Systemic corticosteroids for outpatient respiratory viral infections in lung transplant recipients.

INTRODUCTION: Respiratory viral infections (RVI) in lung transplant recipients (LTR) have variably been associated with rejection and chronic lung allograft dysfunction. Our center has used systemic corticosteroids to treat outpatient RVI in some cases, but evidence is limited. We reviewed all adult LTR diagnosed with outpatient RVI January 2017 to December 2019. The primary outcome was recovery of lung function (forced expiratory volume in 1 s [FEV1]) at next stable visit between 1 and 12 months postinfection, expressed as a ratio over stable preinfection FEV1 (FEV1 recovery ratio). METHODS: We identified 100 adult LTR with outpatient RVI diagnoses eligible for study, 36% of whom received corticosteroids. We modelled the adjusted association between corticosteroid use and FEV1 recovery ratio using linear regression. RESULTS: Steroid-treated patients had a lower FEV1 presentation ratio (0.92 vs. 1.04, p = .0070) and were more likely to have chronic lung allograft dysfunction at time of infection (25% vs. 5%, p = .0077). Mean FEV1 recovery ratio was 1.02 (SD 0.19) with no association with corticosteroid therapy via multivariable linear regression (p = .5888). CONCLUSIONS: Steroid treatment was not associated with FEV1 recovery. This suggests corticosteroids may not have a role in the management of RVI in this population.

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.

Pre-transplant malignancy is associated with increased risk of de novo malignancy post-lung transplantation.

BACKGROUND: At least 20% of lung transplant recipients will be diagnosed with a malignancy within 5 years of transplant. Transplant candidates with a history of pre-transplant malignancy must meet remission criteria before listing to minimize the risk of recurrence, however these patients may have an intrinsic predisposition to developing subsequent cancers which can be amplified by immunosuppression. We assessed whether pre-transplant malignancy was associated with an increased risk of developing malignancy of any type after lung transplant. METHODS: We conducted a single centre retrospective cohort study of patients undergoing lung transplant between January 2006 and December 2017. We used a proportional hazards regression model to test whether preTM was associated with the risk of developing one or more postTM after lung transplant, adjusted for known cancer risk factors. RESULTS: 497 adult patients underwent lung transplantation during the study period and 26 (5.2%) had pre-transplant malignancies. Out of 29 pre-transplant cancer diagnoses, prostate cancer was the most common (17.2%), followed by breast cancer and basal cell carcinoma (13.8% each). 108 (22%) patients developed post-transplant malignancy with a total of 328 cancer diagnoses. The most common post-transplant malignancy was non-melanoma skin cancer (86.3%), followed by solid organ cancers (7.6%). Pre-transplant malignancy was associated with an adjusted HR of 3.24 (95% CI 1.71 to 6.14, p < 0.001) for the development of post-transplant malignancy. Recurrence of the pre-transplant malignancy only occurred in 3 patients post-transplant. CONCLUSIONS: History of pre-transplant malignancy was associated with a more than three times likelihood of development of a post-transplant malignancy compared to recipients without a previous history of cancer, the majority being unrelated to the initial malignancy. These findings highlight the importance of frequent cancer surveillance in lung transplant recipients, especially in those with a history of pre-transplant malignancy.

Mismatched perfusion defects on routine ventilation-perfusion scans after lung transplantation.

BACKGROUND: Incidental pulmonary embolism (PE) is a challenging entity with unclear treatment implications. Our program performs routine ventilation-perfusion (VQ) scans at 3-months post-transplant to establish airway and vascular function. We sought to determine the prevalence and prognostic implications of mismatched perfusion defects (MMPD) found on these studies, hypothesizing they would be associated with a benign prognosis. METHODS: We studied VQ scans obtained routinely at 3-months post-transplant from double lung transplant recipients 2005-2016 for studies with MMPD interpreted as high or intermediate probability for PE. We tested the relationship between MMPD and 1-year survival via chi square testing, overall survival via Kaplan Meier analysis with log rank testing and peak forced expiratory volume in 1 second (FEV1) percent predicted via t-testing. RESULTS: Three hundred and seventy-three patients met inclusion criteria, of whom 35 (9%) had VQ scans with MMPDs interpreted by radiologists as high or intermediate probability for PE. Baseline recipient and donor characteristics were similar between groups. Seven patients (20%) in the MMPD group were treated with therapeutic anticoagulation. Patients with MMPD had similar 1-year survival (100% vs. 98%, P = 1.00), overall survival (log rank P = .90) and peak FEV1% predicted (94% [SD 20%] vs. 92% [SD 21%]; P = .58). Anticoagulation did not affect these relationships. CONCLUSION: Mismatched perfusion defects on routine post-transplant VQ scan were not associated with a difference in survival or lung function. A conservative approach to these changes may be a viable option in the absence of other anticoagulation indications.

