Citations

Abstract Rationale: The D'Nerva Targeted Lung Denervation (TLD) System uses radiofrequency energy delivered bronchoscopically to the main bronchi to disrupt parasympathetic nerve innervation to the lung. AIRFLOW-3 clinical trial was a randomized, double blind, sham controlled study to determine the impact of TLD on COPD exacerbations. Methods: AIRFLOW-3 patients had symptomatic COPD (CAT ≥10) with moderate to very severe airflow obstruction (GOLD stage II-IV: 25% ≤ FEV1 ≤ 80% predicted, FEV1/FVC<0.70) and GOLD E status (≥2 moderate or ≥1 severe exacerbation in the prior 12 months) despite optimal medical therapy. The primary endpoint was a time-to-first event comparison of the probability of subjects having a moderate or severe exacerbation, between the Treatment arm (TLD + optimal medical therapy) and the Sham Control arm (optimal medical therapy). Results: 388 patients were randomized 1:1 at 32 clinical sites across the US, EU, and UK. Patients were 67.8 (SD 7.1) years of age, ex-smokers with a 46.7 (22.0) pack-year smoking history, and 41.0 (11.8) post bronchodilator FEV1% pred. SGRQ-C and CAT scores were 62.5 (17.0) and 23.6 (6.3), respectively. Over 90% of patients were on triple therapy (LAMA+LABA+ICS) at baseline and through 1 year of follow up. 42% of patients had prior-year COPD hospitalization(s). There was no difference between groups in the analysis of the primary endpoint. At 1 year, the sham arm exhibited a statistical decline in lung function (decrease in FEV1 and FVC) and worsening of gas trapping (increase in RV). Lung function and gas trapping were stable in the treatment arm. The treatment arm exhibited a statistically significant improvement in dyspnea at one year compared to sham (mMRC, and TDI). These observations led to the identification of a subgroup of TLD treatment responders corresponding to an airway predominant phenotype (lung hyperinflation in the absence of significant emphysema) that demonstrated clinically and statistically significant improvements in lung function and exacerbation frequency and severity (Table). Conclusions: The AIRFLOW-3 clinical trial failed to meet its prespecified primary endpoint. Post-hoc analysis of this robust dataset led to the identification of a responder profile that achieved significant and sustained improvements in lung function, and exacerbation reduction. A future clinical study is being designed to confirm these findings.

Abstract Rationale: Hematopoietic cell transplantation (HCT) risk scores have seen minimal updates over the past 20 years, despite advancements in clinical practice. Pulmonary function test (PFT) thresholds, initially based on NHANES reference equations, now have alternative reference standards from the Global Lung Function Initiative (GLI) 2012 and GLI-Global, which may reclassify patients and affect outcomes. This study investigates the impact of GLI reclassification on outcomes in HCT, comparing traditional fixed thresholds with continuous (z-score) risk assessment models. Methods: A retrospective review of 3,120 adult patients who underwent autologous HCT at MD Anderson Cancer Center from 1999 to 2015 was conducted. Primary endpoints were ICU admission, mechanical ventilation (IMV), and survival within 120 days post-transplant. PFT measures (FEV1, FVC, DLCO) were calculated using GLI-2012 and GLI-Global reference equations, analyzed both continuously (z-scores) and categorically by ATS/ERS guidelines. Cox proportional hazards and logistic regression models were employed, with AUROC comparisons to evaluate predictive performance. Results: The cohort had a mean age of 49 years (SD 14), with 41% female and 77% White. Of the 3,120 patients included in the study, the cohort consisted of 77% White, 5.4% Black, 3.3% Asian, and 14% identifying as other ethnicities. At 120 days, mortality was 1% (n=41), ICU admission 5% (n=169), and IMV 2% (n=70). Continuous DLCO was associated with a lower risk of mortality (HR: 0.75; p=0.03), ICU admission (OR: 0.83; p=0.01), and IMV (OR: 0.80; p=0.02). GLI-Global's FEV1 z-scores were also significant for mortality (HR: 0.70; p=0.01), ICU admission (OR: 0.74; p<0.0001), and IMV (OR: 0.70; p=0.0003). Categorical analyses showed significant mortality reduction with normal DLCO (HR: 0.46; p=0.01) and ICU admission reduction with normal FEV1 GLI-2012 (OR: 0.63; p=0.02). Reclassification by race, as shown in Figure 1, indicated that race-specific equations overestimated PFT values in Black patients and underestimated them in Asian patients. Conclusion: Reclassification by GLI reference equations, particularly using continuous z-scores, significantly influences post-HCT outcomes, suggesting that continuous assessment may improve risk stratification. Including race does not improve the model's performance. These findings support integrating updated PFT references and continuous risk models into HCT prognostic tools for enhanced clinical decision-making.

