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Lung transplantation for people with cystic fibrosis (PwCF) is a critical therapeutic option, in a disease without a cure to this day, and its overall success in this population is evident. The medical advancements in knowledge, treatment, and clinical care in the field of cystic fibrosis (CF) rapidly expanded and improved over the last several decades, starting from early pathology reports of CF organ involvement in 1938, to the identification of the CF gene in 1989. Lung transplantation for CF has been performed since 1983, and CF now accounts for about 17% of pre-transplantation diagnoses in lung transplantation recipients. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been the latest new therapeutic modality addressing the underlying CF protein defect with the first modulator, ivacaftor, approved in 2012. Fast forward to today, and we now have a growing CF population. More than half of PwCF are now adults, and younger patients face a better life expectancy than they ever did before. Unfortunately, CFTR modulator therapy is not effective in all patients, and efficacy varies among patients; it is not a cure, and CF remains a progressive disease that leads predominantly to respiratory failure. Lung transplantation remains a lifesaving treatment for this disease. Here, we reviewed the current knowledge of lung transplantation in PwCF, the challenges associated with its implementation, and the ongoing changes to the field as we enter a new era in the care of PwCF. Improved life expectancy in PwCF will surely influence the role of transplantation in patient care and may even lead to a change in the demographics of which people benefit most from transplantation.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no known effective therapy. It is often assumed, but has not been objectively evaluated, that pulmonary inflammation subsides as IPF progresses. The goal of this work was to assess changes in the degree of inflammatory cell infiltration, particularly lymphocytic infiltration, over the duration of illness in IPF. Sixteen patients with confirmed IPF were identified in patients whom surgical lung biopsy (SLB) was performed in early disease, and in patients whom lung transplantation was subsequently performed in end stage disease. A numerical scoring system was used to histologically quantify the amount of fibrosis, honeycomb change, fibroblastic foci, and lymphocyte aggregates in each SLB and lung explant tissue sample. Analyses of quantitative scores were performed by comparing paired, matched samples of SLB to lung explant tissue. Median time [1st, 3rd quartiles] from SLB to lung transplantation was 24 [15, 29] months. Histologic fibrosis and honeycomb change were more pronounced in the explant samples compared with SLB (P < 0.001 and P < 0.01, respectively), and most notably, higher numbers of lymphocyte aggregates were observed in the explant samples compared to SLB (P = 0.013). Immunohistochemical analyses revealed abundant CD3+ (T lymphocyte) and CD20+ (B lymphocyte) cells, but not CD68+ (macrophage) cells, within the aggregates. Contrary to the frequent assumption, lymphocyte aggregates were present in greater numbers in advanced disease (explant tissue) compared to early disease (surgical lung biopsy). This finding suggests that active cellular inflammation continues in IPF even in severe end stage disease.

The survival of patients receiving transplanted lungs is poorer than that of patients receiving transplants of many other organs. In this trial, inhaled cyclosporine, in addition to systemic immunosuppression, did not improve rejection rates but was associated with better overall survival and chronic rejection–free survival. In this trial, inhaled cyclosporine, in addition to systemic immunosuppression, did not improve rejection rates but was associated with better overall survival and chronic rejection–free survival. Outcomes after lung transplantation are poor as compared with those after heart, kidney, or liver transplantation, with a three-year survival rate of only 55 percent for recipients of lung transplants. Death is commonly due to chronic rejection, 1 which presents histologically as bronchiolitis obliterans 2 – 7 ); the latter is thought to be a complex response to immunologic, ischemic, and infectious injury. 8 – 11 Preventive and therapeutic strategies for this process have been largely unsuccessful. 12 – 14 Since the immunosuppressive effect of cyclosporine is dose-dependent, targeted delivery of this drug might improve efficacy by increasing the concentration of cyclosporine in the allograft. In animal . . .

Abstract 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are widely used antilipidemic agents that are also immunomodulatory. We evaluated possible effects of these agents after lung transplantation by comparing outcomes of 39 allograft recipients, who were prescribed statins for hyperlipidemia, with those of 161 contemporaneous control recipients who did not receive these drugs. Acute rejection (≥ Grade II) was less frequently found in the statin group (15.1 versus 25.6% of biopsies, p < 0.01). None of 15 recipients started on statins during postoperative Year 1 developed obliterative bronchiolitis, whereas the cumulative incidence of this complication among control subjects was 37% (p < 0.01). Total cellularity, as well as proportions of inflammatory neutrophils and lymphocytes, were significantly lower in bronchoalveolar lavages of statin recipients. Among double lung recipients, those taking statins had significantly better spirometry: FVC (80 ± 2 versus 70 ± 1%) and FEV1 (87 ± 2 versus 70 ± 1%), as percentages of predicted values, and absolute FEV1/FVC (83.4 ± 1.2 versus 78.6 ± 0.5) (all p < 0.01). The 6-year survival of recipients taking statins (91%) was much greater than that of control subjects (54%) (p < 0.01). These data suggest statin use may have substantial clinical benefits after pulmonary transplantation.

