Relative Lung Perfusion on Ventilation-Perfusion Scans After Double Lung Transplant.

BACKGROUND: Pulmonary blood flow can be assessed on ventilation-perfusion (VQ) scan with relative lung perfusion, with a 55% to 45% (or 10%) right-to-left differential considered normal. We hypothesized that wide perfusion differential on routine VQ studies at 3 mo posttransplant would be associated with an increased risk of death or retransplantation, chronic lung allograft (CLAD), and baseline lung allograft dysfunction. METHODS: We conducted a retrospective cohort study on all patients who underwent double-lung transplant in our program between 2005 and 2016, identifying patients with a wide perfusion differential of >10% on a 3-mo VQ scan. We used Kaplan-Meier estimates and proportional hazards models to assess the association between perfusion differential and time to death or retransplant and time to CLAD onset. We used correlation and linear regression to assess the relationship with lung function at time of scan and with baseline lung allograft dysfunction. RESULTS: Of 340 patients who met inclusion criteria, 169 (49%) had a relative perfusion differential of ≥ 10% on a 3-mo VQ scan. Patients with increased perfusion differential had increased risk of death or retransplantation ( P = 0.011) and CLAD onset ( P = 0.012) after adjustment for other radiographic/endoscopic abnormalities. Increased perfusion differential was associated with lower lung function at time of scan. CONCLUSIONS: Wide lung perfusion differential was common after lung transplant in our cohort and associated with increased risk of death, poor lung function, and CLAD onset. The nature of this abnormality and its use as a predictor of future risk warrant further investigation.

Safety of Crossing Donor-specific Antibodies in Lung Transplantation.

BACKGROUND: Donor-specific antibodies (DSAs) have been associated with antibody-mediated rejection, chronic lung allograft dysfunction (CLAD), and increased mortality in lung transplant recipients. Our center performs transplants in the presence of DSA, and we sought to evaluate the safety of this practice with respect to graft loss, CLAD onset, and primary graft dysfunction (PGD). METHODS: We reviewed recipients transplanted from 2010 to 2017, classifying them as DSA positive (DSA + ) or negative. We used Kaplan-Meier estimation to test the association between DSA status and time to death or retransplant and time to CLAD onset. We further tested associations with severe PGD and rejection in the first year using logistic regression and Fisher exact testing. RESULTS: Three hundred thirteen patients met inclusion criteria, 30 (10%) of whom were DSA + . DSA + patients were more likely to be female, bridged to transplant, and receive induction therapy. There was no association between DSA status and time to death or retransplant (log rank P = 0.581) nor death-censored time to CLAD onset (log rank P = 0.278), but DSA + patients were at increased risk of severe PGD (odds ratio 2.88; 95% confidence interval, 1.10-7.29; P = 0.031) and more frequent antibody-mediated rejection in the first posttransplant year. CONCLUSIONS: Crossing DSA at time of lung transplant was not associated with an increased risk of death or CLAD in our cohort, but patients developed severe PGD and antibody-mediated rejection more frequently. However, these risks are likely manageable when balanced against the benefits of expanded access for sensitized candidates.

Heal-me PiONEer (personalized online nutrition and exercise): An RCT assessing 2 levels of app-based programming in individuals with chronic disease.

Background App-based strategies are a promising solution to deliver nutrition and exercise interventions during social distancing. With limited RCT data in individuals with chronic disease, further information is required both to determine impact, and to guide delivery. The Heal-Me app is an evidence-based, theoretically informed nutrition and exercise solution that can be tailored for use across a range of individuals with chronic disease. As compared to controls receiving educational material, the aim of this study is to assess the acceptability, effectiveness, and cost of Heal-Me app programming delivered alongside two levels of dietitian and exercise-specialist support. Methods Heal-Me PiONEer is a 12-week, 3-arm RCT with randomization to one of three study groups (n=72 per group, 216 total). Group 1 (control: educational material), Group 2 (Heal-Me app + virtual group dietitian/exercise-specialist sessions), Group 3 (Heal-Me app + virtual group and 1-to-1 dietitian/exercise-specialist sessions). Inclusion criteria: adults with cancer, chronic lung disease or status post-transplantation from liver or lung transplant; previous completion of an exercise rehabilitation program; access to an internet-connected device. Study outcomes measured at study weeks 0 and 12 include: Primary - Lower Extremity Functional Scale; Secondary - virtual physical function tests, loneliness, resilience, anxiety, well-being and health-related quality of life; Exploratory outcomes - protein intake, behavioral beliefs around exercise and nutrition, adherence, adverse events, acceptability, and cost-utility. Conclusions The Heal-Me PiONEer RCT holds promise to provide a comprehensive understanding of the delivery and impact of app-based nutrition and exercise programming in a diverse group of participants with chronic disease.

