Timothy J. Kroshus

Risk factors for the development of bronchiolitis obliterans syndrome after lung transplantation

OBJECTIVE This study identifies specific clinical and immunologic factors in lung transplant recipients that influence the subsequent development of chronic allograft dysfunction. METHODS The study group consisted of 132 consecutive patients who received lung allografts (76 single, 25 bilateral single, and 31 heart-lung) and survived at least 90 days. One hundred twenty-one patients were used in the analysis that modeled time to development of histologic obliterative bronchiolitis or bronchiolitis obliterans syndrome. RESULTS Variables noted to have an effect on the time to development of bronchiolitis obliterans syndrome included cytomegalovirus pneumonitis (RR = 3.2, p = 0.001), late acute rejection (RR = 1.3, p = 0.02), human leukocyte antigen mismatches at the A loci (RR = 1.8, p = 0.02), total human leukocyte antigen mismatches (RR = 1.4, p = 0.04), and absence of donor antigen-specific hyporeactivity (52% vs 100% survival free from bronchiolitis obliterans syndrome at 2 years; p = 0.005). Cytomegalovirus pneumonitis had a significant effect on time to obliterative bronchiolitis (RR = 3.6, p = 0.0005), as did donor antigen-specific hyporeactivity (52% vs 100% survival free from obliterative bronchiolitis at 2 years; p = 0.01). In multivariate analysis, cytomegalovirus pneumonitis (RR = 3.2, p = 0.02), human leukocyte antigen mismatches at the A loci (RR = 2.4, p = 0.006), and late acute rejection (RR = 1.3, p = 0.02) were identified as predictors of bronchiolitis obliterans syndrome. Cytomegalovirus pneumonitis was associated with time to development of histologic obliterative bronchiolitis (RR = 2.3, p = 0.02). CONCLUSIONS Several risk factors were associated with the development of chronic allograft dysfunction, which, in turn, had a significant impact on long-term survival. Early identification of lung allograft recipients with risk factors for the development of bronchiolitis obliterans syndrome may allow modification in immunosuppression and antiviral therapy to potentially decrease the prevalence of this disorder.

Early and Late Airway Complications After Lung Transplantation: Incidence and Management

BACKGROUND Airway anastomosis complications continue to be a source of morbidity for lung transplant recipients. METHODS This study analyzes incidence, treatment, and follow-up of airway anastomotic complications occurring in 127 consecutive lung transplant airway anastomoses (77 single lung and 25 bilateral sequential lung). Complications were categorized as stenosis (11), granulation tissue (8), infection (7), bronchomalacia (5), or dehiscence (3). Follow-up after treatment ranged from 6 months to 4 years. RESULTS Nineteen airway anastomosis complications (15.0%) occurred in 18 patients. Telescoping the airway anastomosis reduced the complication rate to 12 of 97 (12.4%), compared with 7 of 30 (23.3%) for omental wrapping, (p = 0.15). Complications developed in 13 of 77 single-lung airway anastomoses (16.9%) versus 6 of 50 bilateral sequential lung recipients (12.0%). Treatment consisted of stenting (9 airway anastomoses), bronchodilation (8), laser debridement (4), rigid bronchoscopic debridement (2), operative revision (2), and growth factor application (2). There was no difference in actuarial survival between patients with or without airway anastomosis complications (p = 1.0). CONCLUSIONS Airway anastomosis complications can be successfully managed in the immediate or late postoperative period with good outcome up to 4 years after intervention.

Complement inhibition with an anti-C5 monoclonal antibody prevents acute cardiac tissue injury in an ex vivo model of pig-to-human xenotransplantation.

Prevention of hyperacute xenograft rejection in the pig-to-primate combination has been accomplished by removal of natural antibodies, complement depletion with cobra venom factor, or prevention of C3 activation with the soluble complement inhibitor sCR1. Although these strategies effectively prevent hyperacute rejection, they do not address the relative contribution of early (C3a, C3b) versus late (C5a, C5b-9) activated complement components to xenogeneic organ damage. To better understand the role of the terminal complement components (C5a, C5b-9) in hyperacute rejection, an anti-human C5 mAb was developed and tested in an ex vivo model of cardiac xenograft rejection. In vitro studies demonstrated that the anti-C5 mAb effectively blocked C5 cleavage in a dose-dependent manner that resulted in complete inhibition of both C5a and C5b-9 generation. Addition of anti-C5 mAb to human blood used to perfuse a porcine heart prolonged normal sinus cardiac rhythm from a mean time of 25.2 min in hearts perfused with unmodified blood to 79,296, or > 360 min when anti-C5 mAb was added to the blood at 50 micrograms/ml, 100 micrograms/ml, or 200 micrograms/ml, respectively. In these experiments, activation of the classical complement pathway was completely inhibited. Hearts perfused with blood containing the highest concentration of anti-C5 mAb had no histologic evidence of hyperacute rejection and no deposition of C5b-9. These experiments suggest that the activated terminal complement components C5a and C5b-9, but not C3a or C3b, play a major role in tissue damage in this porcine-to-human model of hyperacute rejection. They also suggest that targeted inhibition of terminal complement activation by anti-C5 mAbs may be useful in clinical xenotransplantation.

Expression of human CD59 in transgenic pig organs enhances organ survival in an ex vivo xenogeneic perfusion model

The serious shortage of available donor organs for patients with end stage organ failure who are in need of solid organ transplantation has led to a heightened interest in xenotransplantation. The major barrier to successful discordant xenotransplantation is hyperacute rejection. Hyperacute rejection results from the deposition of preformed antibodies that activate complement on the luminal surface of the vascular endothelium, leading to vessel occlusion and graft failure within minutes to hours. Endogenous membrane-associated complement inhibitors normally protect endothelial cells from autologous complement -- however, these molecules are species-restricted and therefore are ineffective at inhibiting activated xenogeneic complement. To address the pathogenesis of hyperacute rejection in the pig-to-human combination, F1 offspring were generated from a transgenic founder animal that was engineered to express the human terminal complement inhibitor hCD59. High-level cell surface expression of hCD59 was detected in the hearts and kidneys of these transgenic F1 animals, similar to expression levels in human kidney tissue. The hCD59 was expressed on both large vessel and capillary endothelium. Ex vivo perfusion experiments, using human blood as the perfusate, were performed with transgenic porcine hearts and kidneys to evaluate the ability of hCD59 to inhibit hyperacute rejection. These experiments demonstrated that transgenic organs expressing hCD69 resisted hyperacute rejection, as measured by increased organ function for both the hearts and the kidneys, as compared with control pig organs. Hearts from hCD59-expressing animals demonstrated a five-fold prolongation in function compared with controls, 109.8 +/- 20.7 min versus 21.2 +/- 2.9 min (P = 0.164). The hCD59-expressing kidneys also demonstrated significantly prolonged function at 157.8 +/- 27.0 min compared with 60.0 +/- 6.1 min for controls (P = 0.0174). Deposition of C9 neoantigen In the vasculature of porcine organs perfused with human blood was markedly reduced in organs expressing hCD59. These studies demonstrate that C5b-9 plays an important role in hyperacute rejection of a porcine organ perfused with human blood and suggest that donor pigs transgenic for hCD59 may be an integral component of successful clinical xenotransplantation.

Multidisciplinary Standardized Care for Acute Aortic Dissection Design and Initial Outcomes of a Regional Care Model

> “No physician can diagnose a condition he never thinks about.” > > — Michael DeBakey Patients with acute aortic dissection (AAD) have an in-hospital mortality of 26%, and for those patients with type A AAD, the mortality risk is 1% to 2% per hour until emergency surgical repair is performed.1,2 It is therefore critical that AAD be recognized promptly and that surgical care be provided expeditiously. Data from the International Registry of Acute Aortic Dissection (IRAD) indicate that the median time from emergency department (ED) presentation to definitive diagnosis of AAD is 4.3 hours, with an additional 4 hours between diagnosis and surgical intervention for type A patients.2,3 A portion of the delay to surgery is often the result of the patients presenting to smaller community hospitals underequipped to manage emergent AAD. Transfer to high-volume aortic care centers with highly specialized facilities and expertise is routine, but even at such centers, current surgical mortality is 25%.4 In an effort to address factors that delay AAD recognition and optimal management, a standardized, quality-improvement protocol for the regional treatment of AAD was developed and implemented with the goal of providing consistent, integrated, and coordinated care for patients with AAD throughout all phases of care. Modeled, in part, after a successful regional program for ST-segment elevation myocardial infarction,5, the specific aims of the program were to decrease the time from hospital arrival to diagnosis and treatment and to improve clinical outcomes for patients with AAD. A collaborative team designed program elements directed at (1) increasing awareness and knowledge of AAD among emergency care providers, (2) standardizing optimal care for AAD through the use of a formal protocol, (3) improving care coordination and communication across disciplines, and (4) providing …

Deep venous thrombosis and pulmonary embolism after lung transplantation

The incidence of deep venous thrombosis or pulmonary embolism after lung or heart-lung transplantation has not been well defined. Pulmonary embolism may be of particular concern in the postoperative period owing to an inadequately developed or absent collateral bronchial circulation and potential risk of pulmonary infarction. Fourteen (12.1%) of 116 patients undergoing either lung (n = 87) or heart-lung (n = 29) transplantation developed thromboembolic complications 10 days to 36 months after operation. Deep vein thrombosis developed in nine patients, including three with upper body thrombosis related to indwelling central venous catheters. Seven patients (6%) had pulmonary embolism, and three of them died. Resolution of pulmonary embolism was successfully accomplished by selective pulmonary artery infusion of urokinase in three patients without complications. Our experience indicates that deep vein thrombosis and pulmonary embolism are significant problems after lung transplantation. Mortality is high in those patients in whom pulmonary embolism develops. Therefore, a comprehensive prevention protocol is warranted.

Unilateral volume reduction after single-lung transplantation for emphysema

BACKGROUND Single-lung transplantation has become accepted therapy for patients with end-stage emphysema. Hyperinflation of the native lung can occur after single-lung transplantation with mediastinal shifting and compression of the transplanted lung. A volume reduction operation (pneumectomy) [corrected] may relieve symptoms of dyspnea and improve exercise tolerance. METHODS Three of 66 patients who underwent single-lung transplantation for emphysema had development of native lung hyperexpansion and mediastinal shifting causing compression of the transplanted contralateral lung at 12, 17, and 42 months after transplantation. There were 2 men and 1 woman. Unilateral volume reduction was performed without complication in all 3 patients. RESULTS All patients were noted to have marked improvement in chest radiographs after volume reduction, substantial relief of dyspnea, and improvement in exercise tolerance. An improvement in pulmonary function test results was noted in 1 patient, but tests were not done for the other 2 patients. CONCLUSIONS Patients with chronic obstructive pulmonary disease who undergo single-lung transplantation may have symptomatic hyperexpansion of the native lung requiring volume reduction months to years after transplantation. Unilateral volume reduction can be safely performed in the posttransplantation period.

A recombinant soluble chimeric complement inhibitor composed of human CD46 and CD55 reduces acute cardiac tissue injury in models of pig-to-human heart transplantation

BACKGROUND Inasmuch as complement plays a critical role in many pathological processes and in xenograft rejection, efficient complement inhibitors are of great interest. Because the membrane-associated complement inhibitors are very effective, recombinant soluble molecules have been generated. METHODS We tested the efficacy of complement activation blocker-2 (CAB-2), a recombinant soluble chimeric protein derived from human decay accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46), in two models of pig-to-human xenotransplantation in which tissue injury is complement mediated. The in vitro model consisted of porcine aortic endothelial cells and human serum, and the ex vivo model consisted of a porcine heart perfused with human blood. RESULTS In vitro, addition of CAB-2 to serum inhibited cytotoxicity and the deposition of C4b and iC3b on the endothelial cells. Ex vivo, addition of CAB-2 to human blood prolonged organ survival from 17.3 +/- 6.4 min in controls to 108 +/- 55.6 min with 910 nM (100 microg/ml) CAB-2 and 219.8 +/- 62.7 min with 1820 nM (200 microg/ml) CAB-2. CAB-2 also retarded the onset of increased coronary vascular resistance. The complement activity of the perfusate was reduced by CAB-2, as was the generation of C3a and SC5b-9. The myocardial tissues had similar deposition of IgG, IgM, and Clq; however, CAB-2 reduced the deposition of C3, C4, and C9. Hearts surviving >240 min demonstrated trace to no deposition of C9 and normal histologic architecture. CONCLUSION These results indicate that CAB-2 can function as an inhibitor of complement activation and markedly reduce tissue injury in models of pig-to-human xenotransplantation and thus may represent a useful therapeutic agent for xenotransplantation and other complement-mediated conditions.

Coronary Sinus Injury During Retrograde Cardioplegia: A Report of Three Cases

Abstract Coronary sinus injuries related to the use of retrograde cardioplegia are uncommon. In most cases injuries are encountered with overinflation of the coronary sinus catheter balloon or traumatic catheter insertion. This article describes three cases of coronary sinus injury during retrograde cardioplegia administration in patients with ventricular hypertrophy, while the heart was manually retracted to expose the posterior myocardium. We propose that the risk of coronary sinus injury during retrograde cardioplegia, in patients with left ventricular hypertrophy, can be minimized by avoiding excessive retraction of the heart, deflation of the retrograde catheter during retraction, and the use of a left ventricular vent.

A Model of Unilateral Pulmonary Lobar Transplantation

Unilateral lung transplantation has become an accepted treatment for patients with end-stage pulmonary disease. Donor shortage, however, is a major limitation, with up to 87% of patients dying of their pulmonary disease while awaiting transplantation. This is especially true in neonatal and pediatric patient populations. The use of organ segments from cadaveric or living donors may provide a solution. The purpose of this study, therefore, was to evaluate the function and hemodynamic response to pulmonary lobar transplantation using a swine model. Five transplants were performed for acute study, while 10 were performed for 6-week survival. The left lower lobe was harvested from a 70- to 75-kg donor animal. The lobe was then transplanted into a 20 to 25-kg recipient following left pneumonectomy. Graft function was determined by pulmonary arterial and venous blood gas analysis. Cardiac output, pulmonary pressure, and pulmonary vascular resistance were measured under two experimental conditions: (1) baseline and (2) with the right pulmonary artery occluded, forcing the entire cardiac output through the lobar graft. All grafts showed excellent acute and long-term function with regard to gas exchange. The lobar grafts, however, were characterized by high pulmonary vascular resistance both acutely and 6 weeks post-transplant. Contralateral pulmonary artery occlusion resulted in hemodynamic instability and right heart failure. No animal was able to be solely supported by the lobar transplant for more than one hour. These results have prompted a bilateral lobar transplant model and current studies are in progress.