Scott M. Palmer

Gastroesophageal reflux disease in lung transplant recipients

Abstract: Background: Chronic allograft dysfunction after lung transplantation contributes to poor long‐term survival. A link between gastric aspiration and post‐transplant lung dysfunction has been suggested, but little is known about the significance of gastroesophageal reflux disease (GERD) after lung transplantation.

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.

DEVELOPMENT OF AN ANTIBODY SPECIFIC TO MAJOR HISTOCOMPATIBILITY ANTIGENS DETECTABLE BY FLOW CYTOMETRY AFTER LUNG TRANSPLANT IS ASSOCIATED WITH BRONCHIOLITIS OBLITERANS SYNDROME

Background. Chronic allograft rejection manifested as bronchiolitis obliterans syndrome (BOS) is the leading cause of late death after lung transplantation. Although increasing evidence suggests an association between anti-human leukocyte antigens (HLA) antibodies and chronic rejection of kidney or heart allografts, the clinical significance of anti-HLA antibodies in lung recipients is less clear, especially in previously unsensitized recipients. The use of flow cytometry based panel reactive antibody (flow-PRA) provides a highly sensitive means to identify the development of de novo anti-HLA antibodies in lung recipients. Methods. Flow-PRA testing was used to analyze the pre- and posttransplant sera in stable BOS free lung recipients who survived at least 6 months. Patients without prior sensitization as defined by a negative pretransplant flow-PRA were analyzed posttransplant for the presence of anti-HLA antibodies by flow-PRA. A proportional hazards model was used to determine the impact of anti-HLA antibody on BOS risk. Results. Sera from 90 recipients at Duke University with negative pretransplant flow-PRA were tested by flow-PRA at various time points after transplant. Sera from 11% (10/90) of recipients were found to contain anti-HLA antibodies detectable by flow-PRA. Nine patients (90%) developed anti-HLA antibodies specific for donor antigens, and one patient developed anti-HLA class II antibodies, not specific to donor antigens. Among the nine patients with donor antigen specific antibodies, flow-PRA specificity analysis demonstrated eight were specific for class II antigens and one for class I antigens. In a multivariate model that controls for other BOS risk factors, a positive posttransplant flow-PRA was significantly associated with BOS grades 1,2, or 3 (hazard ratios [HR] 3.19; 95% confidence interval [CI]: 1.41–7.12, P =0.005) and BOS grade 2 or 3 (HR 4.08; 95% CI: 1.66–10.04, P =0.002). Four patients with de novo anti-HLA antibodies died during follow-up; all four had BOS. Among BOS patients, the presence of anti-HLA antibodies was associated with a significantly worse survival (P =0.05, log-rank test). Conclusions. Although uncommon, previously unsensitized lung transplant recipients can develop anti-HLA antibodies to donor class II antigens. The development of de novo anti-HLA antibodies significantly increases the risk for BOS, independent of other posttransplant events. Furthermore, de novo anti-HLA antibodies identify BOS patients with significantly worse survival. Additional studies are needed to determine if class II–directed anti-HLA antibodies contribute mechanistically to the chronic rejection process in lung recipients.

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.

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention. Diagnosis of BOS requires careful exclusion of other complications that can cause delayed lung allograft dysfunction http://ow.ly/AZmbr

Bronchiolitis Obliterans Syndrome: The Final Frontier for Lung Transplantation

Bronchiolitis obliterans syndrome (BOS) is a form of chronic lung allograft dysfunction that affects a majority of lung transplant recipients and is the principal factor limiting long-term transplant survival. BOS is characterized by progressive airflow obstruction unexplained by acute rejection, infection, or other coexistent condition. Although BOS is a proven useful clinical syndrome that identifies patients at increased risk for death, its clinical course and underlying causative factors are now recognized to be increasingly heterogeneous. Regardless of the clinical history, the primary pathologic correlate of BOS is bronchiolitis obliterans, a condition of intraluminal airway fibrosis. This article highlights the body of developing research illustrating the mechanisms by which BOS is mediated, including alloimmune reactivity, the emerging roles of humoral and autoimmunity, activation of innate immune cells, and response to nonimmune-related allograft insults, such as infection and aspiration. In addition, we underscore emerging clinical implications and promising future translational research directions that have the potential to advance our knowledge and improve patient outcomes.

