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Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.

IntroductionThe optimal pain management strategy after lung transplantation is unknown. This study compared analgesic outcomes of intercostal nerve blockade by cryoanalgesia (Cryo) versus thoracic epidural analgesia (TEA).MethodsSeventy-two patients who underwent bilateral lung transplantation via clamshell incision at our center from 2016 to 2018 were managed with TEA (N = 43) or Cryo (N = 29). We evaluated analgesic-specific complications, opioid use in oral morphine equivalents (OME), and pain scores (0-10) through postoperative day7. Adjusted linear regression was used to assess for non-inferiority of Cryo to TEA.ResultsThe overall mean pain scores (Cryo 3.2 vs TEA 3.8, P = 0.21), maximum mean pain scores (Cryo 4.7 vs TEA 5.5, P = 0.16), and the total opioid use (Cryo 484 vs TEA 705 OME, P = 0.12) were similar in both groups, while the utilization of postoperative opioid-sparing analgesia, measured as use of lidocaine patches, was lower in the Cryo group (Cryo 21% vs TEA 84%, P

Fractures negatively impact quality of life and survival. We hypothesized that recipient frailty score and genetic profile measured before transplant would predict risk of fracture after lung transplant. We conducted a retrospective cohort study of bone mineral density (BMD) and fracture among lung transplant recipients at a single center. The association between predictors and outcomes were assessed by multivariable time-dependent Cox models or regression analysis. Among the 284 participants, osteoporosis and fracture were highly prevalent. Approximately 59% of participants had posttransplant osteopenia, and 35% of participants developed at least 1 fracture. Low BMD was associated with a polygenic osteoporosis risk score, and the interaction between genetic score and BMD predicted fracture. Pretransplant frailty was associated with risk for spine and hip fracture, which were not associated with chronic lung allograft dysfunction or death. Chest fractures were the most frequent type of fracture and conferred a 2.2-fold increased risk of chronic lung allograft dysfunction or death (time-dependent P < .001). Pneumonia, pleural effusions, and acute rejection frequently occurred surrounding chest fracture. Pretransplant frailty and recipient genotype may aid clinical risk stratification for fracture after transplant. Fracture carries significant morbidity, underscoring the importance of surveillance and osteoporosis prevention.

Acute and chronic rejections limit the long-term survival after lung transplant. Pulmonary antibody-mediated rejection (AMR) is an incompletely understood driver of long-term outcomes characterized by donor-specific antibodies (DSAs), innate immune infiltration, and evidence of complement activation. Natural killer (NK) cells may recognize DSAs via the CD16 receptor, but this complement-independent mechanism of injury has not been explored in pulmonary AMR. CD16+ NK cells were quantified in 508 prospectively collected bronchoalveolar lavage fluid samples from 195 lung transplant recipients. Associations between CD16+ NK cells and human leukocyte antigen mismatches, DSAs, and AMR grade were assessed by linear models adjusted for participant characteristics and repeat measures. Cox proportional hazards models were used to assess CD16+ NK cell association with chronic lung allograft dysfunction and survival. Bronchoalveolar lavage fluid CD16+ NK cell frequency was associated with increasing human leukocyte antigens mismatches and increased AMR grade. Although NK frequencies were similar between DSA+ and DSA- recipients, CD16+ NK cell frequencies were greater in recipients with AMR and those with concomitant allograft dysfunction. CD16+ NK cells were associated with long-term graft dysfunction after AMR and decreased chronic lung allograft dysfunction-free survival. These data support the role of CD16+ NK cells in pulmonary AMR.

