Subphenotypes of frailty in lung transplant candidates.

Heterogeneous frailty pathobiology might explain the inconsistent associations observed between frailty and lung transplant outcomes. A Subphenotype analysis could refine frailty measurement. In a 3-center pilot cohort study, we measured frailty by the Short Physical Performance Battery, body composition, and serum biomarkers reflecting causes of frailty. We applied latent class modeling for these baseline data. Next, we tested class construct validity with disability, waitlist delisting/death, and early postoperative complications. Among 422 lung transplant candidates, 2 class model fit the best (P = .01). Compared with Subphenotype 1 (n = 333), Subphenotype 2 (n = 89) was characterized by systemic and innate inflammation (higher IL-6, CRP, PTX3, TNF-R1, and IL-1RA); mitochondrial stress (higher GDF-15 and FGF-21); sarcopenia; malnutrition; and lower hemoglobin and walk distance. Subphenotype 2 had a worse disability and higher risk of waitlist delisting or death (hazards ratio: 4.0; 95% confidence interval: 1.8-9.1). Of the total cohort, 257 underwent transplant (Subphenotype 1: 196; Subphenotype 2: 61). Subphenotype 2 had a higher need for take back to the operating room (48% vs 28%; P = .005) and longer posttransplant hospital length of stay (21 days [interquartile range: 14-33] vs 18 days [14-28]; P = .04). Subphenotype 2 trended toward fewer ventilator-free days, needing more postoperative extracorporeal membrane oxygenation and dialysis, and higher need for discharge to rehabilitation facilities (P ≤ .20). In this early phase study, we identified biological frailty Subphenotypes in lung transplant candidates. A hyperinflammatory, sarcopenic Subphenotype seems to be associated with worse clinical outcomes.

Depressive symptoms in lung transplant recipients: trajectory and association with mortality and allograft dysfunction.

OBJECTIVE: Most 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. METHODS: We 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. RESULTS: Among 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. CONCLUSIONS: Depressive 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.

Primary graft dysfunction attenuates improvements in health-related quality of life after lung transplantation, but not disability or depression.

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 3- to 6-month intervals after lung transplantation. We estimated the magnitude of change in disability, depressive symptoms, and HRQL with hierarchical segmented linear mixed-effects models. Among 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- to 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. Among participants with PGD Grade 3, prolonged mechanical ventilation was associated with greater attenuation of improvements. PGD remains a threat to the 2 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 association of post-operative delirium with patient-reported outcomes and mortality after lung transplantation.

Post-operative delirium after lung transplantation is common. Its associations with health-related quality of life (HRQL), depression, and mortality remains unknown. In 236 lung transplant recipients, HRQL and depressive symptoms were assessed as part of a structured survey battery before and after transplantation. Surveys included the Geriatric Depressive Scale (GDS) and Short Form 12 (SF12). Delirium was assessed throughout the post-operative intensive care unit (ICU) stay with Confusion Assessment Method for ICU. Delirium and mortality data were extracted from electronic medical records. We examined associations between delirium and changes in depressive symptoms and HRQL using linear mixed effects models and association between delirium and mortality with Cox-proportional hazard models. Post-operative delirium occurred in 34 participants (14%). Delirium was associated with attenuated improvements in SF12-PCS (difference ₋4.0; 95%CI: -7.4, -0.7) but not SF12-MCS (difference 2.2; 95%CI: -0.7,5.7) or GDS (difference ₋0.4; 95%CI: -1.5,0.7). Thirty-two participants died during the study period. Delirium was associated with increased adjusted hazard risk of mortality (HR 17.9, 95%CI: 4.4,72.5). Delirium after lung transplantation identifies a group at increased risk for poorer HRQL and death within the first post-operative year. Further studies should investigate potential causal links between delirium, and poorer HRQL and mortality risk after lung transplantation.

Mitochondrial DNA Stimulates TLR9-Dependent Neutrophil Extracellular Trap Formation in Primary Graft Dysfunction.

