Parametric Response Mapping as an Imaging Biomarker in Lung Transplant Recipients.

RATIONALE: The predominant cause of chronic lung allograft failure is small airway obstruction arising from bronchiolitis obliterans. However, clinical methodologies for evaluating presence and degree of small airway disease are lacking. OBJECTIVES: To determine if parametric response mapping (PRM), a novel computed tomography voxel-wise methodology, can offer insight into chronic allograft failure phenotypes and provide prognostic information following spirometric decline. METHODS: PRM-based computed tomography metrics quantifying functional small airways disease (PRMfSAD) and parenchymal disease (PRMPD) were compared between bilateral lung transplant recipients with irreversible spirometric decline and control subjects matched by time post-transplant (n = 22). PRMfSAD at spirometric decline was evaluated as a prognostic marker for mortality in a cohort study via multivariable restricted mean models (n = 52). MEASUREMENTS AND MAIN RESULTS: Patients presenting with an isolated decline in FEV1 (FEV1 First) had significantly higher PRMfSAD than control subjects (28% vs. 15%; P = 0.005), whereas patients with concurrent decline in FEV1 and FVC had significantly higher PRMPD than control subjects (39% vs. 20%; P = 0.02). Over 8.3 years of follow-up, FEV1 First patients with PRMfSAD greater than or equal to 30% at spirometric decline lived on average 2.6 years less than those with PRMfSAD less than 30% (P = 0.004). In this group, PRMfSAD greater than or equal to 30% was the strongest predictor of survival in a multivariable model including bronchiolitis obliterans syndrome grade and baseline FEV1% predicted (P = 0.04). CONCLUSIONS: PRM is a novel imaging tool for lung transplant recipients presenting with spirometric decline. Quantifying underlying small airway obstruction via PRMfSAD helps further stratify the risk of death in patients with diverse spirometric decline patterns.

Antifungal Prophylaxis in Lung Transplant Recipients.

Invasive fungal infection remains a serious postoperative complication in lung transplant recipients and is associated with significant morbidity and mortality. Although most lung transplant centers use antifungal prophylaxis, consensus on the strategy, choice of antifungal agent(s), route of administration, and duration of prophylaxis have not been established. This review provides an overview of the epidemiology and risk factors for common fungal infections seen in lung transplant recipients, evaluates the clinical efficacy and toxicity of the various antifungal agents used to prevent infection, and offers recommendations and opportunities for future research. Currently available data evaluating the efficacy of antifungal prophylaxis strategies is limited by a lack of prospective, randomized clinical trial data and variability in patient populations, prophylactic and immunosuppressive strategies, dosing, durations of use of antifungal agents, and definitions of invasive infection. There is controversy regarding significant risk factors for invasive fungal infection, which has limited the development and validation of targeted prophylactic strategies. Inhaled formulations of amphotericin B remain the most widely studied option for universal prophylaxis and have been shown to be effective in reducing the incidence of invasive Aspergillosis as compared with no prophylaxis. Concern over early postoperative extrapulmonary infection may suggest a benefit of initial prophylaxis with a systemic azole. Long-term use of systemic antifungals is not optimal due to emerging evidence of long-term toxicities. Multicenter, randomized trials are needed to ascertain the optimal prophylactic strategy in lung transplant recipients. New agents and delivery mechanisms may offer additional opportunities for comparative research.

Evaluation of a transplantation specialty pharmacy program.