Abstract Rationale: Patients with fibrotic interstitial lung (f-ILD) disease often have decreased physical activity (PA) due to high symptom burden, with shortness of breath, cough, anxiety, and fatigue affecting health-related quality of life (HR-QOL). Previously undiagnosed anxiety and depression has been described in f-ILD though contributing factors remain unknown. We hypothesize that significant rates of disease-related anxiety and depression may be detected but not persist, representing situational or short-term responses to disease burden. We also hypothesize that real-world PA is an important contributor to or reflection of HR-QOL and associated with selected patient-reported outcome measures (PROMs). Methods: This was a single-center prospective observational cohort enrolling adult patients with established f-ILD. PROM questionnaires were sent electronically to patients at study enrollment and 3 months. These included the Modified Medical Research Council (mMRC), Fatigue Severity Scale (FSS), Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Self-Management Ability Scale-30 (SMAS-30), and abbreviated Prolife of Mood States (POMS). PA was defined as mean number of steps per day over a 7-day period as measured by at-home Actigraphy, obtained at enrollment and 3 months (within 2 weeks of completing PROM questionnaires). Results: Forty five patients were included (mean age 69, female 49 %, non-IPF f-ILD 78%, mean forced vital capacity 77%). Baseline GAD-7 anxiety scores were ‘moderate’ in 45% and ‘severe’ in 5%. PHQ-9 depression scores were ‘moderately severe’ in 30% and ‘severe’ in 5%. Mean GAD-7 and PHQ scores were no different at baseline and three months (GAD7 10.18 vs 10, P = 0.653; PHQ-9 12.82 vs 13.32, P = 0.294). mMRC, FSS, and SMAS-30 scores were associated with daily step activity. A one-point increase in mMRC or FSS (greater dyspnea or fatigue) was associated with a decrease in daily steps of 1400 [CI: (-2000, -600), ] or 90 steps [CI: (-160, -15))], respectively. A one-point increase in SMAS-30 (greater self-management) was associated with an increase of 108 steps per day [CI: (25, 190-0.38) ]. Anxiety, depression, and mood did not appear to be associated with step activity GAD-7-4.5 (P = 0.982), PHQ-9-211.5 (P = 0.13), POMS -36.5 (P = 0.096). Conclusions: Clinical symptoms of anxiety and depression are prevalent in patients with f-ILD and do not appear diminished or improved in the short term. Dyspnea, fatigue, and self-management ability are associated with real-world measures of physical activity.

Abstract Rationale. Bronchoscopy can directly assess cells in airway epithelium in participants with COPD, but it is invasive, expensive, difficult to perform at scale, and contraindicated in severe disease. Blood is much more easily available but contains only a limited subset of cell types, many of which are less relevant to lung biology. Recent advances in RNA-sequencing technology have allowed for reliable measurement of transcriptomics in a wider variety of more accessible tissues, including hair follicle cells. We collected and performed bulk RNA-seq on hair follicles as an ancillary study within the NIH-funded SubPopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) and investigated their cell type composition to better understand the opportunities and limitations of this tissue for the study of lung disease. Methods. SPIROMICS recruited individuals with and without COPD aged 40-80 years with ≥ 20 pack-years smoking history. Participant at several sites underwent collection of approximately 10 hair follicles from the head, which were immediately frozen at -80ºC in 2018-21. mRNA in hair follicles was measured by bulk RNA-seq, and cell type deconvolution was performed using GEDIT v1.7 with the provided BlueCodeV1.0.tsv reference matrix. Cell types were collapsed into broader categories by summing the estimated cell type proportions. Results. The cell type deconvolution of the hair follicle bulk RNA-seq from 80 participants with and without COPD estimated that the tissue was largely composed of immune cells (median 36%, including B cells, T cells, neutrophils, macrophages, NK cells, and monocytes) and epithelial cell types (median 31%), with the largest subgroup of epithelial cell types identified as hair follicular keratinocytes (Figure 1). The next largest component was fibroblasts (median 9%), followed by endothelial cells (median 8%). Signals for myocytes (median 5%), melanocytes (median 5%), and chondrocytes (median 5%) were also present. Conclusion. This initial study demonstrated promising signals for a variety of lung-relevant cell types in hair follicles in SPIROMICS, including immune and epithelial cells in addition to fibroblasts and endothelial cells that are not otherwise easily accessible. Hair follicle gene expression profiling shows promise for understanding numerous facets of lung biology and disease that both complements and exceeds that of other noninvasive tissues such as blood.

