Evaluating lung transplant candidates with underlying systemic autoimmune rheumatic diseases is challenging due to a wide spectrum of extrapulmonary manifestations, leading to variable practice among centers. This article aims to define autoimmune disease activity and treatment failure, discuss post-transplant complications of pre-transplant immunosuppression, propose criteria for timely lung transplant referral, and discuss management of rheumatologic manifestations after lung transplant. The guidelines and rheumatological considerations in lung transplant candidates remain unclear, with poorly understood effects of autoimmune disease on lung transplant outcomes and acceptance criteria for these risks. In this review, we will discuss the important gray areas in the rheumatological considerations for lung transplant candidates, specifically addressing diagnostic uncertainty and therapeutic dilemmas involved, as well as the need for standardization protocols among lung transplant centers on rheumatological evaluation and considerations.

Rationale. Sarcopenic obesity is a combined state of low muscle mass and high adiposity associated with amplified morbidity and mortality in diverse populations. The study of body composition in interstitial lung disease (ILD), however, is nascent. We hypothesized that sarcopenic obesity would be associated with frailty, reduced exercise capacity, and reduced forced vital capacity (FVC) in adults with advanced ILD. Methods. In a cross-sectional analysis of two multicenter cohort studies of lung transplant candidates, participants with ILD were categorized by bioelectrical impedance into non-sarcopenic/non-obese; non-sarcopenic/obese; sarcopenic/non-obese; and sarcopenic obese. Two definitions of sarcopenia were considered by appendicular skeletal muscle index: lowest quartile (LQ) and European Working Group on Sarcopenia in Older People 2 (EWGSOP2). Frailty was assessed by Short Physical Performance Battery (SPPB) and Fried Frailty Phenotype (FFP), exercise capacity by six-minute walk distance (6MWD), and FVC by spirometry. We evaluated the association between body composition categories and clinically relevant outcomes using multivariable linear and logistic regression adjusted for age, race, and gender. We further adjusted by FVC to assess the effect of body composition on 6MWD (Table footer defines body composition and frailty thresholds). Results. Among 376 participants, 167 (44%) had idiopathic pulmonary fibrosis while 35 (9.3%) and 17 (4.5%) were sarcopenic obese by LQ and EWGSOP2 definitions, respectively. The median body mass index (BMI) of sarcopenic obese participants by LQ was 26.1 kg/m2[IQR: 4.5]. Sarcopenic obesity was associated with a 3.0-6.5-fold higher odds of frailty by SPPB compared to the non-sarcopenic/non-obese group (LQ: Odds Ratio [OR] 2.6, 95%CI: 1.1 to 5.9; EWGSOP2: OR 6.6, 95%CI: 2.0 to 22.3) and strong trends towards associations with frailty by FFP (Table). Sarcopenic obesity was associated with worse 6MWD (LQ: -57.2 meters, 95%CI: -103.9 to -10.5; EWGSOP2: -132.4 meters, 95%CI: -193.1 to -71.7). Sarcopenic obesity was also associated with lower FVC (LQ: -0.5 liters, 95%CI -0.8 to -0.3; EWGSOP2: -0.6 liters, 95%CI -0.9 to -0.3). Notably, phenotypes by BMI were not associated with either frailty or 6MWD, though BMI-defined obesity was associated with a greater FVC. Conclusions. Sarcopenic obesity is associated with increased risk of frailty, worse exercise capacity, and reduced FVC in advanced ILD. In contrast, this risk is occult when evaluating BMI-based metrics of underweight and obese. If replicated in a general ILD population, our findings suggest that advanced measures of body composition could identify novel explanatory factors for poor outcomes in ILD, and identify those for targeted intervention.

