. By multivariable analysis, only lung injury score (p = 0.0001) was a statistically significant risk factor for 90-day mortality. The risk of 90-day mortality increased by a factor of 4.4 for each 1 point increment in lung injury score. However, none of the analyzed preoperative or postoperative variables were able to statistically predict lung injury score. CONCLUSIONS: Postoperative lung injury is the most important risk factor for early postoperative mortality after lung transplantation.

Lung transplantation for chronic obstructive pulmonary disease.

Lung transplantation is able to provide dramatic gains in pulmonary function to patients with advanced pulmonary emphysema. At the present time, however, transplantation is available to a strictly defined pool of candidates, and outcomes are limited by numerous respiratory and nonrespiratory postoperative complications. Further progress is needed in expanding the supply of donor lungs, minimizing perioperative complications, and optimizing postoperative immunologic management.

Bone loss and fracture after lung transplantation.

BACKGROUND: Osteoporosis is very common in patients with end-stage pulmonary disease. However, there are few prospective data on fracture incidence after lung transplantation. METHODS: We prospectively evaluated changes in bone mass, fracture incidence, and biochemical indices of bone and mineral metabolism in 30 patients who completed 1 year of observation after lung transplantation. All received calcium, vitamin D, and therapy with one or more agents that inhibit bone resorption, initiated shortly after transplantation. RESULTS: Before transplantation, only 20% of the patients had normal lumbar spine (LS) and femoral neck bone mineral density (BMD). After transplantation, 15 patients (50%) sustained significant bone loss at either the LS (-8.6+/-1.0%) or the femoral neck (-11.3+/-2.2%). Eleven (37%) patients (10 women) sustained a total of 54 atraumatic fractures. Pretransplantation LS BMD and T scores were significantly lower in those who sustained fractures (-2.809+/-0.32 versus -1.569+/-0.29; P<0.01). Fracture patients were more likely to have had pretransplantation glucocorticoid therapy (chi-square 5.687; P<0.02). The duration of pretransplantation glucocorticoid therapy was also longer in fracture patients (4.9+/-0.8 versus 1.3+/-0.4 years; P<0.001). Biochemical markers of bone resorption were significantly higher in patients who sustained bone loss and/or fractures. CONCLUSIONS: We conclude that fractures are a significant problem in the first year after lung transplantation, even in patients who receive therapy to prevent bone loss. Women with low pretransplantation BMD and a history of pretransplantation glucocorticoid therapy are at greatest risk.

Salvage by volume reduction of chronic allograft rejection in emphysema.

BACKGROUND: We hypothesized that native lung volume reduction surgery (LVRS) would improve respiratory function in patients who had previously undergone single lung transplantation for emphysema and who were disabled by obliterative bronchiolitis. METHODS: Seven single lung transplant recipients who had advanced bronchiolitis obliterans syndrome (BOS grade 3b), absence of active infection, and suitable anatomy underwent native LVRS. Mean time from lung transplantation to LVRS was 39 +/- 17 months. RESULTS: Mean FEV1 rose from 684 +/- 164 ml before LVRS to 949 +/- 219 ml at 3 months after LVRS, an increment of 40% (p = .002). Mean 6-minute walk rose from 781 +/- 526 ft before LVRS to 887 +/- 539 ft at 3 months after LVRS (p = .031), and mean dyspnea index declined from 3.1 +/- 1.1 before LVRS to 1.6 +/- 0.5 at 3 months after LVRS (p = .010). Mean native lung volume declined from 2956 +/- 648 ml before LVRS to 2541 +/- 621 ml at 3 months after LVRS, but the change was not statistically significant (p = .12). Mean transplant lung volume was little changed before and after LVRS (2099 +/- 411 ml and 1931 +/- 607 ml, respectively, p = NS). There was also a trend toward increased ventilation and perfusion of the native lung and reduction in ventilation and perfusion of the transplant lung, but these changes did not achieve statistical significance. By six months after LVRS, three patients died (two as a consequence respiratory failure), and survivors began to show evidence of deteriorating spirometry. CONCLUSIONS: LVRS is capable of salvaging respiratory function in chronic allograft rejection in emphysema by reducing native lung hyperinflation. These benefits, however, appear to be limited in magnitude and duration by the severity of the underlying allograft dysfunction.

Bone densitometry should be included in the evaluation of candidates for lung transplantation.