Successful Long-Term Outcome After Transplantation of Lungs Affected by Smoke Inhalation Injury.

We report a case of a 43-year-old woman who underwent double lung transplantation from a donor with severe airway burns following a house fire. The recipient's lung function and quality of life remain excellent 24 months following transplantation. This case is the first to report successful long-term outcomes in transplantation of lungs affected by smoke inhalation.

ANOTHER syndrome-Familial presentations of progressive lung disease leading to double lung transplantation: A case report and literature review.

Ectodermal dysplasias (EDs) are a heterogeneous rare group of disorders with an incidence at 1/100,000 live births. Currently, there are limited case reports of patients requiring lung transplantation. Here, we report two brothers who present with a constellation of features including alopecia, nail dystrophy, ophthalmic complications, thyroid disease, hypohidrosis, ephelides, enteropathy and recurrent respiratory tract infections, known as ANOTHER syndrome, a rare autosomal recessive variant of ED. Both presented in early childhood with progressive respiratory decline and eventual failure. Chronic respiratory decline was refractory to standard therapy. Both patients required lung transplantation for sequelae of end-stage lung disease. Pathology demonstrated multifocal bronchiectasis with areas of fibrosis and small airway obstruction. ANOTHER syndrome is rare with a paucity of data in the literature. Given the limited therapeutic options available with natural progression towards respiratory failure, lung transplantation may be considered.

Baseline lung allograft dysfunction in primary graft dysfunction survivors after lung transplantation.

BACKGROUND: Primary graft dysfunction (PGD) after lung transplantation has previously been associated with increased risk of death and chronic lung allograft dysfunction (CLAD), but the relationship to baseline lung allograft dysfunction (BLAD), where graft function fails to normalize, is not known. METHODS: We reviewed all double lung transplant recipients transplanted in our program 2004-2016. We defined PGD and CLAD as per recent consensus definitions and BLAD as failure to achieve both FEV1 and FVC ≥80% predicted on 2 consecutive tests ≥3 weeks apart. We used logistic and proportional hazards regression to test the association between severe high-grade PGD (PGD3) with BLAD and CLAD respectively, adjusting for known and identified confounders. RESULTS: 446 patients met inclusion criteria and 76 (17%) developed PGD3 at 48- or 72-h post-transplant. PGD3 occurred more frequently in patients with interstitial lung disease or pulmonary vascular disease, those with higher BMIs and recipients of older donors. PGD3 was associated with more frequent (58% vs. 36%; p = 0.0008) and more severe BLAD (p < 0.0001) and increased BLAD risk in an adjusted model (OR 2.00 [95% CI 1.13-3.60]; p = 0.0182). PGD3 was not associated with CLAD frequency, severity or time to CLAD onset in an adjusted model (HR 1.10 (95% CI 0.64-1.78), p = 0.7226). CONCLUSION: Severe PGD was associated with increased risk and severity of BLAD but not CLAD. The mechanisms via which PGD may mediate baseline function warrant further investigation.

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.

Atelectasis in primary graft dysfunction survivors after lung transplantation.

