Invited commentary.
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Bronchiolitis Obliterans↗
Biomedical subjects
R Duane Davis
Publications and source records attributed to R Duane Davis.
Upper lobe fibrosis: a novel manifestation of chronic allograft dysfunction in lung transplantation.
BACKGROUND: Lung transplantation is an established treatment modality for a number of chronic lung diseases. Long-term survival after lung transplantation is limited by chronic allograft dysfunction, usually manifested by bronchiolitis obliterans syndrome. We describe a case series with upper lobe fibrosis, a novel presentation of chronic allograft dysfunction. METHODS: We reviewed lung transplants at the Toronto General Hospital and Duke University Hospital from 1990 to 2002 and identified patients with upper lobe fibrosis. RESULTS: Thirteen of 686 patients (6 women) developed upper lobe fibrosis (Toronto, 9; Duke, 4); 12 of 13 had bilateral transplants. The median age at diagnosis was 42 years (range, 19-70). Primary diagnoses were cystic fibrosis, 6; emphysema, 4; sarcoidosis, 1; and pulmonary fibrosis, 2 patients. Radiographic diagnosis was made at a median of 700 days post-transplant (range, 150-2,920). Pulmonary function tests demonstrated predominantly a progressively worsening restrictive pattern. Open lung biopsy specimens revealed dense interstitial fibrosis, with occasional features of obliterative bronchitis, bronchiolitis obliterans obstructive pneumonia, and aspiration. Nine patients died at a median follow-up of 2,310 days (range, 266-3,740), 8 due to respiratory failure. CONCLUSION: Upper lobe fibrosis is a novel presentation of chronic allograft dysfunction in lung transplant recipients and is differentiated from bronchiolitis obliterans syndrome on the basis of physiologic and radiologic findings.
Adult↗
Utility of peritransplant and rescue intravenous immunoglobulin and extracorporeal immunoadsorption in lung transplant recipients sensitized to HLA antigens.
The role of anti-human leukocyte antigen (HLA) antibodies in lung transplantation is not fully clear. The presence of pretransplant third-party anti-HLA antibodies or the development of de novo anti-HLA antibodies has been associated with acute posttransplant complications, bronchiolitis obliterans syndrome (BOS), and early mortality in some studies. However, little has been reported regarding the utility of desensitization therapy in sensitized lung transplant recipients. For approximately 3 years, desensitization therapy consisting of intravenous immunoglobulin (IVIG) and, in most instances, extracorporeal immunoadsorption (ECI) has been administered peritransplant to lung transplant recipients at our institution with third-party anti-HLA antibodies or as rescue therapy to those who develop de novo anti-HLA antibodies. Notably, the administration of peritransplant desensitization therapy to these patients has been associated with improvement in several clinical parameters, including acute rejection and BOS. Furthermore, administration of rescue IVIG with or without ECI has been associated with an overall improvement in the rate of pulmonary function decline. Our experience suggests that desensitization therapy may be beneficial for lung transplant recipients with pretransplant or de novo anti-HLA antibodies. We discuss the appropriateness and clinical impact of IVIG and ECI in sensitized lung transplant recipients as well as cellular mechanisms that may contribute.
Desensitization, Immunologic↗
Emotional distress and quality of life in caregivers of patients awaiting lung transplant.
OBJECTIVE: The aims of this study are to characterize the levels of emotional distress and quality of life among caregivers of lung transplant candidates and to examine the relation of coping styles and perceived caregiver burden to caregivers' self-reported emotional distress. METHODS: A consecutive series of primary caregivers of potential lung transplant candidates completed a battery of psychosocial measures, including the Beck Depression Inventory-II (BDI-II), State-Trait Anxiety Inventory, Medical Coping Modes Questionnaire (MCMQ), Scale for Caregiver Burden (SCB), and Medical Outcomes Survey, Short Form-36 (SF-36). RESULTS: Only 12 of the 82 caregivers (14.6%) who volunteered for the study reported clinically significant levels of depression (BDI-II > or =14), and only 2 caregivers (2.4%) reported clinically significant levels of anxiety (STAI > or =60). Passive coping strategies were associated with higher levels of emotional distress; specifically, resignation was associated with increased depression (r=.27, P<.04), while avoidance was associated with increased anxiety (r=.29, P<.04). In addition, caregivers who reported greater perceived caregiver burden experienced higher levels of depression (r=.45, P<.001) and anxiety (r=.43, P<.01). Moreover, the social functioning of caregivers of lung transplant patients was more than one standard deviation from a normative sample of the population (Cohen's d=1.16), indicating that caregivers of transplant patients experienced greater impairment in this area. DISCUSSION: Although most caregivers of transplant patients do not report significant impairment in functioning, assessing caregivers' coping strategies and caregiving burden may identify those caregivers who experience increased emotional distress.