PURPOSE: The value of a transplantation specialty pharmacy (TSP) program, including its impact on patient and health care provider satisfaction, selected clinical outcomes, and the institution's financial margin, was evaluated. METHODS: Patient and health care provider surveys were distributed to evaluate satisfaction with the TSP program. Medication adherence (using continuous measures of medication adherence), hospital readmissions within 90 days of transplantation, and length of hospitalization were examined. Patients enrolled in the TSP program who received kidney transplants between July 1, 2009, and June 30, 2010, were included. Patients who received kidney transplants at the institution between July 1, 2007, and June 30, 2008, served as the control group. RESULTS: Of the 838 patient surveys distributed, 290 (34.6%) were returned. Most patients (84%) reported being satisfied with the program, and 98% would recommend it to others. Ninety-six percent of providers believed the pharmacy improved continuity of care, and 91% reported spending less time on pharmacy-related problems after the program's initiation. Medication adherence appeared to be higher in patients enrolled in the TSP program compared with historical controls. Hospital readmissions and length of stay did not significantly differ between groups. The TSP program generated $7.5 million in revenue during its first fiscal year. Roughly $5.5 million was spent on incremental operating expenses, resulting in over $2 million in margin. CONCLUSION: A TSP program provided a high level of satisfaction to patients and health care providers, may have influenced some clinical outcomes, and served as a source of positive margin for its institution.

Lung transplantation across donor-specific anti-human leukocyte antigen antibodies: utility of bortezomib therapy in early graft dysfunction.

OBJECTIVE: To report the usefulness of bortezomib therapy in a sensitized lung transplant recipient experiencing antibody-mediated rejection. CASE SUMMARY: During a pretransplant evaluation, a 62-year-old woman with usual interstitial pneumonitis developed a diverticular bleed requiring transfusions, which elevated her panel reactive antibody to 98% for human leukocyte antigen (HLA) class I and 71% for class II. She underwent desensitization to decrease her panel reactive antibody levels. She received a double lung transplant across a weak HLA class II incompatibility but developed respiratory failure due to early graft dysfunction. On postoperative day (POD) 14 she was found to have donor-specific antibodies (DSA) to HLA class I and class II antigens. She received intravenous immunoglobulin (IVIG), plasmapheresis, and bortezomib to reduce the DSA. Repeat DSA testing on POD 80 demonstrated a 50% reduction in DSA, which became undetectable at POD 255. DISCUSSION: Antibody-mediated rejection (AMR) is difficult to diagnose and treat in lung transplantation. Since primary treatment options such as plasmapheresis and IVIG alone may not adequately eradicate DSA, the proteasome inhibitor bortezomib can be of additional value for the treatment of AMR. Bortezomib causes apoptosis of plasma cells, thus eliminating the production of allograft-specific DSA. CONCLUSIONS: This is the first report describing the utility of bortezomib for early graft dysfunction in a highly sensitized lung transplant recipient. Although this patient had preformed donor-specific anti-HLA antibodies, AMR was successfully treated with a combination of plasmapheresis, IVIG, and bortezomib. At time of writing, the patient continued to have excellent graft function 2 years posttransplant. Bortezomib is a potent inhibitor of plasma cell production and it appears to be useful for the treatment of antibody-mediated graft dysfunction.

Abnormal glucose metabolism and metabolic syndrome in non-diabetic kidney transplant recipients early after transplantation.

BACKGROUND: Abnormal glucose metabolism (AGM) and metabolic syndrome (MS) are individually associated with a poor cardiovascular outcome in kidney transplant recipients. We prospectively studied the relationship between AGM and MS in non-diabetic kidney transplant recipients early after transplantation. METHODS: A total of 203 de novo kidney transplant recipients underwent standard 2-hr glucose tolerance test 10 weeks after transplantation. Demographic and clinical characteristics were collected. AGM was defined as impaired fasting glucose, impaired glucose tolerance, and new onset diabetes after transplant according to the WHO criteria, and MS was defined according to the National Cholesterol Education Expert Panel criteria. RESULTS: Overall, 97 patients (47.8%) met the diagnosis of AGM and 98 patients (48.3%) met the criteria of MS. AGM and MS are highly associated (chi, P<0.001). Fasting plasma glucose levels before the transplant are independent predictors common for AGM and MS. Age predicts AGM with and without MS, whereas body mass index before transplant predicts MS. Patients with impaired glucose tolerance and new-onset diabetes after transplant displayed significant worsening of their fasting plasma glucose levels during the 10-week observational period. MS and the components of MS, but not AGM, were associated with reduced transplant renal function (P=0.002). CONCLUSION: The early screening of AGM and MS should be emphasized, and the role of early therapeutic interventions aimed at both conditions explored. The long-term follow-up of these patients will yield more insight on the significance of such findings.

