Search PubMed⌕ Search

Biomedical subjects

R Duane Davis

Publications and source records attributed to R Duane Davis.

At least 19 recordsLinked to original sources

Cytokine gene polymorphisms are not associated with bronchiolitis obliterans syndrome or survival after lung transplant.

BACKGROUND: Cytokine polymorphisms are inconsistently associated with transplant rejection and other adverse outcomes. To address this controversy, we evaluated cytokine single nucleotide polymorphisms (SNPs) in a lung transplant cohort. METHODS: All patients who underwent lung transplantation from 1993 to 1998 and had post-transplant survival of at least 6 months were included in the initial analysis. Subjects were genotyped for: TNF-alpha -308 G/A; IFN-gamma +874 A/T; TGF-beta1 +869 T/C and +915 G/C; IL-10 -1082 A/G, -819 C/T and -592 C/A; and IL-6 -174 G/C. End-points were onset of broncholitis obliterans syndrome (BOS) and survival. RESULTS: In the cohort, 78 subjects, with an overall mean +/- SE survival 2,339 +/- 117 days, had no correlation between onset of BOS1, BOS2 or survival with TNF-alpha, IFN-gamma, TGF-beta1 or IL-10 gene polymorphisms. However, IL-6 polymorphisms GG or GC were associated with an earlier onset of BOS1 (p = 0.039), BOS2 (p = 0.021), and decreased overall post-transplant survival (p = 0.038). A second cohort of more recent lung transplant recipients did not validate an association between IL-6 polymorphisms and earlier onset of BOS1 (p = 0.70), BOS2 (p = 0.54) or overall post-transplant survival (p = 0.25). CONCLUSIONS: Polymorphisms of TNF-alpha, IFN-gamma, TGF-beta1, IL-10 and IL-6 do not appear to influence the onset of BOS or graft survival in recipients.

Adolescent↗

Long-term outcomes of the symmetry vein graft anastomosis device: a matched case-control analysis.

BACKGROUND: The Symmetry Bypass Connector (St. Jude Medical) was developed to rapidly anastomose saphenous vein grafts to the aorta during coronary bypass surgery (CABG) without cross-clamping. Previous uncontrolled studies of this device observed vein graft closures at six months, possibly attributable to neointimal hyperplasia. METHODS AND RESULTS: To assess the long-term clinical outcomes of the Symmetry device, we performed a retrospective matched case-control analysis of patients who underwent CABG at Duke Medical Center between January 1, 2002 and December 31, 2003. In 121 patients, at least one proximal anastomosis used a Symmetry device. Traditional suture methods were used in 178 control patients, matched by age group, gender, use of cardiopulmonary bypass, and Hannan perioperative risk score. One-year outcomes were compared using the log-rank test and Cox proportional hazards regression models. Major adverse events were more frequent among cases compared with controls. By unadjusted Kaplan-Meier analysis for the composite end point of death, nonfatal myocardial infarction, repeat cardiac catheterization, or repeat CABG, there was a trend towards increased events in the Symmetry device group (P=0.053). No significant differences were detected for stroke, all cause mortality, or the combined end point of death or nonfatal myocardial infarction. CONCLUSIONS: Use of the Symmetry Bypass Connector was associated with increased risk for major adverse events at 1 year, suggestive of early graft closure. The potential reductions in operative stroke risk (from the elimination of aortic cross-clamping) must be weighed against the potential risk for later adverse events. These findings encourage close follow-up of patients who received this device.

Aged↗

Effect of an anti-C5a monoclonal antibody indicates a prominent role for anaphylatoxin in pulmonary xenograft dysfunction.