BackgroundWe sought to describe trends in extracorporeal membrane oxygenation (ECMO) use, and define the impact on PGD incidence and early mortality in lung transplantation.MethodsPatients were enrolled from August 2011 to June 2018 at 10 transplant centers in the multi-center Lung Transplant Outcomes Group prospective cohort study. PGD was defined as Grade 3 at 48 or 72 hours, based on the 2016 PGD ISHLT guidelines. Logistic regression and survival models were used to contrast between group effects for event (i.e., PGD and Death) and time-to-event (i.e., death, extubation, discharge) outcomes respectively. Both modeling frameworks accommodate the inclusion of potential confounders.ResultsA total of 1,528 subjects were enrolled with a 25.7% incidence of PGD. Annual PGD incidence (14.3%-38.2%, p=.0002), median LAS (38.0-47.7 p=.009) and the use of ECMO salvage for PGD (5.7%-20.9%, p=.007) increased over the course of the study. PGD was associated with increased 1 year mortality (OR 1.7 [95% C.I. 1.2, 2.3], p=.0001). Bridging strategies were not associated with increased mortality compared to non-bridged patients (p=.66); however, salvage ECMO for PGD was significantly associated with increased mortality (OR 1.9 [1.3, 2.7], p=.0007). Restricted mean survival time comparison at 1-year demonstrated 84.1 days lost in venoarterial salvaged recipients with PGD when compared to those without PGD (ratio 1.3 [1.1, 1.5]) and 27.2 days for venovenous with PGD (ratio 1.1 [1.0, 1.4]).ConclusionsPGD incidence continues to rise in modern transplant practice paralleled by significant increases in recipient severity of illness. Bridging strategies have increased but did not affect PGD incidence or mortality. PGD remains highly associated with mortality and is increasingly treated with salvage ECMO.

The Lung Allocation Score (LAS) was revised in 2015 to improve waiting list mortality and rate of transplant for patients with pulmonary arterial hypertension (PAH).We sought to determine if the 2015 revision achieved its intended goals.Using the Standard Transplant Analysis and Research file, we assessed the impact of the 2015 LAS revision by comparing the pre- and post-revision eras. Registrants were divided into the LAS diagnostic categories: Group A-Chronic Obstructive Pulmonary Disease; Group B-Pulmonary Arterial Hypertension; Group C-Cystic Fibrosis; and Group D-Interstitial Lung Disease. Competing risk regressions were used to assess the two mutually exclusive competing risks of waiting list death and transplant. Cumulative incidence plots were created to visually inspect risks.The LAS at organ matching rose by 14.2 points for registrants with PAH after the 2015 LAS revision, the greatest increase amongst diagnostic categories (Other LAS Categories: Δ -0.9 to +2.8 points). Before the revision, registrants with PAH had the highest risk of death and lowest likelihood of transplant. After the 2015 revision, registrants with PAH still had the highest risk of death, now similar to those with interstitial lung disease, and the lowest rate of transplant, now similar to those with COPD.While the 2015 LAS revision improved access to transplant and reduced the risk of waitlist death for patients with PAH, it did not go far enough. Significant differences in waitlist mortality and likelihood of transplant persist.

The optimal pain management strategy after lung transplantation is unknown. This study compared analgesic outcomes of intercostal nerve blockade by cryoanalgesia (Cryo) versus thoracic epidural analgesia (TEA).Seventy-two patients who underwent bilateral lung transplantation via clamshell incision at our center from 2016 to 2018 were managed with TEA (N = 43) or Cryo (N = 29). We evaluated analgesic-specific complications, opioid use in oral morphine equivalents (OME), and pain scores (0-10) through postoperative day 7. Adjusted linear regression was used to assess for non-inferiority of Cryo to TEA.The overall mean pain scores (Cryo 3.2 vs TEA 3.8, P = 0.21), maximum mean pain scores (Cryo 4.7 vs TEA 5.5, P = 0.16), and the total opioid use (Cryo 484 vs TEA 705 OME, P = 0.12) were similar in both groups, while the utilization of postoperative opioid-sparing analgesia, measured as use of lidocaine patches, was lower in the Cryo group (Cryo 21% vs TEA 84%, P 0.001). Analgesic outcomes remained similar between the cohorts after adjustment for pertinent patient and analgesic characteristics (P = 0.26), as well as after exclusion of Cryo patients requiring rescue TEA (P = 0.32). There were no Cryo complications, with four patients requiring subsequent TEA for pain control. Two TEA patients experienced hemodynamic instability following a test TEA bolus requiring code measures. Additionally, TEA placement was delayed beyond postoperative day 1 in 33% owing to need for anticoagulation or clinical instability.In lung transplantation, Cryo was found to be safe with analgesic effectiveness similar to TEA. Cryo may be advantageous in this complex patient population, as it can be used in all clinical scenarios and eliminates risks and delays associated with TEA.