Bone loss and fractures are common complications of heart and liver transplantation, and are likely related to high-dose immunosuppressive therapy. We have previously demonstrated that many patients with end-stage lung disease already have osteoporosis and may be at even greater risk for fracture after lung transplantation. The purpose of this study is to determine the incidence of fracture in lung transplant recipients on osteoporosis prevention regimens, the relationship of fracture to pretransplant bone mineral density, and the impact of fracture on quality of life after lung transplantation. Twenty-one lung transplant candidates were prospectively evaluated with spine radiographs and bone mineral densitometry. Bone density was expressed as T scores, the number of standard deviations from the mean bone density of a young normal population of the same gender. Of 21 patients, 8 (38%) fractured during the first year. The mean pretransplant lumbar spine T score was significantly lower in the fracture patients (P = .03). Four of the 7 surviving fracture patients and 1 of the 10 patients who survived without fracture believed that chronic pain diminished their quality of life (X2 = 4.408; P = .04). These findings suggest that bone mineral density should be routinely included in the evaluation of lung transplant candidates. Patients with extremely low bone density or osteoporotic fracture should be counseled about the increased risk of fracture after transplantation.

Preliminary experience with mycophenolate mofetil used after lung transplantation.

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

Mismatches at the HLA-DR and HLA-B loci are risk factors for acute rejection after lung transplantation.

Early high-grade acute rejections (pathologic grade A2 or A3) in recipients of lung allografts are a major risk factor for the subsequent development of obliterative bronchiolitis (OB). We analyzed the risk factors for high-grade acute rejections in 152 recipients of single (100) or bilateral (52) lung allografts transplanted at our institution between 1990 and 1996. Using Kaplan-Meier product limit estimate analysis, there was a 50% probability of grade A2 or A3 rejection by 1 yr after transplant. By univariate analysis, the only significant predictor of early high-grade rejections was the presence of one or more mismatches at the HLA-DR locus (p = 0.038). This association was confirmed using the Cox proportional hazards model for multivariable analysis, with HLA-DR locus mismatch being the only risk factor identified for high-grade rejection (p = 0.036). Using repeated rejection analysis, recipients with one or more matches at the HLA-DR locus had a lower cumulative rate of grade A2 or A3 rejections during the first year compared with recipients with no matches at the HLA-DR locus (0.73 versus 1.32). In addition, recipients with one or more HLA-B locus matches had a lower cumulative rate of grade A2 or A3 rejections in the first year than did recipients with no matches at the HLA-B locus (0.59 versus 1.30). These results indicate that mismatches between donors and recipients at the HLA-DR and HLA-B loci are important risk factors for early high-grade rejections after lung transplantation. Immunosuppressive protocols that are more effective in preventing recipient T-cell activation by donor alloantigens are likely to reduce the rate of high-grade acute rejections in recipients of lung transplants, and may directly impact on the time to onset of OB.

Late fatal adenovirus pneumonitis in a lung transplant recipient.

Adenovirus (ADV) is increasingly recognized as a cause of morbidity and mortality in transplant recipients, but ADV pneumonitis has rarely been reported after lung transplantation. The few reported instances of ADV pneumonitis occurred mostly in children immediately after lung transplantation suggesting "primary" infection. We report a fatal case of ADV pneumonitis occurring in an adult, 4 years after unilateral lung transplantation, in whom the premortem diagnosis was not determined. Autopsy revealed severe necrotizing bronchitis, bronchiolitis, and interstitial pneumonitis. Characteristic smudgy intranuclear inclusions, immunohistochemistry for viral protein, in situ hybridization for viral genome, and postmortem lung cultures established ADV as the etiologic agent. ADV can cause fatal, occult respiratory infection in adult lung transplant recipients, remote from transplant surgery.

Spontaneous resolution of pulmonary venous thrombosis after lung transplantation.

Thrombus formation at the pulmonary venous anastomotic site after lung transplantation may have catastrophic consequences, including allograft failure and stroke. However, treatment with systemic anticoagulation may facilitate bleeding in the early postoperative period. In the present report, we describe the clinical and transesophageal echocardiographic findings of pulmonary venous thrombosis in two patients in the immediate postoperative period after lung transplantation. Treatment with systemic anticoagulation was not feasible because of extensive postoperative thoracic bleeding in each instance. A conservative approach was taken on the basis of the small size of each thrombus and lack of accelerated flow velocity at the site of the thrombus. Each thrombus resolved spontaneously without clinical sequelae. These two cases suggest that thrombus size and flow velocity at the anastomotic site may be used to guide the clinical management of pulmonary venous thrombosis after lung transplantation.