Rationale: Sarcopenia, marked by the loss of muscle mass and functional strength, is a risk factor for adverse outcomes in lung transplant candidates. Social determinants of health (SDOH), including race/ethnicity, socioeconomic status, and insurance type, may influence sarcopenia prevalence by affecting access to nutritious food, recreational spaces, and healthcare and introducing treatment disparities. This study aims to investigate the association between sarcopenia and key factors, including race/ethnicity, insurance type, age, and primary diagnosis, among lung transplant candidates to identify patterns that can inform future interventions. Methods: We conducted a cross-sectional analysis of the Lung Transplant Body Composition Study, a multicenter prospective cohort study that examines the impact of preoperative body composition on lung transplant outcomes. Adult lung transplant candidates aged 18 years or older were recruited at the University of California, San Francisco (UCSF), the University of Pennsylvania, and Columbia University Medical Center. For this analysis, we focused on participants from UCSF. Sarcopenia was defined using the limited definition from the European Working Group on Sarcopenia in Older People 2. SDOH exposures included race, ethnicity, and insurance type. Race is considered a social construct, reflecting differences in sociocultural practices as well as differential resource access. Logistic regression models, adjusted for relevant covariates, assessed associations between these factors and sarcopenia. Results: Among 286 lung transplant candidates, 19% had sarcopenia. Sarcopenia prevalence was highest among candidates who identified as Asian (45%), who had higher odds of sarcopenia compared to non-Hispanic White candidates, among whom 13% were sarcopenic (OR 7.07, 95% CI 2.62-19.09). Medicaid recipients had a sarcopenia prevalence of 33%, while those with private insurance had a prevalence of 15%; however, insurance type was not significantly associated with sarcopenia (OR 1.87, 95% CI 0.61-5.76). Medicare recipients had a prevalence of 20%, with no significant association observed. Non-IPF interstitial lung disease showed a trend towards lower odds of sarcopenia compared to COPD (OR 0.36, 95% CI 0.13-0.97). Conclusions: Our exploratory analysis suggests that lung transplant candidates identifying as Asian are more likely to have sarcopenia compared to other racial or ethnic groups, indicating the need for further studies to explore sociocultural mechanisms underlying this disparity. Insurance type was not significantly associated with sarcopenia, possibly due to sample size or specific transplant center characteristics. Further research with larger, diverse cohorts is warranted to clarify these associations and inform interventions.

BACKGROUND:Acute lung allograft dysfunction (ALAD) is a clinical syndrome of forced expiratory volume in 1-second (FEV1) decline concerning for chronic lung allograft dysfunction (CLAD) onset. Novel diagnostic tools are needed to identify those with ALAD who will progress to CLAD and to target appropriate therapies. We hypothesized that progressive ALAD would be associated with changes in small airway cell composition and cell-specific transcription. METHODS:We prospectively identified recipients with undifferentiated ALAD and controls with stable allograft function for small airway brushing and single-cell RNA sequencing analysis. ALAD outcome group was categorized as (1) control (n = 8), or ALAD with (2) recovered (n = 4), (3) persistent (n = 5), or (4) progressive (n = 3) FEV1 decline. Cell compositional changes, pseudobulk Reactome pathways, and the AI2 score, previously linked to CLAD in airway brush transcriptomes, were assessed as a function of ALAD outcome group. RESULTS:Across 68,140 cells, the distribution of cell composition was linked to ALAD outcome group (PERMANOVA, p = 0.004). Worse ALAD outcomes correlated with loss of basal cells, changes in club and ciliated subsets, a loss of macrophages, and expansion of cytotoxic T cells. The AI2 gene score was positively associated with ALAD outcome group, particularly in epithelial cell subsets (p < 0.001). Pathway analysis showed increased interferon signaling and inhibition of cell proliferation in epithelial cells. CONCLUSIONS:In this pilot study, persistent and progressive ALAD was associated with changes in bronchiolar cell composition and transcriptional programs. Molecular phenotyping may help identify and characterize individuals with ALAD at increased risk for progression.