The immune system is designed to robustly respond to pathogenic stimuli but to be tolerant to endogenous ligands to not trigger autoimmunity. Here, we studied an endogenous damage-associated molecular pattern, mitochondrial DNA (mtDNA), during primary graft dysfunction (PGD) after lung transplantation. We hypothesized that cell-free mtDNA released during lung ischemia-reperfusion triggers neutrophil extracellular trap (NET) formation via TLR9 signaling. We found that mtDNA increases in the BAL fluid of experimental PGD (prolonged cold ischemia followed by orthotopic lung transplantation) and not in control transplants with minimal warm ischemia. The adoptive transfer of mtDNA into the minimal warm ischemia graft immediately before lung anastomosis induces NET formation and lung injury. TLR9 deficiency in neutrophils prevents mtDNA-induced NETs, and TLR9 deficiency in either the lung donor or recipient decreases NET formation and lung injury in the PGD model. Compared with human lung transplant recipients without PGD, severe PGD was associated with high levels of BAL mtDNA and NETs, with evidence of relative deficiency in DNaseI. We conclude that mtDNA released during lung ischemia-reperfusion triggers TLR9-dependent NET formation and drives lung injury. In PGD, DNaseI therapy has a potential dual benefit of neutralizing a major NET trigger (mtDNA) in addition to dismantling pathogenic NETs.

Frailty after lung transplantation is associated with impaired health-related quality of life and mortality.

BACKGROUND: Lung transplantation and related medications are associated with pathobiological changes that can induce frailty, a state of decreased physiological reserve. Causes of persistent or emergent frailty after lung transplantation, and whether such transplant-related frailty is associated with key outcomes, are unknown. METHODS: Frailty and health-related quality of life (HRQL) were prospectively measured repeatedly for up to 3 years after lung transplantation. Frailty, quantified by the Short Physical Performance Battery (SPPB), was tested as a time-dependent binary and continuous predictor. The association of transplant-related frailty with HRQL and mortality was evaluated using mixed effects and Cox regression models, respectively, adjusting for age, sex, ethnicity, diagnosis, and for body mass index and lung function as time-dependent covariates. We tested the association between measures of body composition, malnutrition, renal dysfunction and immunosuppressants on the development of frailty using mixed effects models with time-dependent predictors and lagged frailty outcomes. RESULTS: Among 259 adults (56% male; mean age 55.9±12.3 years), transplant-related frailty was associated with lower HRQL. Frailty was also associated with a 2.5-fold higher mortality risk (HR 2.51; 95% CI 1.21 to 5.23). Further, each 1-point worsening in SPPB was associated, on average, with a 13% higher mortality risk (HR 1.13; 95% CI 1.04 to 1.23). Secondarily, we found that sarcopenia, underweight and obesity, malnutrition, and renal dysfunction were associated with the development of frailty after transplant. CONCLUSIONS: Transplant-related frailty is associated with lower HRQL and higher mortality in lung recipients. Abnormal body composition, malnutrition and renal dysfunction may contribute to the development of frailty after transplant. Confirming the role of these potential contributors and developing interventions to mitigate frailty may improve lung transplant success.

Longitudinal assessment of interstitial lung disease in single lung transplant recipients with scleroderma.