The use of donor lungs from victims of drowning remains a rare occurrence, given concerns over lung parenchymal injury and microbial contamination secondary to aspiration. Given this infrequency, there is a relative paucity of literature surrounding the use of organs from drowned donors, with the few that exist on this subject focusing primarily on cases of drowning in naturally occurring bodies of water (i.e., drowning at sea). Little is known regarding the outcomes of utilizing donor lungs from victims of drowning in artificial bodies of water (i.e., swimming pools). Here, we describe three cases of bilateral lung transplantation from donors who drowned in swimming pools, with good short- and long-term outcomes. These cases lend further evidence to the feasibility of using such organs that have traditionally been viewed with much trepidation. With continually growing demand for donor organs, the use of drowned donor lungs may serve as a means to expand the donor pool and lessen the burden of waitlist mortality.

Noninvasive assessment of pulmonary hemodynamics is often performed by echocardiographic estimation of the pulmonary artery systolic pressure (ePASP), despite limitations in the advanced lung disease population. Other noninvasive hemodynamic variables, such as echocardiographic pulmonary vascular resistance (ePVR), have not been studied in this population. We performed a retrospective analysis of 147 advanced lung disease patients who received both echocardiography and right heart catheterization for lung transplant evaluation. The ePVR was estimated by four previously described equations. Noninvasive and invasive hemodynamic parameters were compared in terms of correlation, agreement, and accuracy. The ePVR models strongly correlated with invasively determined PVR and had good accuracy with biases of

BackgroundLung transplant recipients undergo bronchoalveolar lavage (BAL) to detect antecedents of chronic lung allograft dysfunction (CLAD), but routine assessment of BAL cytology is controversial. We hypothesized that inflammation on BAL cytology would predict CLAD-free survival.MethodsIn a single-center retrospective cohort, associations between cytology results and clinical characteristics were compared using generalized-estimating equation-adjusted regression. The association between BAL inflammation and CLAD or death risk was assessed using time-dependent Cox models.ResultsIn 3365 cytology reports from 451 subjects, inflammation was the most common finding (6.2%, 210 cases), followed by fungal forms (5.3%, 178 cases, including 24 cases of suspectedAspergillus). Inflammation on BAL cytology was more common in procedures for symptoms (8.5%) versus surveillance (3.2%, p&nbsp

Disability, depressive symptoms, and impaired health-related quality of life (HRQL) are common among patients with life-threatening respiratory compromise. We sought to determine if primary graft dysfunction (PGD), a syndrome of acute lung injury, attenuates improvements in patient-reported outcomes after transplantation. In a single-center prospective cohort, we assessed disability, depressive symptoms, and HRQL before and at three to six-month intervals after lung transplantation. We estimated the magnitude of change in disability, depressive symptoms, and HRQL with hierarchical segmented linear mixed effects models. Amongst 251 lung transplant recipients, 50 developed PGD Grade 3. Regardless of PGD severity, participants had improvements in disability and depressive symptoms, as well as generic-physical, generic-mental, respiratory-specific, and health-utility HRQL, exceeding 1-4 fold the minimally clinically important difference across all instruments. Participants with PGD Grade 3 had a lower magnitude of improvement in generic-physical HRQL and health-utility than in all other participants. Amongst participants with PGD Grade 3, prolonged mechanical ventilation was associated with greater attenuation of improvements. PGD remains a threat to the two primary aims of lung transplantation, extending survival and improving HRQL. Attenuation of improvement persists long after hospital discharge. Future studies should assess if interventions can mitigate the impact of PGD on patient-reported outcomes.

The early postoperative period after lung transplantation is a critical time. Prompt recognition and treatment of primary graft dysfunction can alter long-term allograft function. Cardiovascular, gastrointestinal, renal, and hematologic derangements are common and require close management to limit their negative sequelae.