BACKGROUND: Primary graft dysfunction (PGD) is an important contributor to early mortality in lung transplant recipients and is associated with impaired lung function. The radiographic sequelae of PGD on computed tomography (CT) have not been characterized. METHODS: We studied adult double lung transplant recipients from 2010 to 2016 for whom protocol 3-month post-transplant CT scans were available. We assessed CTs for changes including pleural effusions, ground glass opacification, atelectasis, centrilobular nodularity, consolidation, interlobular septal thickening, air trapping and fibrosis, and their relationship to prior post-transplant PGD, future lung function, post-transplant baseline lung allograft dysfunction (BLAD), and chronic lung allograft dysfunction (CLAD). RESULTS: Of 237 patients studied, 50 (21%) developed grade 3 PGD (PGD3) at 48 or 72 h. PGD3 was associated with increased interlobular septal thickening (p = .0389) and atelectasis (p = .0001) at 3 months, but only atelectasis remained associated after correction for multiple testing. Atelectasis severity was associated with lower peak forced expiratory volume in 1 s (FEV1) and increased risk of BLAD (p = .0014) but not with future CLAD onset (p = .7789). CONCLUSIONS: Severe PGD was associated with atelectasis on 3-month post-transplant CT in our cohort. Atelectasis on routine CT may be an intermediary identifiable stage between PGD and future poor lung function.

Canadian Society of Transplantation White Paper: Ethical and Legal Considerations for Alcohol and Cannabis Use in Solid Organ Listing and Allocation.

Alcohol and cannabis use as a contraindication to organ transplantation is a controversial issue. Until recently, patients in Canada with alcohol-associated liver disease were required to demonstrate abstinence for 6 mo to receive a liver transplant. There is no equivalent rule that is applied consistently for cannabis use. There is some evidence that alcohol and cannabis use disorder pretransplant could be associated with worse outcomes posttransplantation. However, early liver transplantation for patients with alcohol-associated liver disease in France and in the United States has led to challenges of the 6-mo abstinence rule in Canada in the media. It has also resulted in several legal challenges arguing that the rule violates human rights laws regarding discrimination in the provision of medical services and that the rule is also unconstitutional (this challenge is still before the court). Recent legalization of cannabis use for adults in Canada has led to questions about the appropriateness of limiting transplant access based on cannabis use. The ethics committee of the Canadian Society of Transplantation was asked to provide an ethical analysis of cannabis and alcohol abstinence policies. Our conclusions were as follows: neither cannabis use nor the 6-mo abstinence rule for alcohol use should be an absolute contraindication to transplantation, and transplant could be offered to selected patients, further research should be conducted to ensure evidence-based policies; and the transplant community has a duty not to perpetuate stigma associated with alcohol and cannabis use disorders.

Chest X-ray Sizing for Lung Transplants Reflects Pulmonary Diagnosis and Body Composition and Is Associated With Primary Graft Dysfunction Risk.

BACKGROUND: Donor-recipient oversizing based on predicted total lung capacity (pTLC) is associated with a reduced risk of primary graft dysfunction (PGD) following lung transplant but the effect varies with the recipient's diagnosis. Chest x-ray (CXR) measurements to estimate actual total lung capacity (TLC) could account for disease-related lung volume changes, but their role in size matching is unknown. METHODS: We reviewed adult double lung transplant recipients 2007-2016 and measured apex-to-costophrenic-angle distance (=lung height) on pretransplant donor and recipient CXRs (oversized donor-recipient ratio >1; undersized ≤1]. We tested the relationship between recipient lung height to actual TLC; between lung height ratio and donor/recipient characteristics; and between both lung height ratio or pTLC ratio and grade 3 PGD with logistic regression. RESULTS: Two hundred six patients were included and 32 (16%) developed grade 3 PGD at 48 or 72 hours. Recipient lung height was related to TLC (r2=0.7297). Pulmonary diagnosis, donor BMI, and recipient BMI were the major determinants of lung height ratio (AUC 0.9036). Lung height ratio oversizing was associated with increased risk of grade 3 PGD (odds ratio, 2.51; 95% confidence interval, 1.17-5.47; P = 0.0182) in this cohort, while pTLC ratio oversizing was not. CONCLUSIONS: CXR lung height estimates actual TLC and reflects pulmonary diagnosis and body composition. Oversizing via CXR lung height ratio increased PGD risk moreso than pTLC-based oversizing in our cohort.

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.

Azithromycin prophylaxis after lung transplantation is associated with improved overall survival.