OBJECTIVE: To investigate the natural history of fibrotic lung disease in recipients of a single lung transplant for scleroderma-associated interstitial lung disease (ILD). METHODS: Global ILD (including ground glass, nodular opacities and fibrosis) was categorized into severity quintiles on first and last post-transplant CT scans, and percent fibrosis by manual contouring was also determined, in nine single lung transplant recipients. Quantitative mean lung densities and volumes for the native and allograft lungs were also acquired. RESULTS: In the native lung, global ILD severity quintile worsened in two cases and percent fibrosis worsened in four cases (range 5-28%). In the lung allograft, one case each developed mild, moderate and severe ILD; of these, new fibrotic ILD (involving <10% of lung) occurred in two cases and acute cellular rejection occurred in one. The average change in native lung density over time was +2.2 Hounsfield Units per year and lung volume +1.4 ml per year, whereas the allograft lung density changed by -5.5 Hounsfield Units per year and total volume +27 ml per year (P = 0.011 and P = 0.039 for native vs allograft density and volume comparisons, respectively). CONCLUSIONS: While the course of ILD in the native and transplanted lungs varied in this series, these cases illustrate that disease progression is common in the native lung, suggesting that either the immune process continues to target autoantigens or ongoing fibrotic pathways are active in the native lung. Mild lung disease may occur in the allograft after several years due to either allograft rejection or recurrent mild ILD.

Management and clinical outcomes after lung transplantation in patients with pre-transplant Mycobacterium abscessus infection: A single center experience.

BACKGROUND: Preoperative Mycobacterium abscessus infection is often considered a contraindication to lung transplantation because of its association with poor outcomes after transplant. Detailed strategies for bridging to transplant, post-operative management, and data regarding outcomes are lacking. METHODS: We reviewed outcomes in subjects with M abscessus infection who underwent lung transplantation between 2010 and 2018 at the University of California San Francisco. M abscessus infection was defined by American Thoracic Society (ATS) criteria. Data collected included age, FEV1 , BMI, LAS, antibiotic regimens, and other management decisions. Time to chronic lung allograft dysfunction (CLAD) and survival were also assessed. RESULTS: Of 387 lung transplant recipients, seven were infected with M abscessus at the time of listing. All received multiple antibiotics before transplant. While all subjects converted to smear negative for acid-fast bacilli before listing, five of the seven remained culture-positive at the time of transplant. After transplant, subjects received a median of 6 months of a multi-antibiotic regimen. One subject developed a post-operative M abscessus soft tissue infection that was treated medically. Six of the seven subjects survived the observation period; one died unrelated to M abscessus. Time to CLAD and survival were similar to a contemporary comparator group of CF transplant recipients. CONCLUSION: Lung transplant recipients with M abscessus infection have a low incidence of recurrent infection, excellent survival, and freedom from CLAD when an aggressive management and surveillance strategy is utilized. Given these findings, M abscessus infection may not be considered a contraindication to lung transplantation.

Frailty phenotypes and mortality after lung transplantation: A prospective cohort study.

Frailty is associated with increased mortality among lung transplant candidates. We sought to determine the association between frailty, as measured by the Short Physical Performance Battery (SPPB), and mortality after lung transplantation. In a multicenter prospective cohort study of adults who underwent lung transplantation, preoperative frailty was assessed with the SPPB (n = 318) and, in a secondary analysis, the Fried Frailty Phenotype (FFP; n = 299). We tested the association between preoperative frailty and mortality following lung transplantation with propensity score-adjusted Cox models. We calculated postestimation marginalized standardized risks for 1-year mortality by frailty status using multivariate logistic regression. SPPB frailty was associated with an increased risk of both 1- and 4-year mortality (adjusted hazard ratio [aHR]: 7.5; 95% confidence interval [CI]: 1.6-36.0 and aHR 3.8; 95%CI: 1.8-8.0, respectively). Each 1-point worsening in SPPB was associated with a 20% increased risk of death (aHR: 1.20; 95%CI: 1.08-1.33). Frail subjects had an absolute increased risk of death within the first year after transplantation of 12.2% (95%CI: 3.1%-21%). In secondary analyses, FFP frailty was associated with increased risk of death within the first postoperative year (aHR: 3.8; 95%CI: 1.1-13.2) but not over longer follow-up. Preoperative frailty is associated with an increased risk of death after lung transplantation.

Disturbed sleep after lung transplantation is associated with worse patient-reported outcomes and chronic lung allograft dysfunction.

