R.D. Davis

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

Long-term success in xenotransplantation is currently hampered by acute vascular rejection. The inciting cause of acute vascular rejection is not yet known; however, a variety of observations suggest that the humoral immune response of the recipient against the donor may be involved in the pathogenesis of this process. Using a pig-to-baboon heterotopic cardiac transplant model, we examined the role of antibodies in the development of acute vascular rejection. After transplantation into baboons, hearts from transgenic pigs expressing human decay-accelerating factor and CD59 underwent acute vascular rejection leading to graft failure within 5 d; the histology was characterized by endothelial injury and fibrin thrombi. Hearts from the transgenic pigs transplanted into baboons whose circulating antibodies were depleted using antiimmunoglobulin columns (Therasorb, Unterschleisshein, Germany) did not undergo acute vascular rejection in five of six cases. Biopsies from the xenotransplants in Ig-depleted baboons revealed little or no IgM or IgG, and no histologic evidence of acute vascular rejection in the five cases. Complement activity in the baboons was within the normal range during the period of xenograft survival. In one case, acute vascular rejection of a xenotransplant occurred in a baboon in which the level of antidonor antibody rose after Ig depletion was discontinued. This study provides evidence that antibodies play a significant role in the pathogenesis of acute vascular rejection, and suggests that acute vascular rejection might be prevented or treated by therapies aimed at the humoral immune response to porcine antigens.

Extended Valganciclovir Prophylaxis to Prevent Cytomegalovirus After Lung Transplantation: A Randomized, Controlled Trial

BACKGROUND Cytomegalovirus (CMV) is the most prevalent opportunistic infection after lung transplantation. Current strategies do not prevent CMV in most at-risk patients. OBJECTIVE To determine whether extending prophylaxis with oral valganciclovir from the standard 3 months to 12 months after lung transplantation is efficacious. DESIGN Randomized, clinical trial. Patients were randomly assigned by a central automated system to treatment or placebo. Patients and investigators were blinded to treatment status. (ClinicalTrials.gov registration number: NCT00227370) SETTING Multicenter trial involving 11 U.S. lung transplant centers. PATIENTS 136 lung transplant recipients who completed 3 months of valganciclovir prophylaxis. INTERVENTION 9 additional months of oral valganciclovir (n = 70) or placebo (n = 66). MEASUREMENTS The primary end point was freedom from CMV disease (syndrome or tissue-invasive) on an intention-to-treat basis 300 days after randomization. Secondary end points were CMV disease severity, CMV infection, acute rejection, opportunistic infections, ganciclovir resistance, and safety. RESULTS CMV disease occurred in 32% of the short-course group versus 4% of the extended-course group (P < 0.001). Significant reductions were observed with CMV infection (64% vs. 10%; P < 0.001) and disease severity (110 000 vs. 3200 copies/mL, P = 0.009) with extended treatment. Rates of acute rejection, opportunistic infections, adverse events, CMV UL97 ganciclovir-resistance mutations, and laboratory abnormalities were similar between groups. During the 6 months after study completion, a low incidence of CMV disease was observed in both groups. LIMITATION Longer-term effects of extended prophylaxis were not assessed. CONCLUSION In adult lung transplant recipients who have received 3 months of valganciclovir, extending prophylaxis by an additional 9 months significantly reduces CMV infection, disease, and disease severity without increased ganciclovir resistance or toxicity. A beneficial effect with regard to prevention of CMV disease seems to extend at least through 18 months after transplantation.

Survival After Lung Transplantation of Cystic Fibrosis Patients Infected with Burkholderia cepacia Complex

Within the Burkholderia cepacia complex (Bcc), B. cenocepacia portends increased mortality compared with other species. We investigated the impact of Bcc infection on mortality and re-infection following lung transplant (LT). Species designation for isolates from Bcc-infected patients was determined using 16S rDNA and recA gene analyses. Of 75 cystic fibrosis patients undergoing LT from September 1992 to August 2002, 59 had no Bcc and 16 had Bcc (including 7 B. cenocepacia) isolated in the year before LT. Of the latter, 87.5% had Bcc recovered after transplantation, and all retained their pretransplant strains. Survival was 97%, 92%, 76% and 63% for noninfected patients; 89%, 89%, 67% and 56% for patients infected with Bcc species other than B. cenocepacia; and 71%, 29%, 29% and 29% for patients with B. cenocepacia (p = 0.014) at 1 month, 1 year, 3 years and 5 years, respectively. Patients infected with B. cenocepacia before transplant were six times more likely to die within 1 year of transplant than those infected with other Bcc species (p = 0.04) and eight times than noninfected patients (p < 0.00005). Following LT, infection with Bcc species other than B. cenocepacia does not significantly impact 5-year survival whereas infection with B. cenocepacia pretransplant is associated with decreased survival.

Active Rehabilitation During Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation

BACKGROUND: Patients with end-stage lung disease often progress to critical illness, which dramatically reduces their chance of survival following lung transplantation. Pre-transplant deconditioning has a significant impact on outcomes for all lung transplant patients, and is likely a major contributor to increased mortality in critically ill lung transplant recipients. The aim of this report is to describe a series of patients bridged to lung transplant with extracorporeal membrane oxygenation (ECMO) and to examine the potential impact of active rehabilitation and ambulation during pre-transplant ECMO. METHODS: This retrospective case series reviews all patients bridged to lung transplantation with ECMO at a single tertiary care lung transplant center. Pre-transplant ECMO patients receiving active rehabilitation and ambulation were compared to those patients who were bridged with ECMO but did not receive pre-transplant rehabilitation. RESULTS: Nine consecutive subjects between April 2007 and May 2012 were identified for inclusion. One-year survival for all subjects was 100%, with one subject alive at 4 months post-transplant. The 5 subjects participating in pre-transplant rehabilitation had shorter mean post-transplant mechanical ventilation (4 d vs 34 d, P = .01), ICU stay (11 d vs 45 d, P = .01), and hospital stay (26 d vs 80 d, P = .01). No subject who participated in active rehabilitation had post-transplant myopathy, compared to 3 of 4 subjects who did not participate in pre-transplant rehabilitation on ECMO. CONCLUSIONS: Bridging selected critically ill patients to transplant with ECMO is a viable treatment option, and active participation in physical therapy, including ambulation, may provide a more rapid post-transplantation recovery. This innovative strategy requires further study to fully evaluate potential benefits and risks.

Significance of blood stream infection after lung transplantation: analysis in 176 consecutive patients.

BACKGROUND Although infection is a leading cause of death after lung transplantation, very little is known about the incidence, epidemiology, and clinical significance of bloodstream infections in lung transplant recipients. METHODS All blood cultures were reviewed in 176 consecutive lung transplant recipients over a 6-year period. Data were obtained from a prospectively collected microbiological database. RESULTS Bloodstream infection (BSI) occurred in 25% (44/176) of all lung transplant recipients over the 6-year study period. Staphylococcus aureus, Pseudomonas aeruginosa, and Candida species were the most common bloodstream isolates after lung transplantation. The epidemiology of posttransplant BSI, however, varied considerably between early and late posttransplant time periods and also differed between cystic fibrosis (CF) and non-CF patients. BSI infection after transplantation was associated with significantly worse survival by Kaplan-Meir analysis (P value log rank test=0.0001). In a multivariable logistic regression model, posttransplant BSI was a significant predictor of posttransplant death (odds ratio 5.62, CI 2.41-13.11, P=0.001), independent of other pre- and posttransplant factors. CONCLUSIONS Bloodstream infection represents a serious complication after lung transplantation, occurring more frequently than previously recognized, and independently contributing to posttransplant mortality.

Alemtuzumab in the Treatment of Refractory Acute Rejection and Bronchiolitis Obliterans Syndrome After Human Lung Transplantation

Despite substantial improvements in early survival after lung transplantation, refractory acute rejection (RAR) and bronchiolitis obliterans syndrome (BOS) remain major contributors to transplant‐related morbidity and mortality. We have utilized alemtuzumab, a humanized anti‐CD52 antibody which results in potent lymphocyte depletion, in consecutive patients with RAR (n = 12) or BOS (n = 10). All patients failed conventional treatment with methylprednisolone and antithymocyte globulin and received strict infection prophylaxis. Alemtuzumab significantly improved histological rejection scores in RAR. Total rejection grade/biopsy was 1.98 ± 0.25 preceding alemtuzumab versus 0.33 ± 0.14 posttreatment, p‐value <0.0001 (with a similar number of biopsies/patient per respective time interval). Freedom from BOS was observed in 65% of RAR patients 2 years after alemtuzumab treatment. Although there was no statistically significant change in forced expiratory volume in 1 second (FEV1) before and after alemtuzumab treatment in patients with BOS, a stabilization or improvement in BOS grade occurred in 70% of patients. Patient survival 2 years after alemtuzumab for BOS was 69%. Despite a dramatic decline in CD4 counts in alemtuzumab‐treated patients, only one patient developed a lethal infection. Thus, we provide the first evidence that alemtuzumab is a potentially useful therapy in lung transplant recipients with RAR or BOS.

Laparoscopic antireflux surgery in the lung transplant population

Background: Lung transplantation has emerged as a viable therapeutic option for patients with a variety of end-stage pulmonary diseases. As immediate posttransplant surgical outcomes have improved, the greatest limitation of lung transplantation remains chronic allograft dysfunction. Gastroesophageal reflux disease (GERD) with resultant aspiration has been implicated as a potential contributing factor in allograft dysfunction. GERD is prevalent in end-stage lung disease patients, and it is even more common in patients after transplantation. We report here on the safety of laparoscopic fundoplication surgery for the treatment of GERD in lung transplant patients. Methods: Eighteen of the 298 lung transplants performed at Duke University Medical Center underwent antireflux surgery for documented severe GERD. The safety and benefit of laparoscopic fundoplications in this population was evaluated. Results: The antireflux surgeries included 13 laparoscopic Nissen fundoplications, four laparoscopic Toupets, and one open Nissen (converted secondary to extensive adhesions). Two of the 18 patients reported recurrence of symptoms (11%), and two others reported minor GI complaints postoperatively (nausea, bloating). There were no deaths from the antireflux surgery. After fundoplication surgery, 12 of the 18 patients showed measured improvement in pulmonary function (67%). Conclusions: GERD occurs commonly in the posttransplant lung population. Laparoscopic fundoplication surgery, when indicated, can be done safely with minimal morbidity and mortality. In addition to the resolution of reflux symptoms, improvement in pulmonary function may be seen in this population after fundoplication. Lung transplant patients with severe GERD should be strongly considered for antireflux surgery.

Complement-mediated pulmonary xenograft injury: studies in swine-to-primate orthotopic single lung transplant models.

BACKGROUND The pathogenesis of acute pulmonary xenograft injury has not yet been determined. The present study evaluates the role of complement in mediating pulmonary xenograft dysfunction by using cobra venom factor (CVF) to deplete recipient complement and transgenic swine, which express human regulators of complement activation (human decay-accelerating factor [hDAF] and hCD59). METHODS Fifteen orthotopic lung transplants were performed as follows: group I, swine-to-swine (n=5); group II, unmodified swine-to-baboon (n=3); group III, unmodified swine-to-(CVF treated) baboon (n=3); and group IV, hCD59/hDAF swine-to-baboon (n=4). Left pulmonary artery flow and pulmonary vascular resistance were measured at 30-min intervals. Serial lung biopsies were examined by light microscopy and immunofluorescence. The activation of complement was quantified by measurement of baboon plasma CH50 and C4 functional activity. RESULTS Group II xenotransplants ceased functioning within 30 min of reperfusion. Histopathologic ab normalities included erythrocyte/platelet aggregates and hemorrhagic pulmonary edema. Groups I and IV showed excellent function throughout. hDAF/hCD59 lungs (group IV) showed trace venular fibrin plugs and moderate loss of alveolar architecture. Pretreatment with CVF (group III) was ineffective in preventing xenograft injury. CONCLUSIONS These results characterize the fundamental features of discordant pulmonary xenotransplantation. Correction of the known defects in the regulation of heterologous complement activation was partially effective in preventing pulmonary xenograft dysfunction, suggesting that complement mediates, in part, some of the features of acute lung injury after discordant lung xenotransplantation.

Baseline 6-Min Walk Distance Predicts Survival in Lung Transplant Candidates

In a large, prospectively followed, two‐center cohort of patients listed for lung transplantation (n = 376), we used Cox proportional hazards models to determine the importance of baseline 6‐min walk distance (6MWD) in predicting patient survival. 6MWD used as a continuous variable was a significant predictor of survival after adjusting for other important covariates when transplant was considered as a time‐varying covariate (HR for each 500 ft increase in 6MWD = 0.57, 95% CI: 0.43–0.77, p = 0.0002). 6MWD remained an important predictor of survival in models that considered only survival to transplant (HR for each 500 ft increase in 6MWD = 0.41, 95% CI: 0.27–0.62, p < 0.0001) or survival only after transplant (HR for each 500 ft increase in 6MWD = 0.40, 95% CI: 0.22–0.72, p = 0.002). Unadjusted Kaplan‐Meier analysis demonstrates significantly different survival by 6MWD tertiles (<900, 900–1200, or >1200 ft, p‐value = 0.0001). In the overall model, 6MWD prediction of survival was relatively homogeneous across disease category (6MWD by disease interaction term, p‐value = 0.63). Our results demonstrate a significant relationship between baseline 6MWD and survival among patients listed for lung transplantation that exists across all native disease categories and extends through transplantation. The 6MWD is thus a useful measure of both urgency and utility among patients awaiting lung transplantation.

Prolonged function of macrophage, von willebrand factor-deficient porcine pulmonary xenografts

Porcine von Willebrand factor (vWF) activates human and primate platelets. Having determined the importance of pulmonary intravascular macrophages (PIMs) in pulmonary xenotransplantation, we evaluated whether, in the absence of PIMs, vWF might play a role in pulmonary xenograft dysfunction.