A.B. Cochrane

Current strategies and future trends in immunosuppression after heart transplantation.

Purpose of reviewCurrent immunosuppressive drugs have provided excellent outcomes after heart transplantation. However, more patients suffer from long-term complications of these drugs. A series of prospective randomized trials has been conducted and has offered disparate results. This report reviews the challenges of immunosuppressive therapy during the past decade, describes recent reports and explores potential future trends in immunosuppressive protocols in heart transplantation. Recent findingsThe traditional combination of cyclosporine, azathioprine and steroids has been changed to tacrolimus (Tac) or cyclosporine in combination with mycophenolate mofetil (MMF) and steroids due to the results of several trials. The use of mammalian target of rapamycin inhibitors in combination with Tac or cyclosporine A has not shown a clear benefit compared with MMF. All different combinations have shown some positive effects counteracted by side-effects and negative synergism of combinations. Future protocols need to be adapted according to individual patients needs and risks. SummaryThe changing population of heart transplantation patients has become older and sicker. Immunosuppression strategies should be developed for each patient based on their risk for rejection and their risk for developing important complications of immunosuppressive therapy.

Induction therapy in heart transplantation: where are we now?

Although induction therapy has been used in heart transplantation for many years, its role has not been fully elucidated. Early safety concerns relating to OKT3 or intensive lymphocyte‐depleting regimens have largely been addressed by modern induction protocols using rabbit antithymocyte globulin (rATG [Thymoglobuline® or ATG‐Fresenius]) and interleukin‐2 receptor antagonist (IL‐2RA) agents, but although the number of randomized controlled studies has expanded there are still gaps in the evidence base. Rejection prophylaxis may be somewhat more effective with rATG than IL‐2RA agents, but this has not been proven conclusively. Administration of induction therapy to support delayed introduction of calcineurin inhibitors in patients at risk of renal dysfunction is relatively well documented and widely used. Increasingly, it is recognized that sensitized patients and individuals with primary graft function are suitable candidates for induction therapy, and the possibility that rATG may inhibit cardiac allograft vasculopathy is also of considerable interest. Until the question of whether rATG is associated with increased risk of infection, routine prophylaxis is advisable. IL‐2RA induction has an excellent safety profile. Dosing rATG according to lymphocyte count reduces cumulative dose without compromising efficacy. Further controlled trials are required to determine when and how to deploy induction most effectively following heart transplantation.

An ISHLT consensus document for prevention and management strategies for mechanical circulatory support infection

1053-2498/

Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis

see fron rights reserved. http://dx.doi.org/10.10 Authors’ Disclosure The authors have m Heart and Lung Transp S.A., P.G., M.H., S.M Pediatric Thoracic T Schubert) Nursing, Health Sci Heart Failure and T F.G., A.L., S.P., S.Sch Pharmacy and Phar Mechanical Circulat F.G., A.L., S.P., S.S., The following auth Circulatory Assist Clin Reprint requests: S Arizona, 5777 East M +480 342 0115. Fax: E-mail address: ku CONSENSUS STATEMENT

Impact of the Pharmacy Practice Model Initiative on Clinical Pharmacy Specialist Practice: An Alternative Viewpoint.

BACKGROUND Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation. METHODS We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs. RESULTS Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels. CONCLUSION Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.

The impact of early de novo donor-specific antibodies on lung transplant outcomes: Is timing everything?

The American Society of Health-System Pharmacists’ Pharmacy Practice Model Initiative (PPMI) aims to develop and disseminate pharmacy practice models that optimize the use of pharmacists as direct care providers.1 In their commentary, Jacobi and colleagues highlight opportunities and challenges presented through the PPMI, and draw attention to potential negative consequences for clinical pharmacy specialists.2 We present the transplant specialist perspective. This article is protected by copyright. All rights reserved.

Rapid High Dose Vaccine Series: Increasing Immunity to Hepatitis B in Lung Transplant Candidates

Despite significant advances in the field of lung transplantation (LT), long-term outcomes remain sub-optimal. Survival at 5 years after LT is a dismal 58%, the lowest amongst solidorgan transplants. 1 The disparity in survival between LT and other solid-organ transplants is largely attributable to chronic lung allograft dysfunction (CLAD), which is responsible for more than 40% of deaths occurring beyond 1 year after transplantation. 2,3 Improved understanding of the mechanisms leading to CLAD is essential to the development of preventative or therapeutic strategies for this currently irreversible condition. A number of risk factors for the development of CLAD have been identified, including infections (viral, bacterial, and fungal), primary graft dysfunction, gastroesophageal reflux disease and microaspiration, recipient genetic factors, and acute cellular rejection. 4 An increasingly reported risk factor for CLAD is the development of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs). De novo DSAs develop in 13% to 55% of LT recipients and are associated with decreased allograft and patient survival. 5–12 In this edition of the Journal of Heart and Lung Transplantation, Le Pavec et al 13 present an important new addition to the available literature regarding the effect of de novo DSAs on LT outcomes. The authors prospectively monitored 134 patients with no pre-transplant DSAs who underwent bilateral lung or heart-lung transplantation at their institution during a period of approximately 7 years. Patients were screened for anti-HLA antibodies immediately before and at 1 week, and 1, 3, and 6 months after transplantation. Mean fluorescence intensity (MFI) intervals were used to define the degree of antiHLA antibody positivity (a score of 4 for 500–1,000, a score of 6 for MFI 1,000–3,000, and a score of 8 for an MFI43000). A univariate and multivariate analysis was performed to identify independent predictors of CLAD development and mortality. De novo DSAs developed in 82 patients (61%). It is notable that this is a higher incidence of DSA development than previously reported. The authors propose a number of plausible potential reasons for this, including use of the highly sensitive Luminex assay (Luminex Corp) for DSA detection and a preponderance of female recipients (61%) who may have been predisposed to development of DSAs through sensitizing events such as pregnancy. Although numerous studies have established a link between de novo DSA development and outcomes, this study is unique in that it analyzes the effect of the timing of development of DSAs on outcomes. A multivariate analysis showed only DSAs with an MFI score Z 4 at 1 month posttransplantation were independent predictors of poor survival and CLAD development. The presence of de novo DSAs at 1 month had a profound effect on long-term survival, with 3- and 5-year survival rates of 52% and 41% vs 74% and 70%, respectively, for those with vs without DSAs at 1 month (p ¼ 0.02). DSAs at 3, 6, and 12 months post-transplantation were not associated with adverse effects regardless of the degree of anti-HLA antibody positivity. This study suggests that the early development of DSAs has a more profound effect on outcomes than later development. The authors hypothesize this may be because of increased HLA exposure of the allograft resulting from increased inflammation in the early period after transplantation. The study has several notable limitations. The study population is derived from a single center with a high proportion of acutely ill patients, many of whom had pulmonary hypertension; thus, the findings may not be generalizable to other centers. Although the sample size is