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Background: Acute exacerbation of idiopathic pulmonary fibrosis has become an important outcome measure in clinical trials. This study aimed to explore the concept of suspected acute exacerbation as an outcome measure.Methods: Three investigators retrospectively reviewed subjects enrolled in the Sildenafil Trial of Exercise Performance in IPF who experienced a respiratory serious adverse event during the course of the study. Events were classified as definite acute exacerbation, suspected acute exacerbation, or other, according to established criteria.Results: Thirty-five events were identified. Four were classified as definite acute exacerbation, fourteen as suspected acute exacerbation, and seventeen as other. Definite and suspected acute exacerbations were clinically indistinguishable. Both were most common in the winter and spring months and were associated with a high risk of disease progression and short-term mortality.Conclusions: In this study one half of respiratory serious adverse events were attributed to definite or suspected acute exacerbations. Suspected acute exacerbations are clinically indistinguishable from definite acute exacerbations and represent clinically meaningful events. Clinical trialists should consider capturing both definite and suspected acute exacerbations as outcome measures. © 2013 Collard et al.; licensee BioMed Central Ltd.

Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint-that is, an endpoint that directly measures how a patient feels (symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or functional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints. [ABSTRACT FROM AUTHOR]

Chemokines are increased and may exert effects on both inflammatory and remodeling events in idiopathic pulmonary pneumonia (IIP). Accordingly, we examined the concomitant expression of inflammatory CC chemotactic cytokines or chemokines and their corresponding receptors in surgical lung biopsies obtained at the time of disease diagnosis and pulmonary fibroblasts grown from these biopsies. By gene array analysis, upper and lower lobe biopsies and primary fibroblast lines from patients with usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia, and respiratory bronchiolitis-interstitial lung disease, but not patients without IIP, exhibited CCL7 gene expression. TAQMAN, immunohistochemical, and ELISA analyses confirmed that CCL7 was expressed at significantly higher levels in UIP lung biopsies compared with biopsies from patients with nonspecific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, and from patients without IIP. Higher levels of CCL7 were present in cultures of IIP fibroblasts compared with non-IIP fibroblasts, and CCL5, a CCR5 agonist, significantly increased the synthesis of CCL7 by UIP fibroblasts. Together, these data suggest that CCL7 is highly expressed in biopsies and pulmonary fibroblast lines obtained from patients with UIP relative to patients with other IIP and patients without IIP, and that this CC chemokine may have a major role in the progression of fibrosis in this IIP patient group. [ABSTRACT FROM AUTHOR]

Rationale: Idiopathic pulmonary fibrosis (IPF) and other idiopathic interstitial pneumonias (IIPs) have similar clinical and radiographic features, but their histopathology, response to therapy, and natural history differ. A surgical lung biopsy is often required to distinguish between these entities.Objectives: We sought to determine if clinical variables could predict a histopathologic diagnosis of IPF in patients without honeycomb change on high-resolution computed tomography (HRCT).Methods: Data from 97 patients with biopsy-proven IPF and 38 patients with other IIPs were examined. Logistic regression models were built to identify the clinical variables that predict histopathologic diagnosis of IPF.Measurements and Main Results: Increasing age and average total HRCT interstitial score on HRCT scan of the chest may predict a biopsy confirmation of IPF. Sex, pulmonary function, presence of desaturation, or distance walked during a 6-minute walk test did not help discriminate pulmonary fibrosis from other IIPs.Conclusions: Clinical data may be used to predict a diagnosis of IPF over other IIPs. Validation of these data with a prospective study is needed. [ABSTRACT FROM AUTHOR]

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a poor prognosis. There is great effort to find predictors of outcome. Conclusive data for any serum biomarker are lacking. We have recently documented that serum CCL18 concentrations correlate with the course of pulmonary function data in patients with pulmonary fibrosis of various causes. OBJECTIVES: To test the value of serum CCL18 concentrations in IPF, we included 72 patients in a prospective study. METHODS: IPF was defined according to the ATS/ERS criteria. Serum CCL18 concentrations were measured by a commercially available ELISA. Patients were followed for 24 months. Pulmonary function tests were performed at least every 6 months. MEASUREMENTS AND MAIN RESULTS: Baseline serum CCL18 concentrations predicted the change in TLC and FVC at the 6-month follow-up. Receiver operating characteristics (ROC) revealed a significant relation between survival and baseline CCL18 concentrations. By ROC analysis, the cutoff value with the highest diagnostic accuracy was defined as 150 ng/ml (sensitivity, 0.83; specificity, 0.77). There was a significantly higher mortality in patients with serum CCL18 concentrations above 150 ng/ml (P < 0.0001). The hazard proportional ratio adjusted for age, sex, and baseline pulmonary function data was 8.0. There was a higher incidence of disease progression in the group with high serum CCL18 concentrations. CONCLUSIONS: Our data demonstrate that serum CCL18 concentrations have a predictive value in IPF and may be a useful tool in the clinical management of patients with IPF and in clinical trials. [ABSTRACT FROM AUTHOR]