Many lung transplant recipients fail to derive the expected improvements in functioning, HRQL, or long-term survival. Sleep may represent an important, albeit rarely examined, factor influencing lung transplant outcomes. Within a larger cohort study, 141 lung transplant recipients completed the Medical Outcomes Study (MOS) Sleep Scale along with a broader survey of patient-reported outcome (PRO) measures and frailty assessment. MOS Sleep yields the Sleep Problems Index (SPI); we also derived an insomnia-specific subscale. Potential perioperative predictors of disturbed sleep and time to chronic lung allograft dysfunction (CLAD) and death were derived from medical records. We investigated associations between perioperative predictors on SPI and Insomnia and associations between SPI and Insomnia on PROs and frailty by linear regressions, adjusting for age, sex, and lung function. We evaluated the associations between SPI and Insomnia on time to CLAD and death using Cox models, adjusting for age, sex, and transplant indication. Post-transplant hospital length of stay >30 days was associated with worse sleep by SPI and insomnia (SPI: p=0.01; Insomnia p=0.02). Worse sleep by SPI and insomnia was associated with worse depression, cognitive function, HRQL, physical disability, health utilities, and Fried Frailty Phenotype frailty (all p<0.01). Those in the worst quartile of SPI and insomnia exhibited increased risk of CLAD (HR 2.18; 95%CI: 1.22-3.89 ; p=0.01 for SPI and HR 1.96; 95%CI 1.09-3.53; p=0.03 for insomnia). Worsening in SPI but not insomnia was also associated with mortality (HR: 1.29; 95%CI: 1.05-1.58; p=0.01). Poor sleep after lung transplant may be a novel predictor of patient reported outcomes, frailty, CLAD, and death with potentially important screening and treatment implications.

Macrophage and CD8 T cell discordance are associated with acute lung allograft dysfunction progression.

BACKGROUND: Acute lung allograft dysfunction (ALAD) is an imprecise syndrome denoting concern for the onset of chronic lung allograft dysfunction (CLAD). Mechanistic biomarkers are needed that stratify risk of ALAD progression to CLAD. We hypothesized that single cell investigation of bronchoalveolar lavage (BAL) cells at the time of ALAD would identify immune cells linked to progressive graft dysfunction. METHODS: We prospectively collected BAL from consenting lung transplant recipients for single cell RNA sequencing. ALAD was defined by a ≥10% decrease in FEV1 not caused by infection or acute rejection and samples were matched to BAL from recipients with stable lung function. We examined cell compositional and transcriptional differences across control, ALAD with decline, and ALAD with recovery groups. We also assessed cell-cell communication. RESULTS: BAL was assessed for 17 ALAD cases with subsequent decline (ALAD declined), 13 ALAD cases that resolved (ALAD recovered), and 15 cases with stable lung function. We observed broad differences in frequencies of the 26 unique cell populations across groups (p = 0.02). A CD8 T cell (p = 0.04) and a macrophage cluster (p = 0.01) best identified ALAD declined from the ALAD recovered and stable groups. This macrophage cluster was distinguished by an anti-inflammatory signature and the CD8 T cell cluster resembled a Tissue Resident Memory subset. Anti-inflammatory macrophages signaled to activated CD8 T cells via class I HLA, fibronectin, and galectin pathways (p < 0.05 for each). Recipients with discordance between these cells had a nearly 5-fold increased risk of severe graft dysfunction or death (HR 4.6, 95% CI 1.1-19.2, adjusted p = 0.03). We validated these key findings in 2 public lung transplant genomic datasets. CONCLUSIONS: BAL anti-inflammatory macrophages may protect against CLAD by suppressing CD8 T cells. These populations merit functional and longitudinal assessment in additional cohorts.

Alcohol ingestion disrupts alveolar epithelial barrier function by activation of macrophage-derived transforming growth factor beta1.