The six-minute walk test (6MWT) is a useful tool to predict outcomes in patients with advanced lung diseases. Greater distance walked has been shown to have more favorable prognostic value compared to other recorded variables. We reviewed the medical records of 164 patients with advanced lung disease who underwent lung transplant evaluation. Results of the 6MWT (distance walked, oxygen required, and mean gait speed) were recorded and alyzed with respect to mortality. 6MWT mean oxygen (O2) flow via sal cannula was 3.5 ± 3.7 L/min. The distance walked in meters (m) and % predicted were inversely associated with mortality, OR: 0.995 (0.992-0.998) and 0.970 (0.950-0.990), respectively. Patients who walked < 200 meters (OR: 2.1 (1.1-4.0)) or < 45% of predicted, OR: 2.7 (1.2-5.7) had higher mortality. O2 flow during the test had a direct association with mortality (OR: 1.1 (1.0-1.2). In multivariate alysis, O2 flow > 3.5 L/min remained predictive of mortality, OR: 1.1 (1.0-1.2). Mean gait speed was higher in patient who lived compared with patients who died (mean 0.83 ± 0.35 m/mim vs mean 0.69 ± 0.33 m/min, respectively, p= 0.03). Gait speed was a predictor of survival, OR 3.4 (1.1, 10.6). O2 flow during the 6MWT was an independent predictor of mortality in patients with advanced lung disease. The patients that required more than 3.5 L/m of O2 had a higher mortality. Faster gait speed during the 6MWT was also associated with better survival.

Doppler echocardiography and invasive hemodynamic parameters reflective of right ventricular failure are associated with a poor prognosis in patients with primary pulmonary hypertension (PPH). The aims of the present study were to examine whether ECG features in patients with PPH are associated with a decrease in survival, and to determine the value of the ECG in risk stratification. We analyzed the ECG, New York Heart Association (NYHA) class, and hemodynamic parameters in 51 untreated patients with PPH (88% women; mean age, 41.7 years; 79% NYHA classes III and IV) evaluated between 1992 and 1998. Subsequent treatment included epoprostenol in 37 patients, calcium channel blockers in 10 patients, epoprostenol and atrial septostomy in 2 patients, and lung transplant in 3 patients. As of 1999, 16 patients had died. Based on Kaplan-Meier estimates, median survival was > 6.5 years and estimated survival at 1 year, 3 years, and 5 years was 86%, 71%, and 57%, respectively. Significant predictors of decreased survival by Cox regression analysis include pulmonary vascular resistance (PVR; hazard ratio [HR], 1.11 per Wood unit), cardiac index (HR, 0.22 per L/min/m2), p wave amplitude in lead II (HR, 3.06 per mm), p ≥0.25 mV in lead II (HR, 2.77), qR in V1 (HR, 3.55), and World Health Organization criteria for right ventricular hypertrophy (HR, 4.26). After controlling for PVR, the HRs attributable to the ECG criteria were only slightly diminished. NYHA class and pulmonary artery pressures did not correlate with a decrease in survival. ECG parameters reflective of physiologic and anatomic abnormalities in the right ventricle are associated with decreased survival in patients with PPH, and may be useful for deciding therapeutic choices including the timing for lung transplantation listing.

Abstract Background: Chronic rejection, manifesting as bronchiolitis obliterans, is the leading cause of death in lung transplant recipients. In our previously reported double-blinded, placebo-controlled trial comparing inhaled cyclosporine (ACsA) to aerosol placebo, the rate of bronchiolitis-free survival improved. However, an independent analysis of pulmonary function, a secondary endpoint of the trial, was not performed. We sought to determine the effect of ACsA, in addition to systemic immunosuppression, on pulmonary function. Methods: From 1998–2001, 58 patients were randomly assigned to inhale either 300 mg of ACsA (28 patients) or placebo aerosol (30 patients) 3 days a week for the first 2 years after transplantation. Longitudinal changes in pulmonary function of ACsA patients were compared to aerosol placebo patients. In another analysis, the rate of decline from 6-month maximum FEV1 in randomized patients was compared to the rate of decline in patients receiving conventional immunosuppression from the Novartis transplant database (644 patients, 12 centers worldwide, transplanted from 1990–1995). Results: The average duration of ACsA and aerosol placebo was 400 days ± 306 and 433 ± 256, respectively. The change in FEV1 of ACsA patients (adjusted for Cytomegalovirus (CMV) mismatch and transplant type, followed for a maximum duration of 4.6 years) was superior to the aerosol placebo controls (9.0 ± 71.4 mL/year vs. −107.9 ± 55.3, p = 0.007). The FEF25–75 decreased by −220.3 ± 117.7 L/(second × year) vs. −412.2 ± 139.2, p = 0.07, respectively. Similarly, percent FEV1 decline from maximal values was improved in ACsA patients compared to aerosol placebo and Novartis controls (ACsA −0.43 ± 1.12%/year vs. aerosol placebo −4.08 ± 1.4, p = 0.04; ACsA vs. Novartis −4.7 ± 0.31, p = 0.007). Single-lung recipients receiving ACsA showed improvement in FEV1 compared to Novartis controls (FEV1 −0.8 ± 1.8%/year vs. −4.94 ± 0.4, p = 0.03) but double-lung recipients showed improvement compared to aerosol placebo controls only (FEV1 −0.28 ± 1.22%/year vs. −8.53 ± 5.95, p = 0.048). Conclusions: In this single center trial, ACsA appears to ameliorate important pulmonary function parameters in lung transplant recipients compared to aerosol placebo and historical control patients. Single- and double-lung transplant recipients may not respond uniformly to treatment, and ongoing randomized trials in lung transplant recipients using ACsA may help elucidate our findings.

To define the prevalence of colonization and infection of the lower respiratory tract (LRT) with Aspergillus in lung transplant recipients with and without cystic fibrosis (CF). Retrospective review. Large university lung transplant center. The postoperative course of 31 CF and 53 non-CF double lung or double lobar transplant recipients receiving allografts from April 1991 to February 1996 was reviewed. All recipients were subjected to surveillance bronchoscopy and biopsy at predetermined intervals and when clinically indicated. RAL fluid (RALF) and biopsy material were examined by appropriate fungal culture and staining techniques. Infection was defined by the finding of tissue-invasive disease on biopsy specimens. Seven of the 31 CF recipients (22%) had Aspergillus isolated from cultures of sputum prior to transplantation. Following transplantation, 15 CF recipients (48%) had Aspergillus isolated from either sputum or BALF, including 4 of the 7 recipients identified with the fungus prior to transplantation. By contrast, 21 of the 53 non-CF recipients (40%) had Aspergillus isolated from the LRT following transplantation, none having had the fungus isolated prior to transplantation. The prevalence of Aspergillus did not differ between these groups (p = 0.51). Infections with Aspergillus occurred in 4 of the CF recipients (27%) and did not differ from the 3 infections (14%) identified in the non-CF recipients (p = 0.36). However, three of the four infections in the CF recipients involved the healing bronchial anastomosis and occurred prior to postoperative day 60. All three of these recipients had Aspergillus preoperatively. Postoperative infection was more common in the CF recipients having Aspergillus preoperatively than in those CF recipients without preoperative Aspergillus (p = 0.02). Isolation of Aspergillus from the LRT following double lung transplantation is common and generally not associated with tissue-invasive disease. Those CF recipients with Aspergillus isolated in cultures of sputum preoperatively are at risk for postoperative infections with this agent. The healing bronchial anastomosis is particularly vulnerable.

Human parainfluenza virus (HPIV) is a common cause of seasonal respiratory tract infections. However, little is known about the clinical presentation and impact of HPIV infections in lung transplant recipients. We reviewed HPIV infections at the University of Pittsburgh Medical Center. From January 1990 through May 2000, 32 cases of HPIV infection were identified. HPIV infection was found in 24 lung transplant recipients (75%), all of whom were included in the study group. Diagnosis was established at a median of 2.1 years after transplantation (range, 0.6–5 years). Presenting symptoms included cough (17 patients), shortness of breath (16), and temperature elevation (4). Respiratory failure occurred in 5 patients (21%). The HPIV serotypes were HPIV-1 (7 patients), HPIV-2 (2), and HPIV-3 (15 [63%]). Twenty-two patients underwent transbronchial biopsy, and 18 (82%) showed signs of acute allograft rejection. Seven patients (32%) subsequently were found to have bronchiolitis obliterans.