Chronic lung allograft dysfunction (CLAD) is a syndrome of progressive lung function decline, subcategorized into obstructive, restrictive, and mixed phenotypes. The trajectory of CLAD is variable depending on the phenotype, with restrictive and mixed phenotypes having more rapid progression and lower survival. The mechanisms driving CLAD development remain unclear, though allograft injury during primary graft dysfunction, acute cellular rejection, antibody-mediated rejection, and infections trigger immune responses with long-lasting effects that can lead to CLAD months or years later. Currently, retransplantation is the only effective treatment.

BackgroundTelomere dysfunction is associated with idiopathic pulmonary fibrosis (IPF) and worse outcomes following lung transplantation. Telomere dysfunction may impair immunity by upregulating p53 and arresting proliferation, but its influence on allograft-specific immune responses is unknown. We hypothesized that subjects undergoing lung transplantation for IPF would have impaired T cell proliferation to donor antigens.MethodsWe analyzed peripheral blood mononuclear cells (PBMC) from 14 IPF lung transplant recipients and 12 age-matched non-IPF subjects, before and 2 years after transplantation, as well as PBMC from 9 non-transplant controls. We quantified T cell proliferation and cytokine secretion to donor antigens. Associations between PBMC telomere length, measured by quantitative PCR, and T cell proliferation to alloantigens were evaluated with generalized estimating equation models.ResultsIPF subjects demonstrated impaired CD8+ T cell proliferation to donor antigens pre-transplant (p < 0.05). IL-2, IL-7, and IL-15 cytokine stimulation restored T cell proliferation, while p53 upregulation blocked proliferation. IPF subjects had shorter PBMC telomere lengths than non-IPF subjects (p < 0.001), and short PBMC telomere length was associated with impaired CD8+ T cell proliferation to alloantigens (p=0.002).ConclusionsIPF as an indication for lung transplant is associated with short PBMC telomere length and impaired T cell responses to donor antigens. However, the rescue of proliferation following cytokine exposure suggests that alloimmune anergy could be overcome. Telomere length may inform immunosuppression strategies for IPF recipients.

BACKGROUND: While lung transplantation (LTx) improves health related quality of life (HRQL) in cystic fibrosis (CF), the determinants of this improvement are unknown. In other populations, frailty—a syndrome of vulnerability to physiologic stressors—is associated with disability and poor HRQL. We hypothesized that improvements in frailty would be associated with improved disability and HRQL in adults with CF undergoing LTx. METHODS: In a single-center prospective cohort study from 2010–2017, assessments of frailty, disability, and HRQL were performed before and at 3- and 6-months after LTx. We assessed frailty by the Short Physical Performance Battery (SPPB). We assessed disability with the Lung Transplant Valued Life Activities Scale (LT-VLA) and HRQL by the Medical Outcomes Study Short Form Physical and Mental Component Summary scales (SF12-PCS, -MCS), the Airway Questionnaire 20-Revised (AQ20R), and the Euroqol 5D (EQ5D). We tested the association of concurrent changes in frailty and lung function on disability and HRQL by linear mixed effects models adjusted for sex and body mass index. RESULTS: Among 23 participants with CF, improvements in frailty and lung function were independently associated with improved disability and some HRQL measures. For example, each 1-point improvement in SPPB or 200mL improvement in FEV(1) was associated with improved LT-VLA disability by 0.14 (95%CI: 0.08 to 0.20) and 0.07 (95%CI: 0.05 to 0.09) points and improved EQ5D by 0.05 (95%CI: 0.03 to 0.07) and 0.02 (95%CI: 0.01 to 0.03) points, respectively. CONCLUSION: Improvement in frailty is a novel determinant of improved disability and HRQL in adults with CF undergoing LTx.