BACKGROUND: Azithromycin prophylaxis (AP) in lung transplant recipients has been shown to reduce the composite end-point of death or chronic lung allograft dysfunction (CLAD) onset but without a clear effect on overall survival. Our program began using AP in 2010. We sought to evaluate the association between AP and survival and the risk of CLAD and baseline lung allograft dysfunction (BLAD). METHODS: We studied double lung recipients transplanted between 2004 and 2016. We defined AP as chronic use of azithromycin initiated before CLAD onset. We analyzed the association between AP and death or retransplant using Cox regression with adjustment for potential confounders. We further used Cox and logistic models to assess the relationship between AP and post-transplant CLAD onset and BLAD, respectively. RESULTS: A total of 445 patients were included, and 344 (77%) received AP (median time from transplant: 51 days). Patients receiving AP were more likely to receive induction with interleukin-2 receptor antagonists (57% vs 35%; p < 0.001). AP was associated with improved survival (hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.42-0.82; p = 0.0020) in our fully adjusted model, with a reduced adjusted risk of BLAD (odds ratio: 0.53; 95% CI: 0.33-0.85; p = 0.0460) but no clear reduction in the adjusted risk of CLAD (HR: 0.69; 95% CI: 0.47-1.03; p = 0.0697). CONCLUSIONS: AP is associated with improved survival after lung transplantation, potentially through improved baseline function. These findings build on prior trial results and suggest that AP is beneficial for lung transplant recipients.

Pretransplant Opioid Use and Survival After Lung Transplantation.

BACKGROUND: The impact of opioid use in lung transplant candidates on posttransplant outcomes is unknown. Studies on opioid therapy in kidney and liver transplant candidates have suggested increased risk of graft failure or death. We sought to analyze the relationship between pretransplant opioid use in lung transplant candidates and retransplant-free survival. METHODS: We retrospectively reviewed adult patients transplanted consecutively between November 2004 and August 2015. The exposure was any opioid use at time of transplant listing and primary outcome was retransplant-free survival, analyzed via Cox regression model adjusted for recipient age, gender, ethnicity, diagnosis, and bridging status. Secondary outcomes included duration of ventilation, intensive care unit and hospital length of stay, 3-month and 1-year survival, continuing opioid use at 1 year, and time to onset of chronic lung allograft dysfunction. RESULTS: The prevalence of opioid use at time of listing was 14% (61/425). Median daily oral morphine equivalent dose was 31 mg (18-54). Recipient ethnicity was associated with pretransplant opioid use. Opioid use at time of listing did not increase risk of death or retransplantation in an adjusted model (hazard ratio 1.12 [95% confidence interval 0.65-1.83], P = 0.6570). Secondary outcomes were similar between groups except hospital length of stay (opioid users 35 versus nonusers 27 d, P = 0.014). Continued opioid use at 1-year posttransplant was common (27/56, 48%). CONCLUSIONS: Pretransplant opioid use was not associated with retransplant-free survival in our cohort and should not necessarily preclude listing. Further work stratifying opioid use by indication and the association with opioid use disorder would be worthwhile.

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.

High incidence of clinically significant cytomegalovirus infection in CMV D+/R+ lung transplant recipients receiving 3 months of antiviral prophylaxis.

BACKGROUND: Universal antiviral prophylaxis is the preferred preventive strategy for lung transplant recipients (LTRs) at risk of CMV infection. We compared the risk of CMV infection between CMV D+/R + and D-/R + LTRs after 3 months of prophylaxis. METHODS: This was a retrospective review of CMV R + LTRs transplanted between 2005 and 2013. Patients dying before completing 3 months, or receiving >180 days of prophylaxis were excluded. The primary outcome was proportion of LTRs who developed CMV infection and clinically significant CMV infection defined as CMV infection leading to preemptive therapy or CMV disease. RESULTS: We analyzed 90 D+/R + and 72 D-/R + with a median follow up of 730 days. CMV infection and disease was more common in D+/R + compared to D-/R+ (CMV infection 66% vs 40%; P = 0.001; CMV disease 13% vs 4% P = 0.045). Fifty-nine patients developed at least one episode of clinically significant CMV infection (41/90 [46%] D+/R + and 18/72 [25%] D-/R + P=0.007) with recurrence occurring in 29 LTRs (49% of patients with previous CMV infection), of which 22 (76%) were CMV D+/R+. Thirty percent had side effects related to CMV therapy. CONCLUSION: Three months prophylaxis in D+/R + LTRs was associated with high rates of clinically significant CMV infection and recurrences.