Redo Heart Double-Lung Transplant in a Previous Double-Lung Transplant Recipient With Pneumonectomy: A Case Report.

Placing a new donor lung into a postpneumonectomy pleural space has many potential surgical challenges. We report the technical challenges we faced in a case of a 42-year-old man who had initially undergone a double-lung transplant for idiopathic pulmonary arterial hypertension. Unfortunately, his left transplanted lung failed, which required a left pneumonectomy. Eight years later, his remaining right lung failed. He was evaluated and deemed suitable for retransplant. Our report presents the first successful redo heart double-lung transplant surgery preceded by pneumonectomy. There were significant technical intraoperative challenges; however, the procedure was performed successfully with an uneventful postoperative course and follow-up.

Perspectives on primary care management of obstructive sleep apnea: a qualitative study of patients and health care providers.

STUDY OBJECTIVES: Difficulties in providing timely access to care have prompted interest in primary care delivery models for obstructive sleep apnea (OSA). Sustainable implementation of such models requires codesign with input from key stakeholders. The purpose of this study was to identify patient and provider perspectives on barriers and facilitators to optimal, patient-centered management of OSA in a primary care setting. METHODS: This study was conducted in Alberta, Canada. Data from key stakeholders were collected through an online survey of primary care providers (n = 119), focus groups and interviews with patients living with OSA (n = 28), and workshops with primary care and sleep providers (n = 36). Quantitative survey data were reported using descriptive statistics, and qualitative data were analyzed using an inductive thematic approach. RESULTS: Several barriers were identified, including poor specialist access, variable primary care providers knowledge of OSA, and lack of clarity about provider roles for OSA management. Barriers contributed to patients being poorly informed about OSA, leading them to separate OSA from their overall health and eroding trust in the system. Suggestions for improvement included integration of care providers in a comprehensive model of care, facilitated by improved system navigation and more effective use of technology. Themes were consistent across data collection methods and between stakeholder groups. CONCLUSIONS: Although primary care delivery models may improve access to OSA management, stakeholders identified important challenges in the current system. Innovative models of care, developed with input from patients and providers, may mitigate barriers and support optimal primary care management of OSA.

Clinical judgment versus lung allocation score in predicting lung transplant waitlist mortality.

Canadian lung transplant centers currently use a subjective and dichotomous "Status" ranking to prioritize waitlisted patients for lung transplantation. The lung allocation score (LAS) is an objective composite score derived from clinical parameters associated with both waitlist and post-transplant survival. We performed a retrospective cohort study to determine whether clinical judgment (Status) or LAS better predicted waitlist mortality. All adult patients listed for lung transplantation between 2007 and 2012 at three Canadian lung transplant programs were included. Status and LAS were compared in their ability to predict waitlist mortality using Cox proportional hazards models and C-statistics. Status and LAS were available for 1122 patients. Status 2 patients had a higher LAS compared to Status 1 patients (mean 40.8 (4.4) vs 34.6 (12.5), P = .0001). Higher LAS was associated with higher risk of waitlist mortality (HR 1.06 per unit LAS, 95% CI 1.05, 1.07, P < .001). LAS predicted waitlist mortality better than Status (C-statistic 0.689 vs 0.674). Patients classified as Status 2 and LAS ≥ 37 had the worst survival awaiting transplant, HR of 8.94 (95% CI 5.97, 13.37). LAS predicted waitlist mortality better than Status; however, the best predictor of waitlist mortality may be a combination of both LAS and clinical judgment.