BACKGROUND: In contrast to renal or cardiac xenografts, the inhibition of complement using cobra venom factor (CVF) accelerates pulmonary xenograft failure. By activating C3/C5 convertase, CVF depletes complement while additionally generating C5a and other anaphylatoxins, to which pulmonary xenografts may be uniquely susceptible. The current study investigates the role of C5a in pulmonary xenograft failure in baboons. METHODS: Left orthotopic pulmonary xenografts using swine lungs expressing human CD46 were performed in baboons receiving: I) no other treatment (n=4), II) immunodepletion (n=5), and III) immunodepletion plus a single dose of mouse anti-human C5a monoclonal antibody (anti-C5a, 0.6 mg/kg administered intravenously) (n=3). The extent to which anti-C5a inhibits baboon C5a was assessed in vitro using a hemolytic reaction involving baboon serum and porcine red blood cells and by ELISA. RESULTS: Baboons in Group III exhibited significantly prolonged xenograft survival (mean=722+/-121 min, P=0.02) compared to baboons in Group I (mean=202+/-24 min) and Group II (mean=276+/-79 min). Furthermore, baboons in Groups I and II experienced pronounced hemodynamic compromise requiring inotropic support whereas those in Group III remained hemodynamically stable throughout experimentation without the need for additional pharmacologic intervention. CONCLUSIONS: These findings indicate that C5a exacerbates pulmonary xenograft injury and compromises recipient hemodynamic status. Moreover, blockade of anaphylatoxins, such as C5a, offers a promising approach for future investigations aimed at preventing pulmonary xenograft injury in baboons.

Animals↗

Depletion of pulmonary intravascular macrophages prevents hyperacute pulmonary xenograft dysfunction.

BACKGROUND: Recent years have brought dramatic progress in the field of xenotransplantation, with the development of transgenic swine and various other means of overcoming the rejection mediated by xenoreactive antibodies. Although progress has been rapid with kidney and heart xenografts, progress with pulmonary xenografts has lagged behind. Recent findings have suggested that donor pulmonary intravascular macrophages may play a critical role in the hyperacute dysfunction of pulmonary xenografts. METHODS: The function of pulmonary xenografts from pigs depleted of pulmonary intravascular macrophages was compared with the function of xenografts from normal pigs. RESULTS: Pulmonary xenografts from pigs from which pulmonary intravascular macrophages were depleted survived (23.5+/-0.9 hours) about five times longer than normal (macrophage sufficient) xenografts (4.4+/-1.41 hours) (P< 0.0001). At 21 hours post-reperfusion, the left pulmonary arterial flow was 225.0+/-34 ml/min in lungs depleted of pulmonary intravascular macrophages, whereas all normal xenografts had failed. CONCLUSIONS: These findings indicate that donor macrophages play a critical role in pulmonary xenograft dysfunction. This finding has broad implications for xenotransplantation, suggesting that porcine macrophages might pose a barrier to the engraftment and function of a variety of porcine organ xenografts.

Animals↗

Role of flow cytometry to define unacceptable HLA antigens in lung transplant recipients with HLA-specific antibodies.

BACKGROUND: Antidonor HLA-specific antibodies have been associated with hyperacute rejection and primary graft failure in lung transplant recipients. Thus, transplant candidates with HLA-specific antibodies generally undergo prospective crossmatching to exclude donors with unacceptable HLA antigens. However, the need to perform a prospective crossmatch limits the donor pool and is associated with increased waiting list times and mortality. A virtual crossmatch strategy using flow cytometry, which enables precise determination of HLA-specific antibody specificity, was compared to prospective crossmatching in sensitized lung transplant candidates. METHODS: In all, 341 lung transplant recipients were analyzed retrospectively (April 1992 to July 2003). Sixteen patients with HLA-specific antibodies underwent transplantation based on flow cytometric determination of antibody specificity and 10 underwent prospective crossmatching. RESULTS: Freedom from bronchiolitis obliterans syndrome (BOS) at three years was similar in those undergoing a virtual crossmatch, those undergoing prospective crossmatching, and those without HLA-specific antibodies (80.4% +/- 13.4, 85.7% +/- 13.2, and 73.8% +/- 2.8, respectively, P = 0.88). Three-year survival was also comparable (87.5% +/- 8.3, 70.0% +/- 14.5, and 78.5% +/- 2.4, respectively, P = 0.31). Elimination of prospective crossmatching for sensitized patients was associated with a significant decrease in time on the waiting list (P < 0.01) and in waiting list mortality (P < 0.05). All 16 patients undergoing a virtual crossmatch had negative retrospective crossmatches. CONCLUSIONS: By carefully determining the specificity of HLA-specific antibodies, flow cytometry methodologies enable the prediction of negative crossmatch results with up to 100% accuracy, enabling the determination of appropriateness of donors. Using this virtual crossmatch strategy, crossmatching can be safely omitted prior to lung transplantation, thereby decreasing waiting list time and mortality rates for candidates with HLA-specific antibodies.