This study aimed to identify outcome determinants for extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (BTT) at our institution.This retrospective single-center study reviewed patients on ECMO between 2010 and 2018 and compared clinical characteristics between patients who underwent successful-BTT and those who did not. Additionally, we examined differences between actively versus emergently listed patients and reasons for failure-to-list. Seventy-six patients were placed on ECMO with the intent to bridge to transplant. Of those, 42 were actively on the waitlist (AWL) prior to ECMO initiation, 20 were emergently evaluated and waitlisted (EWL) after ECMO initiation, and 14 failed-to-list. Of the 62 listed patients, 42 (68%) were successfully transplanted. Risk factors of failed-BTT included right ventricular dysfunction prior to ECMO initiation, longer ECMO duration, reduced mobility status, shorter stature, higher prevalence of blood type B, worse kidney and liver function, and increased transfusion requirements. The number of patients transitioned to central VA-ECMO was higher in the failed-BTT group. Thirty-day survival post-transplantation was 98%, with 90% successfully discharged; 1-year survival conditional upon discharge was 97%. AWL and EWL groups had comparable outcomes. Reasons for failure-to-list are not readily modifiable. ECMO-BTT has become a viable option with satisfactory 1-year survival in patients with irreversible lung injury. Our results support rescue transplant for emergently evaluated and waitlisted patients on ECMO. Our data suggests that modification in national organ allocation policies especially as they pertain to high-acuity recipients with rare blood types and short stature could enhance successful outcome.

The COVID-19 pandemic has caused acute lung injury in millions of individuals worldwide. Some patients develop COVID-related acute respiratory distress syndrome (CARDS) and cannot be liberated from mechanical ventilation. Others may develop post-COVID fibrosis, resulting in substantial disability and need for long-term supplemental oxygen. In both of these situations, treatment teams often inquire about the possibility of lung transplantation. In fact, lung transplantation has been successfully employed for both CARDS and post-COVID fibrosis in a limited number of patients worldwide. Lung transplantation after COVID infection presents a number of unique challenges that transplant programs must consider. In those with severe CARDS, the inability to conduct proper psychosocial evaluation and pretransplantation education, marked deconditioning from critical illness, and infectious concerns regarding viral reactivation are major hurdles. In those with post-COVID fibrosis, our limited knowledge about the natural history of recovery after COVID-19 infection is problematic. Increased knowledge of the likelihood and degree of recovery after COVID-19 acute lung injury is essential for appropriate decision-making with regard to transplantation. Transplant physicians must weigh the risks and benefits of lung transplantation differently in a post-COVID fibrosis patient who is likely to remain stable or gradually improve in comparison with a patient with a known progressive fibrosing interstitial lung disease (fILD). Clearly lung transplantation can be a life-saving therapeutic option for some patients with severe lung injury from COVID-19 infection. In this review, we discuss how lung transplant providers from a number of experienced centers approach lung transplantation for CARDS or post-COVID fibrosis.

Advanced donor age is a risk factor for poor survival following lung transplantation. However, recent work identifying epigenetic determinants of aging has shown that biologic age may not always reflect chronologic age and that stressors can accelerate biologic aging. We hypothesized that lung allografts that experienced primary graft dysfunction (PGD), characterized by poor oxygenation in the first three post-transplant days, would have increased biologic age. We cultured airway epithelial cells isolated by transbronchial brush at 1-year bronchoscopies from 13 subjects with severe PGD and 15 controls matched on age and transplant indication. We measured epigenetic age using the Horvath epigenetic clock. Linear models were used to determine the association of airway epigenetic age with chronologic ages and PGD status, adjusted for recipient PGD risk factors. Survival models assessed the association with chronic lung allograft dysfunction (CLAD) or death. Distributions of promoter methylation within pathways were compared between groups. DNA methyltransferase (DNMT) activity was quantified in airway epithelial cells under hypoxic or normoxic conditions. Airway epigenetic age appeared younger but was strongly associated with the age of the allograft (slope 0.38 per year, 95% CI 0.27–0.48). There was no correlation between epigenetic age and recipient age (P = 0.96). Epigenetic age was 6.5 years greater (95% CI 1.7–11.2) in subjects who had experienced PGD, and this effect remained significant after adjusting for donor and recipient characteristics (P = 0.03). Epigenetic age was not associated with CLAD-free survival risk (P = 0.11). Analysis of differential methylation of promoters of key biologic pathways revealed hypomethylation in regions related to hypoxia, inflammation, and metabolism-associated pathways. Accordingly, airway epithelial cells cultured in hypoxic conditions showed suppressed DNMT activity. While airway methylation age was primarily determined by donor chronologic age, early injury in the form of PGD was associated with increased allograft epigenetic age. These data show how PGD might suppress key promoter methylation resulting in long-term impacts on the allograft.