Adaptation, Psychological↗
Antireflux surgery in the setting of lung transplantation: strategies for treating gastroesophageal reflux disease in a high-risk population.
In lung transplant recipients, GERD is associated with increased incidence of acute rejection, earlier onset of chronic rejection, and higher mortality. Surgical treatment of GERD in lung recipients seems to prevent early allograft dysfunction and improve overall survival. A total (360 degrees) fundoplication is shown to be a safe and effective method for treating GERD in lung transplant recipients and is the authors' procedure of choice, in most cases, for this high-risk patient population. The principal goal should be to minimize reflux of enteric contents that may lead to micro- or macroaspiration events in this complicated group of patients. Perioperative care should involve a multidisciplinary approach, including physicians and other health care providers familiar with the complexities of lung transplant recipients.
Bronchiolitis Obliterans↗
Preoperative statin therapy does not reduce cognitive dysfunction after cardiopulmonary bypass.
OBJECTIVE: The purpose of this study was to determine if patients receiving statin therapy before coronary artery bypass grafting surgery would have less cognitive dysfunction after cardiopulmonary bypass as a consequence of a diminished inflammatory response. DESIGN: Retrospective observational study of patients undergoing coronary artery bypass grafting surgery. SETTING: Referral center for cardiothoracic surgery at a university hospital. PARTICIPANTS: Four hundred forty patients undergoing coronary artery bypass grafting surgery with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-five percent of patients received statins in the preoperative period. Multivariable analysis revealed no effect of preoperative statin therapy on cognitive function (p = 0.67). Post hoc analysis revealed that statin therapy at hospital discharge was associated with less improvement in cognitive performance at 6 weeks after surgery (p = 0.011). No significant differences were found between statin therapy groups in either range or maximum value of any of the cytokines (p > 0.05). CONCLUSIONS: Preoperative statin therapy did not decrease the inflammatory response to cardiopulmonary bypass or the cognitive dysfunction commonly seen after cardiac surgery.
C-Reactive Protein↗
Acute renal failure after lung transplantation: incidence, predictors and impact on perioperative morbidity and mortality.
The incidence, predictors and clinical significance of acute renal failure (ARF) after lung transplantation are not well described. We retrospectively collected data on 296 patients transplanted at our center between April 1992 and December 2000; follow-up was extended until December 2002. Patients were initially divided into two groups: ARF (doubling of baseline creatinine within 2 weeks after surgery) and NoARF. The ARF group was subdivided into ARFD (dialyzed) and ARFnD (not dialyzed). The incidence of ARF was 56% (166/296), but most cases were ARFnD (n = 143). Independent predictors of ARFD (n = 23) were: baseline GFR (OR 0.98, CI 0.96-0.99, p = 0.012), pulmonary diagnosis other than COPD (OR 6.80, CI 1.5-30.89, p = 0.013), mechanical ventilation > 1 d (OR 6.16, CI 1.70-22.24, p = 0.006) and parenteral amphotericin B use (OR 3.04, CI 1.03-8.98, p = 0.045). Both ARFnD and ARFD were associated with longer duration of mechanical ventilation, increased hospital stay and increased early mortality. One-year patient survival was 92.3%, 81.8% and 21.7% in the NoARF, ARFnD and ARFD groups, respectively (p < 0.0001). After controlling for important covariates, ARFD remained associated with an increased hazard of dying (HR 6.77, CI 4.00-11.44, p < 0.0001). In conclusion, ARF occurs commonly after lung transplantation and affects important clinical outcomes, especially when dialysis is required.
Acute Kidney Injury↗
Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients.