Clinical and economic outcomes of rabbit antithymocyte globulin induction in adults who received kidney transplants from living unrelated donors and received cyclosporine-based immunosuppression.

STUDY OBJECTIVE: To evaluate the efficacy, safety, and costs of rabbit antithymocyte globulin (TMG) induction in patients who received kidney transplants from living unrelated donors. DESIGN: Retrospective cohort study. SETTING: Large academic medical center. PATIENTS: Eighty-seven patients who received kidney transplants from living unrelated donors: 40 of the recipients underwent transplantation between January 1, 2003, and December 31, 2004, and did not receive TMG induction (no induction group); 47 underwent transplantation between January 1, 2005, and June 30, 2006, and received TMG induction (induction group). All patients received cyclosporine-based immunosuppression. MEASUREMENTS AND MAIN RESULTS: Biopsy-proven acute rejection, posttransplantation complications, and inpatient hospital costs for the first 12 months after transplantation were compared between groups using standard univariate statistical analyses. Induction significantly decreased the occurrence of biopsy-proven acute rejection versus no induction (2% vs 48%, p<0.001). Fifty percent of rejection episodes in the no induction group required hospitalization, and 46% of rejection episodes required TMG treatment. Slightly elevated initial costs associated with TMG induction were offset by lower costs related to rejection treatment. Total inpatient costs for the 12 months after transplantation were comparable between the groups (no induction $66,038 vs induction $74,183, p>0.05). For the no induction versus induction groups, no significant differences in cytomegalovirus disease (5% vs 6%), malignancy (3% vs 2%), graft failures (5% vs 6%), mortality (5% vs 4%), and serum creatinine concentrations (mean +/- SD 1.4 +/- 0.3 vs 1.5 +/- 0.3 mg/dl) were observed at 12 months (p>0.05 for all comparisons). CONCLUSION: Five-day TMG induction effectively reduced the 1-year acute rejection rate without significantly increasing total inpatient costs or posttransplantation complications among recipients of kidney transplants from living unrelated donors.

Six-month prophylaxis is cost effective in transplant patients at high risk for cytomegalovirus infection.

The risk of late-onset cytomegalovirus (CMV) infection remains a concern in seronegative kidney and/or pancreas transplant recipients of seropositive organs despite the use of antiviral prophylaxis. The optimal duration of prophylaxis is unknown. We studied the cost effectiveness of 6- versus 3-mo prophylaxis with valganciclovir. A total of 222 seronegative recipients of seropositive kidney and/or pancreas transplants received valganciclovir prophylaxis for either 3 or 6 mo during two consecutive time periods. We assessed the incidence of CMV infection and disease 12 mo after completion of prophylaxis and performed cost-effectiveness analyses. The overall incidence of CMV infection and disease was 26.7% and 24.4% in the 3-mo group and 20.9% and 12.1% in the 6-mo group, respectively. Six-month prophylaxis was associated with a statistically significant reduction in risk for CMV disease (HR, 0.35; 95% CI, 0.17 to 0.72), but not infection (HR, 0.65; 95% CI, 0.37 to 1.14). Cost-effectiveness analyses showed that 6-mo prophylaxis combined with a one-time viremia determination at the end of the prophylaxis period incurred an incremental cost of $34,362 and $16,215 per case of infection and disease avoided, respectively, and $8,304 per one quality adjusted life-year gained. Sensitivity analyses supported the cost effectiveness of 6-mo prophylaxis over a wide range of valganciclovir and hospital costs, as well as variation in the incidence of CMV disease. In summary, 6-mo prophylaxis with valganciclovir combined with a one-time determination of viremia is cost effective in reducing CMV infection and disease in seronegative recipients of seropositive kidney and/or pancreas transplants.