An assessment of the effects of Iyengar yoga practice on the health-related quality of life of patients with chronic respiratory diseases: a pilot study.

OBJECTIVE: To assess the effects of an Iyengar yoga program (IYP) on patients with chronic respiratory diseases. METHODS: Patients attending lung transplant clinics in a tertiary institution were invited to participate in a two-phase, 12-week IYP that included 2 h biweekly classes. Doctors completed a formal physical and clinical assessment on candidates before enrollment. Patients with New York Association Class III or IV, or dyspnea grade IV were excluded. At baseline and at the end of 12-weeks, patients completed the Hospital Anxiety and Depression Scale (HADS), Chronic Respiratory Questionnaire (CRQ) and Health Utilities Index (HUI). Medication(s), 6 min walk test results and other clinical parameters were also recorded. Patients recorded the effects of the IYP on their daily living in journals. Nonparametric and qualitative methods were used to analyze the data. RESULTS: Twenty-five patients diagnosed with pulmonary arterial hypertension and chronic obstructive pulmonary disease (mean age 60 years) were invited to participate. At the end of the 12-week period, changes in HADS anxiety and CRQ fatigue scores were statistically significant (P<0.05) and changes in HUI ambulation, pain, emotion and overall score were clinically important. The content of the journals revealed patients' improvement in breathing capacity, mobility, energy, sleep and included positive feedback such as: "increased tidal volume with slowing expiration", "I have an overall feeling of wellbeing" and "excellent amount of energy". CONCLUSIONS: The findings suggest that yoga has significant potential to produce benefits. Potential benefits will be further explored in a national multisite study.

Patient-reported outcome 2 years after lung transplantation: does the underlying diagnosis matter?

PURPOSE: Transplantation has the potential to produce profound effects on survival and health-related quality of life (HRQL). The inclusion of the patient's perspective may play an important role in the assessment of the effectiveness of lung transplantation. Patient perspectives are assessed by patient-reported outcome measures, including HRQL measures. We describe how patients' HRQL among different diagnosis groups can be used by clinicians to monitor and evaluate the outcomes associated with transplantation. METHODS: Consecutive lung transplant recipients attending the lung transplant outpatient clinic in a tertiary institution completed the 15-item Health Utilities Index (HUI) questionnaire on a touchscreen computer. The results were available to clinicians at every patient visit. The HUI3 covers a range of severity and comorbidities in eight dimensions of health status. Overall HUI3 scores are on a scale in which dead = 0.00 and perfect health = 1.00; disability categories range from no disability = 1 to severe disability <0.70. Single-attribute and overall HUI3 scores were used to compare patients' HRQL among different diagnosis groups. Random-effect models with time since transplant as a random variable and age, gender, underlying diagnoses, infections, and broncholitis obliterans syndrome as fixed variables were built to identify determinants of health status at 2-years posttransplantation. RESULTS: Two hundred and fourteen lung transplant recipients of whom 61% were male with a mean age of 52 (19-75) years were included in the study. Chronic obstructive pulmonary disease and cystic fibrosis patients displayed moderate disability, while pulmonary fibrosis and pulmonary arterial hypertension patients displayed severe disability. Patients with chronic obstructive pulmonary disease had the worst pain level, whereas patients with pulmonary fibrosis had the worst emotion and cognition levels. A random-effect model confirmed that development of broncholitis obliterans syndrome was the most important determinant of health status (P = 0.03) compared to other variables, such as cytomegalovirus infections and underlying diagnoses. CONCLUSION: Descriptions of patients' HRQL among different diagnosis groups could be used by clinicians to assist individualized patient care.

Generic immunosuppression in solid organ transplantation: a Canadian perspective.

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.

An international survey of cytomegalovirus management practices in lung transplantation.