BACKGROUND: Aerosolized administrations of amphotericin B deoxycholate (AmBd) and amphotericin B lipid complex (ABLC) in lung transplant recipients were compared for safety and tolerability. The incidence of invasive fungal infections in patients receiving aerosolized amphotericin B formulations as sole prophylaxis was determined. METHODS: A prospective, randomized (1:1), double-blinded trial was conducted with 100 subjects. AmBd and ABLC were administered postoperatively by nebulizer at doses of 25 mg and 50 mg, respectively, which were doubled in mechanically ventilated patients. The planned treatment was once every day for 4 days, then once per week for 7 weeks. Treatment-related adverse events and invasive fungal infections were quantitated for 2 months after study drug initiation. RESULTS: Intent-to-treat analysis revealed study drug was discontinued for intolerance in 6 of 49 (12.2%) and 3 of 51 (5.9%) patients in the AmBd- and ABLC-treated groups, respectively (p=0.313). Subjects receiving AmBd were more likely to have experienced an adverse event (odds ratio 2.16, 95% confidence interval 1.10, 4.24, p=0.02). Primary prophylaxis failure within 2 months of study drug initiation was observed in 7 of 49 (14.3%) AmBd-treated patients and 6 of 51 (11.8%) ABLC-treated patients. No fungal pneumonias were observed. Only two (2%) patients experienced documented primary prophylaxis failure with Aspergillus infections within the follow-up period. CONCLUSIONS: Both aerosol AmBd and ABLC appear to be associated with a low rate of invasive pulmonary fungal infection in the early posttransplant period. Patients receiving ABLC were less likely to experience a treatment-related adverse event.
Adolescent↗
J. Maxwell Chamberlain Memorial Paper. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease.
BACKGROUND: Chronic allograft dysfunction limits the long-term success of lung transplantation. Increasing evidence suggests nonimmune mediated injury such as due to reflux contributes to the development of bronchiolitis obliterans syndrome. We have previously demonstrated that fundoplication can reverse bronchiolitis obliterans syndrome in some lung transplant recipients with reflux. We hypothesized that treatment of reflux with early fundoplication would prevent bronchiolitis obliterans syndrome and improve survival. METHODS: A retrospective analysis of 457 patients who underwent lung transplantation from April 1992 through July 2003 was conducted. Patients were stratified into four groups: no history of reflux, history of reflux, history of reflux and early (< 90 days) fundoplication and history of reflux and late fundoplication. RESULTS: Incidence of postoperative reflux was 76% (127 of 167 patients) in pH confirmed subgroups. In 14 patients with early fundoplication, actuarial survival was 100% at 1 and 3 years when compared with those with reflux and no intervention (92% +/- 3.3, 76% +/- 5.8; p < 0.02). Further, those who underwent early fundoplication had improved freedom from bronchiolitis obliterans syndrome at 1 and 3 years (100%, 100%) when compared with no fundoplication in patients with reflux (96% +/- 2.5, 60% +/- 7.5; p < 0.01). CONCLUSIONS: Reflux is a frequent medical complication after lung transplantation. Although the number of patients undergoing early fundoplication is small, our results suggest early aggressive surgical treatment of reflux results in improved rates of bronchiolitis obliterans syndrome and survival. Further research into the mechanisms and treatment of nonalloimmune mediated lung allograft injury is needed to reduce rates of chronic lung failure.
Adult↗
Laparoscopic Nissen fundoplication for treating reflux in lung transplant recipients.
Gastroesophageal reflux disease may contribute to pulmonary injury and the development of bronchiolitis obliterans syndrome in lung transplant patients. As a result, such individuals are increasingly likely to undergo corrective gastrointestinal surgery. The present study collected outcome data for 28 lung transplant patients with documented reflux who underwent an uncomplicated laparoscopic Nissen fundoplication at our institution. The results were compared to data from 63 nontransplant reflux patients who had undergone the procedure over the same time period. All Nissen fundoplications were conducted by the same surgeon. There were no intraoperative or perioperative deaths in either patient group. Operative parameters did not differ but the postoperative hospital stay was significantly greater for the lung transplant patients (P<0.05). Seven transplant patients (25%) were readmitted within 30 days compared to two readmissions (3.2%) in the reflux group. Five transplant patients (17.9%) have died, all from pulmonary complications; on average, death occurred 15.5 months after the Nissen surgery. There have been no deaths in the reflux group. These data indicate that laparoscopic Nissen fundoplication can be performed on lung transplant recipients to treat reflux. The average hospital stay is longer and there are more frequent readmissions in this population, but this does not appear to be due to any Nissen-related morbidity.
Adult↗
Surgical considerations in lung transplantation: transplant operation and early postoperative management.
During the last 20 years improvements in perioperative care have led to improved outcomes for lung transplant recipients. Although uncommon, technical complications can be the source of significant morbidity and mortality. Infections and ischemia-reperfusion injury continue to have the greatest impact on short-term outcomes of lung transplant recipients, and research into the prevention and treatment of these two entities will be necessary to improve these patients' outcomes significantly.
Adult↗
Delay of CMV infection in high-risk CMV mismatch lung transplant recipients due to prophylaxis with oral ganciclovir.