Rationale: Sarcopenia is associated with disability and death. The optimal definition and clinical relevance of sarcopenia in lung transplantation remain unknown. Objectives: To assess the construct and predictive validity of sarcopenia definitions in lung transplant candidates. Methods: In a multicenter prospective cohort of 424 lung transplant candidates, we evaluated limited (muscle mass only) and expanded (muscle mass and quality) sarcopenia definitions from the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), the Foundation for the National Institutes of Health (FNIH), and a cohort-specific distribution-based lowest quartile definition. We assessed construct validity using associations with conceptually related factors. We evaluated the relationship between sarcopenia and frailty using generalized additive models. We also evaluated associations between sarcopenia definitions and key pretransplant outcomes, including disability (quantified by the Lung Transplant Valued Life Activities scale [range, 0–3; higher scores = worse disability; minimally important difference, 0.3]) and waitlist delisting/death, by multivariate linear and Cox regression, respectively. Results: Sarcopenia prevalence ranged from 6% to13% by definition used. The limited EWGSOP2 definition demonstrated the highest construct validity, followed by the expanded EWGSOP2 definition and both limited and expanded FNIH and lowest quartile definitions. Sarcopenia exhibited a linear association with the risk of frailty. The EWGSOP2 and expanded lowest quartile definitions were associated with disability, ranging from 0.20 to 0.25 higher Lung Transplant Valued Life Activities scores. Sarcopenia was associated with increased risk of waitlist delisting or death by the limited and expanded lowest quartile definitions (hazard ratio [HR], 3.8; 95% confidence interval [CI], 1.4–9.9 and HR, 3.5; 95% CI, 1.1–11.0, respectively) and the EWGSOP2 limited definition (HR, 2.8; 95% CI, 0.9–8.6) but not with the three other candidate definitions. Conclusions: The prevalence and validity of sarcopenia vary by definition; the EWGSOP2 limited definition exhibited the broadest validity in lung transplant candidates. The linear relationship between low muscle mass and frailty highlights sarcopenia’s contribution to frailty and also questions the clinical utility of a sarcopenia cut-point in advanced lung disease. The associations between sarcopenia and important pretransplant outcomes support further investigation into using body composition for candidate risk stratification.

Patients with connective tissues disease (CTD) are often on immunomodulatory agents before lung transplantation (LTx). Till now, there's no consensus on the safety of using these agents perioperative and post-transplant. The International Society for Heart and Lung Transplantation-supported consensus document on LTx in patients with CTD addresses the risk and contraindications of perioperative and post-transplant management of the biologic disease-modifying antirheumatic drugs (bDMARD), kinase inhibitor DMARD, and biologic agents used for LTx candidates with underlying CTD, and the recommendations and management of non-gastrointestinal extrapulmonary manifestations, and esophageal disorders by medical and surgical approaches for CTD transplant recipients.