Abstract RATIONALE: Endothelial-to-mesenchymal transition (EndMT) is a cellular process in which endothelial cells (ECs) transition into mesenchymal cells, a mechanism recently linked to pulmonary vascular remodeling in pulmonary hypertension (PH). However, the regulatory mechanisms driving EndMT in PH remain largely undefined. MicroRNA-153 (miR-153), a small non-coding RNA, regulates gene expression by targeting the 3'-untranslated region (3'-UTR) of mRNA, affecting mRNA translation and stability. This study investigates miR-153's role in modulating EndMT in PH. METHODS: Human lung vascular endothelial cells (LVECs) were isolated from healthy individuals and patients with idiopathic pulmonary arterial hypertension (IPAH). In vitro, normal LVECs were exposed to hypoxia (3% O₂) for 72 hours or treated with TGF-β1 (10 ng/mL) for 7 days to induce EndMT. Levels of miR-153 and EndMT markers were quantified by qPCR, Western blotting, or immunostaining. Proliferation and apoptosis of ECs were assessed using EdU and TUNEL assays, respectively. LVECs were transfected with miR-153 inhibitor or mimic, then exposed to normoxic or hypoxic conditions, respectively for 72 hours. In vivo, mice were subjected to either hypoxia (10% O₂ for 6 weeks, Hx-PH) or Sugen5416/hypoxia (20 mg/kg i.p. plus 10% O₂ for 6 weeks, SuHx-PH) to induce PH. The PH phenotype in mice was evaluated by hemodynamic measurements and histological analysis of H&E-stained lung tissues. RESULTS:In silico analysis identified miR-153 as a direct regulator of human SNAI1 and SNAI2 genes via binding to their 3'-UTR. Downregulation of miR-153 in IPAH LVECs was correlated with elevated SNAI1/2 expression, increased EndMT, and higher proliferation compared to normal LVECs. Hypoxia or TGF-β1 treatment reduced miR-153 expression, increased EndMT transcription factors (SNAI1/2), mesenchymal markers (SM-22, vimentin), and reduced EC markers (CD31, VE-cadherin). In normoxic LVECs, miR-153 inhibition significantly upregulated SNAI1/2, increased EndMT and EC proliferation, and reduced apoptosis. Conversely, miR-153 mimic abolished hypoxia- and TGF-β1-induced EndMT. Overexpression of miR-153 attenuated hypoxia-induced EC survival. In PH mouse models, reduced miR-153 levels were associated with activated SNAI1/2, EndMT, and pulmonary vascular remodeling. CONCLUSIONS: Downregulation of miR-153 drives phenotypic transition of LVECs to proliferative mesenchymal cells via SNAI-mediated EndMT, contributing to pulmonary vascular remodeling and PH. Therefore, miR-153 could be a potential therapeutic target for PH treatment.

Abstract Introduction: Calcineurin inhibitor (CNI) nephrotoxicity is a common complication following lung transplant. This is usually treated with dose reduction of CNI, addition of mammalian target of rapamycin inhibitor (mTORi), or rarely, CNI withdrawal which poses the risk of acute and chronic lung allograft rejection. Complete CNI withdrawal and transition to a mTORi based regimen for renal protection is scarcely described in literature with mixed results. Methods: We performed a single center, retrospective chart review of adult lung transplant recipients from January 2010-December 2022 to identify those who underwent complete CNI withdrawal and transition to a mTORi based immunosuppression regimen. Dual organ transplants and external transplant surgeries were excluded. Demographics, and clinical information on immunosuppressive regimens, renal function, rejection episodes, and outcomes were collected. This study was approved by the Mayo Clinic Institutional Review Board. Descriptive statistics were employed. Data is presented as N (%) or median (IQR). Results: A total of 52 patients who underwent CNI withdrawal were identified, and 38 patients (73.1%) were transitioned to a mTORi based regimen for renal failure. The median age at transplant was 59.1 years (IQR 54.2-63.3) and 57.9% were male. The most common transplant indication was pulmonary fibrosis (N = 21, 55.3%). No patients had pre-transplant chronic kidney disease stage 3 or higher. The median length of time from transplant to CNI withdrawal was 13.0 months (IQR 10.0-28.6). Most patients (N = 35 out of 38, 92%) discontinued mTORi and returned to a CNI based regimen after a median duration of use of 4.5 months (IQR 2.4-12.0) for an upcoming procedure/facilitate wound healing (N = 7, 20%), hypervolemia (N =7, 20%), death (N = 6, 17%), lung toxicity (N = 5, 14%), or worsening allograft function (N=5, 14%). Five patients (13.2%) developed ≥ A2 acute cellular rejection. Ten patients (26.3%) developed chronic lung allograft dysfunction. There was no change in creatinine at baseline (just prior to CNI withdrawal) compared to 12 (+/- 3) months after mTORi initiation (p = 0.36). Thirteen patients required dialysis (34.2%), four patients received renal transplants (10.5%), and 1 patient died on the renal transplant waitlist. Conclusions: Our case series demonstrates complete CNI withdrawal and transition to mTORi regimen is associated with short duration of therapy for most patients due to side effects and no change in creatinine one year after transition.