Cytomegalovirus (CMV) is a common opportunistic infection in lung transplant recipients. Despite the use of early post-operative intravenous ganciclovir, most high-risk patients develop CMV infection. We conducted this retrospective study to determine the efficacy of extended CMV prophylaxis with oral ganciclovir in high-risk, donor-positive-recipient-negative, lung recipients. All patients initially received 3 months of intravenous ganciclovir and CMV hyperimmune globulin. Clinical outcomes in all CMV mismatch patients undergoing lung transplant surviving at least 3 months were included (n = 42). Since 1998, 14 patients received no oral ganciclovir prophylaxis (group 1) and 28 patients received indefinite oral ganciclovir after completion of intravenous therapy (group 2). In those patients receiving oral ganciclovir, the prevalence of post-transplant CMV infection was significantly reduced over the first 180 d post-transplant (50% in group 1 vs. 4% in group 2; p < 0.001). Although some CMV events were observed with additional follow-up in group 2, there remained a significantly greater freedom from CMV infection by Kaplan-Meier analysis in group 2 as compared with group 1, with over 30 months follow-up time in each group (log-rank, p = 0.02). A moderate rate of drug discontinuation was observed in group 2, and no severe drug-related events occurred. In high-risk lung transplant recipients, CMV prophylaxis with intravenous ganciclovir, followed by indefinite oral ganciclovir, significantly delays and reduces post-transplant CMV infections. A larger prospective randomized study is needed to confirm the benefits of oral ganciclovir on CMV prevention.
Administration, Oral↗
Living-related lobar lung transplantation.
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Adult↗
Pulmonary xenotransplantation: rapidly progressing into the unknown.
As one approach to circumventing the dire shortage of human lungs for transplantation, a handful of investigators have begun to probe the possibility of pulmonary xenotransplantation. The immunologic and perhaps physiologic barriers encountered by these investigators are considerable and progress in pulmonary xenotransplantation has lagged behind progress in cardiac and kidney xenotransplantation. However, during the last few years there have been substantial advances in the field of pulmonary xenotransplantation including, most noticeably, significant progress in attenuating hyperacute dysfunction. Progress has been made in understanding the barriers imposed by xenoreactive antibodies, complement, coagulation incompatibility and porcine pulmonary intravascular macrophages. Although our understanding of the barriers to pulmonary xenotransplantation is far from complete and the clinical application of pulmonary xenotransplantation is not yet in sight, current progress is fast paced. This progress provides a basis for future work and for a hope that the shortage of human lungs for transplantation will not always be a matter of life and death.
Animals↗
Outcome of lung transplant patients admitted to the medical ICU.
INTRODUCTION: Lung transplantation is an acceptable treatment option for end-stage lung disease. Short-term survival has improved, but lung transplant recipients remain at high risk for a variety of complications that can necessitate care in an ICU. Little is known about the epidemiology, clinical outcomes, and risk factors for survival among lung transplant recipients admitted to the ICU. METHODS: All lung transplant recipients at a single institution discharged from the hospital after their transplant and subsequently admitted to the medical ICU (MICU) between March 1, 1999, and February 28, 2001, were included. Patients were followed until death or February 28, 2002. Demographic data collected included transplant type and date, APACHE (acute physiology and chronic health evaluation) III scores, last preadmission and best posttransplant FEV(1) in liters, admitting diagnosis, use of mechanical ventilation, and previous MICU admission. RESULTS: There were 51 patients admitted to the MICU during the study period (73 total admissions). Their demographic data, pretransplant diagnoses, and type of transplant were similar to those of the rest of Duke University Medical Center lung transplant patients. Fifty-three percent (27 of 51 patients) required mechanical ventilation during their first MICU admission. Thirty-seven percent (19 of 51 patients) died during their first MICU admission. Fifty-nine percent (16 of 27 patients) receiving mechanical ventilation died. Patients who died had lower FEV(1) to posttransplant best FEV(1) ratio prior to MICU admission, and also had higher APACHE III scores on MICU admission compared to survivors: FEV(1), 51.3 +/- 21.9% (n = 14) vs 75.5 +/- 20.4% (n = 30) [p = 0.001]; APACHE III score, 77.7 +/- 21.4 (n = 19) vs 60.1 +/- 16.5 (n = 32) [p = 0.002]. Survival rates by Kaplan-Meier analysis at 1 year and 2 years after initial MICU admission were 43.1% and 40.9%, respectively. The longest survivor is currently alive 1,087 days after initial MICU admission. CONCLUSION: Admission to the MICU is common in lung transplant recipients. MICU care, including mechanical ventilation, is associated with a poor prognosis in lung transplant recipients, but is appropriate for selected patients with good allograft function.
APACHE↗
Atrial fibrillation after pulmonary transplant.