Summary Background Donor lung use for transplantation is the lowest among solid organ tranplants because of several complex and multifactorial reasons; one area that could have a substantial role is the limited capabilities of cold ischaemic storage. The aim of the EXPAND trial was to evaluate the efficacy of normothermic portable Organ Care System (OCS) Lung perfusion and ventilation on donor lung use from extended-criteria donors and donors after circulatory death, which are rarely used. Methods In this single-arm, pivotal trial done in eight institutions across the USA, Germany, and Belgium, lungs from extended-criteria donors were included if fulfilling one or more of the following criteria: a ratio of partial pressure of arterial oxygen (PaO2) to fractional concentration of oxygen inspired air (FiO2) in the donor lung of 300 mm Hg or less; expected ischaemic time longer than 6 h; donor age 55 years or older; or lungs from donors after circulatory death that were recruited and assessed using OCS Lung. Lungs were transplanted if they showed stability of OCS Lung variables, PaO2:FiO2 was more than 300 mm Hg, and they were accepted by the transplanting surgeon. Patients were adult bilateral lung transplant recipients. The primary efficacy endpoint was a composite of patient survival at day 30 post-transplant and absence of The International Society for Heart & Lung Tranplantation primary-graft dysfunction grade 3 (PGD3) within 72 h post-transplantation, with a prespecified objective performance goal of 65%. The primary analysis population was all transplanted recipients. This trial is registered with ClinicalTrials.gov, number NCT01963780, and is now complete. Findings Between Jan 23, 2014, and Oct 23, 2016, 93 lung pairs were perfused, ventilated, and assessed on the OCS Lung. 12 lungs did not meet OCS transplantation criteria so 81 lungs were suitable for transplantation. Two lungs were excluded for logistical reasons, hence 79 (87%) of eligible lungs were transplanted. The primary endpoint was achieved in 43 (54%) of 79 patients and did not meet the objective performance goal. 35 (44%) of 79 patients had PGD3 within the initial 72 h. 78 (99%) of 79 patients had survived at 30 days post-transplant. The mean number of lung graft-related serious adverse events (respiratory failure and major pulmonary-related infection) was 0·3 events per patient (SD 0·5). Interpretation Despite missing the objective primary endpoint, the portable OCS Lung resulted in 87% donor lung use for transplantation with excellent clinical outcomes. Many lungs declined by other transplant centres were successfully transplanted using this new technology, which implies its use has the potential to increase the number of lung transplants performed worldwide. Whether similar outcomes could be obtained if these lungs were preserved on ice is unknown and remains an area for future research. Funding TransMedics Inc.

ObjectiveMost studies observing an association between depressive symptoms following lung transplantation and mortality are limited to depressive symptom measurement at a single time point, unrelated to allograft function. We aimed to test the association of depressive symptoms over multiple assessments with allograft dysfunction and with mortality.MethodsWe assessed depressive symptoms before and serially up to 3 years after lung transplantation in lung transplant recipients. We quantified depressive symptoms with the Geriatric Depression Scale (GDS; range 0–15; minimally important difference (MID): 2). We quantified changes in GDS using linear mixed effects models and tested the association with mortality using Cox proportional hazards models with GDS as a time-dependent predictor. To determine if worsening in GDS preceded declines in lung function, we tested the association of GDS as a time-dependent predictor with the lagged outcome of FEV1 at the following study visit.ResultsAmong 266 participants, depressive symptoms improved early after transplantation. Worsening in post-transplant GDS by the MID was associated with mortality (HR 1.25, 95% CI 1.05 to 1.50), and in lagged outcome analyses with decreased per cent predicted FEV1 (Δ, −1.62%, 95% CI −2.49 to –0.76). Visual analyses of temporal changes in GDS demonstrated that worsening depressive symptoms could precede chronic lung allograft dysfunction.ConclusionsDepressive symptoms generally improve after lung transplantation. When they worsen, however, there is an association with declines in lung function and mortality. Depression is one of the few, potentially modifiable, risk factors for chronic lung allograft dysfunction and death.

Author(s): Lee, Joyce S; La, Janet; Aziz, Sara; Dobrinskikh, Evgenia; Brownell, Robert; Jones, Kirk D; Achtar-Zadeh, Natalia; Green, Gary; Elicker, Brett M; Golden, Jeffrey A; Matthay, Michael A; Kukreja, Jasleen; Schwartz, David A; Wolters, Paul J | Abstract: AimsIdiopathic pulmonary fibrosis (IPF) is a genetically mediated, age-associated, progressive form of pulmonary fibrosis characterised pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (non-IPF UIP), whose clinical course is similarly poor, suggesting common molecular drivers. This study investigates whether IPF and non-IPF UIP lungs similarly express markers of telomere dysfunction and senescence.Methods and resultsTo test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissues from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Histopathological changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci, and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, non-caseating granulomas, airway-centred inflammation, or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs than in those of age-similar, unused donor, controls. Levels of molecular markers of senescence (p16 and p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localised expression of these proteins to AECII cells. The mucin 5B (MUC5B) gene promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients, and MUC5B expression was similar in IPF and non-IPF UIP lungs.ConclusionsMolecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.