Abstract RATIONALE: Long-term survival after lung transplantation is challenging, with limited research on risk and protective factors. Clinical factors such as younger age, female sex, fewer acute rejection hospitalizations, and double lung transplants are associated with better outcomes. However, the role of psychosocial health and socioeconomic status (SES) remains underexplored. This study aimed to assess the influence of pre-transplant psychosocial health and SES on long-term survival in adult lung transplant recipients. METHODS: We conducted a single-center, retrospective case-control study using the Mayo Clinic Rochester lung transplant registry. Cases (survivors ≥ 6 years) and controls (survivors <6 years) were matched by transplant date (+/- 5 years) and indication for transplant, resulting in 190 subjects (63 cases, 127 controls). We assessed the impact of pre-transplant psychosocial health and SES on long-term survival using initial PACT scores (<2), the HOUSES index, and the national/state area deprivation index (ADI). Additional factors included proximity to the transplant center, insurance type, marital status, primary caregiver status, and employment status. Statistical analyses used the paired Wilcoxon rank-sum test for continuous variables and McNemar's test for categorical variables, with results reported as median (IQR) or percentages. RESULTS: Donor characteristics (age, sex, smoking history, risk criteria, cause of death) and recipient characteristics (age at transplant, sex, BMI, medical condition, functional status, type of transplant) were similar between cases and controls, with no statistically significant differences (all p>0.05). CMV mismatch, waitlist time, and transplant hospital length of stay were also comparable (all p>0.05). Psychosocial health indicators, including proximity to the transplant center, pre-transplant initial PACT score, insurance type, marital status, primary caregiver, and employment status, did not differ significantly between groups (all p>0.05). The HOUSES index was similar between cases and controls (p=0.179). However, long-term survivors had significantly higher national and state ADI scores than controls (national ADI: p=0.029; state ADI: p=0.019). CONCLUSIONS: Pre-transplant psychosocial health indicators, including proximity to the transplant center, initial PACT score, and caregiver support, did not differ significantly between long-term lung transplant survivors and those with shorter survival. Although SES measured by the HOUSES index was not associated with long-term survival, higher national and state ADI scores were linked to increased long-term survival, suggesting unique protective factors for patients from socioeconomically deprived areas. These findings highlight the complex role of socioeconomic factors in lung transplant outcomes and underscore the need for further research into how specific socioeconomic and environmental factors influence long-term survival.

Abstract Rationale: Pulmonary alveolar proteinosis (PAP) is a rare lung disorder characterized by the accumulation of surfactant in the alveoli, primarily seen in autoimmune PAP (aPAP), which accounts for over 90% of cases. The COVID-19 pandemic has highlighted the potential for viral infections to exacerbate or induce PAP, complicating diagnosis and treatment. Objective: This study aims to provide updated clinical and demographic characteristics of patients with pulmonary alveolar proteinosis (PAP) and to analyze trends in the use of whole lung lavage before the COVID-19 pandemic, as well as assess the impact of the pandemic on WLL utilization. Methods: Using data from the National Inpatient Sample from 2017 to 2021, the authors identified PAP, other diagnoses, and procedures. using the respective ICD-10 codes. Statistical analysis was performed on the trends of whole lung lavage and other outcomes across the five years. Results: A total of 3,030 hospitalized PAP patients were included in the study, with demographic and clinical characteristics reported for the cohort. Although the use of WLL increased from 11.55% pre-pandemic to 14.67% during the pandemic, this difference was not statistically significant. However, there was a significant rise in the incidence of acute respiratory failure during the pandemic (35.7% vs. 45.78%, p = 0.02). While transbronchial lung biopsies increased and open lung biopsies declined, these trends were not statistically significant. Conclusion: In recent years, despite a decline in the use of WLL for treating PAP and open lung biopsies for diagnosis, the rates have risen due to the impact of the COVID-19 pandemic.

