• Gait-speed and oxygen flow during six-minute walk test predicts mortality in patients with advanced lung disease

      Timofte, I.; Diaz-Abad, M.; Verceles, A.; Iacono, A.; Terrin, M.L.; Wijesinha, M. (PAGEPress Publications, 2020)
      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 independent prognostic value. 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 to maintain oxygen saturation >90%, and gait speed) were recorded and analyzed with respect to mortality. 6MWT mean oxygen (O2) flow via nasal cannula was 3.5±3.7 l/min. The distance walked in meters (m) and percent predicted distance were inversely associated with mortality, hazard ratio (HR): 0.995 per meter (95% CI 0.992-0.998) for walk distance in meters and 0.970 per % predicted distance (95% CI 0.950-0.990). Patients who walked <200 meters [HR: 2.1 (95% CI 1.1-4.0)] or <45% of predicted, HR: 2.7 (95% CI 1.2-5.7) had higher mortality. O2 flow during the test had a direct association with mortality (HR: 1.1 per L/min (95% CI 1.0-1.2). In multivariate analysis, O2 flow >3.5 L/min remained predictive of mortality, HR: 1.1 per l/min (95% CI 1.0-1.2). Gait speed was higher in patients who survived through follow-up compared to patients who died (mean 0.83±0.35 m/s vs 0.69±0.33 m/s, p=0.03). Gait speed >0.8 m/s was a predictor of survival, HR 3.4 (1.1, 10.6). In summary, distance walked and O2 flow during the 6MWT were predictors of mortality in patients with advanced lung disease. Patients who required more than 3.5 l/m of O2 to maintain oxygen saturation >90% had a higher mortality. Faster gait speed during the 6MWT was also associated with better survival. Copyright the Author(s), 2020.
    • Prophylactic epinephrine for the prevention of transbronchial lung biopsy-related bleeding in lung transplant recipients (PROPHET) study: A protocol for a multicentre randomised, double-blind, placebo-controlled trial

      Kalchiem-Dekel, O.; Iacono, A.; Pickering, E.M. (BMJ Publishing Group, 2019)
      Introduction Transbronchial lung biopsy (TBLB) is frequently performed in single-lung and double-lung transplant recipients for evaluation of clinical and radiological findings as well as routine surveillance for acute cellular rejection. While rates of clinically significant TBLB-related haemorrhage are <1% for all comers, the incidence in lung transplant recipients is reported to be higher, presumably due to persistent allograft inflammation and alterations in allograft blood flow. While routinely performed by some bronchoscopists, the efficacy and safety profile of prophylactic administration of topical intrabronchial diluted epinephrine for the prevention of TBLB-related haemorrhage has not been explored in a prospective manner. Methods and analysis In this randomised, double-blind, placebo-controlled multicentre trial (PROPHET Study), single-lung and double-lung transplant adult recipients from participating institutions who are scheduled for bronchoscopy with TBLB for clinical indications will be identified. Potential participants who meet inclusion and exclusion criteria and sign an informed consent will be randomised to receive either diluted epinephrine or placebo prior to performance of TBLB. The degree of TBLB-related haemorrhage will be graded by the performing bronchoscopist as well as independent observers. The primary analysis will compare the rates of severe and very severe bleeding in participants treated with epinephrine or placebo. The study will also evaluate the safety profile of prophylactic topical epinephrine including the occurrence of serious cardiovascular and haemodynamic adverse events. Additional secondary outcomes to be explored include rates of non-severe TBLB-related haemorrhage, overall yield of the bronchoscopic procedure and non-serious cardiovascular and haemodynamic adverse effects. Ethics and dissemination The study procedures were reviewed and approved by institutional review boards in participating institutions. This study is being externally monitored, and a data and safety monitoring committee has been assembled to monitor patient safety and to evaluate the efficacy of the intervention. The results of this study will be published in peer-reviewed scientific journals and presented at relevant academic conferences. Trial registration number NCT03126968; Pre-results. Copyright Author(s) (or their employer(s)) 2019.
    • A randomised single-centre trial of inhaled liposomal cyclosporine for bronchiolitis obliterans syndrome post-lung transplantation

      Iacono, A.; Wijesinha, M.; Murdock, N.; Timofte, I.; Griffith, B.; Terrin, M. (European Respiratory Society, 2019)
      Introduction: No proven treatments exist for bronchiolitis obliterans syndrome (BOS) following lung transplantation. Inhaled liposomal cyclosporine (L-CsA) may prevent BOS progression. Methods: A 48-week phase IIb randomised clinical trial was conducted in 21 lung transplant patients with BOS assigned to either L-CsA with standard-of-care (SOC) oral immunosuppression (L-CsA group) or SOC (SOC-alone group). Efficacy end-points were BOS progression-free survival (defined as absence of ⩾20% decline in forced expiratory volume in 1 s (FEV1) from randomisation, re-transplantation or death) and BOS grade change. Results: BOS progression-free survival was 82% for L-CsA versus 50% for SOC-alone (p=0.1) and BOS grade worsened in 18% for L-CsA versus 60% for SOC-alone (p=0.05). Mean changes in ΔFEV1 and forced vital capacity, respectively, stabilised with L-CsA: +0.005 (95% CI −0.004–+0.013) and −0.005 (95% CI −0.015–+0.006) L·month−1, but worsened with SOC-alone: −0.023 (95% CI −0.033–−0.013) and −0.026 (95% CI −0.039–−0.014) L·month−1 (p<0.0001 and p=0.009). Median survival (4.1 versus 2.9 years; p=0.03) and infection rate (45% versus 60%; p=0.7) improved with L-CsA versus SOC-alone; creatinine and tacrolimus levels were similar. Conclusions: L-CsA was well tolerated and stabilised lung function in lung transplant recipients affected by BOS without systemic toxicity, providing a basis for a global phase III trial using L-CsA.
    • Survival Associated With Sirolimus Plus Tacrolimus Maintenance Without Induction Therapy Compared With Standard Immunosuppression After Lung Transplant

      Wijesinha, M.; Hirshon, J.M.; Terrin, M.; Magder, L.; Brown, C.; Stafford, K.; Iacono, A. (JAMA Network Open, 2019)
      Importance: Median survival after lung transplant is less than 6 years. Standard maintenance therapy typically includes tacrolimus and an antimetabolite (mycophenolate mofetil or azathioprine). Replacing the antimetabolite with sirolimus after postoperative wound healing may improve long-term survival due to antifibrotic, antiproliferative, and antiaging effects of sirolimus. Objectives: To compare survival between patients receiving sirolimus plus tacrolimus vs mycophenolate mofetil plus tacrolimus (the most common maintenance therapy) and to identify the combination of induction and maintenance therapy associated with the highest survival. Design, Setting, and Participants: This cohort study of US recipients of lung transplants from January 1, 2003, through August 31, 2016, analyzed United Network for Organ Sharing (UNOS) data from January 1 through September 13, 2018. Because initiation of sirolimus therapy is usually delayed 3 to 12 months after lung transplant, primary analyses were based on patients alive and free of chronic rejection and malignant disease at 1 year in all groups, whereas sensitivity analyses used appropriate methods to include all patients from transplant time. Regression models adjusted for available potential confounders, including transplant center performance. Exposures: Cell cycle inhibitor maintenance therapies, including sirolimus (n = 219), mycophenolate mofetil (n = 5782), mycophenolate sodium (n = 408), azathioprine (n = 2556), and concurrent sirolimus plus mycophenolate mofetil (n = 54), were compared within a tacrolimus-based regimen. Combinations of each induction (basiliximab, daclizumab, antithymocyte globulin, alemtuzumab, or none) and maintenance (tacrolimus plus sirolimus, mycophenolate mofetil, or azathioprine) therapy were also compared. Main Outcomes and Measures: Survival was the primary outcome; chronic rejection incidence and subsequent mortality were secondary outcomes. Results: Among this population of 9019 patients (median age, 57 years [interquartile range {IQR}, 46-63 years]; 5194 men [57.6%]), sirolimus plus tacrolimus was associated with better survival than mycophenolate mofetil plus tacrolimus (median, 8.9 years [IQR, 4.4-12.7 years] vs 7.1 years [IQR, 3.6-12.1 years]; adjusted hazard ratio [aHR], 0.71; 95% CI, 0.56-0.89; P = .003). Chronic rejection incidence (aHR, 0.75; 95% CI, 0.61-0.92) and mortality after chronic rejection (aHR, 0.52; 95% CI, 0.31-0.81) were lower with sirolimus plus tacrolimus. Compared with mycophenolate mofetil plus tacrolimus, survival differences for sirolimus plus mycophenolate mofetil plus tacrolimus (aHR, 1.14; 95% CI, 0.79-1.65), mycophenolate sodium plus tacrolimus (aHR, 0.95; 95% CI, 0.77-1.17), and azathioprine plus tacrolimus (aHR, 0.93; 95% CI, 0.84-1.02) were not significant. The induction-maintenance combination with the highest survival was sirolimus plus tacrolimus without induction therapy (median survival, 10.7 years [IQR, 7.3-12.7 years]; aHR, 0.48; 95% CI, 0.31-0.76; P = .002) compared with mycophenolate mofetil plus tacrolimus with induction therapy (median survival, 7.4 years [IQR, 3.9-12.6 years]). Conclusions and Relevance: Sirolimus plus tacrolimus was associated with improved patient survival after lung transplant compared with mycophenolate mofetil plus tacrolimus; no antibody induction therapy with sirolimus plus tacrolimus was associated with maximal survival.