The Role of Hyaluronan Degradation Products as Innate Alloimmune Agonists

Dendritic cells (DCs) play a key role in initiating alloimmunity yet the substances that activate them during the host response to transplantation remain elusive. In this study we examined the potential roles of endogenous innate immune agonists in activating dendritic cell‐dependent alloimmunity. Using a murine in vitro culture system, we show that 135 KDa fragments of the extracellular matrix glycosaminoglycan hyaluronan induce dendritic cell maturation and initiate alloimmunity. Priming of alloimmunity by hyaluronan‐activated DCs was dependent on signaling via TIR‐associated protein, a Toll‐like receptor (TLR) adaptor downstream of TLRs 2 and 4. However, this effect was independent of alternate TLR adaptors, MyD88 or Trif. Using an in vivo murine transplant model, we show that hyaluronan accumulated during skin transplant rejection. Examination of human lung transplant recipients demonstrated that increased levels of intragraft hyaluronan were associated with bronchiolitis obliterans syndrome. In conclusion, our study suggests that fragments of hyaluronan can act as innate immune agonists that activate alloimmunity.

Safety of aerosolized amphotericin B lipid complex in lung transplant recipients

Background. Fungal infections remain an important cause of morbidity and mortality in lung transplant recipients. Aerosolized amphotericin B lipid complex (ABLC) may be more efficacious than conventional amphotericin B in the prevention of fungal infections in animal models, but experience with aerosolized ABLC in humans is lacking. Methods. We conducted a prospective, noncomparative study designed to evaluate safety of aerosolized ABLC in lung or heart-lung transplant recipients. Results. A total of 381 treatments were administered to 51 patients. Complete spirometry records were available for 335 treatments (69 in intubated patients, 266 in extubated patients). ABLC was subjectively well tolerated in 98% of patients. Pulmonary mechanics worsened by 20% or more posttreatment in less than 5% of all treatments. There were no significant adverse events related to study medication in any patient, and 1-year survival for all enrolled patients was 78%. Conclusion. Administration of nebulized ABLC is safe in the short-term and well-tolerated in lung transplant recipients. Additional prospective, randomized studies are needed to determine the efficacy of aerosolized ABLC alone or in conjunction with systemic therapies in the prevention of fungal infections in lung transplant recipients.

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.

Acute Rejection and Humoral Sensitization in Lung Transplant Recipients

Despite the recent introduction of many improved immunosuppressive agents for use in transplantation, acute rejection affects up to 55% of lung transplant recipients within the first year after transplant. Acute lung allograft rejection is defined as perivascular or peribronchiolar mononuclear inflammation. Although histopathologic signs of rejection often resolve with treatment, the frequency and severity of acute rejections represent the most important risk factor for the subsequent development of bronchiolitis obliterans syndrome (BOS), a condition of progressive airflow obstruction that limits survival to only 50% at 5 years after lung transplantation. Recent evidence demonstrates that peribronchiolar mononuclear inflammation (also known as lymphocytic bronchiolitis) or even a single episode of minimal perivascular inflammation significantly increase the risk for BOS. We comprehensively review the clinical presentation, diagnosis, histopathologic features, and mechanisms of acute cellular lung rejection. In addition, we consider emerging evidence that humoral rejection occurs in lung transplantation, characterized by local complement activation or the presence of antibody to donor human leukocyte antigens (HLA). We discuss in detail methods for HLA antibody detection as well as the clinical relevance, the mechanisms, and the pathologic hallmarks of humoral injury. Treatment options for cellular rejection include high-dose methylprednisolone, antithymocyte globulin, or alemtuzumab. Treatment options for humoral rejection include intravenous immunoglobulin, plasmapheresis, or rituximab. A greater mechanistic understanding of cellular and humoral forms of rejection and their role in the pathogenesis of BOS is critical in developing therapies that extend long-term survival after lung transplantation.