Abstract Rationale: Patients with fibrotic interstitial lung disease (F-ILD) often report high symptom burden with significant impact on their health-related quality of life. Self-reported disease experience may be unique or difficult to quantify yet have implications for functional and survival outcomes. We hypothesize that self-reported mood or affect may be associated with changes in lung function and predict mortality. Methods: This is a post-hoc analysis of a prospective cross-sectional study assessing changes in patient-reported outcome measures (PROM), lung function, and mortality incidence in patients with f-ILD. Serial measures of lung function and PROMs (baseline, 3, 6, and 12 months) were obtained over a 3-year period. The Positive and Negative Affect Scale (PANAS) is a 20-item questionnaire reflecting acute or immediate mood at the time of assessment, with higher scores for each domain highlighting greater positive or negative affect. A ratio of the Positive over the Negative score was used to summarize overall mood, with higher ratios reflecting more positive affect. PANAS scores at the time of lung function measures were assessed for their association with percent predicted forced vital capacity (FVC%) and diffusion capacity for carbon monoxide (DLCO%). Baseline PANAS scores were used to predict of all-cause mortality over the three-year study period. Results: One-hundred and eighty seven patients were included (mean age 69, female 37%, non-IPF f-ILD 67%). PANAS Negative scores were higher (16.9 vs 14.5, P = 0.01)with lower PANAS Ratio scores (2.5 vs 2.2, P = 0.08) in patients with non-IPF f-ILD, suggesting more negative affect or mood. A mixed effects model for repeated measures with each subject as a random effect found changes in the PANAS Positive score (point estimate 0.16, (0.01-0.32), P = 0.038) and Ratio score (1.43 (0.15-2.72), P = 0.029) were associated with changes in FVC% but not DLCO%. Baseline PANAS Negative (hazard ratios 1.06 (1.02-1.10), P = 0.002) and Ratio scores (HR 0.76 (0.61-0.95), P = 0.014) after adjusting for age, sex, FVC%, and diagnosis type (IPF vs non-IPF), were associated with increased all-cause mortality. Conclusions: Measured changes in self-reported mood or affect appear to be associated with changes in lung function and predict all-cause mortality. Direct assessments of patient disease experience may not only reflect symptom burden or disease progression but serve as targets of comprehensive management strategies or correlates of treatment efficacy given their potential association with lung function and survival.

Abstract Rationale Immune checkpoint inhibitors (ICI) have become standard care for many cancers. Their mechanism of action mediates immune related adverse events including ICI pneumonitis. Diagnosis of this is difficult to differentiate from infectious and radiation pneumonitis as it is a diagnosis of exclusion often requiring bronchoscopy and imaging interpreted by expert radiologists. This study investigates the use of CALIPER, a computer-aided lung informatics program, in identifying differences between Computed Tomography (CT) patterns in ICI, radiation, and infectious pneumonitis that may aid in diagnosis noninvasively. Methods CT images of ten patients with ICI pneumonitis, ten patients with infectious pneumonitis, and nine patients with radiation pneumonitis, all diagnosed by clinical expertise and evaluation with bronchoalveolar lavage, were analyzed with CALIPER. CALIPER classified each CT voxel into either vessel-related structures (VRS), normal, mild low-attenuation area (LAA), moderate LAA, severe LAA, reticular (R), honeycomb (HC) or ground-glass (GG) features. Each lung was divided into upper, middle, and lower lobes. Exploratory analyses explored the relationship between CALIPER components and diagnosis, comparing ICI and radiation pneumonitis with infectious pneumonitis. Diagnosis was analyzed using multinomial logistic regression adjusted for presence of pleural effusion. Additionally, diagnosis was assessed as infectious versus a pooled group of radiation and ICI pneumonitis and analyzed using logistic regression adjusted for pleural effusion. Due to the exploratory nature of analysis, no correction was applied for multiplicity of testing. Results Twenty-nine patients were analyzed. ICI pneumonitis patients had less moderate low attenuation in the left upper (p = 0.016) and middle peripheral lung (p = 0.038), and radiation pneumonitis patients had less moderate low attenuation in the left upper peripheral lung (p = 0.031). When comparing the pooled group of ICI and radiation pneumonitis images with infectious pneumonitis, there was more moderate LAA in left upper (0.012) and middle (0.034) peripheral lung in the pooled group compared to infectious pneumonitis. There was no association with VRS, GG, HC, R, mild, or severe LAA patterns. Conclusions Although areas of moderate low attenuation were more prevalent for infectious pneumonitis, these results taken in the context of low sample size, exploratory analysis, and lack of clinical reasoning to support these findings make them likely insignificant. Based on this limited exploratory analysis, it is unlikely that we can solely use CALIPER as noninvasive evaluation to differentiate radiation and ICI pneumonitis from infectious pneumonitis. This highlights the need for a more robust program to aid in noninvasive diagnosis.