BACKGROUND: Although atrial fibrillation or flutter (AF) is thought to occur commonly after pulmonary transplantation, little is known about the epidemiology, risk factors, or clinical significance of arrhythmia in this population. The aim of the current study was to determine the incidence, clinical predictors, and associated morbidity of AF after lung transplant. METHODS: The records of 200 consecutive adult patients who underwent lung transplantation at a single institution from August 1998 to June 2002 were studied. Multivariate logistic regression analysis was performed to define the predictors for posttransplant AF. RESULTS: Indications for transplant included COPD in 43%, cystic fibrosis in 18%, and idiopathic pulmonary fibrosis (IPF) in 17%. The transplants were bilateral (79%) or single lung (21%). The mean age of the patients was 50 years (range, 19 to 66 years; median, 54 years). Postoperative AF within 14 days of transplant occurred in 78 patients (39%), with a mean onset of 3.8 +/- 3.0 days (+/- SD). Significant predictors of AF were as follows: age >or= 50 years (odds ratio [OR], 2.1; p = 0.01), IPF (OR, 2.3; p = 0.03), existing coronary disease (OR, 2.0; p = 0.009), enlarged left atrium (LA) on echocardiography (OR, 3.9; p = 0.05), and number of postoperative vasopressors (OR, 1.5; p = 0.03). Patients with AF had longer hospital stays (32.4 +/- 60.0 days vs 17.5 +/- 24.1 days, p = 0.04), were more likely to undergo tracheostomy (OR, 3.6; p = 0.0003), and had more in-hospital deaths (OR, 5.7; p = 0.0005) than patients without AF. CONCLUSIONS: AF is a frequent complication after lung transplant. Advanced age, IPF, known coronary disease, enlarged LA, and use of postoperative vasopressors increase the risk for developing AF. The development of posttransplant AF is associated with significantly prolonged hospital stay and increased mortality. Prospective studies designed to prevent posttransplant AF are needed to clarify the extent to which AF impacts on posttransplant outcomes.
Adult↗
Prevention of acute lung injury in swine: depletion of pulmonary intravascular macrophages using liposomal clodronate.
BACKGROUND: Swine contain large numbers of pulmonary intravascular macrophages (PIMs) that mediate the physiological response observed in acute lung injury (ALI). As the hyperacute dysfunction observed in pulmonary xenotransplantation is similar to endotoxin-induced ALI, PIMs may play a critical role in pulmonary xenograft dysfunction. We used liposomal clodronate to eliminate the PIM population in a model of acute swine lung injury. MATERIALS AND METHODS: Experimental swine (n = 6) received liposomal clodronate (1.25 g/10 kg) and control swine (n = 5) received saline containing liposomes before infusion of lipopolysaccharide (450 ng/kg). RESULTS: Control swine demonstrated higher peak pulmonary artery pressures (41.8 +/- 2.2 versus 16.8 +/- 1.2 mm Hg; P < 0.0001) and higher peak pulmonary vascular resistances (1405 +/- 209 versus 353 +/- 81 dynes. s. cm(-5); P = 0.0016) in response to lipopolysaccharide infusion. Clodronate treated swine also had significantly lower serum levels of tumor necrosis factor-alpha, interleukin-6, and thrombin. CONCLUSIONS: Liposomal clodronate effectively attenuates acute swine lung injury induced by endotoxin. This method of depletion of the PIM population presents a promising new treatment of swine lungs before xenotransplantation.
Acute Disease↗
The role of innate immunity in acute allograft rejection after lung transplantation.
Although innate immunity is crucial to pulmonary host defense and can initiate immune and inflammatory responses independent of adaptive immunity, it remains unstudied in the context of transplant rejection. To investigate the role of innate immunity in the development of allograft rejection, we assessed the impact of two functional polymorphisms in the toll-like receptor 4 (TLR4) associated with endotoxin hyporesponsiveness on the development of acute rejection after human lung transplantation. Patients and donors were screened for the TLR4 Asp299Gly and Thr399Ile polymorphisms by polymerase chain reaction using sequence-specific primers. The rate of acute rejection at 6 months was significantly reduced in recipients, but not in donors, with the Asp299Gly or Thr399Ile alleles as compared with wild type (29 vs. 56%, respectively, p = 0.05). This association was confirmed in Cox proportional hazards and multivariate logistic regression models. Our results suggest activation of innate immunity in lung transplant recipients through TLR4 contributes to the development acute rejection after lung transplantation. Therapies directed at inhibition of innate immune responses mediated by TLR4 may represent a novel and effective means to prevent acute rejection after lung transplantation.
Acute Disease↗