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea, impaired gas exchange, and ultimate mortality.Objectives: To test the hypothesis that maximal oxygen uptake during cardiopulmonary exercise testing at baseline and with short-term longitudinal measures would predict mortality in patients with idiopathic pulmonary fibrosis.Methods: Data from 117 patients with IPF and longitudinal cardiopulmonary exercise tests were examined retrospectively. Survival was calculated from the date of the first cardiopulmonary exercise test.Measurements and Main Results: Patients with baseline maximal oxygen uptake less than 8.3 ml/kg/min had an increased risk of death (n = 8; hazard ratio, 3.24; 95% confidence interval, 1.10-9.56; P = 0.03) after adjusting for age, gender, smoking status, baseline forced vital capacity, and baseline diffusion capacity for carbon monoxide. We were unable to define a unit change in maximal oxygen uptake that predicted survival in our cohort.Conclusions: We conclude that a threshold maximal oxygen uptake of 8.3 ml/kg/min during cardiopulmonary exercise testing at baseline adds prognostic information for patients with IPF. [ABSTRACT FROM AUTHOR]

Rationale: The 2002 American Thoracic Society/European Respiratory Society classification of idiopathic interstitial pneumonias identified nonspecific interstitial pneumonia (NSIP) as a provisional diagnosis. Concern was expressed that NSIP was a "wastebasket" category, difficult to distinguish from other idiopathic interstitial pneumonias. Objectives: The following questions were addressed: (1) Is idiopathic NSIP a distinct entity? 2) If so, what are its clinical, radiologic and pathologic characteristics? (3) What is the role of radiology and pathology in establishing the diagnosis? (4) To make a diagnosis of idiopathic NSIP, what other disorders need to be excluded and how should this be done? Methods: Investigators who had previously reported cases of idiopathic NSIP were invited to submit cases for review (n = 305). After initial review, cases with complete clinical, radiologic, and pathologic information (n = 193) were reviewed in a series of workshops. Measurements and Main Results: Sixty-seven cases were identified as NSIP. Mean age was 52 years, 67% were women, 69% were never-smokers, and 46% were from Asian countries. The most common symptoms were dyspnea (96%) and cough (87%); 69% had restriction. By high-resolution computed tomography, the lower lung zones were predominantly involved in 92% of cases; 46% had a peripheral distribution; 47% were diffuse. Most showed a reticular pattern (87%) with traction bronchiectasis (82%) and volume loss (77%). Lung biopsies showed uniform thickening of alveolar walls with a spectrum of cellular to fibrosing patterns. Five-year survival was 82.3%. Conclusions: Idiopathic NSIP is a distinct clinical entity that occurs mostly in middle-aged women who are never-smokers. The prognosis of NSIP is very good. [ABSTRACT FROM AUTHOR]

Rationale: Treatment and prognoses of diffuse parenchymal lung diseases (DPLDs) varies by diagnosis. Obtaining a uniform diagnosis among observers is difficult.Objectives: Evaluate diagnostic agreement between academic and community-based physicians for patients with DPLDs, and determine if an interactive approach between clinicians, radiologists, and pathologists improved diagnostic agreement in community and academic centers.Methods: Retrospective review of 39 patients with DPLD. A total of 19 participants reviewed cases at 2 community locations and 1 academic location. Information from the history, physical examination, pulmonary function testing, high-resolution computed tomography, and surgical lung biopsy was collected. Data were presented in the same sequential fashion to three groups of physicians on separate days.Measurements and Main Results: Each observer's diagnosis was coded into one of eight categories. A kappa statistic allowing for multiple raters was used to assess agreement in diagnosis. Interactions between clinicians, radiologists, and pathologists improved interobserver agreement at both community and academic sites; however, final agreement was better within academic centers (kappa = 0.55-0.71) than within community centers (kappa = 0.32-0.44). Clinically significant disagreement was present between academic and community-based physicians (kappa = 0.11-0.56). Community physicians were more likely to assign a final diagnosis of idiopathic pulmonary fibrosis compared with academic physicians.Conclusions: Significant disagreement exists in the diagnosis of DPLD between physicians based in communities compared with those in academic centers. Wherever possible, patients should be referred to centers with expertise in diffuse parenchymal lung disorders to help clarify the diagnosis and provide suggestions regarding treatment options. [ABSTRACT FROM AUTHOR]