Background. Lung transplantation aims to improve health-related quality of life (HRQL) and survival. Although improvements in lung function are associated with these outcomes, the role of physical functioning is less clear. We investigated the association between changes in patient-reported physical functioning and HRQL, chronic lung allograft dysfunction (CLAD), and survival after lung transplantation. Methods. This single-center prospective cohort study analyzed 220 lung transplant recipients who completed a 15-item Lung Transplant-Valued Life Activities (LT-VLA) before and repeatedly after transplantation. HRQL was measured using validated generic, disease-specific, and utility measures. Associations between 0.3-point changes (the minimally important difference) in LT-VLA as time-varying predictors of HRQL, CLAD, and mortality were tested using linear mixed-effects models for HRQL and Cox proportional hazard models with LT-VLA as a time-varying predictor for CLAD and mortality. Mixed-effects models treated time as a categorical variable to account for possible nonlinear changes over time. Models were adjusted for demographics, disease diagnosis, and postoperative lung function as time-varying covariates. Results. Participants were 45% women and 75% White, with a mean age of 56 (±12) y. Each 0.3-point improvement in the LT-VLA was associated with significantly improved HRQL across all measures (adjusted P < 0.01). Each 0.3-point improvement in LT-VLA was associated with a 13% reduced hazard of CLAD (adjusted hazard ratio: 0.87, 95% confidence interval: 0.76-0.99, P = 0.03) and a 19% reduced hazard of mortality (adjusted hazard ratio: 0.81, 95% confidence interval: 0.67-0.95, P = 0.01). Conclusions. Improvements in patient-reported physical functioning after lung transplantation are associated with improved HRQL and a reduced risk of CLAD and death, independent of allograft function. The simplicity of LT-VLA suggests that it could be a valuable monitoring or outcome measure in both clinical and research settings.

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 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. (c) Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://

Purpose: Dysfunctional bronchiolar epithelial repair may contribute to chronic lung allograft dysfunction (CLAD), a major barrier to long-term post-transplant survival. Bulk RNA Sequencing revealed CLAD-specific signatures, yet may be confounded by differences in cell composition. We hypothesized that single cell transcriptomics would identify epithelial cell compositional changes linked to CLAD.

Purpose: Treatment of airway infections identified by bronchoscopy may protect recipients from chronic lung allograft dysfunction (CLAD), but there are limited data on the differential impact of airway infections on CLAD risk. We hypothesized that select pathogens would be associated with increased airway inflammation and CLAD risk.

Purpose: In May 2020, we implemented a novel lung transplant (LT) outpatient (OP) management intervention, combining home spirometry with telehealth visits (HS/THV). This intervention replaced 6 OP visits and in-lab spirometry with HS/THV over the first 2 years after LT. We sought to understand the impact of HS/THV on healthcare utilization and survival.

BACKGROUND:Chronic lung allograft dysfunction (CLAD) limits survival following lung transplant, but substantial lung damage occurs before diagnosis by traditional methods. We hypothesized that small airway gene expression patterns could identify CLAD risk before spirometric diagnosis and predict subsequent graft failure. METHODS:Candidate genes from 4 rejection-associated transcript sets were assessed for associations with CLAD or graft failure in a derivation cohort of 156 small airway brushes from 45 CLAD cases and 37 time-matched controls with >1-year stable lung function. Candidate genes not associated with CLAD and time to graft failure were excluded, yielding the Airway Inflammation 2 (AI2) gene set. Area under the receiver operating curve (AUC) for CLAD and competing risks of death or graft failure were assessed in an independent validation cohort of 37 CLAD cases and 37 controls. RESULTS:Thirty-two candidate genes were associated with CLAD and graft failure, comprising the AI2 score, which clustered into 3 subcomponents. The AI2 score identified CLAD before its onset, in early and late post-CLAD brushes, as well as in the validation cohort (AUC 0.69-0.88). The AI2 score association with CLAD was independent of positive microbiology, CLAD stage, or CLAD subtype. However, transcripts most associated with CLAD evolved over time from CLAD onset. The AI2 score predicted time to graft failure and retransplant-free survival in both cohorts (p ≤ 0.03). CONCLUSIONS:This airway inflammation gene score is associated with CLAD development, graft failure, and death. Future studies defining the molecular heterogeneity of airway inflammation could lead to endotype-targeted therapies.

Purpose: Gene expression analysis of small airway cytology brushings has been proposed as a novel strategy to diagnose and subtype chronic lung allograft dysfunction (CLAD). Although multiple gene sets have shown promise, it is not known whether this approach can predict CLAD before its onset.