Adult↗

Successful bilateral lung transplant outcomes in recipients 61 years of age and older.

BACKGROUND: Controversy exists regarding the optimal use of bilateral lung transplant (BLT) in older recipients in diseases where either single or bilateral transplant is appropriate. International Society for Heart and Lung Transplant (ISHLT) guidelines suggest an upper age limit of 60 for BLT, despite limited data regarding outcomes with BLT in patients over 60. We hypothesize that BLT offers comparable, if not superior, clinical outcomes to SLT in all patients independent of recipient age. METHODS: In order to test our hypothesis, we conducted a case-control study to compare the effect of transplant operation on survival and the onset of bronchiolitis obliterans syndrome (BOS) in consecutive lung transplant recipients 61 years of age or older using Kaplan- Meier analysis and Cox proportional hazard models. RESULTS: We identified 107 consecutive lung transplant recipients 61 or older at the time of transplant. Patients received SLT (n=46) or BLT (n=61) based on donor organ availability. Comparable survival was achieved with BLT in older patients vs. SLT P=0.19). One-, two-, and five-year survival estimates in BLT were 82%, 75% and 68%, respectively, vs. in SLT 78%, 70% and 44%, respectively. A comparable onset of BOS was also observed in the patients who received BLT vs. SLT (P=0.23). CONCLUSION: Successful short- and medium-term outcomes are achieved with BLT in older recipients and are comparable to those achieved with SLT. Our results suggest that age over 60 should not exclude patients from consideration of BLT.

Age Factors↗

Case report: optimizing intraoperative detection of pulmonary embolism using contrast-enhanced echocardiography.

PURPOSE: Perioperative pulmonary embolism (PE) is associated with significant morbidity and mortality. Intraoperatively, the clinical management of patients with PE can be enhanced by the use of transesophageal echocardiography (TEE) to visualize emboli, assess pulmonary artery (PA) anatomy, and monitor the function of the right ventricle. However, the sensitivity of intraoperative TEE to detect thromboemboli is reported to be below 50%. In this report, we describe the use of contrast-enhanced TEE (CE-TEE) to improve the visualization of PE. CLINICAL FEATURES: A 44-yr-old female with chronic thrombo-embolic pulmonary hypertension was scheduled for pulmonary thromboendarterectomy. The precardiopulmonary bypass TEE exam demonstrated signs of PA obstruction and right ventricle dysfunction, but the borders of the thrombus in the right PA were only minimally visualized. Perflutren lipid microspheres, composed of octafluoropropane encapsulated in an outer lipid shell, were injected as a 0.3 mL iv bolus, while visualizing the right PA with harmonic ultrasound imaging. The CE-TEE image clearly visualized a large mobile thrombus along with a distinct pattern consistent with pulmonary flow obstruction. The postcardiopulmonary bypass CE-TEE confirmed thrombus evacuation and absence of PA flow abnormalities. CONCLUSION: Contrast-enhanced-TEE may decrease operator dependency and increase the sensitivity necessary to detect central, surgically accessible PE.

Adult↗

High frequency of bronchogenic carcinoma after single-lung transplantation.

BACKGROUND: Lung transplantation is a commonly employed therapy in the treatment of patients with advanced lung diseases related to tobacco use. Little is known about the long-term incidence or risk factors for primary lung cancer after lung transplantation. To determine the frequency, clinical features and risk factors for primary bronchogenic malignancy after lung transplantation, we designed a matched cohort study of single and bilateral lung transplant recipients with extended follow-up. METHODS: We retrospectively reviewed the records of 262 lung transplant recipients who survived > or =90 days post-transplant and assessed for the development of primary lung cancer. One hundred thirty-one consecutive single-lung transplant (SLTx) recipients were matched to 131 consecutive bilateral lung transplant (BLTx) recipients by native disease. Risk factors for lung cancer development were derived using univariate and multivariate proportional hazards models. RESULTS: Of the SLTx recipients, 6.9% developed primary lung cancer after transplantation as compared with 0% of the BLTx recipients (p = 0.002), after a mean of 52 months. Histologically, non-small-cell cancers were present in the native lung, which led to death in 67% (6 of 9) of the patients despite treatment. Significant risk factors for the development of primary lung cancer were increasing age (p = 0.004), >60-pack-year smoking history (p = 0.03), and SLTx as compared with BLTx (p < 0.001). CONCLUSIONS: Single-lung transplant confers a significantly elevated risk of developing primary post-transplant lung cancer as compared with BLTx in patients with comparable native disease, age and tobacco history.