BACKGROUND: Chronic alcohol abuse causes oxidative stress and impairs alveolar epithelial barrier integrity, thereby rendering the lung susceptible to acute edematous injury. Experimentally, alcohol-induced oxidative stress increases the expression of transforming growth factor ß1 (TGFß1) in the lung; however, we do not know the precise contribution of various alveolar cells in this process. In the present study, we focused on cell-cell interactions between alveolar macrophages and epithelial cells and the potential mechanisms by which TGFß1 may become activated in the alveolar space of the alcoholic lung. METHODS: Primary alveolar macrophages and epithelial cells were isolated from control- and alcohol-fed Sprague-Dawley rats. Expression of TGFß1 and the epithelial integrin αvß6 were examined by real time PCR and either immunocytochemistry or flow cytometry. Alveolar epithelial cells were cultured on transwell supports in the presence of macrophage cell lysate from control- or alcohol-fed rats or in the presence of viable macrophages ± alcohol. Epithelial barrier function was assessed by transepithelial resistance (TER) and paracellular flux of Texas Red dextran. RESULTS: TGFß1 expression was increased in alveolar macrophages from alcohol-fed rats, and TGFß1 protein was predominantly membrane-bound. Importantly, alveolar macrophage cellular lysate from alcohol-fed rats decreased TER and increased paracellular dextran flux in primary alveolar epithelial cell monolayers as compared to the lysates from control-fed rats. Alcohol-induced epithelial barrier dysfunction was prevented by anti-TGFß1 antibody treatment, indicating the presence of bioactive TGFß1 in the macrophage lysate. In addition, co-culturing macrophages and epithelial cells in the presence of alcohol decreased epithelial barrier function, which also was prevented by anti-TGFß1 and anti-αvß6 treatment. In parallel, chronic alcohol ingestion in vivo, or direct treatment with active TGFß1 in vitro, increased the expression of αvß6 integrin, which is known to activate TGFß1, in alveolar epithelial cells. CONCLUSIONS: Taken together, these data suggest that interactions between alveolar epithelial cells and macrophages contribute to the alcohol-mediated disruption of epithelial barrier function via the expression and activation of TGFß1 at points of cell-cell contact.

The Association Between Frailty and Chronic Lung Allograft Dysfunction After Lung Transplantation.

BACKGROUND: After lung transplantation, both frailty and chronic lung allograft dysfunction (CLAD) commonly develop, and when they do, are associated with poorer outcomes. Given their potential shared mechanisms, we sought to explore the temporal relationship between frailty and CLAD onset. METHODS: In a single center, we prospectively measured frailty by the short physical performance battery (SPPB) repeatedly after transplant. Because of the nature of the relationship between frailty and CLAD is unknown, we tested the association between frailty, modeled as a time-dependent predictor, and CLAD development as well as CLAD development, modeled as a time-dependent predictor, and frailty development. To do so, we used Cox proportional cause-specific hazards and conditional logistic regression models adjusted for age, sex, race, diagnosis, cytomegalovirus serostatus, posttransplant body mass index, and acute cellular rejection episodes as time-dependent covariates. We tested SPPB frailty as a binary (≤9 points) and continuous predictor (12-point scale); as an outcome, we defined frailty as SPPB ≤9. RESULTS: The 231 participants were a mean age of 55.7 y (SD 12.1). After adjusting for covariates, the development of frailty within 3 y after lung transplant was associated with cause-specific CLAD risk (adjusted cause-specific hazard ratio: 1.76; 95% confidence interval [CI], 1.05-2.92 when defining frailty as SPPB ≤9 and adjusted cause-specific hazard ratio: 1.10, 95% CI, 1.03-1.18 per 1-point worsening in SPPB). CLAD onset did not appear to be a risk factor for subsequent frailty (odds ratio, 4.0; 95% CI, 0.4-197.0). CONCLUSIONS: Studying the mechanisms underlying frailty and CLAD could provide new insights into the pathobiology of both and potential targets for intervention.

Design and implementation of a digital health home spirometry intervention for remote monitoring of lung transplant function.

BACKGROUND: We developed an automated, chat-based, digital health intervention using Bluetooth-enabled home spirometers to monitor for complications of lung transplantation in a real-world application. METHODS: A chat-based application prompted patients to perform home spirometry, enter their forced expiratory volume in 1 second (FEV1), answer symptom queries, and provided patient education. The program alerted patients and providers to substantial FEV1 decreases and concerning symptoms. Data was integrated into the electronic health record (EHR) system and dashboards were developed for program monitoring. RESULT: Between May 2020 and December 2021, 544 patients were invited to enroll, of whom 427 were invited remotely and 117 were enrolled in-person. 371 (68%) participated by submitting ≥1 FEV1 values. Overall engagement was high, with an average of 197 unique patients submitting FEV1 data per month. In-person enrollees submitted an average of 4.6 FEV1 values per month and responded to 55% of scheduled chats. Home and laboratory FEV1 values correlated closely (rho = 0.93). There was an average of 133 ± 59 FEV1 decline alerts and 59 ± 23 symptom alerts per month. 72% of patients accessed education modules, and the program had a high net promoter score (53) amongst users. CONCLUSIONS: We demonstrate that a novel, automated, chat-based, and EHR-integrated home spirometry intervention is well accepted, generates reliable assessments of graft function, and can deliver automated feedback and education resulting in moderately-high adherence rates. We found that in-person onboarding yields better engagement and adherence. Future work will aim to demonstrate the impact of remote care monitoring on early detection of lung transplant complications.

CCR5 drives NK cell-associated airway damage in pulmonary ischemia-reperfusion injury.

Primary graft dysfunction (PGD) limits clinical benefit after lung transplantation, a life-prolonging therapy for patients with end-stage disease. PGD is the clinical syndrome resulting from pulmonary ischemia-reperfusion injury (IRI), driven by innate immune inflammation. We recently demonstrated a key role for NK cells in the airways of mouse models and human tissue samples of IRI. Here, we used 2 mouse models paired with human lung transplant samples to investigate the mechanisms whereby NK cells migrate to the airways to mediate lung injury. We demonstrate that chemokine receptor ligand transcripts and proteins are increased in mouse and human disease. CCR5 ligand transcripts were correlated with NK cell gene signatures independently of NK cell CCR5 ligand secretion. NK cells expressing CCR5 were increased in the lung and airways during IRI and had increased markers of tissue residency and maturation. Allosteric CCR5 drug blockade reduced the migration of NK cells to the site of injury. CCR5 blockade also blunted quantitative measures of experimental IRI. Additionally, in human lung transplant bronchoalveolar lavage samples, we found that CCR5 ligand was associated with increased patient morbidity and that the CCR5 receptor was increased in expression on human NK cells following PGD. These data support a potential mechanism for NK cell migration during lung injury and identify a plausible preventative treatment for PGD.

Development of the Lung Transplant Frailty Scale (LT-FS).