BACKGROUND: Cytomegalovirus (CMV) is an important infection in lung transplant recipients. Center-to-center variation in preventive and treatment strategies is unknown. METHODS: An electronic survey was sent to 102 lung transplant programs registered with the International Society of Heart and Lung Transplantation and United Network for Organ Sharing. RESULTS: Fifty-nine (58%) programs responded to the survey. For CMV prevention (D+/R-), 56 of the 59 (94.9%) programs used prophylaxis and two (3.4%) of them used preemptive therapy. For R+ patients, 86.4% used prophylaxis and 13.6% used preemptive strategy. Duration of prophylaxis was extremely variable ranging from 3 months to indefinite. Adjunctive prophylactic strategies included routine viral monitoring (51% D+/R-; 44% R+) and CMV immunoglobulin (32% D+/R-; 14% R+). The medication used for prophylaxis was valganciclovir with approximately half starting with intravenous ganciclovir. 9 of the 59 (15.2%) centers reported using specific CMV prophylaxis in D-/R- patients. Methods for viral monitoring included peripheral blood polymerase chain reaction, antigenemia, bronchoalveolar lavage viral culture, and bronchoalveolar lavage polymerase chain reaction. For treatment of CMV viremia, valganciclovir or intravenous ganciclovir were used. A total of 47.5% of centers routinely decreased immunosuppression at the time of viremia. Secondary antiviral prophylaxis was used routinely by 36 of the 59 (61%) centers. CONCLUSIONS: Although prophylaxis is the most commonly used preventive strategy, significant variation exists in the way it is implemented. Specifically, duration of prophylaxis is extremely variable. Uniform international guidelines would be of value in this population.

Assessing the use of health-related quality of life measures in the routine clinical care of lung-transplant patients.

PURPOSE: This randomized controlled clinical trial examined the usefulness of including an assessment of health-related quality of life (HRQL) in the routine clinical care of lung-transplant patients. We hypothesized that the inclusion of HRQL in routine clinical care would improve patient-clinician communication, affect clinical management, and improve patients' HRQL. METHODS: At the outpatient clinic, University of Alberta Hospital, patients were randomly assigned to intervention (completion of Health Utilities Index Mark 2 (HUI2) and Mark 3 (HUI3) on touch-screen computer with feedback to clinicians) and control group (completion of HUI2 and HUI3 on touch-screen computer without feedback). Feedback involved a graphical representation included in patients' chart. All clinical encounters were audio-taped. Changes in clinical management (medication changes, number of referrals and test ordered) were summed to produce an overall management composite. At the end of every visit, patients completed the EQ-5D. RESULTS: Two hundred and thirteen patients were randomized (108 to intervention and 105 to control groups). There were statistically significant differences between the groups in mean number of issues discussed per encounter (P = 0.003; Cohen's d = 0.03) and mean management composite score (P = 0.001; Cohen's d = 0.41). EQ-5D index was not statistically significant different between the groups (P = 0.48). CONCLUSIONS: We detected very small effects on patient-clinician communication and small effects on patient management, without detecting improvement in patient outcome.

Risk factors and outcomes for the development of malignancy in lung and heart-lung transplant recipients.

BACKGROUND: Many factors may limit survival from lung and heartlung transplantation, including malignancy. OBJECTIVE: To investigate factors associated with the development of malignancy following transplantation and its effect on survival by retrospectively reviewing a population of lung transplant recipients. METHODS: Data from 342 consecutive lung transplant patients were collected. Results were analyzed by fitting variables into a multivariate logistic regression model predicting the development of post-transplant malignancies. Covariates were selected based on crude associations that reached a level of significance at P ≤ 0.10. Length of survival was analyzed using the Kaplan-Meier method. RESULTS: Fifty-eight subjects developed post-transplant malignancies, which were the cause of death of 14 patients. Twenty-one patients had a pretransplant malignancy, of whom six developed a malignancy posttransplant--of these, two were fatal recurrences. No risk factors were significantly associated with all forms of post-transplant malignancy. When adjusted for age at transplantation and donor smoking history, Epstein-Barr virus seropositivity at the time of transplant was significantly associated with a reduced risk of a post-transplant lymphoproliferative disorder (OR 0.17; 95% CI 0.05 to 0.59). The median survival time in individuals without a post-transplant malignancy was significantly shorter than in those with a post-transplant malignancy (P = 0.018 Wilcoxon [Breslow]). This may be secondary to the length of time required to develop malignancy and the fact that not all malignancies that developed were fatal. The median time to develop malignancy was greater than two years. In addition, the 14 patients who died as a result of their malignancy had a significantly shorter survival time than the 44 who died because of nonmalignant causes (P < 0.001). CONCLUSIONS: Malignancy was not associated with an overall decrease in survival time when compared with those who did not develop a malignancy. Risk factors specific for the development of malignancies remain difficult to specify.

Lung and heart lung transplantation at the University of Alberta 1986-2010.

The lung transplantation program at the University of Alberta has been in existence for 25 years. The current volume is 35-40 new lung transplants per year. We offer single-lung, bilateral lung, heart/lung and bilateral living lobar transplantation as options. Experience has allowed for widening of the indications and acceptance of patients with more risk. Donor evaluation and management has allowed for extended donors to be included in the donor pool. Results will likely continue to improve with increased understanding of the mechanisms and management of bronchiolitis obliterans syndrome. Our research interests have been in the areas of risk analysis, outcome assessment, and quality of life changes from transplantation.

A randomized, controlled trial of daclizumab vs anti-thymocyte globulin induction for lung transplantation.

BACKGROUND: Rejection remains a significant cause of morbidity and mortality after lung transplantation. The purpose of this study was to test the efficacy and safety of daclizumab (DZM) vs anti-thymocyte globulin (ATG) as a component of induction therapy. METHODS: Fifty adults undergoing lung transplantation were randomized to receive either ATG or DZM during induction therapy. Patients were followed for 1 year after transplant. RESULTS: Although there was no significant difference in the number of acute or chronic rejections between groups, there was a trend toward a delay in time to first acute rejection with DZM induction. Average absolute lymphocytes and average platelet count were significantly higher in the DZM group. Cytomegalovirus (CMV) serology mismatch was higher in the DZM group (7 vs 1, p = 0.05). The DZM group had a greater number of infections (83 vs 47, p = 0.02); however, the number of CMV infections was also significantly greater (18 vs 6, p = 0.03), corresponding to a higher incidence of CMV mismatch. A cost analysis revealed no difference between total drug costs, intensive-care unit (ICU) costs and total hospital costs. One-year survival was 96% in the DZM group and 88% in the ATG group. CONCLUSIONS: DZM is a safe component of induction therapy in lung transplantation. In addition, DZM may prolong freedom from acute rejection. Significant infections were more frequent in the DZM group, but this was likely due to a higher incidence of CMV mismatch. Both methods of induction therapy worked well, with excellent 1-year survival.

Effects of nocturnal noninvasive mechanical ventilation on heart rate variability of patients with advanced COPD.

BACKGROUND: Cardiovascular comorbidities have a negative impact on the health status and prognosis of patients with COPD. We determined whether nocturnal noninvasive (positive) mechanical ventilation (NIMV) can improve heart rate variability (HRV), decrease circulating natriuretic peptide levels, and improve functional performance of patients with very advanced COPD. METHODS: A randomized, double-blind, parallel controlled trial was conducted in 23 participants with stable but advanced COPD. Participants received standard medical therapy plus nocturnal NIMV or standard medical therapy plus sham NIMV for 3 months. RESULTS: After 3 months of NIMV therapy, the 24-h triangular interpolation of N-N intervals increased from 322 to 473 ms (p = 0.034), the 24-h HRV index (HRVI) increased from 21.8 to 29.9 ms (p = 0.035), nocturnal HRVI increased from 6.1 to 8.0 ms (p = 0.026), and the SD of the average N-N interval increased from 37 to 41 ms (p = 0.020). None of these indexes changed significantly in the control group. Additionally, compared with the control group, the pro-atrial natriuretic peptide levels declined significantly in the NIMV group (p = 0.013). CONCLUSIONS: NIMV applied nocturnally over 3 months may improve HRV, reduce circulating natriuretic peptide levels, and enhance the functional performance of patients with advanced but stable COPD. While not definitive due to small sample size, these data suggest that nocturnal NIMV may reduce the impact of cardiac comorbidities in COPD patients.