Age Factors↗

Telephone-based coping skills training for patients awaiting lung transplantation.

Impaired quality of life is associated with increased mortality in patients with advanced lung disease. Using a randomized controlled trial with allocation concealment and blinded outcome assessment at 2 tertiary care teaching hospitals, the authors randomly assigned 328 patients with end-stage lung disease awaiting lung transplantation to 12 weeks of telephone-based coping skills training (CST) or to usual medical care (UMC). Patients completed a battery of quality of life instruments and were followed for up to 3.4 years to assess all-cause mortality. Compared with UMC, CST produced lower scores on perceived stress, anxiety, depressive symptoms, and negative affect and improved scores on mental health functioning, optimism, vitality, and perceived social support. There were 29 deaths (9%) over a mean follow-up period of 1.1 year. Survival analyses revealed that there was no difference in survival between the 2 groups. The authors conclude that a telephone-based CST intervention can be effectively delivered to patients awaiting lung transplantation. Despite the severity of pulmonary disease in this patient population, significant improvements in quality of life, but not somatic measures or survival to transplant, were achieved.

Adaptation, Psychological↗

Primary graft dysfunction in lung transplantation.

Following the initial successful lung transplants reported by the Toronto Lung Transplant Group in 1986, lung transplantation has evolved into an effective treatment of isolated pulmonary failure and has been performed in more than 20,000 recipients. Increased experience, adjustments, and additions to the surgical technique and improved perioperative care have combined to decrease morbidity and improve survival in lung transplant recipients. An area in which improvements have been made but that continues to cause major morbidity, mortality, and impact on long-term allograft function is primary allograft dysfunction, which occurs in 11 to 60% transplant patients, depending on the diagnostic criteria applied. The basis of this potentially devastating complication is likely ischemia reperfusion injury of the donor allograft with activation of recipient innate immunity. This article discusses mechanisms of primary graft dysfunction in light of recent International Society for Heart and Lung Transplantation consensus definitions, and considers successful strategies for prevention and treatment of primary graft dysfunction.

Graft Rejection↗

Pathologic correlates of bronchiolitis obliterans syndrome in pulmonary retransplant recipients.

RATIONALE: The main hindrance to long-term success of lung transplantation is bronchiolitis obliterans syndrome (BOS), generally thought to be a manifestation of chronic allograft rejection. BOS is associated histologically with epithelial injury, bronchocentric mononuclear inflammation, and fibrosis of small airways known as bronchiolitis obliterans (BO). Few studies have directly compared clinical, radiographic, and histologic findings of BOS and BO, particularly in the era of improved immunosuppression and infection prophylaxis. Patients undergoing pulmonary retransplantation for BOS provide a unique opportunity to investigate these relationships. METHODS: All patients who underwent pulmonary retransplantation for BOS from 1992 to 2004 at Duke University Medical Center were reviewed. Pathology findings in explanted lung allografts were compared with clinical, radiographic, and transbronchial biopsy data. RESULTS: Over the 12-year study period, 12 patients underwent pulmonary retransplantation for BOS. The median time to BOS was 517 days (intraquartile range, 396 to 819.8 days). BOS scores prior to retransplantation were 2 in 2 patients and 3 in 10 patients. We developed a semiquantitative scoring system for epithelial, inflammatory, and fibrotic changes in affected airways to permit better comparison between BO and BOS. Somewhat surprisingly, only 50% (6 of 12 patients) had severe fibrotic changes, although all had some degree of epithelial injury, fibrosis, or inflammation centered around the bronchi and bronchioles. Furthermore, pathology findings other than BO were present in most explanted allografts and included cholesterol clefts (n = 4), focal invasive aspergillosis (n = 1), interstitial fibrosis (n = 2), and chronic vascular rejection (n = 1). CONCLUSIONS: In this series of patients with advanced BOS undergoing retransplantation, at least some degree of BO was present in all explanted allografts. However, the degree of epithelial changes, fibrosis, and inflammation present among affected bronchi varied considerably. Furthermore, a wide range of pathologic processes of potential clinical significance were evident in half of the patients. We conclude that significant histologic heterogeneity exists among patients undergoing retransplantation for BOS, potentially contributing to the variability of patient responses to treatment.

Adult↗

Chronic aspiration of gastric fluid accelerates pulmonary allograft dysfunction in a rat model of lung transplantation.

OBJECTIVE: Emerging clinical evidence suggests that gastroesophageal reflux disease is associated with pulmonary allograft dysfunction. In this study, we used a model of rat lung transplantation to test the hypothesis that chronic aspiration of gastric contents accelerates pulmonary allograft dysfunction. METHODS: We evaluated the effects of chronic aspiration on pulmonary isografts (strain F344) and pulmonary allografts (strain WKY to strain F344). Chronic aspiration consisted of 0.5 mL/kg of filtered gastric contents injected weekly into the left lung for 4 to 8 weeks beginning 1 week after transplantation. Seven days after the last aspiration, animals were killed, and grafts were evaluated grossly and by histologic and immunochemical analyses, including Masson trichrome staining for collagen and immunostaining for CD68+ and CD8+ cells. Serum cytokine concentrations were determined by bead-based immunoassays or enzyme-linked immunosorbent assay. RESULTS: Allografts without aspiration (n = 12) demonstrated a relatively normal architecture with diffuse International Society for Heart and Lung Transplantation grade 3 acute rejection; occasional grade 4 rejection was noted. In contrast, allografts with chronic aspiration (n = 7) demonstrated severe grade 4 acute rejection with significant monocyte infiltration, fibrosis, and loss of normal alveolar anatomy. Grossly, 8 (67%) of 12 allografts without aspiration seemed to inflate and perfuse normally, whereas all allografts exposed to chronic aspiration were firm and shrunken, without the ability to ventilate (P = .013; Fisher exact test). Aspiration was associated with increases in graft-infiltrating macrophages and CD8+ T cells and higher levels of serum transforming growth factor beta. CONCLUSIONS: Chronic aspiration of gastric contents promotes accelerated allograft failure and may promote a profibrotic environment.

Animals↗

Risk-adjusted short- and long-term outcomes for on-pump versus off-pump coronary artery bypass surgery.

BACKGROUND: Surgeons have adopted off-pump coronary artery bypass grafting (OPCAB) in an effort to reduce the morbidity of surgical revascularization. However, long-term outcome of OPCAB compared with conventional coronary artery bypass grafting (CABG) remains poorly defined. METHODS AND RESULTS: Using logistic regression analysis and proportional hazards modeling, short-term and long-term outcomes (perioperative mortality and complications, risk-adjusted survival, and survival/freedom from revascularization) were investigated for patients who underwent OPCAB (641 patients) and CABG-cardiopulmonary bypass (5026 patients) from 1998 to 2003 at our institution. For these variables, follow-up was 98% complete. OPCAB patients were less likely to receive transfusion (odds ratio for OPCAB, 0.80; P=0.037), and there were trends toward improvement in other short-term outcomes compared with CABG-cardiopulmonary bypass. Long-term outcomes analysis demonstrated no difference in survival, but OPCAB patients were more likely to require repeat revascularization (OPCAB hazard ratio, 1.29; P=0.020). CONCLUSIONS: OPCAB patients were less likely to receive transfusion during their hospitalization for surgery but had higher risk for revascularization in follow-up. These results highlight the need for a large randomized, controlled trial to compare these 2 techniques.

Aged↗

Hepatitis B core antibody positive donors as a safe and effective therapeutic option to increase available organs for lung transplantation.

BACKGROUND: The use of hepatitis B core antibody (HBcAb+) and hepatitis C antibody (HCV Ab+) positive donors represents one strategy to increase available donor organs, but this remains controversial because of concern for viral transmission to recipients. We hypothesized that isolated HBcAb+ donors represent minimal risk of viral transmission in vaccinated lung transplant (LTx) recipients. METHODS: A retrospective study was performed of LTx recipients who received HBcAb+ or HCV Ab+ pulmonary allografts. We analyzed liver function studies, viral hepatitis screening tests, quantitative polymerase chain reaction for hepatitis B viral DNA (HBV DNA) and hepatitis C viral RNA (HCV RNA), freedom from bronchiolitis obliterans syndrome, acute rejection, and survival. RESULTS: Between April 1992 and August 2003, 456 LTx operations were performed. Twenty-nine patients (HB group) received HBcAb+ allograft transplants with a median posttransplant follow-up of 24.5 months. Three critically ill patients (HC group) received HCV Ab+ allografts with a median follow-up of 21.5 months. One-year survival for the HB group is 83% versus 82% for all patients who received non-HB organs (P=0.36). No patient in the HB group developed clinical liver disease because of viral hepatitis, and all patients alive (n=21) at follow-up are, to date, HBV DNA and/or HBcAb negative. All patients in the HC group tested HCV RNA positive; one patient died of liver failure at 22 months. CONCLUSIONS: Risk of viral transmission with HCV Ab+ allografts seems high after LTx. However, the use of HBcAb+ pulmonary allografts in recipients with prior hepatitis B vaccination seems to be a safe and effective strategy to increase organ availability.

Adult↗

Innate immunity influences long-term outcomes after human lung transplant.

RATIONALE: Lung transplantation is characterized by very high rates of acute and chronic allograft rejection. We hypothesize that activation of innate immunity augments adaptive immunity, leading to rejection after lung transplantation. In support of this idea, we have recently demonstrated that lung recipients heterozygous for either of two functional polymorphisms (Asp299Gly or Thr399Ile) in Toll-like receptor 4 (TLR4) associated with endotoxin hyporesponsiveness have decreased acute rejection over the first 6 months after transplant. OBJECTIVES: In the current analysis, we sought to extend our initial observations and investigate the effect of these TLR4 polymorphisms on post-transplant acute rejection beyond the first 6 months, bacterial infections, bronchiolitis obliterans syndrome, and survival. METHODS: Genotyping was performed on 170 lung transplant recipients. MEASUREMENTS AND MAIN RESULTS: Recipients heterozygous for either Asp299Gly or Thr399Ile had significantly reduced frequency (p = 0.02) and incidence of acute rejection (p = 0.04) sustained over 3 years after transplant, but no differences were observed in the overall onset of bronchiolitis obliterans syndrome. A trend, however, toward reduced onset of bronchiolitis obliterans syndrome grade 2 or 3 was observed in TLR4 heterozygotes. CONCLUSION: Our results demonstrate that activation of recipient innate immune responses through TLR4 has a significant and sustained effect on the development of acute lung rejection. Targeting innate immune signaling represents a promising area for future clinical studies in the prevention of lung allograft rejection.

Adult↗

Improved results treating lung allograft failure with venovenous extracorporeal membrane oxygenation.

BACKGROUND: Primary graft failure remains a significant source of mortality after lung transplantation. Extracorporeal membrane oxygenation (ECMO) provides treatment for affected recipients. We hypothesized that venovenous membrane oxygenation provides a safer alternative than venoarterial support for lung recipients suffering from primary graft failure. METHODS: We conducted an analysis of 522 patients who underwent lung transplantation from April 1992 to July 2004. Twenty-three (4.5%) patients required membrane oxygenation secondary to primary graft failure unresponsive to conventional treatment. Of these recipients, 15 (65%) were treated with venoarterial, while 8 (35%) underwent venovenous membrane oxygenation. RESULTS: Median days to initiation and duration of membrane oxygenation did not differ between groups. Eight of 15 patients (53%) from the venoarterial group were successfully weaned from life support, with one surviving greater than 45 days. This lone long-term survivor required retransplantation 4 days after initial transplant. In contrast, all venovenous patients were weaned from support, with 7 of 8 surviving greater than 30 days. The 30-day survival for venovenous recipients (88%) approximates that of all lung recipients at our center (94%, p = 0.42). Noted complications for ECMO patients included renal failure (n = 16), neurologic catastrophes (n = 8), sepsis (n = 5), and hemorrhage (n = 10). The venoarterial recipients suffered 30 of 39 total complications. Most of the complications for venovenous recipients involved renal failure, but by hospital discharge these patients demonstrated a mean creatinine of 0.9 mg/dL. CONCLUSIONS: For lung recipients with primary graft failure, venovenous membrane oxygenation provides better outcomes, with fewer complications, than venoarterial membrane oxygenation.

Extracorporeal Membrane Oxygenation↗

Invited commentary.

Explore the source record for details and available documents.

Bronchiolitis Obliterans↗