BACKGROUND: Existing measures of frailty developed in community dwelling older adults may misclassify frailty in lung transplant candidates. We aimed to develop a novel frailty scale for lung transplantation with improved performance characteristics. METHODS: We measured the short physical performance battery (SPPB), fried frailty phenotype (FFP), Body Composition, and serum Biomarkers representative of putative frailty mechanisms. We applied a 4-step established approach (identify frailty domain variable bivariate associations with the outcome of waitlist delisting or death; build models sequentially incorporating variables from each frailty domain cluster; retain variables that improved model performance ability by c-statistic or AIC) to develop 3 candidate "Lung Transplant Frailty Scale (LT-FS)" measures: 1 incorporating readily available clinical data; 1 adding muscle mass, and 1 adding muscle mass and research-grade Biomarkers. We compared construct and predictive validity of LT-FS models to the SPPB and FFP by ANOVA, ANCOVA, and Cox proportional-hazard modeling. RESULTS: In 342 lung transplant candidates, LT-FS models exhibited superior construct and predictive validity compared to the SPPB and FFP. The addition of muscle mass and Biomarkers improved model performance. Frailty by all measures was associated with waitlist disability, poorer HRQL, and waitlist delisting/death. LT-FS models exhibited stronger associations with waitlist delisting/death than SPPB or FFP (C-statistic range: 0.73-0.78 vs. 0.57 and 0.55 for SPPB and FFP, respectively). Compared to SPPB and FFP, LT-FS models were generally more strongly associated with delisting/death and improved delisting/death net reclassification, with greater improvements with increasing LT-FS model complexity (range: 0.11-0.34). For example, LT-FS-Body Composition hazard ratio for delisting/death: 6.0 (95%CI: 2.5, 14.2), SPPB HR: 2.5 (95%CI: 1.1, 5.8), FFP HR: 4.3 (95%CI: 1.8, 10.1). Pre-transplant LT-FS frailty, but not SPPB or FFP, was associated with mortality after transplant. CONCLUSIONS: The LT-FS is a disease-specific physical frailty measure with face and construct validity that has superior predictive validity over established measures.

Chronic Lung Allograft Dysfunction.

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.

Extracellular Matrix Stiffness in Lung Health and Disease.

The extracellular matrix (ECM) provides structural support and imparts a wide variety of environmental cues to cells. In the past decade, a growing body of work revealed that the mechanical properties of the ECM, commonly known as matrix stiffness, regulate the fundamental cellular processes of the lung. There is growing appreciation that mechanical interplays between cells and associated ECM are essential to maintain lung homeostasis. Dysregulation of ECM-derived mechanical signaling via altered mechanosensing and mechanotransduction pathways is associated with many common lung diseases. Matrix stiffening is a hallmark of lung fibrosis. The stiffened ECM is not merely a sequelae of lung fibrosis but can actively drive the progression of fibrotic lung disease. In this article, we provide a comprehensive view on the role of matrix stiffness in lung health and disease. We begin by summarizing the effects of matrix stiffness on the function and behavior of various lung cell types and on regulation of biomolecule activity and key physiological processes, including host immune response and cellular metabolism. We discuss the potential mechanisms by which cells probe matrix stiffness and convert mechanical signals to regulate gene expression. We highlight the factors that govern matrix stiffness and outline the role of matrix stiffness in lung development and the pathogenesis of pulmonary fibrosis, pulmonary hypertension, asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. We envision targeting of deleterious matrix mechanical cues for treatment of fibrotic lung disease. Advances in technologies for matrix stiffness measurements and design of stiffness-tunable matrix substrates are also explored. © 2022 American Physiological Society. Compr Physiol 12:3523-3558, 2022.

NKG2D receptor activation drives primary graft dysfunction severity and poor lung transplantation outcomes.

Clinical outcomes after lung transplantation, a life-saving therapy for patients with end-stage lung diseases, are limited by primary graft dysfunction (PGD). PGD is an early form of acute lung injury with no specific pharmacologic therapies. Here, we present a large multicenter study of plasma and bronchoalveolar lavage (BAL) samples collected on the first posttransplant day, a critical time for investigations of immune pathways related to PGD. We demonstrated that ligands for NKG2D receptors were increased in the BAL from participants who developed severe PGD and were associated with increased time to extubation, prolonged intensive care unit length of stay, and poor peak lung function. Neutrophil extracellular traps (NETs) were increased in PGD and correlated with BAL TNF-α and IFN-γ cytokines. Mechanistically, we found that airway epithelial cell NKG2D ligands were increased following hypoxic challenge. NK cell killing of hypoxic airway epithelial cells was abrogated with NKG2D receptor blockade, and TNF-α and IFN-γ provoked neutrophils to release NETs in culture. These data support an aberrant NK cell/neutrophil axis in human PGD pathogenesis. Early measurement of stress ligands and blockade of the NKG2D receptor hold promise for risk stratification and management of PGD.