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 pro-gram 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 spi-rometry 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. J Heart Lung Transplant 2023;42:828-837 (c) Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation.

Purpose Advance Care Planning (ACP) allows patients to specify the type of care they receive in the event that they become incapacitated. ACP documentation is often not accessible, up-to-date, or clinically meaningful. Racial inequities in ACP are well-documented. Although ACP after lung transplant (LT) is important, efforts to improve ACP documentation in post-LT patients are not well described. Methods This Quality Improvement (QI) project targeted post-LT patients at a single center between August 2021 and October 2022. Gap analysis consisted of qualitative patient and provider interviews to assess issues underlying ACP deficiencies, followed by thematic analysis using a fishbone diagram. Based on identified gaps, provider education was performed, and a patient education pamphlet was designed and distributed to define ACP, facilitate patient-provider ACP discussions, and empower patients to select surrogate medical decision makers. The primary outcome was the percentage of patients with clinically meaningful ACP, defined as acquisition of ".acp" documentation in the electronic medical record (EMR) at or after the first post-LT visit. Patient demographics and rates of ACP were obtained from the EMR. Results Gap analysis revealed: (1) Lack of consensus on ACP definitions and timeline; (2) Lack of communication between patients, surrogate decision makers, and medical staff; (3) Differences in ACP documentation methods; and (4) Lack of resources for LT-specific settings. Provider education interventions and the patient education pamphlet were associated with an increase in ACP documentation from 11.2% in August 2021 and 18.3% in October 2022 (Image 1). Conclusion This QI project identified barriers to ACP completion. The patient education pamphlet and provider education interventions were associated with an increase in clinically meaningful ACP documentation. Next steps include analysis of best practices for pamphlet implementation and decreasing inequities in ACP.

BACKGROUND: Existing measures of frailty developed in community dwelling older adults may mis-classify frailty in lung transplant candidates. We aimed to develop a novel frailty scale for lung trans-plantation 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 -trans-plant 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 valid-ity that has superior predictive validity over established measures. J Heart Lung Transplant 2023;42:892-904 & COPY; 2023 International Society for Heart and Lung Transplantation. All rights reserved.

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.

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.

Purpose: Cardiac allograft vasculopathy (CAV) limits long term graft survival among heart transplant patients.Hepatitis C infection is implicated as a potent trigger of the inflammatory cascade and may be associated with CAV.We report the differences in coronary artery physiology and anatomy by fractional flow reserve (FFR) in HCV-viremic donors; nucleic amplification test positive: NAT (+) vs non-viremic donors: NAT (-).Methods: A retrospective analysis of coronary physiologic parameters was performed in patients who received NAT (+) and NAT (-) donor hearts between January 2014 and July 2020 at a single academic medical center.Donor-derived acute HCV infection was treated with a direct-acting antiviral agent.FFR of the entire LAD was recorded following maximally induced hyperemia.Two-sample t tests were performed for continuous variables.Chi-square or Fisher's exact test were used for categorical variables.Of 71 patients included, 33 patients received HCV NAT (+) donor hearts.Mean recipient age was 57 years in both the NAT (+) and NAT (-) groups; 9% and 18% were female, respectively.NAT (+) and NAT (-) donors were an average 35 years old, with no significant difference in cardiac risk factors including tobacco use, hypertension, and diabetes.Results: At 1 year, 23.8% vs 9.3% (p = 0.151) and 21.1% vs 16% at 3 years (p=0.667)demonstrated FFR positive LAD disease (FFR ≤ 0.85) among NAT (+) vs NAT (-) patients, Figure 1.Within 4 years post-transplant, mortality was seen in 5/71 (7%), and requisite for PCI was seen in 4/71 (5.6%) of the overall cohort; statistical differences between NAT (+) and NAT (-) groups were not observed.Conclusion: Among heart transplant recipients from HCV viremic donors our data show no statistically significant difference in FFR significant disease at 1 or 3 years.Further study is needed to assess FFR outcomes in this population.