Rationale and Hypothesis: Idiopathic pulmonary fibrosis is a fatal disease with a variable rate of progression. We hypothesized that changes in distance walked and quantity of desaturation during a six-minute-walk test (6MWT) would add prognostic information to changes in FVC or diffusing capacity for carbon monoxide.Methods: One hundred ninety-seven patients with idiopathic pulmonary fibrosis were evaluated. Desaturation during the 6MWT was associated with increased mortality even if a threshold of 88% was not reached. Baseline walk distance predicted subsequent walk distance but was not a reliable predictor of subsequent mortality in multivariate survival models. The predictive ability of serial changes in physiology varied when patients were stratified by the presence/absence of desaturation < or = 88% during a baseline 6MWT. For patients with a baseline saturation < or = 88% during a 6MWT, the strongest observed predictor of mortality was serial change in diffusing capacity for carbon monoxide. For patients with saturation > 88% during their baseline walk test, serial decreases in FVC and increases in desaturation area significantly predicted subsequent mortality, whereas decreases in walk distance and in diffusing capacity for carbon monoxide displayed less consistent statistical evidence of increasing mortality in our patients.Conclusion: These data highlight the importance of stratifying patients by degree of desaturation during a 6MWT before attributing prognostic value to serial changes in other physiologic variables. [ABSTRACT FROM AUTHOR]

Rationale: Myofibroblasts are primary effector cells in idiopathic pulmonary fibrosis (IPF). Defining mechanisms of myofibroblast differentiation may be critical to the development of novel therapeutic agents.Objective: To show that myofibroblast differentiation is regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) activity in vivo, and to identify a potential mechanism by which this occurs.Methods: We used tissue sections of surgical lung biopsies from patients with IPF to localize expression of PTEN and alpha-smooth muscle actin (alpha-SMA). We used cell culture of pten(-/-) and wild-type fibroblasts, as well as adenoviral strategies and pharmacologic inhibitors, to determine the mechanism by which PTEN inhibits alpha-SMA, fibroblast proliferation, and collagen production.Results: In human lung specimens of IPF, myofibroblasts within fibroblastic foci demonstrated diminished PTEN expression. Furthermore, inhibition of PTEN in mice worsened bleomycin-induced fibrosis. In pten(-/-) fibroblasts, and in normal fibroblasts in which PTEN was inhibited, alpha-SMA, proliferation, and collagen production was upregulated. Addition of transforming growth factor-beta to wild-type cells, but not pten(-/-) cells, resulted in increased alpha-SMA expression in a time-dependent fashion. In pten(-/-) cells, reconstitution of PTEN decreased alpha-SMA expression, proliferation, and collagen production, whereas overexpression of PTEN in wild-type cells inhibited transforming growth factor-beta-induced myofibroblast differentiation. It was observed that both the protein and lipid phosphatase actions of PTEN were capable of modulating the myofibroblast phenotype.Conclusions: The results indicate that in IPF, myofibroblasts have diminished PTEN expression. Inhibition of PTEN in vivo promotes fibrosis, and PTEN inhibits myofibroblast differentiation in vitro. [ABSTRACT FROM AUTHOR]

Rationale: Early diagnosis of bronchiolitis obliterans syndrome (BOS) is critical in understanding pathogenesis and devising therapeutic trials. Although potential-BOS stage (BOS 0-p), encompassing early changes in FEV(1) and forced expiratory flow, midexpiratory phase (FEF(25-75%)), has been proposed, there is a paucity of data validating its utility in single-lung transplantation.Objective: The aim of this study was to define the predictive ability of BOS 0-p in single-lung transplantation.Methods: We retrospectively analyzed spirometric data for 197 single-lung recipients. Sensitivity, specificity, and positive predictive value of BOS 0-p were examined over time using Kaplan-Meier methodology.Results: BOS 0-p FEV(1) was associated with higher sensitivity, specificity, and positive predictive value than the FEF(25-75%) criterion over different time periods investigated. The probability of testing positive for BOS 0-p FEV(1) in patients with BOS (sensitivity) was 71% at 2 years before the onset of BOS. The probability of being free from development of BOS 0-p FEV(1) in patients free of BOS at follow-up (specificity) was 93% within the last year. Of patients who met the BOS 0-p FEV(1) criterion, 81% developed BOS or died within 3 years. The specificity and positive predictive value curves for the BOS 0-p FEV(1) were significantly different between patients with underlying restrictive versus obstructive physiology (p = 0.05 and 0.01, respectively).Conclusion: The FEV(1) criterion for BOS 0-p provides useful predictive information regarding the risk of development of BOS or death in single-lung recipients. The predictive value of this criterion is higher in patients with underlying restriction and is superior to the FEF(25-75%) criterion. [ABSTRACT FROM AUTHOR]

Current guidelines recommend that the clinician, radiologist, and pathologist work together to establish a diagnosis of idiopathic interstitial pneumonia. Three clinicians, two radiologists, and two pathologists reviewed 58 consecutive cases of suspected idiopathic interstitial pneumonia. Each participant was provided information in a sequential manner and was asked to record their diagnostic impression and level of confidence at each step. Interobserver agreement improved from the beginning to the end of the review. After the presentation of histopathologic information, radiologists changed their diagnostic impression more often than did clinicians. In general, as more information was provided the confidence level for a given diagnosis improved, and the diagnoses rendered with a high level of confidence were more likely congruent with the final pathologic consensus diagnosis. The final consensus pathologist diagnosis was idiopathic pulmonary fibrosis in 30 cases. Clinicians identified 75% and radiologists identified 48% of these cases before presentation of the histopathologic information. Histopathologic information has the greatest impact on the final diagnosis, especially when the initial clinical/radiographic diagnosis is not idiopathic pulmonary fibrosis. We conclude that dynamic interactions between clinicians, radiologists, and pathologists improve interobserver agreement and diagnostic confidence. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate selection criteria and duration of benefit for patients undergoing lung volume reduction surgery (LVRS).Methods: Eighty-nine consecutive patients with severe emphysema who underwent bilateral LVRS were prospectively followed up for up to 3 years. Patients underwent preoperative pulmonary function testing, 6-min walk, chest CT, and answered a baseline dyspnea questionnaire. CT scans in 65 patients were analyzed for emphysema extent and distribution using the percentage of emphysema in the lung, percentage of normal lower lung, and the CT emphysema ratio (CTR, an index of the craniocaudal distribution of emphysema). All patients underwent at least 6 weeks of pulmonary rehabilitation prior to surgery. Outcome measures were FEV(1), 6-min walk distance, and transitional dyspnea index (TDI).Results: Compared to baseline, FEV(1) was significantly increased at 3, 6, 12, 18, 24, and 36 months after surgery (p < or = 0.008). The 6-min walk distance increased from 871 feet (baseline) to 1,110 feet (3 months), 1,214 feet (6 months), 1,326 feet (12 months), 1,342 feet (18 months), 1,371 feet (24 months), and 1,390 feet (36 months) after surgery. Despite a decline in FEV(1) over time, 6-min walk distance was preserved. Dyspnea as measured by TDI improved at 3, 6, 12, 18, 24, and 36 months after surgery. A high CTR was the best predictor of a 12% increase over baseline and an absolute increase of 200 mL in FEV(1), although with a low area under the receiver operating characteristic curve. In addition, the sensitivity and negative predictive value of the CTR were limited. No radiographic or physiologic predictor was able to consistently predict a successful increase in walk distance or TDI.Conclusion: LVRS improves pulmonary function, decreases dyspnea, and enhances exercise capacity in many patients with severe emphysema, although improvement wanes 36 months after surgery. [ABSTRACT FROM AUTHOR]

More than 150,00 patients a year present to their physicians with the diagnostic dilemma of a solitary pulmonary nodule (SPN) found either on chest radiography or chest CT. A thoughtful and timely workup of this finding is essential if lung cancer is to be recognized early and the chance for cure optimized. Based on the literature to date, recommendations are made for appropriate imaging modalities and diagnostic testing, as well as indications for obtaining preoperative tissue diagnosis for the patient with an SPN. [ABSTRACT FROM AUTHOR]

Background: We sought consensus among practising respiratory physicians on the prediction, identification and monitoring of progression in patients with fibrosing interstitial lung disease (ILD) using a modified Delphi process., Methods: Following a literature review, statements on the prediction, identification and monitoring of progression of ILD were developed by a panel of physicians with specialist expertise. Practising respiratory physicians were sent a survey asking them to indicate their level of agreement with these statements on a binary scale or 7-point Likert scale (- 3 to 3), or to select answers from a list. Consensus was considered to be achieved if ≥ 70% of respondents selected the same answer, or, for responses on a Likert scale, the median score was ≤ -2 (disagree/not important) or ≥ 2 (agree/important) with an interquartile range ≤ 1. There were three rounds of the survey., Results: Surveys 1, 2 and 3 were completed by 207, 131 and 94 physicians, respectively, between March 2022 and July 2023. Decline in forced vital capacity (FVC), decline in diffusing capacity of the lungs for carbon monoxide, and increased fibrosis on high-resolution computed tomography (HRCT) were ranked as the most important endpoints for determining progression. Consensus was reached that progression on HRCT or a decline in FVC ≥ 10% from baseline is sufficient to determine progression, and that small declines in multiple endpoints indicates progression. Consensus was reached that a histological pattern of usual interstitial pneumonia (UIP) is a risk factor for progression of ILD, but that a biopsy to look for a UIP pattern should not be performed solely for prognostic reasons. Consensus was not reached on the time period over which progression should be defined. There was consensus that appropriate management of ILD depends on the type of ILD, and that 'despite adequate management' or 'despite usual management' should be included in the definition of progression., Conclusions: This modified Delphi process provided consensus statements on the identification of ILD progression that were supported by a broad group of clinicians and may help to inform clinical practice until robust evidence-based guidelines are available., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: Athol U Wells reports consulting fees from Boehringer Ingelheim, Roche and Veracyte and speaker fees from Boehringer Ingelheim and Roche. Simon LF Walsh reports grants from Boehringer Ingelheim, Galapagos and the National Institute for Health and Research; consulting fees from Boehringer Ingelheim, CSL Behring, Galapagos, OncoArendi Therapeutics, the Open Source Imaging Consortium, Pliant, PureTech, Roche and Sanofi-Genzyme; speaker fees from Boehringer Ingelheim, Galapagos and Roche; he is the Chief Scientific Officer of Qureight. Ayodeji Adegunsoye reports grants from the National Institutes of Health (K23HL146942); consulting fees from Boehringer Ingelheim, Genentech/Roche and Inogen; and speaker fees from Boehringer Ingelheim. Vincent Cottin reports grants from Boehringer Ingelheim; consulting fees from Boehringer Ingelheim, Celgene/Bristol-Myers Squibb, CSL Behring, Ferrer, Galapagos, GlaxoSmithKline, Plaint, PureTech, Redx, Roche, Sanofi and Shionogi; speaker fees from Boehringer Ingelheim, Ferrer and Roche; support for attending meetings from Boehringer Ingelheim and Ferrer; and has participated on data safety monitoring boards/advisory boards for Celgene/Bristol-Myers Squibb, FibroGen, Galapagos, Galecto and Roche. Sonye K Danoff reports grants from Boehringer Ingelheim, Bristol-Myers Squibb and Genentech/Roche; royalties or licenses from UptoDate; consulting fees from Boehringer Ingelheim and Lupin Pharma; speaker fees from the France Foundation; support for travel from Boehringer Ingelheim; has participated on data safety monitoring boards/advisory boards for Galapagos and Galecto; and has leadership roles at the American Thoracic Society and Pulmonary Fibrosis Foundation. Anand Devaraj reports consulting fees from Brainomix, Boehringer Ingelheim, Roche, Astra Zeneca, GSK, Genentech, Pharmamar, and Vicore and stock options from Brainomix. Kevin R Flaherty reports grants paid to his institution from Boehringer Ingelheim; royalties or licences from UpToDate; and consulting fees from Arrowhead, AstraZeneca, Bellerophon, CSL Behring, Daewoong, DevPro, Dispersol, FibroGen, Horizon Therapeutics, Immunet, Insilico, Lupin, NeRRe Therapeutics, Pliant, Polarean, Pure Health, PureTech, Respivant, Roche/Genentech, Shionogi, Sun Pharmaceuticals, Trevi, United Therapeutics and Vicore. Peter M George reports personal fees from AstraZeneca, Avalyn, Brainomix, Boehringer Ingelheim, Cipla, Daiichi-Sankyo, GSK, Roche, Teva; grants from Boehringer Ingelheim and Roche; stock options from Brainomix. Kerri A Johannson reports grants paid to her institution from Three Lakes Foundation and University Hospital Foundation; consulting fees from Boehringer Ingelheim, Brainomix, Hoffman La Roche and Pliant Therapeutics; speaker fees from Abbvie and Boehringer Ingelheim; support for attending meetings from Boehringer Ingelheim; has participated on a data safety monitoring board for the PFOX trial; and stock or stock options from Thyron SAB. Martin Kolb reports research funding from Boehringer Ingelheim, Pieris and Roche; consulting fees from AbbVie, Algernon, Bellerophon, Boehringer Ingelheim, Cipla, CSL Behring, Horizon, LabCorp, Roche, ShouTi and United Therapeutics; speaker fees from Boehringer Ingelheim, Novartis and Roche; payment for expert testimony from Roche; has participated on data safety monitoring boards/advisory boards for LabCorp and United Therapeutics; and has a leadership role at the European Respiratory Journal. Yasuhiro Kondoh reports consulting fees from Asahi Kasei Pharma Corp, Boehringer Ingelheim, Chugai Pharmaceutical Co., Ltd., Healios K.K., Janssen Pharmaceutical K.K., Shionogi & Co., Ltd. and Taiho Pharmaceutical Co.; and speaker fees from Asahi Kasei Pharma Corp, Bristol-Myers Squibb, Boehringer Ingelheim, Eisai Co., Janssen Pharmaceutical K.K., KYORIN Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, NIPPON SHINYAKU CO., Ltd., Novartis Pharma KK, Shionogi & Co., Ltd. and Teijin Pharma Ltd. Andrew G Nicholson reports consulting fees from Galapagos, Medical Quantitative Image Analysis, Roche, Boehringer Ingelheim and payment for presentations from Boehringer Ingelheim and Up to Date. Sara Tomassetti reports consulting fees, speaker fees and support for attending meetings from Boehringer Ingelheim and Roche. Elizabeth R Volkmann reports payments made to her institution from Boehringer Ingelheim, Forbius, Horizon, Kadmon, the National Heart, Lung and Blood Institute, Prometheus; consulting fees from Boehringer Ingelheim, GlaxoSmithKline, Roche; speaker fees from Boehringer Ingelheim. Kevin K Brown reports grants from the National Heart, Lung and Blood Institute; consulting fees, speaker fees, support for attending meetings and participation on data safety monitoring boards/advisory boards from AbbVie, Biogen, Blade Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, DevPro Biopharma, Dispersol, Eleven P15, Galapagos NV, Galecto, Huitai Biomedicine, Humanetics, the Open Source Imaging Consortium, Pliant, Redx Pharma, Sanofi, Third Pole, Translate Bio; and has leadership roles at the Fleischner Society and Open Source Imaging Consortium., (© 2024. Crown.)

Background: Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are debilitating diseases associated with divergent histopathological changes in the lungs. At present, due to cost and technical limitations, profiling cell types is not practical in large epidemiology cohorts (n > 1000). Here, we used computational deconvolution to identify cell types in COPD and IPF lungs whose abundances and cell type-specific gene expression are associated with disease diagnosis and severity., Results: We analyzed lung tissue RNA-seq data from 1026 subjects (COPD, n = 465; IPF, n = 213; control, n = 348) from the Lung Tissue Research Consortium. We performed RNA-seq deconvolution, querying thirty-eight discrete cell-type varieties in the lungs. We tested whether deconvoluted cell-type abundance and cell type-specific gene expression were associated with disease severity. The abundance score of twenty cell types significantly differed between IPF and control lungs. In IPF subjects, eleven and nine cell types were significantly associated with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (D L CO), respectively. Aberrant basaloid cells, a rare cells found in fibrotic lungs, were associated with worse FVC and D L CO in IPF subjects, indicating that this aberrant epithelial population increased with disease severity. Alveolar type 1 and vascular endothelial (VE) capillary A were decreased in COPD lungs compared to controls. An increase in macrophages and classical monocytes was associated with lower D L CO in IPF and COPD subjects. In both diseases, lower non-classical monocytes and VE capillary A cells were associated with increased disease severity. Alveolar type 2 cells and alveolar macrophages had the highest number of genes with cell type-specific differential expression by disease severity in COPD and IPF. In IPF, genes implicated in the pathogenesis of IPF, such as matrix metallopeptidase 7, growth differentiation factor 15, and eph receptor B2, were associated with disease severity in a cell type-specific manner., Conclusions: Utilization of RNA-seq deconvolution enabled us to pinpoint cell types present in the lungs that are associated with the severity of COPD and IPF. This knowledge offers valuable insight into the alterations within tissues in more advanced illness, ultimately providing a better understanding of the underlying pathological processes that drive disease progression., Competing Interests: Declarations. Ethics approval and consent to participate: The participating centers’ Institutional Review Boards approved the study, and all subjects provided written informed consent. Consent for publication: Not applicable. Competing interests: Dr. Hersh reports grant support from Bayer, Boehringer-Ingelheim, and Vertex, and consulting fees from Chiesi, Sanofi, and Takeda, unrelated to this manuscript. Dr. Silverman reports grant support from Bayer and Northpond Laboratories. Dr. Cho reports grant support from Bayer. Dr. DeMeo reports grant support from Bayer and Alpha-1 Foundation. Dr. Castaldi reports grant support from Bayer, Sanofi and consulting fees from Verona Pharmaceuticals. Dr. Yun reports grant support from Bayer and consulting fees from Bridge Biotherapeutics, and travel reimbursement from the Korean Academy of Tuberculosis and Respiratory Disease unrelated to this manuscript. Dr. Flaherty reports grant funding from Boehringer Ingelheim unrelated to this manuscript. Dr. Martinez reports grant supports from NHLBI, AstraZeneca, Chiesi, Boehringer-Ingelheim, GalaxoSmithCline, Novartis, Polarean, Sanofi/Regeneron, Sunovion, and TEVA Pharmaceuticals. Dr. Martinez reports receiving consulting fee from AstraZeneca, Boehringer-Ingelheim and Bristol Myers Squibb. Dr. Wise reports receiving consulting fees from Boehringer-Ingelheim, AstraZenica, Abb-Vie, and Galderma., (© 2024. The Author(s).)

Background: Acute exacerbations of fibrosing interstitial lung diseases (ILDs) are associated with high mortality. We used prospective data from the INBUILD trial to investigate risk factors for acute exacerbations and the impact of these events in patients with progressive pulmonary fibrosis., Methods: Patients with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF) were randomised to receive nintedanib or placebo. Associations between baseline characteristics and time to first acute exacerbation were assessed using pooled data from both treatment groups using Cox proportional hazard models, firstly univariable models and then a multivariable model using forward stepwise selection. The risk of death was estimated based on the Kaplan-Meier method., Results: Over a median follow-up of approximately 19 months, acute exacerbations were reported in 58 (8.7%) of 663 patients. In the risk factor analysis, the final model included diffusing capacity of the lung for carbon monoxide ( D LCO ) % predicted, treatment and age. Lower D LCO % predicted was associated with an increased risk of acute exacerbation with a hazard ratio (HR) of 1.56 (95% CI 1.21-2.02) per 10 units lower (p<0.001). Age ≥65 years was associated with a numerically increased risk (HR 1.55, 95% CI 0.87-2.77; p=0.14). Treatment with nintedanib conferred a numerically reduced risk versus placebo (HR 0.60, 95% CI 0.35-1.02; p=0.06). The estimated risks of death ≤30 days and ≤90 days after an acute exacerbation were 19.0% (95% CI 8.9-29.2) and 32.0% (95% CI 19.7-44.2)., Conclusions: Acute exacerbations of progressive pulmonary fibrosis may have similar risk factors and prognostic impact as acute exacerbations of IPF., Competing Interests: Conflict of interest: M. Kreuter reports grants, consulting fees and fees for speaking from Boehringer Ingelheim and Roche; and holds leadership or fiduciary roles with the Deutsche Gesellschaft für Pneumologie, European Respiratory Society and German Respiratory Society. E.A. Belloli reports fees from Boehringer Ingelheim for participation in an advisory board meeting. E. Bendstrup reports an unrestricted grant from Boehringer Ingelheim; fees for speaking from Boehringer Ingelheim, Chiesi, Daiichi Sankyo, GlaxoSmithKline, AstraZeneca and Roche; support for travel from Boehringer Ingelheim and Roche; and has participated on Data Safety Monitoring Boards or advisory boards for AbbVie, Veracyte and Boehringer Ingelheim. S. Cerri reports fees for speaking from Boehringer Ingelheim. K.R. Flaherty reports grants paid to his institution from Boehringer Ingelheim; royalties from UpToDate; consulting fees from Arrowhead, AstraZeneca, Bellerophon, CSL Behring, Daewoong, DevPro, Dispersol, FibroGen, Horizon, Immunet, Insilico, Lupin, NeRRe, Pliant, Polarean, Pure Health, PureTech, Respivant, Roche/Genentech, Shionogi, Sun Pharmaceuticals, Trevi, United Therapeutics and Vicore; he is a Steering Committee Chair for the Pulmonary Fibrosis Foundation and was a member of the INBUILD trial Steering Committee. S. Shapera reports grants to support fellowship training from the Canadian Pulmonary Fibrosis Foundation; has participated on advisory boards for AstraZeneca and Hoffmann-La Roche; and has received fees for speaking from Boehringer Ingelheim and AstraZeneca. J.W. Song was supported by grants from the Basic Science Research Program and the Bio & Medical Technology Development Program of the National Research Foundation of Korea funded by the Ministry of Science & ICT and is supported by a National Institute of Health research project and by the Korea Environment Industry & Technology Institute through Core Technology Development Project for Environmental Diseases Prevention and Management Program funded by the Korea Ministry of Environment; he reports fees for consulting or lectures from Boehringer Ingelheim, BMS, Taiho and Daewoong. H. Mueller and K.B. Rohr are employees of Boehringer Ingelheim. Y. Kondoh reports consulting fees from Asahi Kasei, Boehringer Ingelheim, Chugai, Healios, Janssen, Shionogi and Taiho; and fees for lectures from Asahi Kasei, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Janssen, KYORIN, Mitsubishi Tanabe, Nippon Shinyaku, Novartis, Shionogi and Teijin., (Copyright ©The authors 2024.)

Rationale: Inhaled nitric oxide (iNO) has been shown to result in benefits in moderate to vigorous physical activity (MVPA) in patients with fibrotic interstitial lung disease (f-ILD) receiving supplemental oxygen in two independent trials. Objective: This phase III randomized, double-blind, placebo-controlled study sought to validate the benefit of ambulatory iNO in patients with f-ILD requiring supplemental oxygen. Methods: Patients with f-ILD receiving supplemental long-term oxygen were randomized in a 1:1 fashion to iNO at 45 μg/kg ideal body weight per hour or placebo for 16 weeks. The primary outcome was the change from baseline to Week 16 in MVPA assessed by accelerometry. Secondary outcomes included overall activity, 6-minute-walk distance and patient-reported outcomes. Results: 145 patients were enrolled; 75 were assigned to receive iNO and 70 placebo. The changes from baseline in MVPA at 16 weeks were -9.2 min/d (standard error, 3.51) in the iNO45 group and -3.7 min/d (3.76) in the placebo group (difference, 5.5; P  = 0.265). No statistically significant differences between the two treatment arms were found for any of the secondary outcomes. A subgroup analysis of patients with an intermediate or high probability of pulmonary hypertension on echocardiography did not demonstrate any benefit. The most common adverse events reported were respiratory tract infections, but the therapy was generally very well tolerated. Conclusions: There was no demonstrable benefit to iNO in patients with f-ILD receiving supplemental oxygen in daily physical activity assessed by actigraphy, a potential novel clinical trial endpoint. Clinical trial registered with www.clinicaltrials.gov (NCT03267108).

NKG2D ligands (NKG2DLs) are broadly expressed in cancer. To target these, we describe an adaptor chimeric antigen receptor (CAR) termed NKG2D/Dap10-12. Herein, T cells are engineered to co-express NKG2D with a fusion protein that comprises Dap10 joined to a Dap12 endodomain. NKG2D/Dap10-12 T cells elicit compelling efficacy, eradicating or controlling NKG2DL-expressing tumors in several established xenograft models. Importantly, durable responses, long-term survival, and rejection of tumor re-challenge are reproducibly achieved. Efficacy is markedly superior to a clinical stage CAR analog, comprising an NKG2D-CD3ζ fusion. Structure-function analysis using an extended CAR panel demonstrates that potency is dependent on membrane proximity of signaling units, high NKG2D cell surface expression, adaptor structure, provision of exogenous Dap10, and inclusion of one rather than three immune tyrosine activation motifs per signaling unit. Potent therapeutic impact of NKG2D/Dap10-12 T cells is also underpinned by enhanced oxidative phosphorylation, reduced senescence, and transcriptomic re-programming for increased ribosomal biogenesis., Competing Interests: Declaration of interests J.M. is CSO, scientific founder, and shareholder of Leucid Bio. M.G., F.K., C.M.H., R.M., C.B., C.T., and D.M.D. are employees of Leucid Bio while P.D. is a former Leucid Bio employee. D.L.-Y. is undertaking a PhD studentship funded by Leucid Bio and has acted as a consultant for Leucid Bio. J.M., D.M.D., D.L.-Y., and F.K. are co-inventors on patent filings in relation to adaptor CAR technology., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: Accelerated biological aging has been implicated in the development of interstitial lung disease (ILD) and other diseases of aging but remains poorly understood. Objectives: To identify plasma proteins that mediate the relationship between chronological age and survival association in patients with ILD. Methods: Causal mediation analysis was performed to identify plasma proteins that mediated the chronological age-survival relationship in an idiopathic pulmonary fibrosis discovery cohort. Proteins mediating this relationship after adjustment for false discovery were advanced for testing in an independent ILD validation cohort and explored in a chronic obstructive pulmonary disease cohort. A proteomic-based measure of biological age was constructed and survival analysis performed, assessing the impact of biological age and peripheral blood telomere length on the chronological age-survival relationship. Measurements and Main Results: Twenty-two proteins mediated the chronological age-survival relationship after adjustment for false discovery in the idiopathic pulmonary fibrosis discovery cohort ( n  = 874), with 19 remaining significant mediators of this relationship in the ILD validation cohort ( n  = 983) and one mediating this relationship in the chronic obstructive pulmonary disease cohort. Latent transforming growth factor-β binding protein 2 and ectodysplasin A2 receptor showed the strongest mediation across cohorts. A proteomic measure of biological age completely attenuated the chronological age-survival association and better discriminated survival than chronological age. Results were robust to adjustment for peripheral blood telomere length, which did not mediate the chronological age-survival relationship. Conclusions: Molecular measures of aging completely mediate the relationship between chronological age and survival, suggesting that chronological age has no direct effect on ILD survival.

Background: Chronic lung allograft dysfunction (CLAD) is the leading long-term cause of poor outcomes after transplant and manifests by fibrotic remodeling of small airways and/or pleuroparenchymal fibroelastosis. This study evaluated the effect of pirfenidone on quantitative radiographic and pulmonary function assessment in patients with CLAD., Methods: We performed a single-center, 6-month, randomized, placebo-controlled trial of pirfenidone in patients with CLAD. Randomization was stratified by CLAD phenotype. The primary outcome for this study was change in radiographic assessment of small airways disease, quantified as percentage of lung volume using parametric response mapping analysis of computed tomography scans (PRM fSAD ); secondary outcomes included change in forced expiratory volume in 1 second (FEV 1 ), change in forced vital capacity (FVC), and change in radiographic quantification of parenchymal disease (PRM PD ). Linear mixed models were used to evaluate the treatment effect on outcome measures., Results: The goal enrollment of 60 patients was not met due to the coronavirus disease of 2019 pandemic, with 23 patients included in the analysis. There was no significant difference over the study period between the pirfenidone vs placebo groups with regards to the observed change in PRM fSAD (+4.2% vs -0.4%; p = 0.22), FEV 1 (-3.5% vs -3.6%; p = 0.97), FVC (-1.9% vs -4.6%; p = 0.41), or PRM PD (-0.6% vs -2.5%; p = 0.30). The study treatment tolerance and adverse events were generally similar between the pirfenidone and placebo groups., Conclusions: Pirfenidone had no apparent impact on radiographic evidence of allograft dysfunction or pulmonary function decline in a single-center randomized trial of CLAD patients that did not meet enrollment goals but had an acceptable tolerance and side-effect profile., Competing Interests: Disclosure statement The authors report the following financial conflicts of interest: Consulting fees from Roche/Genentech, Bellerophon, Respivant, Shionogi, DevPro, AstraZeneca, Pure Health, Horizon, FibroGen, Sun Pharmaceuticals, Pliant, United Therapeutics, Arrowhead, Lupin, Polarean, PureTech, Trevi, CSL Behring, Daewoong, Dispersol, Immunet, NeRRe Therapeutics, Insilco, Vicore, Glaxo Smith Kline, and Merck (all K.R.F.), RRD International LLC (S.M.), Coinventor of PRM currently licensed to Imbio (C.J.G.). We thank all the patients who generously participated in this research, to the University of Michigan research coordinator team, and Dennis M. Lyu, MD, who served as the data safety monitor for the study. This investigator-initiated clinical trial was funded by Genentech Inc. (San Francisco, CA). The funders did not participate in data collection, analysis, or preparation of the manuscript, tables, or figures., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)