Author(s): Hoover, Jonathan; Mintz, Michelle A; Deiter, Fred; Aminian, Emily; Chen, Joy; Hays, Steven R; Singer, Jonathan P; Calabrese, Daniel R; Kukreja, Jasleen; Greenland, John R | Abstract: BackgroundAirway infections are difficult to distinguish from acute rejection in lung transplant recipients. Traditional culture techniques take time that may delay treatment. We hypothesized that a rapid multiplex molecular assay could improve time to diagnosis and appropriate clinical decision making.MethodsIn a prospective observational study of recipients undergoing bronchoscopy, we assessed the BioFire® FilmArray® Pneumonia Panel (BFPP) in parallel to standard of care (SOC) diagnostics. Research clinicians performed shadow (research only) clinical decision making in real time. Time to report and interpretation were reported as median and interquartile ranges and compared by Wilcoxon signed-ranked test. Agreement was defined based on detection of any species targeted in the molecular assay.ResultsFor the 150 enrolled subjects, BFPP results were available 3.8nhours (IQR 2.8-5.1) following bronchoscopy, compared to 13nhours for viral SOC (IQR 10-34, Pnln.001) results and 48nhours for bacterial SOC (IQR 46-70, Pnln.001) results. Positive BFPP results were interpreted in 9nhours (IQR 5-20) following bronchoscopy, compared to 74nhours for SOC (IQR 37-110, Pnln.001). Assays agreed for 138 (92%) of the 150 subjects. Of 22 BFPP diagnoses, five (23%) resulted in a shadow antibiotic recommendation. Notable BFPP deficiencies included fungal species and H parainfluenzae, accounting for 15 (27%) and 13 (23%) of the 56 actionable SOC results, respectively.ConclusionsThis molecular diagnostic including bacterial targets has the potential to shorten time to diagnosis and augment current clinical decision making but cannot replace SOC culture methods.

We evaluated the feasibility, safety, and efficacy of a mHealth-supported physical rehabilitation intervention to treat frailty in a pilot study of 18 lung transplant recipients. Frail recipients were defined by a short physical performance battery (SPPB score ≤7). The primary intervention modality was Aidcube, a customizable rehabilitation mHealth platform. Our primary aims included tolerability, feasibility, and acceptability of use of the platform, and secondary outcomes were changes in SPPB and in scores of physical activity, and disability measured using the Duke Activity Status Index (DASI) and Lung Transplant-Value Life Activities (LT-VLA). Notably, no adverse events were reported. Subjects reported the app was easy to use, usability improved over time, and the app enhanced motivation to engage in rehabilitation. Comments highlighted the complexities of immediate post-transplant rehabilitation, including functional decline, pain, tremor, and fatigue. At the end of the intervention, SPPB scores improved a median of 5 points from a baseline of 4. Physical activity and patient-reported disability also improved. The DASI improved from 4.5 to 19.8 and LT-VLA score improved from 2 to 0.59 at closeout. Overall, utilization of a mHealth rehabilitation platform was safe and well received. Remote rehabilitation was associated with improvements in frailty, physical activity and disability. Future studies should evaluate mHealth treatment modalities in larger-scale randomized trials of lung transplant recipients.

Pulmonary ischemia-reperfusion injury (IRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. IRI causes early mortality and has no effective therapies. While NK cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, we demonstrated that NK cells were increased in frequency and cytotoxicity in 2 different IRI mouse models. We showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell-deficient mouse strain but restored with adoptive transfer of NK cells. Mechanistically, NK cell NKG2D receptor ligands were induced on lung endothelial and epithelial cells following IRI, and antibody-mediated NK cell depletion or NKG2D stress receptor blockade abrogated acute lung injury. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury.